Jean-Philippe Desilles

Diabetes mellitus, admission glucose, and outcomes after stroke thrombolysis: a registry and systematic review

Background and Purpose— The potential detrimental effect of diabetes mellitus and admission glucose level (AGL) on outcomes after stroke thrombolysis is unclear. We evaluated outcomes of patients treated by intravenous and/or intra-arterial therapy, according to diabetes mellitus and AGL. Methods— We analyzed data from a patient registry (n=704) and conducted a systematic review of previous observational studies. The primary study outcome was the percentage of patients who achieved a favorable outcome (modified Rankin score ⩽2 at 3 months). Results— We identified 54 previous reports that evaluated the effect of diabetes mellitus or AGL on outcomes after thrombolysis. In an unadjusted meta-analysis that included our registry data and previous available observational data, diabetes mellitus was associated with less favorable outcome (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.73–0.79) and more symptomatic intracranial hemorrhage (OR, 1.38; 95% CI, 1.21–1.56). However, in multivariable analysis, diabetes mellitus remained associated with less favorable outcome (OR, 0.77; 95% CI, 0.69–0.87) but not with symptomatic intracranial hemorrhage (OR, 1.11; 95% CI, 0.83–1.48). In unadjusted and in adjusted meta-analysis, higher AGL was associated with less favorable outcome and more symptomatic intracranial hemorrhage; the adjusted OR (95% CI) per 1 mmol/L increase in AGL was 0.92 (0.90–0.94) for favorable outcome, and 1.09 (1.04–1.14) for symptomatic intracranial hemorrhage. Conclusions— These results confirm that AGL and history of diabetes mellitus are associated with poor clinical outcome after thrombolysis. AGL may be a surrogate marker of brain infarction severity rather than a causal factor. However, randomized controlled evidences are needed to address the significance of a tight glucose control during thrombolysis on clinical outcome.

Blood–brain barrier disruption is associated with increased mortality after endovascular therapy

Objective: To evaluate the incidence, baseline characteristics, and clinical prognosis of blood–brain barrier (BBB) disruption after endovascular therapy in acute ischemic stroke patients. Methods: A total of 220 patients treated with endovascular therapy between April 2007 and October 2011 were identified from a prospective, clinical, thrombolysis registry. All patients underwent a nonenhanced CT scan immediately after treatment. CT scan or MRI was systematically realized at 24 hours to assess intracranial hemorrhage complications. BBB disruption was defined as a hyperdense lesion on the posttreatment CT scan. Results: BBB disruption was found in 128 patients (58.2%; 95% confidence interval [CI], 51.4%–64.9%). Cardioembolic etiology, high admission NIH Stroke Scale score, high blood glucose level, internal carotid artery occlusion, and use of combined endovascular therapy (chemical and mechanical revascularization) were independently associated with BBB disruption. Patients with BBB disruption had lower rates of early major neurologic improvement (8.6% vs 31.5%, p < 0.001), favorable outcome (39.8% vs 61.8%, p = 0.002), and higher rates of 90-day mortality (34.4% vs 14.6%, p = 0.001) and hemorrhagic complications (42.2% vs 8.7%, p < 0.001) than those without BBB disruption. By multivariable analysis, patients with BBB disruption remained with a lower rate of early neurologic improvement (adjusted odds ratio [OR], 0.28; 95% CI, 0.11–0.70) and with a higher rate of mortality (adjusted OR, 2.37; 95% CI, 1.06–5.32) and hemorrhagic complications (adjusted OR, 6.38; 95% CI, 2.66–15.28). Conclusion: BBB disruption has a detrimental effect on outcome and is independently associated with mortality after endovascular therapy. BBB disruption assessment may have a role in prognosis staging in these patients.

Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke

Background and Purpose— Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral artery occlusion (MCAO) rat stroke model. Methods— Rats were subjected to 60-minute transient MCAO. Alteplase (10 mg/kg) was administered 30 minutes after the beginning of MCAO. Real-time intravital fluorescence microscopy through a dura-sparing craniotomy was used to visualize circulating blood cells and fibrinogen. Cerebral microvessel patency was quantitatively evaluated by fluorescein isothiocyanate-dextran perfusion. Results— Immediately after MCAO, platelet and leukocyte accumulation were observed mostly in the venous compartment. Within 30 minutes after MCAO, microthrombi and parietal fibrin deposits were detected in postcapillary microvessels. Alteplase treatment significantly (P=0.006) reduced infarct volume and increased the percentage of perfused vessels during MCAO (P=0.02) compared with saline. Plasma levels of fibrinogen from alteplase-treated rats showed a rapid and profound hypofibrinogenemia. In vitro platelet aggregation demonstrated that alteplase reduced platelet aggregation (P=0.0001) and facilitated platelet disaggregation (P=0.001). These effects were reversible in the presence of exogenous fibrinogen. Conclusions— Our data demonstrate that DMT is an early phenomenon initiated before recanalization. We further show that alteplase-dependent maintenance of downstream perfusion during MCAO improves acute ischemic stroke outcome through a fibrinogen-dependent platelet aggregation reduction. Our results indicate that early targeting of DMT represents a therapeutic strategy to improve the benefit of large artery recanalization in acute ischemic stroke.

Impact of Modified TICI 3 versus Modified TICI 2b Reperfusion Score to Predict Good Outcome following Endovascular Therapy

BACKGROUND AND PURPOSE: The TICI score is widely used to evaluate cerebral perfusion before and after the endovascular treatment of stroke. Recent studies showing the effectiveness and safety of mechanical thrombectomy combine modified TICI 2b and modified TICI 3 to assess the technical success of endovascular treatment. The purpose of this study was to determine how much clinical outcomes differ between patients achieving modified TICI 2b and modified TICI 3 reperfusion. MATERIALS AND METHODS: We analyzed 222 consecutive patients with acute large intracranial artery occlusion of the anterior circulation having achieved modified TICI 2b or modified TICI 3 reperfusion after thrombectomy. The primary end point was the rate of favorable outcome defined as the achievement of a modified Rankin Scale score of 0–2 at 3 months. RESULTS: Patients with modified TICI 3 more often had favorable collateral circulation and atherosclerosis etiology, with a shorter time from onset to reperfusion than patients with modified TICI 2b (all P < .05). The number of total passes to achieve reperfusion was higher in the modified TICI 2b group (median, 2; interquartile range, 1–3, 1–9) versus (median, 1; interquartile range, 1–2, 1–8) in the modified TICI 3 group (P = .0002). Favorable outcome was reached more often for patients with modified TICI 3 than for those with modified TICI 2b (71.7% versus 50.5%, P = .001), with a similar difference when considering excellent outcome. In addition, patients with modified TICI 3 had a lower intracerebral hemorrhage rate (23.0% versus 45.0%, P < .001). CONCLUSIONS: Patients with modified TICI 3 reperfusion have better functional outcomes than those with modified TICI 2b. Given the improving reperfusion rates obtained with thrombectomy devices, future thrombectomy trials should consider modified TICI 2b and modified TICI 3 status separately.

Impact of Diffusion-Weighted Imaging Lesion Volume on the Success of Endovascular Reperfusion Therapy

Background and Purpose— Diffusion-weighted imaging (DWI) lesion volume is associated with poor outcome after thrombolysis, and it is unclear whether endovascular therapies are beneficial for large DWI lesion. Our aim was to assess the impact of pretreatment DWI lesion volume on outcomes after endovascular therapy, with a special emphasis on patients with complete recanalization. Methods— We analyzed data collected between April 2007 and November 2011 in a prospective clinical registry. All acute ischemic stroke patients with complete occlusion of internal carotid artery or middle cerebral artery treated by endovascular therapy were included. DWI lesion volumes were measured by the RAPID software. Favorable outcome was defined by modified Rankin Scale of 0 to 2 at 90 days. Results— A total of 139 acute ischemic stroke patients were included. Median DWI lesion volume was 14 cc (interquartile range, 5–43) after a median onset time to imaging of 110 minutes (interquartile range, 77–178). Higher volume was associated with less favorable outcome (adjusted odds ratio, 0.55; 95% confidence interval, 0.31–0.96). A complete recanalization was achieved in 65 (47%) patients after a median onset time of 238 minutes (interquartile range, 206–285). After adjustment for volume, complete recanalization was associated with more favorable outcome (adjusted odds ratio, 6.32; 95% confidence interval, 2.90–13.78). After stratification of volume by tertiles, complete recanalization was similarly associated with favorable outcome in the upper 2 tertiles (P<0.005). Conclusions— Our results emphasize the importance of initial DWI volume and recanalization on clinical outcome after endovascular treatment. Large DWI lesions may still benefit from recanalization in selected patients.

Dramatic Recovery in Acute Ischemic Stroke Is Associated With Arterial Recanalization Grade and Speed

Background and Purpose— Dramatic recovery (DR) is a predictor of stroke outcome among others. However, after successful recanalization, systematic favorable outcome is not the rule. We sought to analyze the impact of recanalization on DR in patients with acute ischemic stroke eligible for any revascularization strategies (either intravenous or endovascular). Methods— We analyzed data collected between April 2007 and May 2011 in our prospective clinical registry. All patients with acute ischemic stroke with National Institutes of Health Stroke Scale ≥10 at admission and an identification of arterial status before treatment were included. DR was defined as National Institutes of Health Stroke Scale ⩽3 at 24 hours or a decrease of ≥10 points within 24 hours. Results— DR occurred in 75 of 255 patients with acute ischemic stroke (29.4%). Patients with persistent occlusion had a low DR rate (11.1%) than those with no documented occlusion (36.5%) and those with occlusion followed by recanalization (35.3%; both P<0.001). Among patients with recanalization monitored by angiography, DR was higher among patients with complete recanalization than among those with partial recanalization (46.8% versus 14.3%; P<0.001) and increased with tertiles of time to recanalization (Ptrend=0.002). In multivariable logistic regression analysis, grade and time to recanalization appeared independently associated with DR; the adjusted ORs were 4.17 (95% CI, 1.61–10.77) for complete recanalization and 1.24 (95% CI, 1.04–1.48) for each 30-minute time decrease. Patients with versus without DR more frequently had modified Rankin Scale ⩽1 (67.6% versus 9.0%; P<0.001) and less frequently had hemorrhage (17.3% versus 33.9%; P=0.024). Conclusions— DR is strongly associated with favorable clinical outcome and is dependent on complete recanalization and time to recanalization.

High-density Lipoprotein–based Therapy Reduces the Hemorrhagic Complications Associated With Tissue Plasminogen Activator Treatment in Experimental Stroke

Background and Purpose— We have previously reported that intravenous injection of high-density lipoproteins (HDLs) was neuroprotective in an embolic stroke model. We hypothesized that HDL vasculoprotective actions on the blood–brain barrier (BBB) may decrease hemorrhagic transformation-associated with tissue plasminogen activator (tPA) administration in acute stroke. Methods— We used tPA alone or in combination with HDLs in vivo in 2 models of focal middle cerebral artery occlusion (MCAO) (embolic and 4-hour monofilament MCAO) and in vitro in a model of BBB. Sprague–Dawley rats were submitted to MCAO, n=12 per group. The rats were then randomly injected with tPA (10 mg/kg) or saline with or without human plasma purified-HDL (10 mg/kg). The therapeutic effects of HDL and BBB integrity were assessed blindly 24 hours later. The integrity of the BBB was also tested using an in vitro model of human cerebral endothelial cells under oxygen–glucose deprivation. Results— tPA-treated groups had significantly higher mortality and rate of hemorrhagic transformation at 24 hours in both MCAO models. Cotreatment with HDL significantly reduced stroke-induced mortality versus tPA alone (by 42% in filament MCAO, P=0.009; by 73% in embolic MCAO, P=0.05) and tPA-induced intracerebral parenchymal hematoma (by 92% in filament MCAO, by 100% in embolic MCAO; P<0.0001). This was consistent with an improved BBB integrity. In vitro, HDLs decreased oxygen–glucose deprivation–induced BBB permeability (P<0.05) and vascular endothelial cadherin disorganization. Conclusions— HDL injection decreased tPA-induced hemorrhagic transformation in rat models of MCAO. Both in vivo and in vitro results support the vasculoprotective action of HDLs on BBB under ischemic conditions.

Outcomes after thrombolysis in AIS according to prior statin use A registry and review

Background: The impact of prior statin use on outcomes after thrombolysis is unclear. We evaluated outcomes of patients treated by IV, intra-arterial (IA) thrombolysis, or combined therapy, according to prior statin use. Methods: We analyzed data from a patient registry (606 patients) and conducted a systematic review. Results: We identified 11 previous studies (6,438 patients) that evaluated the effect of statin use on outcomes after IV thrombolysis (8 studies), IA thrombolysis (2 studies), or a single/combined approach (1 study). In our registry and in most of the retrieved studies, statin users had more risk factors and concomitant antiplatelet treatment than nonstatin users. Regardless of treatment strategy, prior statin use was not associated with favorable outcome (adjusted odds ratio [OR] 1.36; 95 confidence interval [CI] 0.86–2.16), symptomatic intracranial hemorrhage (sICH) (OR 0.57; 95% CI 0.22–1.49), or recanalization (OR 1.87; 95% CI 0.69–5.03). In meta-analysis, prior statin use was not associated with favorable outcome (crude OR 0.99; 95% CI 0.88–1.12), but was associated with an increased risk of sICH (crude OR 1.55; 95% CI 1.23–1.95). However, when the available multivariable associations were combined (5 studies), the effect of prior statin use on risk of sICH was not significant (OR 1.31; 95% CI 0.97–1.76). Conclusions: These results suggest no beneficial or detrimental effect of prior statin use in acute stroke patients treated by IV thrombolysis, IA thrombolysis, or combined therapy, although the numbers of patients treated by IA thrombolysis or combined therapy are too small to exclude an effect.

Successful Reperfusion With Mechanical Thrombectomy Is Associated With Reduced Disability and Mortality in Patients With Pretreatment Diffusion-Weighted Imaging–Alberta Stroke Program Early Computed Tomography Score ≤6

Background and Purpose— In acute ischemic stroke patients, diffusion-weighted imaging (DWI)–Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is correlated with infarct volume and is an independent factor of functional outcome. Patients with pretreatment DWI-ASPECTS ⩽6 were excluded or under-represented in the recent randomized mechanical thrombectomy trials. Our aim was to assess the impact of reperfusion in pretreatment DWI-ASPECTS ⩽6 patients treated with mechanical thrombectomy. Methods— We analyzed data collected between January 2012 and August 2015 in a bicentric prospective clinical registry of consecutive acute ischemic stroke patients treated with mechanical thrombectomy. Every patient with a documented internal carotid artery or middle cerebral artery occlusion with pretreatment DWI-ASPECTS ⩽6 was eligible for this study. The primary end point was a favorable outcome defined by a modified Rankin Scale score ⩽2 at 90 days. Results— Two hundred and eighteen patients with a DWI-ASPECTS ⩽6 were included. Among them, 145 (66%) patients had successful reperfusion at the end of mechanical thrombectomy. Reperfused patients had an increased rate of favorable outcome (38.7% versus 17.4%; P=0.002) and a decreased rate of mortality at 3 months (22.5% versus 39.1%; P=0.013) compared with nonreperfused patients. The symptomatic intracranial hemorrhage rate was not different between the 2 groups (13.0% versus 14.1%; P=0.83). However, in patients with DWI-ASPECTS <5, favorable outcome was low (13.0% versus 9.5%; P=0.68) with a high mortality rate (45.7% versus 57.1%; P=0.38) with or without successful reperfusion. Conclusions— Successful reperfusion is associated with reduced mortality and disability in patients with a pretreatment DWI-ASPECTS ⩽6. Further data from randomized studies are needed, particularly in patients with DWI-ASPECTS <5.

Exacerbation of Thromboinflammation by Hyperglycemia Precipitates Cerebral Infarct Growth and Hemorrhagic Transformation

Background and Purpose— Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. Methods— Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy. Results— Hyperglycemic rats had an increased infarct volume with an increased blood–brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments. Conclusions— We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion–induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood–brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a possible target for reduction of the deleterious impact of hyperglycemia in acute ischemic stroke.