Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage.

BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).

Safe Use of Cenobamate in Super Refractory Status Epilepticus: A Case Series.

Cenobamate is an effective new adjunctive antiseizure medication (ASM) for treatment resistant focal epilepsy. It has broad spectrum anticonvulsant activity and may be a useful medication for super refractory status epilepticus (SRSE), but has not yet been studied in generalized seizures or an inpatient setting. Here we describe 2 SRSE cases where cenobamate was added safely to other treatments. It was uptitrated slowly to reduce the risk of hypersensitivity reactions which have been observed previously with rapid increasing dosages. Both patients achieved seizure control and liberation from intensive care. They have remained seizure free with continued treatment and have not experienced any side effects attributable to cenobamate. Cenobamate warrants further examination in patients with refractory status epilepticus.

Efficacy of novel SPAK inhibitor ZT-1a derivatives (1c, 1d, 1g & 1h) on improving post-stroke neurological outcome and brain lesion in mice.

SPAK inhibitor ZT-1a was previously shown to be neuroprotective in murine ischemic stroke models. In this study, we further examined the efficacy of four ZT-1a derivatives (ZT-1c, -1d, -1g and -1h) on reducing stroke-induced sensorimotor function impairment and brain lesions. Vehicle control (Veh) or ZT-1 derivatives were administered via osmotic pump to adult C57BL/6J mice during 3-21 h post-stroke. Neurological behavior of these mice was assessed at days 1, 3, 5, and 7 post-stroke and MRI T2WI and DTI analysis was subsequently conducted in ex vivo brains. Veh-treated stroke mice displayed sensorimotor function deficits compared to Sham mice. In contrast, mice receiving ZT-1a derivatives displayed significantly lower neurological deficits at days 3-7 post-stroke (p < 0.05), with ZT-1a, ZT-1c and ZT-1d showing greater impact than ZT-1h and ZT-1g. ZT-1a treatment was the most effective in reducing brain lesion volume on T2WI and in preserving NeuN + neurons (p < 0.01), followed by ZT-1d > -1c > -1g > -1h. The Veh-treated stroke mice displayed white matter tissue injury, reflected by reduced fractional anisotropy (FA) or axial diffusivity (AD) values in external capsule, internal capsule and hippocampus. In contrast, only ZT-1a-as well as ZT-1c-treated stroke mice exhibited significantly higher FA and AD values. These findings demonstrate that post-stroke administration of SPAK inhibitor ZT-1a and its derivatives (ZT-1c and ZT-1d) is effective in protecting gray and white matter tissues in ischemic brains, showing a potential for ischemic stroke therapy development.

Hypoxanthine is a pharmacodynamic marker of ischemic brain edema modified by glibenclamide.

Brain edema after a large stroke causes significant morbidity and mortality. Here, we seek to identify pharmacodynamic markers of edema that are modified by intravenous (i.v.) glibenclamide (glyburide; BIIB093) treatment. Using metabolomic profiling of 399 plasma samples from patients enrolled in the phase 2 Glyburide Advantage in Malignant Edema and Stroke (GAMES)-RP trial, 152 analytes are measured using liquid chromatography-tandem mass spectrometry. Associations with midline shift (MLS) and the matrix metalloproteinase-9 (MMP-9) level that are further modified by glibenclamide treatment are compared with placebo. Hypoxanthine is the only measured metabolite that associates with MLS and MMP-9. In sensitivity analyses, greater hypoxanthine levels also associate with increased net water uptake (NWU), as measured on serial head computed tomography (CT) scans. Finally, we find that treatment with i.v. glibenclamide reduces plasma hypoxanthine levels across all post-treatment time points. Hypoxanthine, which has been previously linked to inflammation, is a biomarker of brain edema and a treatment response marker of i.v. glibenclamide treatment.

NF-κB Signaling-Mediated Activation of WNK-SPAK-NKCC1 Cascade in Worsened Stroke Outcomes of Ang II-Hypertensive Mice.

BACKGROUND: Worsened stroke outcomes with hypertension comorbidity are insensitive to blood pressure-lowering therapies. In an experimental stroke model with comorbid hypertension, we investigated causal roles of ang II (angiotensin II)-mediated stimulation of the brain WNK (with no lysine [K] kinases)-SPAK (STE20/SPS1-related proline/alanine-rich kinase)-NKCC1 (Na-K-Cl cotransporter) complex in worsened outcomes. METHODS: Saline- or ang II-infused C57BL/6J male mice underwent stroke induced by permanent occlusion of the distal branches of the middle cerebral artery. Mice were randomly assigned to receive either vehicle dimethyl sulfoxide/PBS (2 mL/kg body weight/day, IP), a novel SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide (ZT-1a' 5 mg/kg per day, IP) or a NF-κB (nuclear factor-κB) inhibitor TAT-NBD (transactivator of transcription-NEMO-binding domain' 20 mg/kg per day, IP). Activation of brain NF-κB and WNK-SPAK-NKCC1 cascade as well as ischemic stroke outcomes were examined. RESULTS: Stroke triggered a 2- to 5-fold increase of WNK (isoforms 1, 2, 4), SPAK/OSR1 (oxidative stress-responsive kinase 1), and NKCC1 protein in the ang II-infused hypertensive mouse brains at 24 hours after stroke, which was associated with increased nuclear translocation of phospho-NF-κB protein in the cortical neurons (a Pearson correlation r of 0.77, P<0.005). The upregulation of WNK-SPAK-NKCC1 cascade proteins resulted from increased NF-κB recruitment on Wnk1, Wnk2, Wnk4, Spak, and Nkcc1 gene promoters and was attenuated by NF-κB inhibitor TAT-NBD. Poststroke administration of SPAK inhibitor ZT-1a significantly reduced WNK-SPAK-NKCC1 complex activation, brain lesion size, and neurological function deficits in the ang II-hypertensive mice without affecting blood pressure and cerebral blood flow. CONCLUSIONS: The ang II-induced stimulation of NF-κB transcriptional activity upregulates brain WNK-SPAK-NKCC1 cascade and contributes to worsened ischemic stroke outcomes, illustrating the brain WNK-SPAK-NKCC1 complex as a therapeutic target for stroke with comorbid hypertension.

Reliability of the Telemedicine Examination in the Neurologic Diagnosis of Death.

OBJECTIVE: To determine whether telemedicine technology can be used to reliably determine the neurologic diagnosis of death (NDD) in patients with catastrophic brain injury (CBI). METHODS: We included a convenience sample of patients with CBI at a single academic medical center from November 2016 through June 2018. We simultaneously performed brain death evaluation at the bedside and remotely via telemedicine. Remote examiners were neurointensivists who were experienced and knowledgeable in the NDD. In addition to standard clinical examination, we used quantitative pupillometry to evaluate pupil size and reactivity. We determined the proportion of agreement for each NDD examination element and the overall diagnosis of brain death between bedside and remote examiners. RESULTS: Twenty-nine patients with mean age 46 ± 18 years underwent 30 paired NDD examinations. Twenty-eight (97%) patients met the NDD criteria and were pronounced dead. One patient did not meet the NDD criteria and died after withdrawal of life support. With the exception of qualitative assessment of pupillary reactivity, we observed excellent agreement (97%-100% across NDD examination elements) between bedside and remote examiners and 97% agreement on the overall diagnosis of brain death. Unlike qualitative pupillary assessment, quantitative pupillometry was consistently interpretable by remote examiners. CONCLUSIONS: Our results suggest that remote telemedicine technology can be used to verify the findings of bedside examiners performing NDD examinations when a pupillometer is used to assess pupillary reactivity. When performed by neurocritical care experts, the telemedicine NDD examination has potential to facilitate timely and accurate certification of brain death in patients with CBI. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the concordance of neurologic diagnosis of death by telemedicine and bedside examiners.

Remote Longitudinal Inpatient Acute Stroke Care Via Telestroke.

OBJECTIVES: While telestroke 'hub-and-spoke' systems are a well-established model for improving acute stroke care at spoke facilities, utility beyond the hyperacute phase is unknown. In patients receiving intravenous thrombolysis via telemedicine, care at spoke facilities has been shown to be associated with longer length of stay and worse outcomes. We sought to explore the impact of ongoing stroke care by a vascular neurologist via telemedicine compared to care provided by local neurologists. METHODS: A network spoke facility protocol was revised to pilot telestroke consultation with a hub vascular neurologist for all patients presenting to the emergency department with ischemic stroke or transient ischemic attack regardless of time since onset or severity. Subsequent telestroke rounds were performed for patients who received initial telestroke consultation. Key outcome measures were length of stay, 30-day readmission and mortality and 90-day mRS. Results during the pilot (post-cohort) were compared to the same hospital's previous outcomes (pre-cohort). RESULTS: Of 257 enrolled patients, 67% were in the post-cohort. Forty percent (69) of the post-cohort received an initial telestroke consult. In spoke-retained patients followed by telestroke rounds (55), median length of stay decreased by 0.8 days (P = 0.01). Readmission and mortality rates did not differ significantly between groups (19.5 vs. 9.1%, P = 0.14 and 3.9 vs. 3.6%, P = 1, respectively). The favorable functional outcome rate was similar between groups (47.3% vs 65.9%, P = 0.50). CONCLUSIONS: Longitudinal stroke care via telestroke may be economically viable through length of stay reduction. Randomized prospective studies are needed to confirm our findings and further investigate this model's potential benefits.

Lessons from Recent Advances in Ischemic Stroke Management and Targeting Kv2.1 for Neuroprotection.

Achieving neuroprotection in ischemic stroke patients has been a multidecade medical challenge. Numerous clinical trials were discontinued in futility and many were terminated in response to deleterious treatment effects. Recently, however, several positive reports have generated the much-needed excitement surrounding stroke therapy. In this review, we describe the clinical studies that significantly expanded the time window of eligibility for patients to receive mechanical endovascular thrombectomy. We further summarize the results available thus far for nerinetide, a promising neuroprotective agent for stroke treatment. Lastly, we reflect upon aspects of these impactful trials in our own studies targeting the Kv2.1-mediated cell death pathway in neurons for neuroprotection. We argue that recent changes in the clinical landscape should be adapted by preclinical research in order to continue progressing toward the development of efficacious neuroprotective therapies for ischemic stroke.

Delayed functional independence after thrombectomy: temporal characteristics and predictors.

BACKGROUND: Variability in early neurological improvement after endovascular thrombectomy (EVT) for large vessel occlusion (LVO) stroke is well documented. Understanding the temporal progression of functional independence after EVT, especially delayed functional independence in patients who do not experience early improvement, is essential for prognostication and rehabilitation. OBJECTIVE: To determine the incidence of early and delayed functional independence and identify associated predictors after EVT. METHODS: A retrospective analysis of prospectively collected data on patients undergoing EVT in the setting of anterior circulation LVO was performed. Demographic, clinical, radiological, treatment, and procedural information were analyzed. Incidence and predictors of early functional independence (EFI, modified Rankin Scale (mRS) score 0-2 at discharge) and delayed functional independence (DFI, mRS score 0-2 at 90 days in non-EFI patients) were analyzed. RESULTS: Three hundred and fifty-five patients met the study criteria. 55% were women and mean age was 71±15. Mean National Institutes of Health Stroke Scale (NIHSS) score was 17±6 and median Alberta Stroke Program Early CT Score was 9 (8-10). EFI was observed in 21% (73) of patients. Among non-EFI patients (282), DFI was observed in 30% (85) of patients. Shorter time to treatment (p=0.03), lower 24 hours NIHSS score (p<0.001), and smaller follow-up infarct volume (p=0.003) were independent predictors of EFI. Younger age (p=0.011), lower 24 hours NIHSS score (p=0.001), and absence of parenchymal hemorrhage (PH2; p=0.039) were independent predictors of DFI. CONCLUSION: Approximately one-fifth of patients experience EFI and one-third of non-early improvers experience DFI. Younger age, lower 24 hours NIHSS score, and absence of parenchymal hemorrhage were independent predictors of DFI among non-early improvers. Further studies are required to improve our understanding of DFI.

Large Infarct Volume Post Thrombectomy: Characteristics, Outcomes, and Predictors.

BACKGROUND: Despite increasing interest in endovascular therapy (EVT) for large-core strokes, little is known about the predictors of good outcome in these patients. The aim of this study was to analyze patients with large-core strokes post-EVT and to define the predictors of favorable outcome in this population. METHODS: A retrospective analysis of prospectively collected data on anterior circulation strokes undergoing EVT between January 2015 and February 2018 was performed. Patients with good baseline functional status who underwent EVT for occlusion of an anterior circulation artery and achieved successful recanalization (modified Treatment in Cerebral Ischemia score ≥2b) but had large follow-up infarct volume (FIV ≥70 cm3) were included in the study. Demographic characteristics, clinical and radiologic data, treatment and postprocedural outcomes were extracted and analyzed. The primary outcome was 90-day modified Rankin Scale (mRS) score, stratified by favorable (mRS 0-3) versus unfavorable (mRS 4-6). RESULTS: Of 355 patients meeting inclusion criteria, 85 (24%) had large FIV on follow-up imaging after EVT and constituted the study cohort. No patients achieved mRS score 0-2 at hospital discharge; 32% had 90-day mRS score 0-3. On multivariate logistic regression analysis, lower FIV (OR, -0.96 [0.95-0.99]; P = 0.007), male sex (OR, -1.29 [1.07-12.3]; P = 0.026), and intravenous tissue plasminogen activator use (OR, 3.6 [2.01-8.9]; P = 0.003) were independent predictors of favorable outcome. Independent predictors of mortality on multivariate analysis were higher FIV (OR, -1.01 [1.007-1.02]; P = 0.001) and female sex (OR, 4.08 [1.25-13.3]; P = 0.02). CONCLUSIONS: For patients with large-core strokes (≥70 cm3) after EVT, approximately one third have favorable outcome at 90 days. Independent predictors of favorable 90-day outcomes include male sex, intravenous tissue plasminogen activator use, and lower FIV.

Osmotherapy for malignant cerebral edema in a phase 2 prospective, double blind, randomized, placebo-controlled study of IV glibenclamide.

BACKGROUND/OBJECTIVE: Malignant edema can be a life-threatening complication of large hemispheric infarction (LHI), and is often treated with osmotherapy. In this exploratory analysis of data from the GAMES-RP study, we hypothesized that patients receiving osmotherapy had symptomatic cerebral edema, and that treatment with intravenous (IV) glibenclamide would modify osmotherapy use as compared with placebo. METHODS: GAMES-RP was a phase 2 multi-center prospective, double blind, randomized, placebo-controlled study in LHI. Patients were randomized to IV glibenclamide (e.g. IV glyburide) or placebo. Cerebral edema therapies included osmotherapy and/or decompressive craniectomy at the discretion of the treating team. Total bolus osmotherapy dosing was quantified by "osmolar load". Radiographic edema was defined by dichotomizing midline shift at 24 h. Clinical changes were defined as any increase in NIHSS1a. RESULTS: Osmotherapy was administered to 40 of the 77 patients at a median of 39 [27-55] h after stroke onset. The median baseline DWI lesion volume was significantly larger in the osmotherapy treated group (167 [146-211] mL v. 139 [112-170] mL; P=0.046). Adjudicated malignant edema (75% v. 16%; P<0.001) was more common in the osmotherapy treated group. There were no differences in the proportion of patients receiving osmotherapy or the median total osmolar load between treatment arms. Most patients (76%) had a decrease in consciousness (NIHSS item 1A ≥1) on the day they began receiving osmotherapy. CONCLUSIONS: In the GAMES-RP trial, osmolar therapies were most often administered in response to clinical symptoms of decreased consciousness. However, the optimal timing of administration and impact on outcome after LHI have yet to be defined.

Interaction between time, ASPECTS, and clinical mismatch.

BACKGROUND: Imaging-based patient selection for neurothrombectomy is reliant on the identification of irreversibly damaged brain tissue (core) and salvageable tissue (penumbra). The DAWN trial used the clinical-core mismatch (CCM) paradigm (clinical deficit out of proportion to infarct volume). We aim to determine the prevalence of CCM in large vessel occlusion (LVO) strokes and study the impact of time and the Alberta Stroke Program Early CT Score (ASPECTS) on the likelihood of mismatch. METHODS: We performed a retrospective observational analysis of internal carotid artery/middle cerebral artery M1 occlusions with available advanced imaging (relative cerebral blood flow/MRI). We used automated software for infarct volume analysis and ASPECTS determination. The prevalence of CCM and the impact of time and ASPECTS were analyzed. RESULT: One hundred and eighty-five LVO strokes were included. Mean age was 71±15 years and median National Institutes of Health Stroke Scale score was 17 (range 12-21). Mean ischemic core volume was 50±69 mL. Within 0-24 hours, CCM was present in 53% and ranged from 63% in 0-3 hours to 25% at 21-24 hours (p=0.03). Prevalence of mismatch reduced 1.6% for every 1 hour increase in time to imaging. CCM prevalence by ASPECTS groups was: ASPECTS 9-10: 77%, ASPECTS 6-8: 65%, ASPECTS 0-5: 13% (p<0.01), with a 6.4% decrement for every 1 point decrease in ASPECTS. The prevalence of mismatch did not diminish over time among ASPECTS groups and higher ASPECTS was an independent predictor of CCM (OR 1.4 (95% CI 1.1 to 1.7), p<0.001). CONCLUSIONS: CCM is present in 57% and 50% of LVO strokes in the 0-6 and 6-24 hour window, respectively. The prevalence of mismatch declines with increasing time (1.6%/hour) and decreasing ASPECTS (6.4%/point). Among ASPECTS groups the prevalence of mismatch does not decline over time. These data support the use of an ASPECTS-based paradigm for late window patient selection.

Modulation of brain cation-Cl- cotransport via the SPAK kinase inhibitor ZT-1a.

The SLC12A cation-Cl- cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.

Organ donation after resuscitation from cardiac arrest.

BACKGROUND: We compared the characteristics and outcomes of post-arrest donors to those of other donors, described the proportion of post-arrest decedents who donated, and compared their characteristics to post-arrest decedents who did not donate. METHODS: We performed a retrospective cohort study including patients who died at a single academic medical center from January 1, 2010 to February 28, 2019. We linked our registry of consecutive post-arrest patients to donation-related data from the Center for Organ Procurement and Recovery (CORE). We used data from CORE to identify donor eligibility, first person designation, family approaches to seek consent for donation, and approach outcomes. We determined number of organs procured and number transplanted, stratified by donor type (brain death donors (BDD) vs donors after circulatory determination of death (DCD)). RESULTS: There were 12,130 decedents; 1525 (13%) were resuscitated from cardiac arrest. CORE staff approached families of 836 (260 (31%) post-arrest, 576 (69%) not post-arrest) to request donation. Post-arrest patients and families were more likely to authorize donation (172/260 (66%) vs 331/576 (57%), P = 0.02), and more likely to be DCDs (50/146 (34%) vs 55/289 (19%), P < 0.001). Overall, 4.1 ±â€¯1.5 organs were procured and 2.9 ±â€¯1.9 transplanted per BDD, which did not differ by post-arrest status, 3.2 ±â€¯1.2 organs were procured and 1.8 ±â€¯1.1 transplanted per DCD. Number of organs transplanted per DCD did not differ by post-arrest status. Unfavorable arrest characteristics were more common among post-arrest organ donors compared to non-donors. CONCLUSION: Patients resuscitated from cardiac arrest with irrecoverable brain injury have excellent potential to become organ donors.

Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction.

Background and Purpose- Prior studies have shown a linear relationship between computed tomography (CT)-derived radiodensity and water uptake, or brain edema, within stroke lesions. To test the hypothesis that intravenous glibenclamide (glyburide; BIIB093) reduces ischemic brain water uptake, we quantified the lesional net water uptake (NWU) on serial CT scans from patients enrolled in the phase 2 GAMES-RP Trial (Glyburide Advantage in Malignant Edema and Stroke). Methods- This was a post hoc exploratory analysis of the GAMES-RP study. Noncontrast CT scans performed between admission and day 7 (n=264) were analyzed in the GAMES-RP modified intention-to-treat sample. Quantitative change in CT radiodensity (ie, NWU) and midline shift (MLS) was measured. The gray and white matter NWU were also examined separately. Repeated-measures mixed-effects models were used to assess the effect of intravenous glibenclamide on MLS or NWU. Results- A median of 3 CT scans (interquartile range, 2-4) were performed per patient during the first 7 days after stroke. In a repeated-measures regression model, greater NWU was associated with increased MLS (ß=0.23; 95% CI, 0.20-0.26; P<0.001). Treatment with intravenous glibenclamide was associated with reduced NWU (ß=-2.80; 95% CI, -5.07 to -0.53; P=0.016) and reduced MLS (ß=-1.50; 95% CI, -2.71 to -0.28; P=0.016). Treatment with intravenous glibenclamide reduced both gray and white matter water uptake. In mediation analysis, gray matter NWU (ß=0.15; 95% CI, 0.11-0.20; P<0.001) contributed to a greater proportion of MLS mass effect, as compared with white matter NWU (ß=0.08; 95% CI, 0.03-0.13; P=0.001). Conclusions- In this phase 2 post hoc analysis, intravenous glibenclamide reduced both water accumulation and mass effect after large hemispheric infarction. This study demonstrates NWU is a quantitative and modifiable biomarker of ischemic brain edema accumulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01794182.

Automated Calculation of Alberta Stroke Program Early CT Score: Validation in Patients With Large Hemispheric Infarct.

Background and Purpose- We compared the Alberta Stroke Program Early CT Score (ASPECTS), calculated using a machine learning-based automatic software tool, RAPID ASPECTS, as well as the median score from 4 experienced readers, with the diffusion-weighted imaging (DWI) ASPECTS obtained following the baseline computed tomography (CT) in patients with large hemispheric infarcts. Methods- CT and magnetic resonance imaging scans from the GAMES-RP study, which enrolled patients with large hemispheric infarctions (82-300 mL) documented on DWI-magnetic resonance imaging, were evaluated by blinded experienced readers to determine both CT and DWI ASPECTS. The CT scans were also evaluated by an automated software program (RAPID ASPECTS). Using the DWI ASPECTS as a reference standard, the median CT ASPECTS of the clinicians and the automated score were compared using the interclass correlation coefficient. Results- The median CT ASPECTS for the clinicians was 5 (interquartile range, 4-7), for RAPID ASPECTS 3 (interquartile range, 1-6), and for DWI ASPECTS 3 (2-4). Median error for RAPID ASPECTS was 1 (interquartile range, -1 to 3) versus 3 (interquartile range, 1-4) for clinicians (P<0.001). The automated score had a higher level of agreement with the median of the DWI ASPECTS, both for the full scale and when dichotomized at <6 versus 6 or more (difference in intraclass correlation coefficient, P=0.001). Conclusions- RAPID ASPECTS was more accurate than experienced clinicians in identifying early evidence of brain ischemia as documented by DWI.

Acute Ischemic Stroke with Vessel Occlusion-Prevalence and Thrombectomy Eligibility at a Comprehensive Stroke Center.

INTRODUCTION: Endovascular thrombectomy (ET) for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO) can prevent severe disability and mortality. There is currently limited data on the epidemiology of LVO strokes and ET eligibility. We aim to determine the incidence of intracranial vessel occlusion (IVO) strokes eligible for ET per 2018 American Heart Association (AHA) guidelines and characteristics of an AHA ineligible population at a comprehensive stroke center (CSC). METHODS: Retrospective chart review of all consecutive AISs at a CSC between November 2014 and February 2017. Demographic, clinical, and radiographic data were analyzed to determine ET eligibility per AHA guidelines and characteristics of ineligible patients were investigated. RESULTS: Twenty-four percent of AIS harbor an IVO. Thirty percent of IVO strokes and 47% of anterior circulation LVO strokes are thrombectomy eligible per AHA guidelines. Most common reasons for thrombectomy ineligibility among IVO strokes are presence of IVO other than anterior circulation LVO (35%, n = 224), presence of large stroke burden (15%, n = 93), baseline modified Rankin scale greater than or equal to 2 (14%, n = 89), and NIHSS score less than 6 (15%, n = 96). CONCLUSIONS: At a CSC, 1 in 4 AISs harbor an IVO. Seven in 100 acute ischemic strokes, 3 in 10 strokes with vessel occlusion, and 1 in 2 strokes with internal carotid or middle cerebral artery M1 occlusion are thrombectomy eligible per AHA 2018 guidelines. These data highlight that current guidelines render a majority of strokes thrombectomy ineligible and a large window of opportunity exists for clinical investigation.

A Novel Na+-K+-Cl- Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke.

Background and Purpose- Inhibition of brain NKCC1 (Na+-K+-Cl- cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.

Differential association of subtypes of epileptiform activity with outcome after cardiac arrest.

BACKGROUND: Epileptiform activity is common after cardiac arrest, although intensity of electroencephalographic (EEG) monitoring may affect detection rates. Prior work has grouped these patterns together as "malignant," without considering discrete subtypes. We describe the incidence of distinct patterns in the ictal-interictal spectrum at two centers and their association with outcomes. METHODS: We analyzed a retrospective cohort of comatose post-arrest patients admitted at two academic centers from January 2011 to October 2014. One center uses routine continuous EEG, the other acquires "spot" EEG at the treating physicians' discretion. We reviewed all available EEG data and classified epileptiform patterns. We abstracted antiepileptic drugs (AEDs) administrations from the electronic medical record. We compared apparent incidence of each pattern between centers, and compared outcomes (awakening from coma, survival to discharge, discharge modified Rankin Scale (mRS) 0-2) across EEG patterns and number of AEDs administered. RESULTS: We included 818 patients. Routine continuous EEG was associated with a higher apparent incidence of polyspike burst-suppression (25% vs 13% P < 0.001). Frequency of other epileptiform findings did not differ. Among patients with any epileptiform pattern, only 2/258 (1%, 95%CI 0-3%) were discharged with mRS 0-2, although 24/258 (9%, 95%CI 6-14%) awakened and 36/258 (14%, 95%CI 10-19%) survived. The proportions that awakened and survived decreased in a stepwise manner with progressively worse EEG patterns (range 38% to 2% and 32% to 7%, respectively). Among patients receiving ≥3 AEDs, only 5/80 (6%, 95%CI 2-14%) awakened and 1/80 (1%, 95%CI 0-7%) had a mRS 0-2. CONCLUSION: We found high rates of epileptiform EEG findings, regardless of intensity of EEG monitoring. The association of distinct ictal-interictal EEG findings with outcome was variable.