Editor's Choice - Relevance of Infarct Size, Timing of Surgery, and Peri-operative Management for Non-ischaemic Cerebral Complications After Carotid Endarterectomy.

OBJECTIVE: To assess the incidence of post-operative non-ischaemic cerebral complications as a pivotal outcome parameter with respect to size of cerebral infarction, timing of surgery, and peri-operative management in patients with symptomatic carotid stenosis who underwent carotid endarterectomy (CEA). METHODS: Retrospective analysis of prospectively collected single centre CEA registry data. Consecutive patients with symptomatic carotid stenosis were subjected to standard patch endarterectomy. Brain infarct size was measured from the axial slice of pre-operative computed tomography/magnetic resonance imaging demonstrating the largest infarct dimension and was categorised as large (> 4 cm2), small (≤ 4 cm2), or absent. CEA was performed early (within 14 days) or delayed (15 - 180 days) after the ischaemic event. Peri-operative antiplatelet regimen (none, single, dual) and mean arterial blood pressure during surgery and at post-operative stroke unit monitoring were registered. Non-ischaemic post-operative cerebral complications were recorded comprising haemorrhagic stroke and encephalopathy, i.e., prolonged unconsciousness, delirium, epileptic seizure, or headache. RESULTS: 646 symptomatic patients were enrolled of whom 340 (52.6%) underwent early CEA; 367 patients (56.8%) demonstrated brain infarction corresponding to stenosis induced symptoms which was small in 266 (41.2%) and large in 101 (15.6%). Post-operative non-ischaemic cerebral complications occurred in 12 patients (1.9%; 10 encephalopathies, two haemorrhagic strokes) and were independently associated with large infarcts (adjusted odds ratio [OR] 6.839; 95% confidence interval [CI] 1.699 - 27.534) and median intra-operative mean arterial blood pressure in the upper quartile, i.e., above 120 mmHg (adjusted OR 13.318; 95% CI 2.749 - 64.519). Timing of CEA after the ischaemic event, pre-operative antiplatelet regimen, and post-operative blood pressure were not associated with non-ischaemic cerebral complications. CONCLUSION: Infarct size and unintended high peri-operative blood pressure may increase the risk of non-ischaemic complications at CEA independently of whether performed early or delayed.

Modification of In-Hospital Recommendation and Prescription of Anticoagulants for Secondary Prevention of Stroke after Launch of Direct Oral Anticoagulants and Change of National Guidelines.

INTRODUCTION: Approximately 1 out of 4 stroke patients suffers ischemic stroke secondary to atrial fibrillation (AF). Although indicated, withholding of anticoagulants for secondary prevention is a widespread phenomenon. OBJECTIVE: We examined the longitudinal change of recommendation and prescription of secondary preventive anticoagulation in AF patients in an acute stroke center setting focusing on the impact of the introduction of direct oral anticoagulants (DOACs) and the change of national stroke prevention guidelines. METHODS: Consecutive patients admitted with an acute cerebrovascular ischemic event underwent regular diagnostic work-up. Pseudonymized clinical data were entered into the institution's stroke registry. In those patients with AF, discharge letters were collected and evaluated for temporal trends and affecting factors of recommended and prescribed antithrombotic secondary medication at the time of discharge from hospital. RESULTS: Of 7,175 patients admitted between January 2009 and December 2018, 1,812 (25.3%) suffered stroke caused by AF. Frequency of patients with recommended anticoagulation increased within the observation period from 66.7 to 95.8% (per year; adjusted odds ratio [OR], 1.309; confidence interval [CI], 1.153-1.486). Independently from this time trend, DOAC approval (adjusted OR, 4.026; CI 1.962-8.265) and guideline change (adjusted OR, 2.184; CI, 1.006-4.743) were associated with an increasing frequency of recommendation for anticoagulation. The rate of patients already receiving recommended anticoagulation for secondary prevention at discharge increased from 42.1 to 62.5%. Introduction of DOACs was not associated with this trend, and guideline change was even associated with decreasing frequency of anticoagulated patients at hospital discharge (adjusted OR, 0.641; CI, 0.414-0.991). Fear of early intracerebral bleeding was the most common reason for withholding anticoagulation (37%) at hospital discharge and stayed stable during the observation period. CONCLUSIONS: Changing national guidelines with discard of contraindications for anticoagulation and the introduction of DOACs led to a broader recommendation of oral anticoagulation. However, both, new guidelines and DOACs, were not found to be associated with an increasing percentage of patients discharged from our hospital already on recommended anticoagulant prevention. This might be explained by the decreasing length of hospital stay during the study period and a missing evidence of early bleeding risk of DOACs in patients with acute brain infarction. Evidence-based data to close this therapeutic gap are needed.

Acute symptomatic extracranial internal carotid occlusion - natural course and clinical impact.

Background: To assess the vascular and clinical course of acute symptomatic extracranial internal carotid artery (ICA) occlusion. Patients and methods: Patients with an acute ischemic event in the anterior circulation and corresponding extracranial ICA occlusion at CT angiography and/or color-coded duplex sonography underwent recurrent duplex follow-up for detection of spontaneous recanalization. Stroke recurrence and functional outcome 4.5 months after the ischemic index event assessed by modified Rankin scale served as secondary outcome parameters. Results: 133 patients (91 men, mean age 62.3 years, SD 10.8) demonstrated symptomatic occlusion of the extracranial ICA with open intracranial ICA and open middle cerebral artery and were followed-up for spontaneous recanalization. Twenty-eight recanalized spontaneously, 25 to high-grade focal stenosis within 12 days, revealing an early cumulative recanalization rate of 23 %. Detection of recanalization was independently associated with de novo dual anti-platelet therapy (adjusted odds ratio [OR], 3.24; 95 % confidence interval [CI], 1.34 to 7.80). Ischemic recurrence occurred in 16 patients, of which 10 deemed to be embolic and 5 hemodynamic. Spontaneous ICA recanalization and an exhausted cerebrovascular reserve in the hemisphere distal to the occluded ICA were both independently associated with the occurrence of a recurrent ischemic event at Cox regression. An increasing NIHSS score at admission, a decreasing middle cerebral artery flow velocity and an ischemic recurrence independently predicted poor outcome (modified Rankin scale 3 to 6) in multivariate analysis. Conclusions: Acute symptomatic extracranial ICA occlusion is an unstable condition with frequent spontaneous recanalization to severe stenosis and early embolic stroke recurrence, demanding appropriate prevention especially in those patients with only mild deficit.

Growth arrest specific 2-like protein 1 expression is upregulated in podocytes through advanced glycation end-products.

Background: Growth arrest specific 2-like protein 1 (GAS2L1) protein is a member of the GAS2 family of proteins, known to regulate apoptosis and cellular cytoskeleton reorganization in different cells. Recently we identified that Gas2l1 gene expression in podocytes is influenced by advanced glycation end product-bovine serum albumin(AGE-BSA). Methods: The study was performed employing cultured podocytes and diabetic ( db/db ) mice, a model of type 2 diabetes. Akbuminuria as wellas urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion as measured with specific ELISAs. Gene expression was analysed via semiquantitative and real-time polymerase chain reaction. The protein levels were determined by western blotting and immunostaining. Results: We found that the Gas2l1 α isoform is expressed in podocytes. Treatment with AGE-BSA induced Gas2l1 α and Gas2 mRNA levels compared with controls incubated with non-glycated control BSA (Co-BSA). Moreover, application of the recombinant soluble receptor of AGEs (sRAGE), a competitor of cellular RAGE, reversed the AGE-BSA effect. Interestingly, AGE-BSA also increased the protein levels of GAS2L1α in a RAGE-dependent manner, but did not affect the GAS2 expression. Periodic acid-Schiff staining and albuminuria as well as urinary NGAL excretion revealed that db/db mice progressively developed diabetic nephropathy with renal accumulation of N ε -carboxy-methyl-lysine (immunohistochemistry, western blots). Analyses of GAS2L1α and GAS2 proteins in diabetic mice revealed that both were significantly elevated relative to their non-diabetic littermates. In addition, GAS2L1α and GAS2 proteins positively correlated with the accumulation of AGEs in the blood plasma of diabetic mice and the administration of sRAGE in diabetic mice reduced the glomerular expression of both proteins. Conclusions: We show for the first time that the protein expression of GAS2L1α in vitro and in vivo is regulated by the AGE-RAGE axis. The suppression of AGE ligation with their RAGE in diabetic mice with progressive nephropathy reversed the GAS2L1α expression, thus suggesting a role of GAS2L1α in the development of diabetic disease, which needs to be further elucidated.