Aquaporin expression after thrombin preconditioning in ischemic mouse brain

Background: Aquaporin-4 (AQP4), a water channel, is induced early after stroke.The role of AQP4 in the development and resolution of oedema after stroke remainsdebated. The absence of AQP4 in KO-mice reduces the cytotoxic oedema formationbut in contrast aggravates the vasogenic edema. Thrombin at high dose is known toinduce an oedema and at a low dose (thrombin preconditioning, TPC), to inducetolerance to ischemia. We studied the expression of AQPs in ischemic mouse brainsafter TPC and correlation with oedema formation.Methods: For thrombin preconditioning (TPC), mice were injected intracerebroventricularlywith a low dose of thrombin (0.1U in 2?l), followed 24 hours laterby a 30 min transient middle cerebral occlusion (MCAo). AQP4 expression wasevaluated by immunohistochemistry 1h and 48h after ischemia and correlated withoedema formation in vehicle injected and TPC mice.Results: After TPC, oedema formation, assessed by hemispheric enlargement, wassignificantly attenuated at 1h (4.5 ± 2% vs 11.0 ± 5% in CTL, p<0.05, n=8),which was confirmed by wet weight/dry weight ratio (79.6 ± 0.3% vs 80.1 ± 0.1in ctl, p<0.05, n=0.05). At the same time-point, AQP4 expression was significantlyincreased in TPC mice, (148.9% of the control, P<0.05, n=6) in the ischemicstriatum. The oedema was still reduced at 48h after stroke onset in TPC mice. At48h, the level of expression for AQP4 was still higher for TPC animal although notreaching significance (NS). The lesion size was significantly reduced at 48h afterstroke in TPC mice (5.1 ± 1.6 vs 10.6 ± 1.8 mm2 in CTL, n=5).Discussion: The correlation between the early induction of AQP4 and the decreaseof oedema formation in TPC mice suggests that the induction of AQP4 preventsthe development of oedema.Funding: FNS #3100A0-108001, #3200 68306.02 & #3100A0-112484 and Swiss-Heart foundation.

Periprocedural Hemodynamic Depression Is Associated With a Higher Number of New Ischemic Brain Lesions After Stenting in the International Carotid Stenting Study-MRI Substudy.

BACKGROUND AND PURPOSE: Carotid artery stenting (CAS) is associated with a higher risk of both hemodynamic depression and new ischemic brain lesions on diffusion-weighted imaging than carotid endarterectomy (CEA). We assessed whether the occurrence of hemodynamic depression is associated with these lesions in patients with symptomatic carotid stenosis treated by CAS or CEA in the randomized International Carotid Stenting Study (ICSS)-MRI substudy. METHODS: The number and total volume of new ischemic lesions on diffusion-weighted imaging 1 to 3 days after CAS or CEA was measured in the ICSS-MRI substudy. Hemodynamic depression was defined as periprocedural bradycardia, asystole, or hypotension requiring treatment. The number of new ischemic lesions was the primary outcome measure. We calculated risk ratios and 95% confidence intervals per treatment with Poisson regression comparing the number of lesions in patients with or without hemodynamic depression. RESULTS: A total of 229 patients were included (122 allocated CAS; 107 CEA). After CAS, patients with hemodynamic depression had a mean of 13 new diffusion-weighted imaging lesions, compared with a mean of 4 in those without hemodynamic depression (risk ratio, 3.36; 95% confidence interval, 1.73-6.50). The number of lesions after CEA was too small for reliable analysis. Lesion volumes did not differ between patients with or without hemodynamic depression. CONCLUSIONS: In patients treated by CAS, periprocedural hemodynamic depression is associated with an excess of new ischemic lesions on diffusion-weighted imaging. The findings support the hypothesis that hypoperfusion increases the susceptibility of the brain to embolism. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25337470.

Extent of Hypoattenuation On CT Angiography Source Images In Basilar Artery Occlusion: Prognostic Accuracy Of Posterior Circulation ASPECTS And The Pons-midbrain Score In The Basilar Artery International Cooperation Study

Background: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) and the combined Pons-midbrain score quantify the extent of early ischemic changes in the posterior circulation. We compared the prognostic accuracy of both scores if applied to CT angiography (CTA) source images (CTA-SI) of patients in the Basilar Artery International Cooperation Study (BASICS).Methods: BASICS was a prospective, observational, multi-centre, registry of consecutive patients who presented with acute symptomatic basilar artery occlusion (BAO). Functional outcome was assessed at 1 month. We applied pc-ASPECTS and the combined Pons-midbrain score to CTA-SI by 3-reader-consensus. Readers were blinded to clinical data. We performed multivariable logistic regression analysis, adjusting for thrombolysis, baseline NIHSS score and age, and used the output to derive ROC curves to compare the ability of both scores to discriminate patients with favourable (modified Rankin Scale [mRS] scores 0-3) from patients with unfavourable (mRS scores 4-6) functional outcome.Results: We reviewed CTAs of 158 patients (64% men, mean age 65 _ 15 years, median NIHSS score 25 [0-38], median GCS score 7 [3-15], median onset-to-CTA time 234 minutes [11-7380]). At 1 month, 40 (25%) patients had a favourable outcome, 49 (31%) had an unfavourable outcome (mRS score 4-5) and 69 (44%) were deceased. Both techniques of assessing CTA-SI hypoattenuation in the posterior circulation showed equally good discriminative value in predicting final outcome (C-statistics; area under ROC curve 0.74 versus 0.75, respectively; p_0.37). Pc-ASPECTS dichotomized at _6 versus _6 was an independent predictor of favourable functional outcome (RR _ 2.2; CI95 1.1-4.7; p _ 0.034).Conclusion: Compared to the combined Pons-midbrain score, the pc-ASPECTS score has similar prognostic accuracy to identify patients with a favourable functional outcome in BASICS. Dichotomized pc-ASPECTS (_6 versus _6) is an independent predictor of favourable functional outcome in this population. Author Disclosures: V. Puetz: None. A. Khomenko: None. M.D. Hill: None. I. Dzialowski: None. P. Michel: None. C. Weimar: None. C.A.C. Wijman: None. H. Mattle: None. K. Muir: None. T. Pfefferkorn: None. D. Tanne: None. S. Engelter: None. K. Szabo: None. A. Algra: None. A.M. Demchuk: None. W.J. Schonewille: None.

Etiology of first-ever ischaemic stroke in European young adults: the 15 cities young stroke study.

BACKGROUND AND PURPOSE: Risk factors for IS in young adults differ between genders and evolve with age, but data on the age- and gender-specific differences by stroke etiology are scare. These features were compared based on individual patient data from 15 European stroke centers. METHODS: Stroke etiology was reported in detail for 3331 patients aged 15-49 years with first-ever IS according to Trial of Org in Acute Stroke Treatment (TOAST) criteria: large-artery atherosclerosis (LAA), cardioembolism (CE), small-vessel occlusion (SVO), other determined etiology, or undetermined etiology. CE was categorized into low- and high-risk sources. Other determined group was divided into dissection and other non-dissection causes. Comparisons were done using logistic regression, adjusting for age, gender, and center heterogeneity. RESULTS: Etiology remained undetermined in 39.6%. Other determined etiology was found in 21.6%, CE in 17.3%, SVO in 12.2%, and LAA in 9.3%. Other determined etiology was more common in females and younger patients, with cervical artery dissection being the single most common etiology (12.8%). CE was more common in younger patients. Within CE, the most frequent high-risk sources were atrial fibrillation/flutter (15.1%) and cardiomyopathy (11.5%). LAA, high-risk sources of CE, and SVO were more common in males. LAA and SVO showed an increasing frequency with age. No significant etiologic distribution differences were found amongst southern, central, or northern Europe. CONCLUSIONS: The etiology of IS in young adults has clear gender-specific patterns that change with age. A notable portion of these patients remains without an evident stroke mechanism according to TOAST criteria.

Is pretreatment with Beta-blockers beneficial in patients with acute coronary syndrome?

OBJECTIVES: The role of beta-blockers in the treatment of hypertension is discussed controversially and the data showing a clear benefit in acute coronary syndromes (ACS) were obtained in the thrombolysis era. The goal of this study was to analyze the role of pretreatment with beta-blockers in patients with ACS. METHODS: Using data from the Acute Myocardial Infarction in Switzerland (AMIS Plus) registry, we analyzed outcomes of patients with beta-blocker pretreatment in whom they were continued during hospitalization (group A), those without beta-blocker pretreatment but with administration after admission (group B) and those who never received them (group C). Major adverse cardiac events defined as composed endpoint of re-infarction and stroke (during hospitalization) and/or in-hospital death were compared between the groups. RESULTS: A total of 24,709 patients were included in the study (6,234 in group A, 12,344 in group B, 6,131 in group C). Patients of group B were younger compared to patients of group A and C (62.5, 67.6 and 68.4, respectively). In the multivariate analysis, odds ratio for major adverse cardiac events was 0.59 (CI 0.47-0.74) for group A and 0.66 (CI 0.55-0.83) for group B, while group C was taken as a reference. CONCLUSIONS: beta-Blocker therapy is beneficial in ACS and they should be started in those who are not pretreated and continued in stable patients who had been on chronic beta-blocker therapy before.

Autonomic Function Is Impaired in Elderly Stroke Survivors

Impaired autonomic function is common in the acute poststroke phase but little is known about the longer term effects, particularly in older people. This study sought to determine if autonomic function is impaired after stroke recovery in older patients. This is a cross-sectional case-control study comparing autonomic function in 76 nondemented stroke patients with 70 community-living controls aged older than 75 years.

Extent of hypoattenuation on CT angiography source images in basilar artery occlusion: prognostic value in the Basilar Artery International Cooperation Study.

BACKGROUND AND PURPOSE: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) quantifies the extent of early ischemic changes in the posterior circulation with a 10-point grading system. We hypothesized that pc-ASPECTS applied to CT angiography source images predicts functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS). METHODS: BASICS was a prospective, observational registry of consecutive patients with acute symptomatic basilar artery occlusion. Functional outcome was assessed at 1 month. We applied pc-ASPECTS to CT angiography source images of patients with CT angiography for confirmation of basilar artery occlusion. We calculated unadjusted and adjusted risk ratios (RRs) of pc-ASPECTS dichotomized at ≥8 versus <8. Primary outcome measure was favorable outcome (modified Rankin Scale scores 0-3). Secondary outcome measures were mortality and functional independence (modified Rankin Scale scores 0-2). RESULTS: Of 158 patients included, 78 patients had a CT angiography source images pc-ASPECTS≥8. Patients with a pc-ASPECTS≥8 more often had a favorable outcome than patients with a pc-ASPECTS<8 (crude RR, 1.7; 95% CI, 0.98-3.0). After adjustment for age, baseline National Institutes of Health Stroke Scale score, and thrombolysis, pc-ASPECTS≥8 was not related to favorable outcome (RR, 1.3; 95% CI, 0.8-2.2), but it was related to reduced mortality (RR, 0.7; 95% CI, 0.5-0.98) and functional independence (RR, 2.0; 95% CI, 1.1-3.8). In post hoc analysis, pc-ASPECTS dichotomized at ≥6 versus <6 predicted a favorable outcome (adjusted RR, 3.1; 95% CI, 1.2-7.5). CONCLUSIONS: pc-ASPECTS on CT angiography source images independently predicted death and functional independence at 1 month in the CT angiography subgroup of patients in the BASICS registry.

Anti-TNF Therapy in the Treatment of Psoriasis in a Patient with Acute-on-Chronic Pancreatitis.

Background: Psoriasis is accepted as a multisystemic disease with several important systemic manifestations. Thus, underlying comorbidities have to be taken into account in the choice of treatment. Objective: To explore the role of anti-TNF therapy in the treatment of psoriasis in a patient with acute-on-chronic pancreatitis. Methods: Here, we present the case of a 75-year-old patient with severe psoriasis also suffering from chronic alcohol-induced pancreatitis with recurrent acute flares. A recent life-threatening episode of acute pancreatitis and ischemic liver precluded the reintroduction of methotrexate. Cyclosporine was also excluded as it has been reported to induce acute pancreatitis. Thus, an anti-TNF treatment was initiated in close collaboration with a gastroenterologist. Results: A year after starting anti-TNF therapy the patient continues to show complete clinical remission of his psoriasis. No side effects, particularly no bacterial infections, were reported. No relapses of the patient's underlying chronic pancreatitis were observed throughout the entire treatment with regular clinical and laboratory monitoring, suggesting that chronic pancreatitis is not per se a contraindication for anti-TNF therapy. Conclusion: This case study opens the way for further questioning on the role of TNF in the pathogenesis of chronic and acute pancreatitis and the use of anti-TNF therapy in its treatment. © 2013 S. Karger AG, Basel.

Recurrent Wernicke's aphasia: migraine and not stroke!

We report the clinical findings of a 40-year-old woman with recurrent migraine presenting with Wernicke's aphasia in accordance with the results of a standardized battery for language assessment (Boston Aphasia Diagnostic Examination). The patient had no evidence of parenchymal or vascular lesions on MRI and showed delta and theta slowing over the left posterior temporal leads on the EEG. Although the acute onset of a fluent aphasia suggested stroke as a likely etiology, the recurrence of aphasia as the initial symptom of migraine was related to cortical spreading depression and not to stroke.

Predicting outcome after acute basilar artery occlusion based on admission characteristics.

OBJECTIVE: To develop a simple prognostic model to predict outcome at 1 month after acute basilar artery occlusion (BAO) with readily available predictors. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational, international registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO. We considered predictors available at hospital admission in multivariable logistic regression models to predict poor outcome (modified Rankin Scale [mRS] score 4-5 or death) at 1 month. We used receiver operator characteristic curves to assess the discriminatory performance of the models. RESULTS: Of the 619 patients, 429 (69%) had a poor outcome at 1 month: 74 (12%) had a mRS score of 4, 115 (19%) had a mRS score of 5, and 240 (39%) had died. The main predictors of poor outcome were older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIH Stroke Scale (NIHSS) score, and longer time to treatment. A prognostic model that combined demographic data and stroke risk factors had an area under the receiver operating characteristic curve (AUC) of 0.64. This performance improved by including findings from the neurologic examination (AUC 0.79) and CT imaging (AUC 0.80). A risk chart showed predictions of poor outcome at 1 month varying from 25 to 96%. CONCLUSION: Poor outcome after BAO can be reliably predicted by a simple model that includes older age, absence of hyperlipidemia, presence of prodromal minor stroke, higher NIHSS score, and longer time to treatment.

Hypertension. La pression artérielle dans la phase aiguë des accidents cérébrovasculaires [Hypertension. Arterial pressure in the acute phase of cerebrovascular accidents]

Blood pressure is abnormally elevated in acute stroke in most patients. This blood pressure increase is usually transient and associated with a poor prognosis. Lowering blood pressure too importantly during this period may worsen the outcome of the patient. Antihypertensive therapy is therefore required only when blood pressure is severely increased, especially in the presence of intracerebral haemorrhage. Initiating treatment before admission to the hospital is not recommended. The medications to be preferred are the blockers of the renin-angiotensin system, the beta-blocker labetalol (which possesses also alpha-blocking properties) and NO donors.

Perfusion computed tomography-guided subacute endovascular reperfusion in a patient with carotid occlusion.

Most patients with symptomatic internal carotid artery occlusion have a single minor or major hemispheric stroke. A minority of patients have ipsilateral retinal ischemia, recurrent strokes, or transient ischemic attacks. Whereas spontaneous carotid recanalization is rare, acute surgical recanalization has been attempted, with mixed results. Recently, acute endovascular recanalization has been performed and described as feasible and relatively safe. We describe a patient with symptom recurrence related to hemodynamic factors after occlusion of the carotid artery who was successfully treated 14 days after symptom onset.

La revascularisation transmyocardique au laser--un risque potentiel en condition aiguë [Laser transmyocardial revascularization--a potential risk in an acute situation?]

Morphological and functional effects of transmyocardial laser revascularization (TMLR) are analyzed in an acute setting on a porcine model. Ten channels were drilled in the left lateral wall of the heart of 15 pigs (mean weight, 73 +/- 4 kg) with a Holmium-YAG laser (wavelength: 2.1 mu, probe diameter: 1.75 mm). Echocardiographic control was performed before the TMLR procedure as well as 5 min and 30 min thereafter. Echocardiographic parameters were recorded in short-axis at the level of the laser channels, and included left ventricular ejection fraction, fractional shortening and segmental wall motility of the channels' area (scale 0-3: 0 = normal, 1 = hypokinesia, 2 = akinesia, 3 = dyskinesia). After sacrifice the lased region was sliced perpendicularly to the channels for histological and morphometrical analysis. Five minutes after the drilling of the channels, all the echocardiographic index worsened significantly in comparison with baseline values (p < 0.01). All recovered after 30 min and showed no difference with baseline values. Cross-section of the channel lesions measured 8.8 +/- 2.4 mm2 which is more than three times that of the probe (p < 0.01). In acute conditions, the lesions due to the TMLR probe are significantly larger than the probe itself and cause a transient drop of the segmental wall motility on a healthy myocardium. These results suggest that TMLR should be used cautiously in the clinical setting for patients with an impaired ventricular function.

Treatment and outcomes of acute basilar artery occlusion in the Basilar Artery International Cooperation Study (BASICS): a prospective registry study.

BACKGROUND: Treatment strategies for acute basilar artery occlusion (BAO) are based on case series and data that have been extrapolated from stroke intervention trials in other cerebrovascular territories, and information on the efficacy of different treatments in unselected patients with BAO is scarce. We therefore assessed outcomes and differences in treatment response after BAO. METHODS: The Basilar Artery International Cooperation Study (BASICS) is a prospective, observational registry of consecutive patients who presented with an acute symptomatic and radiologically confirmed BAO between November 1, 2002, and October 1, 2007. Stroke severity at time of treatment was dichotomised as severe (coma, locked-in state, or tetraplegia) or mild to moderate (any deficit that was less than severe). Outcome was assessed at 1 month. Poor outcome was defined as a modified Rankin scale score of 4 or 5, or death. Patients were divided into three groups according to the treatment they received: antithrombotic treatment only (AT), which comprised antiplatelet drugs or systemic anticoagulation; primary intravenous thrombolysis (IVT), including subsequent intra-arterial thrombolysis; or intra-arterial therapy (IAT), which comprised thrombolysis, mechanical thrombectomy, stenting, or a combination of these approaches. Risk ratios (RR) for treatment effects were adjusted for age, the severity of neurological deficits at the time of treatment, time to treatment, prodromal minor stroke, location of the occlusion, and diabetes. FINDINGS: 619 patients were entered in the registry. 27 patients were excluded from the analyses because they did not receive AT, IVT, or IAT, and all had a poor outcome. Of the 592 patients who were analysed, 183 were treated with only AT, 121 with IVT, and 288 with IAT. Overall, 402 (68%) of the analysed patients had a poor outcome. No statistically significant superiority was found for any treatment strategy. Compared with outcome after AT, patients with a mild-to-moderate deficit (n=245) had about the same risk of poor outcome after IVT (adjusted RR 0.94, 95% CI 0.60-1.45) or after IAT (adjusted RR 1.29, 0.97-1.72) but had a worse outcome after IAT compared with IVT (adjusted RR 1.49, 1.00-2.23). Compared with AT, patients with a severe deficit (n=347) had a lower risk of poor outcome after IVT (adjusted RR 0.88, 0.76-1.01) or IAT (adjusted RR 0.94, 0.86-1.02), whereas outcomes were similar after treatment with IAT or IVT (adjusted RR 1.06, 0.91-1.22). INTERPRETATION: Most patients in the BASICS registry received IAT. Our results do not support unequivocal superiority of IAT over IVT, and the efficacy of IAT versus IVT in patients with an acute BAO needs to be assessed in a randomised controlled trial. FUNDING: Department of Neurology, University Medical Center Utrecht.