Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium.

BACKGROUND: Cerebral cavernous malformations, also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurological deficits, whereas others remain asymptomatic. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. METHODS: We established a chronic mouse model of cerebral cavernous malformations, induced by postnatal ablation of Krit1 with Pdgfb-CreERT2, and examined lesion progression in these mice with T2-weighted 7T magnetic resonance imaging (MRI). We also established a modified protocol for dynamic contrast-enhanced MRI and produced quantitative maps of gadolinium tracer gadobenate dimeglumine. After terminal imaging, brain slices were stained with antibodies against microglia, astrocytes, and endothelial cells. RESULTS: These mice develop cerebral cavernous malformations lesions gradually over 4 to 5 months of age throughout the brain. Precise volumetric analysis of individual lesions revealed nonmonotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and after about 2 months followed a power trend. Using dynamic contrast-enhanced MRI, we produced quantitative maps of gadolinium in the lesions, indicating a high degree of heterogeneity in lesional permeability. MRI properties of the lesions were correlated with cellular markers for endothelial cells, astrocytes, and microglia. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial and glial cells revealed that increased cell density surrounding lesions correlates with stability, whereas denser vasculature within and surrounding the lesions may correlate with high permeability. CONCLUSIONS: Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive preclinical platform for testing new drug and gene therapies for controlling cerebral cavernous malformations.

Hemorrhage and Recurrence of Obliterated Brain Arteriovenous Malformations Treated With Stereotactic Radiosurgery.

BACKGROUND: Although complete nidal obliteration of brain arteriovenous malformations (AVM) is generally presumed to represent durable cure, postobliteration hemorrhage, and AVM recurrence have become increasingly recognized phenomena. The goal of the study was to define hemorrhage and nidal recurrence risks of obliterated AVMs treated with stereotactic radiosurgery (SRS). METHODS: This is a retrospective cohort study from the International Radiosurgery Research Foundation comprising AVM patients treated between 1987 and 2020. Patients with AVM obliteration on digital subtraction angiography (DSA) were included. Outcomes were (1) hemorrhage and (2) AVM recurrence. Follow-up duration began at the time of AVM obliteration and was censored at subsequent hemorrhage, AVM recurrence, additional AVM treatment, or loss to follow-up. Annualized risk and survival analyses were performed. A sensitivity analysis comprising patients with AVM obliteration on magnetic resonance imaging or DSA was also performed for postobliteration hemorrhage. RESULTS: The study cohort comprised 1632 SRS-treated patients with AVM obliteration on DSA. Pediatric patients comprised 15% of the cohort, and 42% of AVMs were previously ruptured. The mean imaging follow-up after AVM obliteration was 22 months. Among 1607 patients with DSA-confirmed AVM obliteration, 16 hemorrhages (1.0%) occurred over 2223 patient-years of follow-up (0.72%/y). Of the 1543 patients with DSA-confirmed AVM obliteration, 5 AVM recurrences (0.32%) occurred over 2071 patient-years of follow-up (0.24%/y). Of the 16 patients with postobliteration hemorrhage, AVM recurrence was identified in 2 (12.5%). In the sensitivity analysis comprising 1939 patients with post-SRS AVM obliteration on magnetic resonance imaging or DSA, 16 hemorrhages (0.83%) occurred over 2560 patient-years of follow-up (0.63%/y). CONCLUSIONS: Intracranial hemorrhage and recurrent arteriovenous shunting after complete nidal obliteration are rare in AVM patients treated with SRS, and each phenomenon harbors an annual risk of <1%. Although routine postobliteration DSA cannot be recommended to SRS-treated AVM patients, long-term neuroimaging may be advisable in these patients.

Quantification of hematoma and perihematomal edema volumes in intracerebral hemorrhage study: Design considerations in an artificial intelligence validation (QUANTUM) study.

BACKGROUND: Hematoma and perihematomal edema volumes are important radiographic markers in spontaneous intracerebral hemorrhage. Accurate, reliable, and efficient quantification of these volumes will be paramount to their utility as measures of treatment effect in future clinical studies. Both manual and semi-automated quantification methods of hematoma and perihematomal edema volumetry are time-consuming and susceptible to inter-rater variability. Efforts are now underway to develop a fully automated algorithm that can replace them. A (QUANTUM) study to establish inter-quantification method measurement equivalency, which deviates from the traditional use of measures of agreement and a comparison hypothesis testing paradigm to indirectly infer quantification method measurement equivalence, is described in this article. The Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study aims to determine whether a fully automated quantification method and a semi-automated quantification method for quantification of hematoma and perihematomal edema volumes are equivalent to the hematoma and perihematomal edema volumes of the manual quantification method. METHODS/DESIGN: Hematoma and perihematomal edema volumes of supratentorial intracerebral hemorrhage on 252 computed tomography scans will be prospectively quantified in random order by six raters using the fully automated, semi-automated, and manual quantification methods. Primary outcome measures for hematoma and perihematomal edema volumes will be quantified via computed tomography scan on admission (<24 h from symptom onset) and on day 3 (72 ± 12 h from symptom onset), respectively. Equivalence hypothesis testing will be conducted to determine if the hematoma and perihematomal edema volume measurements of the fully automated and semi-automated quantification methods are within 7.5% of the hematoma and perihematomal edema volume measurements of the manual quantification reference method. DISCUSSION: By allowing direct equivalence hypothesis testing, the Quantification of Hematoma and Perihematomal Edema Volumes in Intracerebral Hemorrhage study offers advantages over radiology validation studies which utilize measures of agreement to indirectly infer measurement equivalence and studies which mistakenly try to infer measurement equivalence based on the failure of a comparison two-sided null hypothesis test to reach the significance level for rejection. The equivalence hypothesis testing paradigm applied to artificial intelligence application validation is relatively uncharted and warrants further investigation. The challenges encountered in the design of this study may influence future studies seeking to translate artificial intelligence medical technology into clinical practice.

A systematic review of endovascular stent-electrode arrays, a minimally invasive approach to brain-machine interfaces.

OBJECTIVE: The goal of this study was to systematically review the feasibility and safety of minimally invasive neurovascular approaches to brain-machine interfaces (BMIs). METHODS: A systematic literature review was performed using the PubMed database for studies published between 1986 and 2019. All studies assessing endovascular neural interfaces were included. Additional studies were selected based on review of references of selected articles and review articles. RESULTS: Of the 53 total articles identified in the original literature search, 12 studies were ultimately selected. An additional 10 articles were included from other sources, resulting in a total of 22 studies included in this systematic review. This includes primarily preclinical studies comparing endovascular electrode recordings with subdural and epidural electrodes, as well as studies evaluating stent-electrode gauge and material type. In addition, several clinical studies are also included. CONCLUSIONS: Endovascular stent-electrode arrays provide a minimally invasive approach to BMIs. Stent-electrode placement has been shown to be both efficacious and safe, although further data are necessary to draw comparisons between subdural and epidural electrode measurements given the heterogeneity of the studies included. Greater access to deep-seated brain regions is now more feasible with stent-electrode arrays; however, further validation is needed in large clinical trials to optimize this neural interface. This includes the determination of ideal electrode material type, venous versus arterial approaches, the feasibility of deep brain stimulation, and more streamlined computational decoding techniques.

The Drug Excipient Cyclodextrin Interacts With d-Luciferin and Interferes With Bioluminescence Imaging.

Cyclodextrins are well-characterized, barrel-shaped molecules that can solubilize organic small molecules in aqueous solution via host-guest interactions. As such, cyclodextrins are used as excipients for experimental therapeutics in vivo. We observed unanticipated modifications to bioluminescence imaging (BLI) signal intensity when 2-hydroxy-propyl-ß-cyclodextrin (HPCD) was coinjected as an excipient. We hypothesized that HPCD bindsd-luciferin and interferes with the BLI signal. Using luciferase-expressing cell lines, we showed that HPCD lowers the BLI signal in a concentration-dependent manner. Flow cytometry revealed that HPCD resulted in reduced cellular accumulation ofd-luciferin, and mass spectrometry revealedd-luciferin HPCD species, confirming a direct interaction. In vivo imaging using a luciferase mouse model demonstrated that HPCD reduced luciferin-mediated BLI compared to luciferin alone. The implications of using HPCD as an excipient in BLI studies are discussed.

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein.

Since its development, tariquidar (TQR; XR9576; N-[2-[[4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC) transporter family. A third-generation inhibitor, TQR exhibits high affinity for P-gp, although it is also a substrate of another ABC transporter, breast cancer resistance protein (BCRP). Recently, several studies have questioned the mechanism by which TQR interfaces with P-gp, suggesting that TQR is a substrate for P-gp instead of a noncompetitive inhibitor. We investigated TQR and its interaction with human and mouse P-gp to determine if TQR is a substrate of P-gp in vitro. To address these questions, we used multiple in vitro transporter assays, including cytotoxicity, flow cytometry, accumulation, ATPase, and transwell assays. A newly generated BCRP cell line was used as a positive control that demonstrates TQR-mediated transport. Based on our results, we conclude that TQR is a potent inhibitor of both human and mouse P-gp and shows no signs of being a substrate at the concentrations tested. These in vitro data further support our position that the in vivo uptake of [(11)C]TQR into the brain can be explained by its high-affinity binding to P-gp and by it being a substrate of BCRP, followed by amplification of the brain signal by ionic trapping in acidic lysosomes.

Mammalian colonocytes possess a carrier-mediated mechanism for uptake of vitamin B3 (niacin): studies utilizing human and mouse colonic preparations.

Niacin (vitamin B3; nicotinic acid) plays an important role in maintaining redox state of cells and is obtained from endogenous and exogenous sources. The latter source has generally been assumed to be the dietary niacin, but another exogenous source that has been ignored is the niacin that is produced by the normal microflora of the large intestine. For this source of niacin to be bioavailable, it needs to be absorbed, but little is known about the ability of the large intestine to absorb niacin and the mechanism involved. Here we addressed these issues using the nontransformed human colonic epithelial NCM460 cells, native human colonic apical membrane vesicles (AMV) isolated from organ donors, and mouse colonic loops in vivo as models. Uptake of ³H-nicotinic acid by NCM460 cells was: 1) acidic pH (but not Na⁺) dependent; 2) saturable (apparent Km = 2.5 ± 0.8 µM); 3) inhibited by unlabeled nicotinic acid, nicotinamide, and probenecid; 4) neither affected by other bacterially produced monocarboxylates, monocarboxylate transport inhibitor, or by substrates of the human organic anion transporter-10; 5) affected by modulators of the intracellular protein tyrosine kinase- and Ca²âº-calmodulin-regulatory pathways; and 6) adaptively regulated by extracellular nicotinate level. Uptake of nicotinic acid by human colonic AMV in vitro and by mouse colonic loops in vivo was also carrier mediated. These findings report, for the first time, that mammalian colonocytes possess a high-affinity carrier-mediated mechanism for nicotinate uptake and show that the process is affected by intracellular and extracellular factors.

Intraarterial Transplantation of Mitochondria After Ischemic Stroke Reduces Cerebral Infarction.

Background-: Transplantation of autologous mitochondria into ischemic tissue may mitigate injury caused by ischemia and reperfusion. Methods-: Using murine stroke models of middle cerebral artery occlusion, we sought to evaluate feasibility of delivery of viable mitochondria to ischemic brain parenchyma. We evaluated the effects of concurrent focused ultrasound activation of microbubbles, which serves to open the blood-brain barrier, on efficacy of delivery of mitochondria. Results-: Following intra-arterial delivery, mitochondria distribute through the stroked hemisphere and integrate into neural and glial cells in the brain parenchyma. Consistent with functional integration in the ischemic tissue, the transplanted mitochondria elevate concentration of adenosine triphosphate in the stroked hemisphere, reduce infarct volume and increase cell viability. Additional of focused ultrasound leads to improved blood brain barrier opening without hemorrhagic complications. Conclusions-: Our results have implications for the development of interventional strategies after ischemic stroke and suggest a novel potential modality of therapy after mechanical thrombectomy.

Is a picture-perfect thrombectomy necessary in acute ischemic stroke?

BACKGROUND: The benefit of complete reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) 3) over near-complete reperfusion (≥90%, mTICI 2c) remains unclear. The goal of this study is to compare clinical outcomes between mechanical thrombectomy (MT)-treated stroke patients with mTICI 2c versus 3. METHODS: This is a retrospective study from the Stroke Thrombectomy and Aneurysm Registry (STAR) comprising 33 centers. Adults with anterior circulation arterial vessel occlusion who underwent MT yielding mTICI 2c or mTICI 3 reperfusion were included. Patients were categorized based on reperfusion grade achieved. Primary outcome was modified Rankin Scale (mRS) 0-2 at 90 days. Secondary outcomes were mRS scores at discharge and 90 days, National Institutes of Health Stroke Scale score at discharge, procedure-related complications, and symptomatic intracerebral hemorrhage. RESULTS: The unmatched mTICI 2c and mTICI 3 cohorts comprised 519 and 1923 patients, respectively. There was no difference in primary (42.4% vs 45.1%; p=0.264) or secondary outcomes between the unmatched cohorts. Reperfusion status (mTICI 2c vs 3) was also not predictive of the primary outcome in non-imputed and imputed multivariable models. The matched cohorts each comprised 191 patients. Primary (39.8% vs 47.6%; p=0.122) and secondary outcomes were also similar between the matched cohorts, except the 90-day mRS which was lower in the matched mTICI 3 cohort (p=0.049). There were increased odds of the primary outcome with mTICI 3 in patients with baseline mRS ≥2 (36% vs 7.7%; p=0.011; pinteraction=0.014) and a history of stroke (42.3% vs 15.4%; p=0.027; pinteraction=0.041). CONCLUSIONS: Complete and near-complete reperfusion after MT appear to confer comparable outcomes in patients with acute stroke.

Inhibition of intestinal biotin absorption by chronic alcohol feeding: cellular and molecular mechanisms.

The water-soluble vitamin biotin is essential for normal cellular functions and its deficiency leads to a variety of clinical abnormalities. Mammals obtain biotin from exogenous sources via intestinal absorption, a process mediated by the sodium-dependent multivitamin transporter (SMVT). Chronic alcohol use in humans is associated with a significant reduction in plasma biotin levels, and animal studies have shown inhibition in intestinal biotin absorption by chronic alcohol feeding. Little, however, is known about the cellular and molecular mechanisms involved in the inhibition in intestinal biotin transport by chronic alcohol use. These mechanisms were investigated in this study by using rats and transgenic mice carrying the human full-length SLC5A6 5'-regulatory region chronically fed alcohol liquid diets; human intestinal epithelial Caco-2 cells chronically exposed to alcohol were also used as models. The results showed chronic alcohol feeding of rats to lead to a significant inhibition in carrier-mediated biotin transport events across jejunal brush border and basolateral membrane domains. This inhibition was associated with a significant reduction in level of expression of the SMVT protein, mRNA, and heterogenous nuclear RNA. Chronic alcohol feeding also inhibited carrier-mediated biotin uptake in rat colon. Studies with transgenic mice confirmed the above findings and further showed chronic alcohol feeding significantly inhibited the activity of SLC5A6 5'-regulatory region. Finally, chronic exposure of Caco-2 cells to alcohol led to a significant decrease in the activity of both promoters P1 and P2 of the human SLC5A6 gene. These studies identify for the first time the cellular and molecular parameters of the intestinal biotin absorptive processes that are affected by chronic alcohol feeding.

Antiplatelet therapy and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

OBJECTIVE: Delayed cerebral ischemia (DCI) is a potentially preventable cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The authors performed a meta-analysis to assess the effect of antiplatelet therapy (APT) on DCI in patients with aSAH. METHODS: A systematic review of the PubMed and MEDLINE databases was performed. Study inclusion criteria were 1) ≥ 5 aSAH patients; 2) direct comparison between aSAH management with APT and without APT; and 3) reporting of DCI, angiographic, or symptomatic vasospasm rates for patients treated with versus without APT. The primary efficacy outcome was DCI. The outcomes of the APT versus no-APT cohorts were compared. Bias was assessed using the Downs and Black checklist. RESULTS: The overall cohort comprised 2039 patients from 15 studies. DCI occurred less commonly in the APT compared with the no-APT cohort (pooled = 15.9% vs 28.6%; OR 0.47, p < 0.01). Angiographic (pooled = 51.6% vs 68.7%; OR 0.46, p < 0.01) and symptomatic (pooled = 23.6% vs 37.7%; OR 0.51, p = 0.01) vasospasm rates were lower in the APT cohort. In-hospital mortality (pooled = 1.7% vs 4.1%; OR 0.53, p = 0.01) and functional dependence (pooled = 21.0% vs 35.7%; OR 0.53, p < 0.01) rates were also lower in the APT cohort. Bleeding event rates were comparable between the two cohorts. Subgroup analysis of cilostazol monotherapy compared with no APT demonstrated a lower DCI rate in the cilostazol cohort (pooled = 10.6% vs 28.1%; OR 0.31, p < 0.01). Subgroup analysis of surgically treated aneurysms demonstrated a lower DCI rate for the APT cohort (pooled = 18.4% vs 33.9%; OR 0.43, p = 0.02). CONCLUSIONS: APT is associated with improved outcomes in aSAH without an increased risk of bleeding events, particularly in patients who underwent surgical aneurysm repair and those treated with cilostazol. Although study heterogeneity is the most significant limitation of the analysis, the findings suggest that APT is worth exploring in patients with aSAH, particularly in a randomized controlled trial setting.

Tele-robotics and artificial-intelligence in stroke care.

In the last forty years, the field of medicine has experienced dramatic shifts in technology-enhanced surgical procedures - from its initial use in 1985 for neurosurgical biopsies to current implementation of systems such as magnetic-guided catheters for endovascular procedures. Systems such as the Niobe Magnetic Navigation system and CorPath GRX have allowed for utilization of a fully integrated surgical robotic systems for perioperative manipulation, as well as tele-controlled manipulation systems for telemedicine. These robotic systems hold tremendous potential for future implementation in cerebrovascular procedures, but lack of relevant clinical experience and uncharted ethical and legal territory for real-life tele-robotics have stalled their adoption for neurovascular surgery, and might present significant challenges for future development and widespread implementation. Yet, the promise that these technologies hold for dramatically improving the quality and accessibility of cerebrovascular procedures such as thrombectomy for acute stroke, drives the research and development of surgical robotics. These technologies, coupled with artificial intelligence (AI) capabilities such as machine learning, deep-learning, and outcome-based analyses and modifications, have the capability to uncover new dimensions within the realm of cerebrovascular surgery.

Mitochondrial dysfunction in neurological disorders: Exploring mitochondrial transplantation.

Mitochondria are fundamental for metabolic homeostasis in all multicellular eukaryotes. In the nervous system, mitochondria-generated adenosine triphosphate (ATP) is required to establish appropriate electrochemical gradients and reliable synaptic transmission. Notably, several mitochondrial defects have been identified in central nervous system disorders. Membrane leakage and electrolyte imbalances, pro-apoptotic pathway activation, and mitophagy are among the mechanisms implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's disease, as well as ischemic stroke. In this review, we summarize mitochondrial pathways that contribute to disease progression. Further, we discuss pathological states that damaged mitochondria impose on normal nervous system processes and explore new therapeutic approaches to mitochondrial diseases.

Enteropathogenic Escherichia coli inhibits intestinal vitamin B1 (thiamin) uptake: studies with human-derived intestinal epithelial Caco-2 cells.

Infection with the gram-negative enteropathogenic Escherichia coli (EPEC), a food-borne pathogen, represents a significant risk to human health. Whereas diarrhea is a major consequence of this infection, malnutrition also occurs especially in severe and prolonged cases, which may aggravate the health status of the infected hosts. Here we examined the effect of EPEC infection on the intestinal uptake of the water-soluble vitamin B1 (thiamin) using an established human intestinal epithelial Caco-2 cell model. The results showed that infecting Caco-2 cells with wild-type EPEC (but not with nonpathogenic E. coli, killed EPEC, or filtered supernatant) leads to a significant (P < 0.01) inhibition in thiamin uptake. Kinetic parameters of both the nanomolar (mediated by THTR-2) and the micromolar (mediated by THTR-1) saturable thiamin uptake processes were affected by EPEC infection. Cell surface expression of hTHTR-1 and -2 proteins, (determined by the biotinylation method) showed a significantly (P < 0.01) lower expression in EPEC-treated cells compared with controls. EPEC infection also affected the steady-state mRNA levels as well as promoter activity of the SLC19A2 and SLC19A3 genes. Infecting Caco-2 cells with EPEC mutants that harbor mutations in the escN gene (which encodes a putative ATPase for the EPEC type III secretion system, TTSS) or the espA, espB, or espD genes (which encode structural components of the TTSS) did not affect thiamin uptake. On the other hand, mutations in espF and espH genes (which encode effector proteins) exhibited partial inhibition in thiamin uptake. These results demonstrate for the first time that EPEC infection of human intestinal epithelial cells leads to inhibition in thiamin uptake via effects on physiological and molecular parameters of hTHTR-1 and -2. Furthermore, the inhibition appears to be dependent on a functional TTSS of EPEC.

High-Grade Aneurysmal Subarachnoid Hemorrhage: Predictors of Functional Outcome.

BACKGROUND: Because the prognosis of high-grade aneurysmal subarachnoid hemorrhage (aSAH), classified as World Federation of Neurosurgical Societies (WFNS) grade IV-V, is generally poor, the functional outcomes of survivors have not been thoroughly explored. The aim of this retrospective cohort study is to determine predictors of functional independence in patients who survive a high-grade aSAH. METHODS: We retrospectively evaluated consecutive patients with aSAH admitted to a single institution from January 2000 to April 2015. Adult (age ≥18 years) patients with WFNS grade IV-V aSAH were included for analysis. Patients without sufficient baseline data, those who died before discharge, and those without follow-up data were excluded. Univariable and multivariable logistic regression analyses were used to identify factors associated with functional independence, defined as a modified Rankin Scale score of 0-2, at last follow-up. RESULTS: Of the 260 patients with a WFNS grade IV-V aSAH during the study period, 139 met the inclusion criteria. After a mean follow-up of 6.3 months, functional independence was achieved in 73% of high-grade aSAH survivors (101/139 patients) and in 39% of all high-grade aSAH cases (101/260 patients). Only a lack of cerebrospinal fluid shunt placement was found to be an independent predictor of functional independence in the multivariable analysis (odds ratio 0.28 [0.109-0.722]; P = 0.008). CONCLUSIONS: Because functional independence can be achieved in the majority of high-grade aSAH survivors, aggressive initial management of high-grade aSAH is warranted. Strategies that reduce the need for permanent cerebrospinal fluid diversion may improve functional outcomes in survivors of high-grade aSAH.

Dangers of outpatient nimodipine use after spontaneous subarachnoid hemorrhage in accordance with the Comprehensive Stroke Center guidelines.

Despite the adverse effects and unclear benefit of the complete 21-day course of nimodipine therapy, The Joint Commission mandates adherence to nimodipine treatment for 21 days after hemorrhage or after hospital discharge if discharged within 21 days for Comprehensive Stroke Center (CSC) certification. We hereby present a 67 year-old male patient with Hunt-Hess grade 2 and Fisher grade 3 non-aneurysmal spontaneous subarachnoid hemorrhage who was discharged with oral nimodipine as stipulated by the CSC guidelines, and subsequently developed symptomatic hypotension. This report underscores the danger of outpatient nimodipine use and questions the optimal length of nimodipine therapy, especially in patients with low risk of vasospasm. Future studies, including randomized controlled trials and cost-effectiveness studies, are necessary to clarify the benefit of 21-day nimodipine therapy compared to a shortened duration of nimodipine.

Seizure Outcomes After Radiosurgery for Cerebral Arteriovenous Malformations: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: The seizure outcomes for patients with brain arteriovenous malformations (AVM) who undergo intervention with stereotactic radiosurgery (SRS) are incompletely understood. We sought to determine, in a systematic review and meta-analysis, the rates of seizure control after SRS for patients with AVM-associated seizures and identify predictive factors. METHODS: We performed a systematic review of PubMed and MEDLINE databases from January 1987 to January 2018, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies reporting post-SRS outcomes data for ≥5 patients with AVM-associated seizures were included. The seizure outcomes and factors associated with seizure freedom were evaluated using meta-analysis. RESULTS: A total of 27 studies, comprising 4826 patients, met the inclusion criteria for analysis. One or more seizures occurred in 1456 of 4826 patients (34.7% [26.0-43.9%]), and the mean follow-up was 48 ± 7 months. Seizure control (seizure freedom or seizure improvement) was achieved in 910 of 1312 patients (73.1% [66.9-78.9%]). Seizure freedom was achieved in 597 of 1245 patients (55.7% [44.5-66.6%]). Of 259 patients with seizure freedom, cessation of antiepileptic drugs was achieved in 175 patients (67.3% [46.3-85.1%]). AVM obliteration (odds ratio [OR] 4.61; P < 0.001), shorter seizure duration (OR 6.80; P < 0.001), generalized seizure type (OR 2.27; P = 0.007), and previous AVM hemorrhage (OR 5.10; P < 0.001) were significantly associated with seizure freedom. CONCLUSIONS: SRS affords seizure control to the majority of patients with AVM-associated seizures, and approximately two thirds of those with seizure freedom are able cease anticonvulsants. Nidal obliteration appears to improve the likelihood of seizure freedom, and thus remains the primary goal of intervention with SRS.

Stereotactic Radiosurgery for High-Grade Intracranial Dural Arteriovenous Fistulas.

OBJECTIVE: Factors associated with favorable outcome after stereotactic radiosurgery (SRS) for dural arteriovenous fistulas (DAVFs) with cortical venous reflux (CVR) are not completely understood. The aim of this retrospective cohort study was to assess the outcomes after SRS for high-grade DAVFs and identify predictors. METHODS: We performed a retrospective review of consecutive patients with high-grade DAVFs, defined as the presence of CVR, who underwent SRS between 1989 and 2017. The primary outcome was defined as DAVF obliteration without a new permanent neurologic deficit. Predictors of outcomes were determined using multivariate logistic regression. RESULTS: The study cohort was composed of 41 high-grade DAVF patients with a mean age of 52 years. DAVF obliteration without a new permanent neurologic deficit was achieved in 62% of patients (13/21). The rates of complete obliteration and new permanent neurologic deficit were 63% (17/27) and 23% (7/30) of patients, respectively. No independent predictors of the primary outcome or angiographic obliteration were identified in the multivariate model. Presentation with a nonhemorrhagic neurologic deficit (NHND) was found to be an independent predictor of a new permanent neurologic deficit after SRS (odds ratio, 14.176; 95% confidence interval, 1.119-179.540; P = 0.041). CONCLUSIONS: Obliteration without a new permanent neurologic deficit can be achieved in most appropriately selected patients with high-grade DAVFs after treatment with SRS. NHND at presentation is a risk factor for new permanent neurologic deficit after SRS.

Bioluminescent imaging of ABCG2 efflux activity at the blood-placenta barrier.

Physiologic barriers such as the blood placenta barrier (BPB) and the blood brain barrier protect the underlying parenchyma from pathogens and toxins. ATP-binding cassette (ABC) transporters are transmembrane proteins found at these barriers, and function to efflux xenobiotics and maintain chemical homeostasis. Despite the plethora of ex vivo and in vitro data showing the function and expression of ABC transporters, no imaging modality exists to study ABC transporter activity in vivo at the BPB. In the present study, we show that in vitro models of the placenta possess ABCG2 activity and can specifically transport D-luciferin, the endogenous substrate of firefly luciferase. To test ABCG2 transport activity at the BPB, we devised a breeding strategy to generate a bioluminescent pregnant mouse model to demonstrate transporter function in vivo. We found that coadministering the ABCG2 inhibitors Ko143 and gefitinib with D-luciferin increased bioluminescent signal from fetuses and placentae, whereas the control P-gp inhibitor DCPQ had no effect. We believe that our bioluminescent pregnant mouse model will facilitate greater understanding of the BPB and ABCG2 activity in health and disease.