Clinical relevance of intracranial hemorrhage after thrombectomy versus medical management for large core infarct: a secondary analysis of the SELECT2 randomized trial.

BACKGROUND: The incidence of intracerebral hemorrhage (ICH) and its effect on the outcomes after endovascular thrombectomy (EVT) for patients with large core infarcts have not been well-characterized. METHODS: SELECT2 trial follow-up imaging was evaluated using the Heidelberg Bleeding Classification (HBC) to define hemorrhage grade. The association of ICH with clinical outcomes and treatment effect was examined. RESULTS: Of 351 included patients, 194 (55%) and 189 (54%) demonstrated intracranial and intracerebral hemorrhage, respectively, with a higher incidence in EVT (134 (75%) and 130 (73%)) versus medical management (MM) (60 (35%) and 59 (34%), both P<0.001). Hemorrhagic infarction type 1 (HBC=1a) and type 2 (HBC=1b) accounted for 93% of all hemorrhages. Parenchymal hematoma (PH) type 1 (HBC=1c) and type 2 (HBC=2) were observed in 1 (0.6%) EVT-treated and 4 (2.2%) MM patients. Symptomatic ICH (sICH) (SITS-MOST definition) was seen in 0.6% EVT patients and 1.2% MM patients. No trend for ICH with core volumes (P=0.10) or Alberta Stroke Program Early CT Score (ASPECTS) (P=0.74) was observed. Among EVT patients, the presence of any ICH did not worsen clinical outcome (modified Rankin Scale (mRS) at 90 days: 4 (3-6) vs 4 (3-6); adjusted generalized OR 1.00, 95% CI 0.68 to 1.47, P>0.99) or modify EVT treatment effect (Pinteraction=0.77). CONCLUSIONS: ICH was present in 75% of the EVT population, but PH or sICH were infrequent. The presence of any ICH did not worsen functional outcomes or modify EVT treatment effect at 90-day follow-up. The high rate of hemorrhages overall still represents an opportunity for adjunctive therapies in EVT patients with a large ischemic core.

Influence of vascular imaging acquisition at local stroke centers on workflows in the drip-n-ship model: a RACECAT post hoc analysis.

BACKGROUND: The influence of vascular imaging acquisition on workflows at local stroke centers (LSCs) not capable of performing thrombectomy in patients with a suspected large vessel occlusion (LVO) stroke remains uncertain. We analyzed the impact of performing vascular imaging (VI+) or not (VI- at LSC arrival on variables related to workflows using data from the RACECAT Trial. OBJECTIVE: To compare workflows at the LSC among patients enrolled in the RACECAT Trial with or without VI acquisition. METHODS: We included patients with a diagnosis of ischemic stroke who were enrolled in the RACECAT Trial, a cluster-randomized trial that compared drip-n-ship versus mothership triage paradigms in patients with suspected acute LVO stroke allocated at the LSC. Outcome measures included time metrics related to workflows and the rate of interhospital transfers and thrombectomy among transferred patients. RESULTS: Among 467 patients allocated to a LSC, vascular imaging was acquired in 277 patients (59%), of whom 198 (71%) had a LVO. As compared with patients without vascular imaging, patients in the VI+ group were transferred less frequently as thrombectomy candidates to a thrombectomy-capable center (58% vs 74%, P=0.004), without significant differences in door-indoor-out time at the LSC (median minutes, VI+ 78 (IQR 69-96) vs VI- 76 (IQR 59-98), P=0.6). Among transferred patients, the VI+ group had higher rate of thrombectomy (69% vs 55%, P=0.016) and shorter door to puncture time (median minutes, VI+ 41 (IQR 26-53) vs VI- 54 (IQR 40-70), P<0.001). CONCLUSION: Among patients with a suspected LVO stroke initially evaluated at a LSC, vascular imaging acquisition might improve workflow times at thrombectomy-capable centers and reduce the rate of futile interhospital transfers. These results deserve further evaluation and should be replicated in other settings and geographies.

European Stroke Organisation (ESO)-European Society for Minimally Invasive Neurological Therapy (ESMINT) expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischemic stroke and anterior circulation large vessel occlusion.

Six randomized controlled clinical trials have assessed whether mechanical thrombectomy (MT) alone is non-inferior to intravenous thrombolysis (IVT) plus MT within 4.5 hours of symptom onset in patients with anterior circulation large vessel occlusion (LVO) ischemic stroke and no contraindication to IVT. An expedited recommendation process was initiated by the European Stroke Organisation (ESO) and conducted with the European Society of Minimally Invasive Neurological Therapy (ESMINT) according to ESO standard operating procedure based on the GRADE system. We identified two relevant Population, Intervention, Comparator, Outcome (PICO) questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote evidence-based recommendations. Expert opinion was provided if insufficient evidence was available to provide recommendations based on the GRADE approach.For stroke patients with anterior circulation LVO directly admitted to a MT-capable center ('mothership') within 4.5 hours of symptom onset and eligible for both treatments, we recommend IVT plus MT over MT alone (moderate evidence, strong recommendation). MT should not prevent the initiation of IVT, nor should IVT delay MT. In stroke patients with anterior circulation LVO admitted to a center without MT facilities and eligible for IVT ≤4.5 hours and MT, we recommend IVT followed by rapid transfer to a MT capable-center ('drip-and-ship') in preference to omitting IVT (low evidence, strong recommendation). Expert consensus statements on ischemic stroke on awakening from sleep are also provided. Patients with anterior circulation LVO stroke should receive IVT in addition to MT if they have no contraindications to either treatment.

Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial.

A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40-60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40-60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50-58% of the 40-60 mg/Kg/day DFO-treated patients.

Clinical improvement within 24 hours from mechanical thrombectomy as a predictor of long-term functional outcome in a multicenter population-based cohort of patients with ischemic stroke.

BACKGROUND: Single-center studies have suggested that the early clinical course after mechanical thrombectomy (MT) in patients with ischemic stroke is a clinical predictor of long-term outcome. OBJECTIVE: To analyze the prognostic value of clinical improvement within 24 hours in a population-based multicenter cohort. METHODS: From a total of 3792 patients with acute ischemic stroke in Catalonia (CICAT registry), 1951 patients were treated with MT. The National Institutes of Health Stroke Scale (NIHSS) score within 24 hours, and follow-up was available in 1666 patients. Percentage variation in the NIHSS score was calculated in relation to a baseline assessment. Good outcome was defined as a modified Rankin Scale score ≤2 at 90 days. Predictive values of clinical improvement and adjusted OR to predict good outcomes were assessed in the whole cohort and the subgroup of patients with posterior circulation stroke (n=166). RESULTS: Good outcome was achieved in 656/1666 patients (39%) overall. Percentage improvements both at the end of MT and at 24 hours predicted good outcome, with higher predictive capacity at 24 hours (C-statistic, 0.85 vs 0.73, p<0.001). Positive and negative predictive values were 70% and 74% for the >30% cut-off point at the end of MT, and 69% and 84% for the >50% cut-off point at 24 hours, respectively. The adjusted OR for good outcome was 5.8 (95% CI 4.2 to 8.1) and 12.9 (95% CI 9.7 to 17.1), respectively. In patients with posterior circulation stroke, the predictive value of the improvement at 24 hours was similar (C-statistic 0.90). CONCLUSION: Clinical improvement of patients within 24 hours of MT is a reliable and robust predictor of long-term prognosis, including patients with posterior circulation occlusions.

Validation of the Spanish Version of the Pain Assessment in Advanced Dementia Scale (PAINAD-Sp) in Hospitalized Patients with Neurologic Disorders and Oncologic Patients Unable to Self-Report Their Pain.

BACKGROUND: Pain has a significant impact on hospitalized patients and is a quality indicator for nursing care. The Pain Assessment in Advanced Dementia (PAINAD) scale measures pain in people with communication disorders and advanced dementia, but it has not been validated in any other population. AIMS: The aim of this study was to validate the Spanish version (PAINAD-Sp) in hospitalized patients with neurologic disorders and in end-of-life cancer patients with difficulty self-reporting. DESIGN: The study had two phases: (1) analysis of the content by a committee of experts and (2) a cross-sectional study. SETTINGS: We collected phase 2 data from January 2017 to December 2017 in four hospitals in Barcelona: Hospital Germans Trias i Pujol, Institut Català d'Oncologia, Hospital Vall d'Hebron, and Hospital de Bellvitge. PARTICIPANTS/SUBJECTS: We included all adults who had either a neurological disorder affecting language or an oncological disease with an end-of-life prognosis and difficulty self-reporting pain. We excluded patients with a diagnosis of dementia. METHODS: The cross-sectional study included 325 patients who were simultaneously evaluated by two observers both at rest and in movement. We analyzed psychometric properties in terms of construct validity, reliability, and sensitivity to change. RESULTS: We obtained Cronbach α > .70 in both situations and an inter-rater reliability of 0.80. Confirmatory factor analysis indicated that the model adjusted adequately to a unidimensional structure. In terms of sensitivity to change, the mean difference was greater in movement than at rest (difference in means was 1.15). CONCLUSIONS: The PAINAD-Sp_Hosp scale had good psychometric qualities in terms of validity and reliability in neurology and oncology patients unable to self-report pain.

Revalidation of the RACE scale after its regional implementation in Catalonia: a triage tool for large vessel occlusion.

BACKGROUND AND PURPOSE: Our aim was to revalidate the RACE scale, a prehospital tool that aims to identify patients with large vessel occlusion (LVO), after its region-wide implementation in Catalonia, and to analyze geographical differences in access to endovascular treatment (EVT). METHODS: We used data from the prospective CICAT registry (Stroke Code Catalan registry) that includes all stroke code activations. The RACE score evaluated by emergency medical services, time metrics, final diagnosis, presence of LVO, and type of revascularization treatment were registered. Sensitivity, specificity, and area under the curve (AUC) for the RACE cut-off value ≥5 for identification of both LVO and eligibility for EVT were calculated. We compared the rate of EVT and time to EVT of patients transferred from referral centers compared with those directly presenting to comprehensive stroke centers (CSC). RESULTS: The RACE scale was evaluated in the field in 1822 patients, showing a strong correlation with the subsequent in-hospital evaluation of the National Institute of Health Stroke Scale evaluated at hospital (r=0.74, P<0.001). A RACE score ≥5 detected LVO with a sensitivity 0.84 and specificity 0.60 (AUC 0.77). Patients with RACE ≥5 harbored a LVO and received EVT more frequently than RACE <5 patients (LVO 35% vs 6%; EVT 20% vs 6%; all P<0.001). Direct admission at a CSC was independently associated with higher odds of receiving EVT compared with admission at a referral center (OR 2.40; 95% CI 1.66 to 3.46), and symtoms onset to groin puncture was 133 min shorter. CONCLUSIONS: This large validation study confirms RACE accuracy to identify stroke patients eligible for EVT, and provides evidence of geographical imbalances in the access to EVT to the detriment of patients located in remote areas.

Iron overload, measured as serum ferritin, increases brain damage induced by focal ischemia and early reperfusion.

High levels of iron, measured as serum ferritin, are associated to a worse outcome after stroke. However, it is not known whether ischemic damage might increase ferritin levels as an acute phase protein or whether iron overload affects stroke outcome. The objectives are to study the effect of stroke on serum ferritin and the contribution of iron overload to ischemic damage. Swiss mice were fed with a standard diet or with a diet supplemented with 2.5% carbonyl iron to produce iron overload. Mice were submitted to permanent (by ligature and by in situ thromboembolic models) or transient focal ischemia (by ligature for 1 or 3h). Treatment with iron diet produced an increase in the basal levels of ferritin in all the groups. However, serum ferritin did not change after ischemia. Animals submitted to permanent ischemia had the same infarct volume in the groups studied. However, in mice submitted to transient ischemia followed by early (1h) but not late reperfusion (3h), iron overload increased ischemic damage and haemorrhagic transformation. Iron worsens ischemic damage induced by transient ischemia and early reperfusion. In addition, ferritin is a good indicator of body iron levels but not an acute phase protein after ischemia.

The human Tp53 Arg72Pro polymorphism explains different functional prognosis in stroke.

The functional outcome after stroke is unpredictable; it is not accurately predicted by clinical pictures upon hospital admission. The presence of apoptotic neurons in the ischemic penumbra and perihematoma area may account for poor prognosis, but whether the highly variable stroke outcome reflects differences in genetic susceptibility to apoptosis is elusive. The p53 tumor suppressor protein, an important transcriptional regulator of apoptosis, naturally occurs in humans in two variants with single nucleotide polymorphisms resulting in Arg or Pro at residue 72. We show that poor functional outcome after either ischemic or hemorrhagic stroke was linked to the Arg/Arg genotype. This genotype was also associated with early neurological deterioration in ischemic stroke and with increased residual cavity volume in intracerebral hemorrhage. In primary cultured neurons, Arg(72)-p53, but not Pro(72)-p53, interacted directly with mitochondrial Bcl-xL and activated the intrinsic apoptotic pathway, increasing vulnerability to ischemia-induced apoptotic cell death. These results suggest that the Tp53 Arg/Arg genotype governs neuronal vulnerability to apoptosis and can be considered as a genetic marker predicting poor functional outcome after stroke.

Iron-related brain damage in patients with intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Iron plays a detrimental role after experimental intracerebral hemorrhage (ICH). This study investigates whether high-serum ferritin levels are associated with poor outcome in patients with ICH. METHODS: We studied 92 consecutive patients with primary hemispheric ICH within the first 12 hours from onset of symptoms (median, 3.3 hours). National Institute of Health Stroke Scale score, ICH, and peripheral edema volumes were measured at admission, 72 hours, and 7 days. Serum levels of ferritin and biomarkers of the inflammatory response were determined. The adjusted effect of ferritin on the full range of Rankin scale was analyzed by a general linear model. RESULTS: Fifty-one patients (55.4%) had poor outcome (Rankin score >2). Older age, higher stroke severity, larger hematoma volume, intraventricular extension, mass effect, and higher IL-6 and ferritin levels at baseline (270.6 [SD 81.4] vs 74.6 [SD 43.4] ng/mL; P<0.001) were associated with poor outcome. The higher the ferritin quartile, the worse the Rankin score. For every ferritin quartile, the Rankin score increased by a mean of 1.4 points (95% CI, 1.04-1.69) after adjusting for prognostic variables. Ferritin levels remained stable for 72 hours and did not correlate with acute phase reactants. CONCLUSIONS: High-serum ferritin levels at admission are independently associated with poor outcome in patients with ICH. These findings may suggest a neurotoxic effect of increased body iron stores in patients with hemorrhagic stroke.