How clot composition influences fibrinolysis in the acute phase of stroke: a proteomic study of cerebral thrombi.

Background: The dramatic clinical improvement offered by mechanical thrombectomy (MT) raised questions about the relevance of prior intravenous thrombolysis (IVT) in large vessel occlusion strokes. Hence, studying IVT susceptibility and its dependence on thrombus composition is crucial. We used observational proteomic study of whole thrombi retrieved by MT to identify factors associated with fibrin content and fibrinolytic activity (FA). Methods: In 104 stroke patients, the thrombi proteome was established by mass spectrometry coupled to liquid chromatography. FA were estimated in clots both outside (FAout) by measuring D-dimer levels at the blood-thrombus interface and inside (FAin) by evaluating the ratio of fibrinogen ⍺ to its plasmin-cleaved forms using proteomics coupled with protein electrophoresis. The factors associated with fibrin content, FAin and FAout were determined by IVT-adjusted linear regression. Results: FAout (p<0.0001) and FAin (p=0.0147) were driven by rt-PA administration (47/104) and thrombus composition. Indeed, FAout was greater with fibrin-rich than erythrocyte-rich thrombi, presumably because of more (r)t-PA substrates. Thus, FAout was increased with cardioembolic thrombi (72/104), which are rich in fibrin (p=0.0300). Opposite results were found inside thrombus, suggesting that (r)t-PA penetrability was hampered by the density of the fibrinous cap. Moreover, blood cells had a strong impact on thrombus structure and susceptibility to (r)t-PA. Indeed, fibrin content was negatively associated with erythrocyte-specific proteins in the thrombus, admission hematocrit (p=0.0139) and hemoglobin level (p=0.0080), which underlines the key role of erythrocytes in thrombus composition. Also, an increased number of neutrophils impaired FAout (p=0.0225), which suggests that their aggregation around the thrombus prevented the (r)t-PA attack. Only FAout was significantly associated with reduced thrombus weight (p=0.0310), increased recanalization rate (p=0.0150), good clinical outcome (p=0.0480) and reduced mortality (p=0.0080). Conclusions: Proteomics can offer new insights into the close relation between thrombus composition and susceptibility to fibrinolysis, paving the way for new adjuvant therapies.

Trial of Thrombectomy for Stroke with a Large Infarct of Unrestricted Size.

BACKGROUND: The use of thrombectomy in patients with acute stroke and a large infarct of unrestricted size has not been well studied. METHODS: We assigned, in a 1:1 ratio, patients with proximal cerebral vessel occlusion in the anterior circulation and a large infarct (as defined by an Alberta Stroke Program Early Computed Tomographic Score of ≤5; values range from 0 to 10) detected on magnetic resonance imaging or computed tomography within 6.5 hours after symptom onset to undergo endovascular thrombectomy and receive medical care (thrombectomy group) or to receive medical care alone (control group). The primary outcome was the score on the modified Rankin scale at 90 days (scores range from 0 to 6, with higher scores indicating greater disability). The primary safety outcome was death from any cause at 90 days, and an ancillary safety outcome was symptomatic intracerebral hemorrhage. RESULTS: A total of 333 patients were assigned to either the thrombectomy group (166 patients) or the control group (167 patients); 9 were excluded from the analysis because of consent withdrawal or legal reasons. The trial was stopped early because results of similar trials favored thrombectomy. Approximately 35% of the patients received thrombolysis therapy. The median modified Rankin scale score at 90 days was 4 in the thrombectomy group and 6 in the control group (generalized odds ratio, 1.63; 95% confidence interval [CI], 1.29 to 2.06; P<0.001). Death from any cause at 90 days occurred in 36.1% of the patients in the thrombectomy group and in 55.5% of those in the control group (adjusted relative risk, 0.65; 95% CI, 0.50 to 0.84), and the percentage of patients with symptomatic intracerebral hemorrhage was 9.6% and 5.7%, respectively (adjusted relative risk, 1.73; 95% CI, 0.78 to 4.68). Eleven procedure-related complications occurred in the thrombectomy group. CONCLUSIONS: In patients with acute stroke and a large infarct of unrestricted size, thrombectomy plus medical care resulted in better functional outcomes and lower mortality than medical care alone but led to a higher incidence of symptomatic intracerebral hemorrhage. (Funded by Montpellier University Hospital; LASTE ClinicalTrials.gov number, NCT03811769.).

Neuroprotective effects of lactate and ketone bodies in acute brain injury.

The goal of neurocritical care is to prevent and reverse the pathologic cascades of secondary brain injury by optimizing cerebral blood flow, oxygen supply and substrate delivery. While glucose is an essential energetic substrate for the brain, we frequently observe a strong decrease in glucose delivery and/or a glucose metabolic dysregulation following acute brain injury. In parallel, during the last decades, lactate and ketone bodies have been identified as potential alternative fuels to provide energy to the brain, both under physiological conditions and in case of glucose shortage. They are now viewed as integral parts of brain metabolism. In addition to their energetic role, experimental evidence also supports their neuroprotective properties after acute brain injury, regulating in particular intracranial pressure control, decreasing ischemic volume, and leading to an improvement in cognitive functions as well as survival. In this review, we present preclinical and clinical evidence exploring the mechanisms underlying their neuroprotective effects and identify research priorities for promoting lactate and ketone bodies use in brain injury.

Acute and chronic kidney dysfunction and prognosis following thrombectomy for ischemic stroke.

INTRODUCTION: Patients with Chronic Kidney Disease (CKD) have an increased risk of stroke and CKD seems associated with worse outcome after a stroke. The main objective of our study RISOTTO was to evaluate the influence of CKD and Acute Kidney Injury (AKI) on the clinical outcome and mortality of ischemic stroke patients after thrombolysis and/or thrombectomy. METHODS: This multicenter cohort study included patients in the acute phase of ischemic stroke due to a large artery occlusion managed by thrombectomy. Functional outcome at 3 months was assessed by modified Rankin Scale (mRS). RESULTS: 280 patients were included in the analysis. Fifty-nine patients (22.6%) had CKD. At 3 months, CKD was associated with similar functional prognosis (mRS 3-6: 50.0% vs. 41.7%, p=0.262) but higher mortality: 24.2% vs. 9.5%, p=0.004. In univariate analysis, patients with CKD had a higher burden of white matter hyperintensities (Fazekas 1.7±0.8 vs. 1.0±0.8, p=0.002), lower initial infarcted volume with equivalent severity, and lower recanalization success (86.4% vs. 97.0%, p=0.008) compared to non-CKD patients. Forty-seven patients (20.0%) developed AKI. AKI was associated with poorer 3-month functional outcome (mRS 3-6: 63.8% vs. 49.0%, p=0.002) and mortality: 23.4% vs. 7.7%, p=0.002. In multivariate analysis, AKI appeared as an independent risk factor for poor functional outcome (mRS 3-6: adjOR 2.79 [1.11-7.02], p=0.029) and mortality: adjOR 2.52 [1.03-6.18], p=0.043 at 3 months, while CKD was not independently associated with 3-month mortality and poor neurological outcome. CONCLUSION: AKI is independently associated with poorer functional outcome and increased mortality at 3 months. CKD was not an independent risk factor for 3-month mortality or poor functional prognosis.

Symptomatic Carotid Free-Floating Thrombus: About Management of 50 Cases in a Referral Neurovascular Center.

BACKGROUND: Carotid free-floating thrombus (CFFT) is an uncommon disorder. The aim of this study was to describe a French cohort of CFFT patients. METHODS: We conducted a retrospective monocentric study from a Stroke Center among patients admitted for stroke with CFFT. RESULTS: Between January 2017 to December 2019, 2038 ischemic strokes were recorded. A total of 50 patients with CFFT were consecutively included (32 men/18 women). The mean age was 58.2 years (±11.7). Their etiologies were atheroma (46%), carotid dissection and web (20%), hypercoagulability disorders (16%) and arrhythmia (10%). Exclusive medical management was performed in 38 patients (76%): 29 (59.2%) were anticoagulated and 9 (18.4%) received antiplatelets alone in the first week. Surgical intervention was performed in the first 30 days for 11 patients (22%). The main surgical indication was a residual carotid stenosis over 70%. Only three patients had a recurrent stroke in the medical group with anticoagulants. No patients in the antiplatelet group or the surgical group had a recurrent stroke. CONCLUSIONS: Our study summarized a large cohort of 50 patients with CFFT. This diagnosis implies the need to search for a local arterial disease and to screen for hypercoagulability states. An initial medical strategy followed by a delayed carotid surgery if the follow-up imaging shows a residual stenosis appears to be safe.

Regional brain glucose metabolism is differentially affected by ketogenic diet: a human semiquantitative positron emission tomography.

PURPOSE: Ketogenic diet (KD) is recommended to avoid intense [18F]FDG myocardial physiologic uptake in PET imaging. Neuroprotective and anti-seizure effects of KD have been suggested, but their mechanisms remain to be elucidated. This [18F]FDG PET study aims to evaluate the effect of KD on glucose brain metabolism. METHOD: Subjects who underwent KD prior to whole-body and brain [18F]FDG PET between January 2019 and December 2020 in our department for suspected endocarditis were retrospectively included. Myocardial glucose suppression (MGS) on whole-body PET was analyzed. Patients with brain abnormalities were excluded. Thirty-four subjects with MGS (mean age: 61.8 ± 17.2 years) were included in the KD population, and 14 subjects without MGS were considered for a partial KD group (mean age: 62.3 ± 15.1 years). Brain SUVmax was first compared between these two KD groups to determine possible global uptake difference. Semiquantitative voxel-based intergroup analyses were secondarily performed to determine possible inter-regional differences by comparing KD groups with and without MGS, separately, to 27 healthy subjects fasting for at least 6 h (mean age of 62.4 ± 10.9 years), and KD groups between them (p-voxel < 0.001, and p-cluster < 0.05, FWE-corrected). RESULTS: A 20% lower brain SUVmax was found in subjects under KD with MGS in comparison to those without MGS (Student's t-test, p = 0.02). Whole-brain voxel-based intergroup analysis revealed that patients under KD with and without MGS had relative hypermetabolism of limbic regions including medial temporal cortices and cerebellum lobes and relative hypometabolism of bilateral posterior regions (occipital), without significant difference between them. CONCLUSION: KD globally reduces brain glucose metabolism but with regional differences, requiring special attention to clinical interpretation. On a pathophysiological perspective, these findings could help understand underlying neurological effects of KD through possible decrease of oxidative stress in posterior regions and functional compensation in the limbic regions.

Kidney disease and stroke: epidemiology and potential mechanisms of susceptibility.

Patients with chronic kidney disease (CKD) have an increased risk of both ischaemic and haemorrhagic stroke compared with the general population. Both acute and chronic kidney impairment are independently associated with poor outcome after the onset of a stroke, after adjustment for confounders. End-stage kidney disease (ESKD) is associated with a 7- and 9-fold increased incidence of both ischaemic and haemorrhagic strokes, respectively, poorer neurological outcome and a 3-fold higher mortality. Acute kidney injury (AKI) occurs in 12% of patients with stroke and is associated with a 4-fold increased mortality and unfavourable functional outcome. CKD patients seem to have less access to revascularisation techniques like thrombolysis and thrombectomy despite their poorer prognosis. Even if CKD patients could benefit from these specific treatments in acute ischaemic stroke, their prognosis remains poor. After thrombolysis, CKD is associated with a 40% increased risk of intracerebral haemorrhage (ICH), a 20% increase in mortality and poorer functional neurological outcomes. After thrombectomy, CKD is not associated with ICH but is still associated with increased mortality, and AKI with unfavourable outcome and mortality. The beneficial impact of gliflozins on the prevention of stroke is still uncertain. Non-traditional risk factors of stroke, like uraemic toxins, can lead to chronic cerebrovascular disease predisposing to stroke in CKD, notably through an increase in the blood-brain barrier permeability and impaired coagulation and thrombosis mechanisms. Preclinical and clinical studies are needed to specifically assess the impact of these non-traditional risk factors on stroke incidence and outcomes, aiming to optimize and identify potential therapeutic targets.

Atrial Fibrillation Detected by Implantable Monitor in Embolic Stroke of Undetermined Source: A New Clinical Entity.

BACKGROUND: High incidence of covert paroxysmal atrial fibrillation (CPAF) detected by an implantable cardiac monitor (ICM) is expected in embolic stroke of undetermined source (ESUS) patients. This study aimed to determine the CPAF rate in an ESUS cohort using ICMs and compare stroke characteristics of patients with CPAF to those with known or inpatient-diagnosed AF (KIDAF). METHODS: ESUS patients with ICMs were enrolled. ESUS diagnosis was defined as a non-lacunar stroke in the absence of symptomatic atherosclerotic stenosis (≥50%), no major-risk cardioembolic source, and no other specific cause. ESUS characteristics of patients with CPAF were compared to ESUS patients without CPAF and to KIDAF stroke patients. RESULTS: During the median follow-up of 476 (371-615) days, CPAF was newly detected in 38/163 (23.31%) patients within 236 (115.50-510.75) days after the stroke. CPAF was independently associated to older age, coronaropathy, left atrial dilation, and atrial hyperexcitability, but not to stroke severity. Compared to KIDAF strokes, ESUS with CPAF had lower rates of proximal occlusion leading to milder clinical severity (NIHSS: 3.00 (1.00-8.25) vs. 14.50 (6.00-21.00)). CONCLUSIONS: Our study revealed a high proportion of CPAF in ESUS. We highlight that CPAF is a distinct clinical entity compared to KIDAF based on differences in stroke characteristics and AF diagnosis temporality.

Diabetes is an Independent Growth Factor of Ischemic Stroke During Reperfusion Phase Leading to Poor Clinical Outcome.

OBJECTIVES: Despite the success of recanalization by bridging therapy, about half of treated stroke patients remain disabled. While numerous reports propose clinical predictors of stroke clinical outcome in this context, we originally aimed to study pre-therapeutic factors influencing infarct growth (IG) and poor clinical outcome in strokes due to large vessel occlusion (LVO) successfully recanalized. MATERIALS AND METHODS: We enrolled 87 consecutive successfully recanalized patients (mTICI: 2b/2c/3) by mechanical thrombectomy (±rt-PA) after stroke due to middle cerebral artery (M1) occlusion within 6 h according to AHA guidelines. IG was defined by subtracting the initial DWI volume to the final 24 h-TDM volume. Statistical associations between poor clinical outcome (mRS≥2), IG and pertinent clinico-radiological variables, were measured using logistic and linear regression models. RESULTS: Among 87 enrolled patients (Age(y): 68.4 ± 17.5; NIHSS: 16.0 ± 5.4), 42/87 (48,28%) patients had a mRS ≥ 2 at 3 months. Diabetic history (OR: 3.70 CI95%[1.03;14.29] and initial NIHSS (/1 point: OR: 1.16 CI95%[1.05;1.27]) were independently associated with poor outcome. IG was significantly higher in stroke patients with poor outcome (+7.57 ± 4.52 vs -7.81 ± 1.67; p = 0.0024). Initial volumes were not significantly different (mRS≥2: 16.18 ± 2.67; mRS[0-1]: 14.70 ± 2.30; p = 0.6771). Explanatory variables of IG in linear regression were diabetic history (ß: 21.26 CI95%[5.43; 37.09]) and NIHSS (ß: 0.83 CI95%[0.02; 1.64]). IG was higher in diabetic stroke patients (23.54 ± 1.43 vs -6.20 ± 9.36; p = 0.0061). CONCLUSIONS: We conclude that diabetes leads to continued IG after complete recanalization, conditioning clinical outcome in LVO strokes successfully recanalized by bridging therapy. We suggest that poor tissular reperfusion by diabetic microangiopathy could explain this result.

Use of the Rocket Technique after Failure of the Direct Aspiration First-Pass Technique in Acute Stroke Thrombectomy.

The technical feasibility of the rocket technique was evaluated for patients treated for stroke where the direct aspiration first-pass technique (ADAPT) failed to reach the occlusion site. This single-center retrospective study included data on consecutive patients with a large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. Of 138 patients, 100 met the inclusion criteria. In 84 patients, a large 0.072-inch inner lumen aspiration catheter was able to reach the occlusion site when deployed with a coaxial microcatheter. In 16 patients, this technique failed, and the microcatheter was replaced with a compliant balloon inflated at the extremity of the aspiration catheter (rocket technique). In 15 of these 16 patients, the rocket technique brought the catheter into contact with the thrombus. In conclusion, when deployment of the ADAPT with a coaxial microcatheter fails to reach the clot site, the rocket technique can safely advance the aspiration catheter to the clot.

Non-ischemic cerebral enhancing lesions after thrombectomy: a multicentric retrospective French national registry.

To report the occurrence of non-ischemic cerebral enhancing (NICE) lesions following mechanical thrombectomy (MT) through the retrospective French nationwide registry of NICE lesions. All thrombectomy capable stroke centers (TSC) in France were invited to fill out a questionnaire disseminated through a trainee-led research network (JENI-RC: Jeunes en Neuroradiologie Interventionnelle-Research Collaborative). NICE lesions were defined according to previous literature as delayed onset punctate, nodular, or annular foci enhancements with peri-lesion edema and vascular distribution in the territory of the MT with no other confounding disease. All 43 TSC French centers responded. Three patients were reported by 3 different centers over a total of 34,824 MT (2015-2020). Patient no. 1 developed symptomatic NICE lesions 8 weeks after MT with combination of aspiration and stentriever for a right middle cerebral artery occlusion. Patient no. 2 developed asymptomatic NICE lesions 5 weeks after MT with direct thromboaspiration for a right middle cerebral artery occlusion. Patient no. 3 developed symptomatic NICE lesions 6 weeks after MT with direct thromboaspiration, and combination of aspiration and stentriever for a basilar artery occlusion. This study provides evidence that NICE lesions following MT are a possible rare complication with a similar presentation as previously described following endovascular aneurysm treatment. Both radiologists and neurologists should be aware of this adverse event and make use of MRI contrast agents in case of unexplained symptoms/images during follow-up after MT.

Recurrence of ischemic stroke on direct oral anticoagulant therapy in a patient with marantic endocarditis related to lung cancer.

Venous thromboembolism (VTE) and arterial thromboembolism (ATE) are frequent complications in cancer patients. For curative treatment of VTE in a neoplastic context, recent randomized controlled trials and meta-analyses suggest that direct oral anticoagulants (DOACs) can be an alternative to conventional treatment by low molecular weight heparins (LMWHs). On the other hand, the role of DOACs in the treatment of cancer-related ATE remains unclear. Here, we report a case of stroke recurrence in a patient initially treated with DOACs that were started for cancer-related VTE. The failure of the DOACs, compared to LMWHs, to prevent the stroke recurrence led us to the infrequent final diagnosis of nonbacterial thrombotic endocarditis (formerly known as marantic endocarditis). This case illustrates the association between ATE and VTE in a patient with marantic endocarditis related to lung cancer and recurrence of ischemic stroke on direct oral anticoagulant therapy. .

Combined Omic Analyzes of Cerebral Thrombi: A New Molecular Approach to Identify Cardioembolic Stroke Origin.

Background and Purpose: The diagnosis of cardioembolic stroke can be challenging for patient management in secondary stroke prevention, particularly in the case of covert paroxysmal atrial fibrillation. The molecular composition of a cerebral thrombus is related to its origin. Therefore, proteomic and metabolomic analyses of the retrieved thrombotic material should allow the identification of biomarkers or signatures to improve the etiological diagnosis of stroke. Methods: In this pilot study, the proteome and metabolome of cerebral thrombi from atherothrombotic and cardioembolic stroke patients were studied according to ASCOD phenotyping (A: atherosclerosis; S: small-vessel disease; C: cardiac pathology; O: other causes; D: dissection), with the highest causality grade, from the ThrombiOMIC cohort (consecutive patients with stroke recanalized by mechanical thrombectomy in an acute phase). Proteomic and metabolomic results were used separately or combined, and the obtained omic signatures were compared with classical cardioembolic stroke predictors using pairwise comparisons of the area under receiver operating characteristics. Results: Among 59 patients of the ThrombiOMIC cohort, 34 patients with stroke showed a cardioembolic phenotype and 7 had an atherothrombotic phenotype. Two thousand four hundred fifty-six proteins and 5019 molecular features of the cerebral thrombi were identified using untargeted proteomic and metabolomic approaches, respectively. Area under receiver operating characteristics to predict the cardioembolic origin of stroke were calculated using the proteomic results (0.945 [95% CI, 0.871­1]), the metabolomic results (0.836 [95% CI, 0.714­0.958]), and combined signatures (0.996 [95% CI, 0.984­1]). The diagnostic performance of the combined signatures was significantly higher than that of classical predictors such as the plasmatic BNP (B-type natriuretic peptide) level (area under receiver operating characteristics, 0.803 [95% CI, 0.629­0.976]). Conclusions: The combined proteomic and metabolomic analyses of retrieved cerebral thrombi is a very promising molecular approach to predict the cardioembolic cause of stroke and to improve secondary stroke prevention strategies.

Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice.

The role of ketone bodies in the cerebral energy homeostasis of neurological diseases has begun to attract recent attention particularly in acute neurological diseases. In ketogenic therapies, ketosis is achieved by either a ketogenic diet or by the administration of exogenous ketone bodies. The oral ingestion of the ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is a new method to generate rapid and significant ketosis (i.e., above 6 mmol/L) in humans. KE is hydrolyzed into ß-hydroxybutyrate (ßHB) and its precursor 1,3-butanediol. Here, we investigate the effect of oral KE administration (3 mg KE/g of body weight) on brain metabolism of non-fasted mice using liquid chromatography in tandem with mass spectrometry. Ketosis (Cmax = 6.83 ± 0.19 mmol/L) was obtained at Tmax = 30 min after oral KE-gavage. We found that ßHB uptake into the brain strongly correlated with the plasma ßHB concentration and was preferentially distributed in the neocortex. We showed for the first time that oral KE led to an increase of acetyl-CoA and citric cycle intermediates in the brain of non-fasted mice. Furthermore, we found that the increased level of acetyl-CoA inhibited glycolysis by a feedback mechanism and thus competed with glucose under physiological conditions. The brain pharmacodynamics of this oral KE strongly suggest that this agent should be considered for acute neurological diseases.

Metabolome of Cerebral Thrombi Reveals an Association between High Glycemia at Stroke Onset and Good Clinical Outcome.

Despite the fact that glucose is the main fuel of the brain, hyperglycemia at hospital admission is generally associated with a poor functional outcome in stroke patients. This paradox may be explained by the lack of information about the blood glucose level at stroke onset. Here, we analyzed the metabolome of blood cells entrapped in cerebral thrombi to gain insight into their metabolism at stroke onset. Fourty-one consecutive stroke patients completely recanalized by mechanical thrombectomy within 6 h were included. The metabolome of retrieved thrombi was analyzed by liquid chromatography tandem with mass spectrometry. Discriminant Analysis (sparse Partial Least Squares Discriminant Analysis (sPLS-DA)) was performed to identify classification models and significant associated features of favorable clinical outcome at 3 months (modified Rankin Scale (mRS) < 2). sPLS-DA of the metabolomes of cerebral thrombi discriminated between stroke patients with a favorable or poor clinical outcome (Area Under the Curve (AUC) = 0.992 (0.931-1)). In addition, our results revealed that high sorbitol and glucose levels in the thrombi positively correlated with favorable clinical outcomes. Sorbitol, a short-term glycemic index reflecting a high blood glucose level at stroke onset, was found to be an independent predictor of good outcome (AUC = 0.908 (0.807-0.995)). This study demonstrates that a high blood glucose level at stroke onset is beneficial to the clinical outcome of the patient.

Effect of hyperglycemia on stroke outcome is not homogeneous to all patients treated with mechanical thrombectomy.

OBJECTIVES: Admission hyperglycemia is a penumbra-modifying factor that is associated with poor functional outcome in acute ischemic stroke (AIS) patients treated with intravenous rt-PA and/or mechanical thrombectomy (MT). Insulin therapy has failed to demonstrate a clinical benefit and the question of the patient selection remains under debate. We assessed the relationship between admission glycemia (AG) and functional outcome in AIS patients treated by MT according to both penumbra characteristics and reperfusion status. PATIENTS AND METHODS: We performed a retrospective analysis of a multi-center registry of consecutive AIS (NIHSS ≥ 10) due to middle cerebral artery occlusion treated by MT (± tissue Plasminogen Activator (tPA)). To evaluate the association between AG and the 3-month functional outcome (modified Rankin Scale (mRS) ≤2), univariable and multivariable analyses were used. Subgroup analyses were performed according to both clinical-ASPECTS Mismatch (CAM2) and the complete recanalization (CR) status defined by a mTICI scale (modified Thrombolysis in Cerebral Infarction) 2b/3. RESULTS: 216 AIS patients were included (Median Age: 68.43[58.12-77.95], median NIHSS: 18[15-21]). 104/216 (48.15%) patients had mRS≤2 at 3 months. AG was an independent predictor of functional outcome (/1 g/L OR: 0.10[0.03-0.37]) after adjusting for potential cofounders. Among subgroups formed by combining CAM2 and CR, AG was found to be predictor of functional outcome only in CAM2+/CR+ and specifically when recanalization was early. CONCLUSION: This study highlights the fact that the relationship between AG and prognosis is not homogeneous for all patients and indicates that AG has a deleterious effect on the ischemic penumbra, thus explaining its statistical association with functional outcome. Stroke neuroprotection by targeting hyperglycemia should be considered in acute stroke patients with mismatch and early complete recanalization. More prospective randomized trials are needed to generalize the conclusions.

Urinary ketone body loss leads to degeneration of brain white matter in elderly SLC5A8-deficient mice.

SLC5A8 is a sodium-coupled monocarboxylate and ketone transporter expressed in various epithelial cells. A putative role of SLC5A8 in neuroenergetics has been also hypothesized. To clarify this issue, we studied the cerebral phenotype of SLC5A8-deficient mice during aging. Elderly SLC5A8-deficient mice presented diffuse leukoencephalopathy characterized by intramyelinic oedema without demyelination suggesting chronic energetic crisis. Hypo-metabolism in the white matter of elderly SLC5A8-deficient mice was found using 99mTc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT). Since the SLC5A8 protein could not be detected in the mouse brain, it was hypothesized that the leukoencephalopathy of aging SLC5A8-deficient mice was caused by the absence of slc5a8 expression in a peripheral organ, i.e. the kidney, where SLC5A8 is strongly expressed. A hyper-excretion of the ketone ß-hydroxybutyrate (BHB) in the urine of SLC5A8-deficient mice was observed and showed that SLC5A8-deficient mice suffered a cerebral BHB insufficiency. Elderly SLC5A8-deficient mice also presented altered glucose metabolism. We propose that the continuous renal loss of BHB leads to a chronic energetic deficiency in the brain of elderly SLC5A8-deficient mice who are unable to counterbalance their glucose deficit. This study highlights the importance of alternative energetic substrates in neuroenergetics especially under conditions of restricted glucose availability.

SURF (stroke with underlying risk of atrial fibrillation): Proposals for a definition.

OBJECTIVES: Diagnosis of occult atrial fibrillation (AF) in stroke patients remains challenging. Several scores predictive of occult AF in stroke patients have been proposed, all based on the positive predictive value of clinical, biological, and radiological parameters, but they failed to modify the management of AF detection after stroke. The aim of this study was to identify a group of Stroke patients with Underlying Risk of Atrial Fibrillation (SURF) excluding stroke patients with low risk of AF. PATIENTS AND METHODS: We enrolled consecutive AF-naive stroke patients without indication of long-term anticoagulation. AF was adjudicated after prolonged Holter ECG and 2 years of follow-up. The negative predictive value (NPV) was determined for each relevant parameter in the acute phase. Firstly, clinico-radiological parameters with NPV > 95% defined the initial exclusion criteria of SURF. Secondly, the ultimate exclusion criterion of SURF was defined by a composite criterion constructed using the beta-coefficient of independent predictive parameters of AF determined by logistic regression. RESULTS: Among 773 AF-naïve patients without indication of anticoagulation, 111(14.4%) AFs were found. Initial SURF exclusion criteria, determined by NPV ≥ 95%, are: symptomatic atherosclerotic stenosis ≥50%, symptomatic arterial dissection or lacunar stroke. The SURF definition was completed by a composite exclusion criterion [Age*10+BNP< = 700] (NPV: 96.8%[92.6-98.9]). In the SURF group, 93/195(47.7%) AFs were diagnosed. CONCLUSIONS: In the SURF group, nearly half of the stroke patients had AF. The criteria used to define such a group are easily obtained in all stroke units, in the acute phase. SURF is a new concept proposal, which aims to improve the effectiveness of AF diagnosis after stroke.

First family case of haemoglobinopathy Titusville in France and literature overview.

Normal haemoglobin is a tetramer molecule, consisting of two α and ß haemoglobin chains. Haemoglobinopathies occur when abnormalities in these proteins are present. More than 1000 naturally occurring human haemoglobin variants with single amino acid substitution throughout the molecule have been identified and can be discovered through their clinical and biological manifestations. Here, we report the case of a 60-year-old woman for whom no oximetry results were obtained during blood gas analysis (BGA) and the values of oxygen saturation obtained from pulse oximetry (73%) and co-oximetry (90%) differed. Haemoglobin analysis demonstrated the presence of a variant in the alpha chain. Clinical history of the patient and her family revealed they carry a haemoglobin variant (Titusville type), thus representing the first French family case reported. Those results raised the question whether the presence of this variant could be the cause of the errors encountered during BGA.

Bevacizumab: Is the lower the better for glioblastoma patients in progression?

INTRODUCTION: Based on the radiological responses obtained with a schedule of ten mg/kg every two weeks bevacizumab was approved by the FDA for recurrent glioblastomas. Due to the negative results concerning overall survival of patients receiving bevacizumab, the European application was rejected. Despite this, many centers apply an off-label prescription. Our aim was to evaluate the safety and efficacy of schedules of low doses of bevacizumab. METHODS: From September 2013 to August 2016, we recruited patients with progressive glioblastoma, whatever the previous treatments. We compared a routine control group (CG) of ten mg/kg, to a low dose group (LDG) composed of 5 subgroups: G5: five mg/kg, G4: four mg/kg, G3: three mg/kg, G2: two mg/kg, G1: one mg/kg; each patient was treated with the same dose every two weeks. RESULTS: Fifty-three patients were treated: 20 women and 33 men, 24 in the CG and 29 in the LDG. The median age at diagnosis was 62 years [35.0-77.0]. No statistical difference was found in overall survival either for the CG or the LDG (P=0.086) or among groups (P=0.251), with even a trend toward improvement for LDG: 62 weeks [20-145] versus 73 weeks [18-178]. The median progression free survival was comparable: 19.5 weeks [6.0-54.0] for the CG and 15.0 weeks [0.0-134.0] for the LDG (P=0.221). Bevacizumab was stopped either due to progression (45.1%) or toxicity (52.9%), without significant differences between doses but maybe less toxicities in the LDG (16.7% for toxicity in G1). DISCUSSION: Use of bevacizumab at progression at lower than usual doses seems to give the same results as the standard dose without giving additional toxicity.