Elevated glucose is associated with hemorrhagic transformation after mechanical thrombectomy in acute ischemic stroke patients with severe pretreatment hypoperfusion

Several pretreatment variables such as elevated glucose and hypoperfusion severity are related to brain hemorrhage after endovascular treatment of acute stroke. We evaluated whether elevated glucose and severe hypoperfusion have synergistic effects in the promotion of parenchymal hemorrhage (PH) after mechanical thrombectomy (MT). We included 258 patients MT-treated who had a pretreatment computed tomography perfusion (CTP) and a post-treatment follow-up MRI. Severe hypoperfusion was defined as regions with cerebral blood volume (CBV) values < 2.5% of normal brain [very-low CBV (VLCBV)-regions]. Median baseline glucose levels were 119 (IQR = 105-141) mg/dL. Thirty-nine (15%) patients had pretreatment VLCBV-regions, and 42 (16%) developed a PH after MT. In adjusted models, pretreatment glucose levels interacted significantly with VLCBV on the prediction of PH (p-interaction = 0.011). In patients with VLCBV-regions, higher glucose was significantly associated with PH (adjusted-OR = 3.15; 95% CI = 1.08-9.19, p = 0.036), whereas this association was not significant in patients without VLCBV-regions. CBV values measured at pretreatment CTP in coregistered regions that developed PH or infarct at follow-up were not correlated with pretreatment glucose levels, thus suggesting the existence of alternative deleterious mechanisms other than direct glucose-driven hemodynamic impairments. Overall, these results suggest that both severe hypoperfusion and glucose levels should be considered in the evaluation of adjunctive neuroprotective strategies

Effectiveness of Thrombectomy in Stroke According to Baseline Prognostic Factors: Inverse Probability of Treatment Weighting Analysis of a Population-Based Registry

Background and Purpose In real-world practice, the benefit of mechanical thrombectomy (MT) is uncertain in stroke patients with very favorable or poor prognostic profiles at baseline. We studied the effectiveness of MT versus medical treatment stratifying by different baseline prognostic factors. Methods Retrospective analysis of 2,588 patients with an ischemic stroke due to large vessel occlusion nested in the population-based registry of stroke code activations in Catalonia from January 2017 to June 2019. The effect of MT on good functional outcome (modified Rankin Score 85 years, National Institutes of Health Stroke Scale [NIHSS] >25, time from onset >6 hours, Alberta Stroke Program Early CT Score 3), good (if NIHSS <6 or distal occlusion, in the absence of poor prognostic factors), or reference (not meeting other groups' criteria). Results Patients receiving MT (n=1,996, 77%) were younger, had less pre-stroke disability, and received systemic thrombolysis less frequently. These differences were balanced after the IPTW stratified by prognosis. MT was associated with good functional outcome in the reference (odds ratio [OR], 2.9; 95% confidence interval [CI], 2.0 to 4.4), and especially in the poor baseline prognostic stratum (OR, 3.9; 95% CI, 2.6 to 5.9), but not in the good prognostic stratum. MT was associated with survival only in the poor prognostic stratum (OR, 2.6; 95% CI, 2.0 to 3.3). Conclusions Despite their worse overall outcomes, the impact of thrombectomy over medical management was more substantial in patients with poorer baseline prognostic factors than patients with good prognostic factors

Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator

Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a photochemical reaction prompting the active-drug's release, which effectively controls mGlu5 receptor activity both in ectopic expressing systems and in striatal primary neurons. Systemic administration in mice followed by local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induced JF-NP-26-mediated light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models. These data offer the first example of optical control of analgesia in vivo using a photocaged mGlu5 receptor negative allosteric modulator. This approach shows potential for precisely targeting, in time and space, endogenous receptors, which may allow a better management of difficult-to-treat disorders

Table_3_A Polygenic Risk Score Based on a Cardioembolic Stroke Multitrait Analysis Improves a Clinical Prediction Model for This Stroke Subtype.DOCX

[Background] Occult atrial fibrillation (AF) is one of the major causes of embolic stroke of undetermined source (ESUS). Knowing the underlying etiology of an ESUS will reduce stroke recurrence and/or unnecessary use of anticoagulants. Understanding cardioembolic strokes (CES), whose main cause is AF, will provide tools to select patients who would benefit from anticoagulants among those with ESUS or AF. We aimed to discover novel loci associated with CES and create a polygenetic risk score (PRS) for a more efficient CES risk stratification.[Methods] Multitrait analysis of GWAS (MTAG) was performed with MEGASTROKE-CES cohort (n = 362,661) and AF cohort (n = 1,030,836). We considered significant variants and replicated those variants with MTAG p-value < 5 × 10−8 influencing both traits (GWAS-pairwise) with a p-value < 0.05 in the original GWAS and in an independent cohort (n = 9,105). The PRS was created with PRSice-2 and evaluated in the independent cohort.[Results] We found and replicated eleven loci associated with CES. Eight were novel loci. Seven of them had been previously associated with AF, namely, CAV1, ESR2, GORAB, IGF1R, NEURL1, WIPF1, and ZEB2. KIAA1755 locus had never been associated with CES/AF, leading its index variant to a missense change (R1045W). The PRS generated has been significantly associated with CES improving discrimination and patient reclassification of a model with age, sex, and hypertension.[Conclusion] The loci found significantly associated with CES in the MTAG, together with the creation of a PRS that improves the predictive clinical models of CES, might help guide future clinical trials of anticoagulant therapy in patients with ESUS or AF.Peer reviewe

Monocytes are major players in the prognosis and risk of infection after acute stroke

[Background and Purpose]: Monocytes participate in adaptive and innate immune responses. Monocyte numbers increase in patients with stroke associated infection (S AI) or severe stroke. Whether changes in monocytes are related to specific effects, or simply mark brain damage, remains unsettled. [Methods]: We used flow cytometry in 45 consecutive strokes and 12 healthy controls to assess the time course of monocytes, their phenotype, and the production of cytokines after stimulation. Cortisol, TNF-α, IFN-γ, and IL-10 were measured in serum and metanephrine in plasma. The effects of humoral and cellular parameters on the risk of SAI and poor outcome were tested in multivariate analyses adjusted for confounders (NIHSS score, age, and tube feeding). [Results]: Surface expression of human leukocyte antigen-DR, Toll-like receptor-2, and production of TNF-a in monocytes were independently associated with stroke. Distinct immune mechanisms were related with functional outcome and the risk of SAI; the signature of SAI included an increase of cortisol, metanephrine, and IL-10 in serum, and reduced production of TNF-α in monocytes; poor outcome was associated with increased expression of Toll-like receptor-4 in monocytes (OR, 9.61; 95% CI, 1.27-72.47). SAI did not predict poor outcome (OR, 5.63; 95% CI, 0.45-70.42; P=0.18). [Conclusions]: In human stroke, poor outcome is associated to innate responses mediated by Toll-like receptor-4 in monocytes. SAI may result from the immunosuppressive and antiinflammatory effects of corticoids, catecholamines, IL-10, and deactivated monocytes. Early treated SAI does not contribute significantly to additional brain damage. These findings encourage the exploration of strategies aimed to inhibit Toll-like receptor-4 signaling in acute stroke. © 2009 American Heart Association, Inc.This work was supported by a grant from the Fundación de Investigaciones Científicas (PI06/0909), and the partial support of the Fundación Melchor Colet. Xabier Urra and Álvaro Cervera are recipients of grants from Instituto Carlos III, Spanish Ministry of Health.Peer Reviewe

Risks and Benefits of Early Antithrombotic Therapy after Thrombolytic Treatment in Patients with Acute Stroke

Background: Current guidelines recommend withholding antithrombotic therapy (ATT) for at least 24 h in patients with acute ischemic stroke treated with thrombolytic therapy. Herein, we report a retrospective analysis of a single-centre experience on the safety and efficacy of antithrombotic therapy (ATT) started before or after 24 h of intravenous thrombolysis in a cohort of acute ischemic stroke patients. Methods: A total of 139 patients (Rapid ATT group) received antithrombotic therapy before 24 h of thrombolysis, and 33 patients (Standard ATT group) after 24 h. The brain parenchyma and vessel status were assessed using simple CT scan on admission, multimodal CT scan at the end of thrombolysis, and angio-CT/MRI scan at day 3. Functional outcome was scored using the modified Rankin Scale (mRS) at day 90. Results: The two ATT groups had similar demographics, stroke subtypes, baseline NIHSS, thrombolytic strategies, vesselpatency rates at the end of thrombolysis, and incidence of bleeding complications at follow up. At day 3, the Rapid ATT group had a non-significant improved vessel-patency rate than the Standard ATT group. At day 90, a greater proportion of patients in the rapid ATT group had shifted down the mRS, and had improved in the NIHSS score. Conclusions: ATT initiated before 24 h of intravenous thrombolytic therapy in acute stroke patients disclosed no safety concerns compared with a conventional antithrombotic therapy delay of 24 h and showed better functional outcome at follow up. The value of early initiation of ATT after thrombolysis deserves further assessment in randomized controlled trial

Response to letter by Dawson et al [10]

Peer Reviewe

Uric acid levels are relevant in patients with stroke treated with thrombolysis

Background and Purpose: Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke. Methods-A total of 317 consecutive patients treated with thrombolysis were included in a prospective stroke registry. Demographics, laboratory data, neurological course, and infarction volume were prospectively collected. Excellent outcome was defined as achieving a modified Rankin Scale score <2 at 90 days. Binary and ordinal logistic regression models were used to analyze modified Rankin Scale score at 90 days. Results-UA levels were significantly higher in patients with an excellent outcome than in patients with a poor outcome (5.82 [1.39] versus 5.42 [1.81], P=0.029). In multivariate models, increased UA levels (OR, 1.23; 95% CI, 1.03 to 1.49; P=0.025) were associated with an excellent outcome and with an increased risk of shifting to a better category across the modified Rankin Scale (OR, 1.19; 95% CI, 1.04 to 1.38; P=0.014) independently of the effect of confounders. The levels of UA and the volume of final infarction were inversely correlated (r=-0.216, P<0.001) and the inverse correlation remained after adjustment for age, sex, and baseline National Institutes of Health Stroke Scale score (t value=-2.54, P=0.01). Significantly lower UA levels were found in patients with malignant middle cerebral artery infarction and parenchymal hemorrhage postthrombolysis. Conclusions: Increased UA serum levels are associated with better outcome in patients with stroke treated with reperfusion therapies. These results support the assessment of the potential neuroprotective role of the exogenous administration of UA in patients with stroke treated with thrombolysis. © 2010 American Heart Association, Inc.The study was supported by the Fondo de Investigaciones Sanitarias (FIS) of the Spanish Ministry of Health EC07-90276 and the Fundación Melchor Colet. Xabier Urra is a Fellow of the FIS.Peer Reviewe

The outcome of patients with mild stroke improves after treatment with systemic thrombolysis.

INTRODUCTION: In up to one third of patients with mild stroke suitable to receive systemic thrombolysis the treatment is not administered because the treating physicians estimate a good spontaneous recovery. However, it is not settled whether the fate of these patients is equivalent to those who are thrombolysed. METHODS: We analyzed 203 consecutive patients (134 men and 69 women, mean age 69±14 years) without premorbid disability and a NIHSS score ≤5 at admission [median 3 (IQR 2-4)]. Intravenous thrombolysis was administered within 4.5 hours from stroke onset (n = 119), or it was withheld (n = 84) whenever the treating physician predicted a spontaneous recovery. The baseline risk factors, clinical course, infarction volume, bleeding complications, and functional outcome at 3 months were analyzed and declared to a Web-based registry which was accessible to the local Health Authorities. RESULTS: Expectedly, not thrombolysed patients had the mildest strokes at admission [median 2 (IQR 1-3.75)]. At day 2 to 5, the infarct volume on DWI-MRI was similar in both groups. There were no symptomatic cerebral bleedings in the study. An ordinal regression model adjusted for baseline stroke severity showed that thrombolysis was associated with a greater proportion of patients who shifted down on the modified Rankin Scale score at 3 months (OR 2.66; 95% CI 1.49-4.74, p = 0.001). CONCLUSIONS: Intravenous thrombolysis seems to be safe in patients with mild stroke and may be associated with improved outcome compared with untreated patients. These results support the evaluation of the efficacy of intravenous thrombolysis in mild stroke patients in randomized clinical trials