Partial coil embolization before surgical clipping of ruptured intracranial aneurysms.

OBJECTIVE: Intraoperative rupture (IOR) is the most common adverse event encountered during surgical clip obliteration of ruptured intracranial aneurysms. Besides increasing surgeon experience and early proximal control, no methods exist to decrease IOR risk. Thus, our objective was to assess if partial endovascular coil embolization to protect the aneurysm before clipping decreases IOR. METHODS: We conducted a retrospective analysis of patients with ruptured intracranial aneurysms that were treated with surgical clipping at two tertiary academic centers. We compared patient characteristics and outcomes of those who underwent partial endovascular coil embolization to protect the aneurysm before clipping to those who did not. The primary outcome was IOR. Secondary outcomes were inpatient mortality and discharge destination. RESULTS: We analyzed 100 patients. Partial endovascular aneurysm protection was performed in 27 patients. Age, sex, subarachnoid hemorrhage severity, and aneurysm location were similar between the partially-embolized and non-embolized groups. The median size of the partially-embolized aneurysms was larger (7.0 mm [interquartile range 5.95-8.7] vs. 4.6 mm [3.3-6.0]; P < 0.001). During surgical clipping, IOR occurred less frequently in the partially-embolized aneurysms than non-embolized aneurysms (2/27, 7.4%, vs. 30/73, 41%; P = 0.001). Inpatient mortality was 14.8% (4/27) in patients with partially-embolized aneurysms and 28.8% (21/73) in patients without embolization (P = 0.20). Discharge to home or inpatient rehabilitation was 74.0% in patients with partially-embolized aneurysms and 56.2% in patients without embolization (P = 0.11). A complication from partial embolization occurred in 2/27 (7.4%) patients. CONCLUSIONS: Preoperative partial endovascular coil embolization of ruptured aneurysms is associated with a reduced frequency of IOR during definitive treatment with surgical clip obliteration. These results and the impact of preoperative partial endovascular coil embolization on functional outcomes should be confirmed with a randomized trial.

Impact of fludrocortisone on the outcomes of subarachnoid hemorrhage patients: A retrospective analysis.

BACKGROUND: Whether the use of fludrocortisone affects outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a retrospective analysis of 78 consecutive patients with a ruptured aSAH at a single academic center in the United States. The primary outcome was the score on the modified Rankin scale (mRS, range, 0 [no symptoms] to 6 [death]) at 90 days. The primary outcome was adjusted for age, hypertension, aSAH grade, and time from aSAH onset to aneurysm treatment. Secondary outcomes were neurologic and cardiopulmonary dysfunction events. RESULTS: Among 78 patients at a single center, the median age was 58 years [IQR, 49 to 64.5]; 64 % were female, and 41 (53 %) received fludrocortisone. The adjusted common odds ratio, aOR, of a proportional odds regression model of fludrocortisone use with mRS was 0.33 (95 % CI, 0.14-0.80; P = 0.02), with values <1.0 favoring fludrocortisone. Organ-specific dysfunction events were not statistically different: delayed cerebral ischemia (22 % vs. 39 %, P = 0.16); cardiac dysfunction (0 % vs. 11 %; P = 0.10); and pulmonary edema (15 % vs. 8 %; P = 0.59). CONCLUSIONS: The risk of disability or death at 90 days was lower with the use of fludrocortisone in aSAH patients.

Dynamic interaction between cerebrospinal fluid and sinovenous pressure in idiopathic intracranial hypertension: a case report.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a common neurosurgical condition, and the exact pathophysiology remains elusive. Cerebral sinovenous stenosis (CSS) and the resultant decreased venous outflow have been labelled as a potential contributors to the pathophysiology of IIH. We describe the effect of cerebrospinal fluid (CSF) drainage on sinovenous pressure in a patient with IIH and a radiographic evidence of CSS. CASE DESCRIPTION: A patient in their 40s with a diagnoses of IIH and imaging finding of focal stenosis of the distal left transverse sinus. To assess the nature of the stenosis, we performed venous sinus pressure monitoring with concurrent CSF drainage (5 ml at one minute intervals) through a lumbar drain with continuous mean sinovenous pressures recording. We observed a progressive decline in the pressure recording while draining CSF, after draining 40 ml of CSF, the final pressure gradient recording of the TS-SS trans-stenotic was (7 mm Hg from 27 mm Hg), mean SSS pressure (37 mm Hg from 60 mm Hg), and mean TS pressure (35 mm Hg from 56 mm Hg). The mean SS pressure remained relatively unperturbed. CONCLUSION: Our findings indicate that the cerebral sinovenous pressure response to CSF removal generally conforms to a monophasic exponential decay model.

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.

Stereotactic radiosurgery for melanoma brain metastases: dose-size response relationship in the era of immunotherapy.

PURPOSE/OBJECTIVE(S): To determine, for intact melanoma brain metastases (MBM) treated with single-fraction stereotactic radiosurgery (SRS), whether planning parameter peripheral dose per lesion diameter (PDLDm, Gy/mm) and lesion control (LC) differs with versus without immunotherapy (IO). MATERIALS/METHODS: We performed a retrospective analysis of patients with intact MBM treated with SRS from 2008 to 2019. Cox-frailty models were constructed to include confounders selected by penalized Cox regression models with a LASSO selector. Interaction effect testing was used to determine whether a significant effect between IO and PDLDm could be demonstrated with respect to LC. RESULTS: The study cohort comprised 67 patients with 244 MBMs treated with SRS (30 patients with 122 lesions treated with both SRS and IO) were included. The logarithm of PDLDm was selected as a predictor of LC (HR 0.307, 95% CI 0.098-0.441), adjusting for IO receipt (HR 0.363, 95% CI 0.108-1.224). Interaction effect testing demonstrated a differential effect of PDLDm by IO receipt, with respect to LC (p = 0.048). Twelve-month LC rates for a 7.5 mm lesion receiving SRS (18 Gy) with IO versus without IO were 87.8% (95% CI 69.0-98.3%) versus 79.8% (95% CI 55.1-93.8%) respectively. CONCLUSION: PDLDm predicted LC in patients with small MBMs treated with single-fraction SRS. We found a differential effect of dose per lesion size and LC by immunotherapy receipt. Future studies are needed to determine whether lower doses of single-fraction SRS afford similarly effective LC for patients with small MBMs receiving immunotherapy.

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.

History of Nonsteroidal Anti-inflammatory Drug Use and Functional Outcomes After Spontaneous Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Preclinical and clinical studies have suggested a potential benefit from COX-2 inhibition on secondary injury activation after spontaneous intracerebral hemorrhage (ICH). The aim of this study was to investigate the effect of pre-admission NSAID use on functional recovery in spontaneous ICH patients. METHODS: Consecutive adult ICH patients enrolled in the Intracerebral Hemorrhage Outcomes Project (2009-2018) with available 90-day follow-up data were included. Patients were categorized as NSAID (daily COX inhibitor use ≤ 7 days prior to ICH) and non-NSAID users (no daily COX inhibitor use ≤ 7 days prior to ICH). Primary outcome was the ordinal 90-day modified Rankin Scale (mRS) score. Outcomes were compared between cohorts using multivariable regression and propensity score-matched analyses. A secondary analysis excluding aspirin users was performed. RESULTS: The NSAID and non-NSAID cohorts comprised 228 and 361 patients, respectively. After 1:1 matching, the matched cohorts each comprised 140 patients. The 90-day mRS were comparable between the NSAID and non-NSAID cohorts in both the unmatched (aOR = 0.914 [0.626-1.336], p = 0.644) and matched (aOR = 0.650 [0.392-1.080], p = 0.097) analyses. The likelihood of recurrent ICH at 90 days was also comparable between the NSAID and non-NSAID cohorts in both the unmatched (aOR = 0.845 [0.359-1.992], p = 0.701) and matched analyses (aOR = 0.732 [0.241-2.220], p = 0.581). In the secondary analysis, the non-aspirin NSAID and non-NSAID cohorts comprised 38 and 361 patients, respectively. After 1:1 matching, the matched cohorts each comprised 38 patients. The 90-day mRS were comparable between the non-aspirin NSAID and non-NSAID cohorts in both the unmatched (aOR = 0.615 [0.343-1.101], p = 0.102) and matched (aOR = 0.525 [0.219-1.254], p = 0.147) analyses. The likelihood of recurrent ICH at 90 days was also comparable between the non-aspirin NSAID and non-NSAID cohorts in both the unmatched (aOR = 2.644 [0.258-27.091], p = 0.413) and matched (aOR = 2.586 [0.228-29.309], p = 0.443) analyses. After the exclusion of patients with DNR or withdrawal of care status, NSAID use was associated with lower mRS at 90 days (aOR = 0.379 [0.212-0.679], p = 0.001), lower mRS at hospital discharge (aOR = 0.505 [0.278-0.919], p = 0.025) and lower 90-day mortality rates (aOR = 0.309 [0.108-0.877], p = 0.027). CONCLUSIONS: History of nonselective COX inhibition may affect functional outcomes in ICH patients. Pre-admission NSAID use did not appear to worsen the severity of presenting ICH or increase the risk of recurrent ICH. Additional clinical studies may be warranted to investigate the effects of pre-admission NSAID use on ICH outcomes.

Neuroprotective Therapies for Spontaneous Intracerebral Hemorrhage.

Patients who survive the initial ictus of spontaneous intracerebral hemorrhage (ICH) remain vulnerable to subsequent injury of the perilesional parenchyma by molecular and cellular responses to the hematoma. Secondary brain injury after ICH, which contributes to long-term functional impairment and mortality, has emerged as an attractive therapeutic target. This review summarizes preclinical and clinical evidence for neuroprotective therapies targeting secondary injury pathways following ICH. A focus on therapies with pleiotropic antiinflammatory effects that target thrombin-mediated chemotaxis and inflammatory cell migration has led to studies investigating statins, anticholinergics, sphingosine-1-phosphate receptor modulators, peroxisome proliferator activated receptor gamma agonists, and magnesium. Attempts to modulate ICH-induced blood-brain barrier breakdown and perihematomal edema formation has prompted studies of nonsteroidal antiinflammatory agents, matrix metalloproteinase inhibitors, and complement inhibitors. Iron chelators, such as deferoxamine and albumin, have been used to reduce the free radical injury that ensues from erythrocyte lysis. Stem cell transplantation has been assessed for its potential to enhance subacute neurogenesis and functional recovery. Despite promising preclinical results of numerous agents, their outcomes have not yet translated into positive clinical trials in patients with ICH. Further studies are necessary to improve our understanding of the molecular events that promote damage and inflammation of the perihematomal parenchyma after ICH. Elucidating the temporal and pathophysiologic features of this secondary brain injury could enhance the clinical efficacy of neuroprotective therapies for ICH.

Fully Automated Segmentation Algorithm for Perihematomal Edema Volumetry After Spontaneous Intracerebral Hemorrhage.

Background and Purpose- Perihematomal edema (PHE) is a promising surrogate marker of secondary brain injury in patients with spontaneous intracerebral hemorrhage, but it can be challenging to accurately and rapidly quantify. The aims of this study are to derive and internally validate a fully automated segmentation algorithm for volumetric analysis of PHE. Methods- Inpatient computed tomography scans of 400 consecutive adults with spontaneous, supratentorial intracerebral hemorrhage enrolled in the Intracerebral Hemorrhage Outcomes Project (2009-2018) were separated into training (n=360) and test (n=40) datasets. A fully automated segmentation algorithm was derived from manual segmentations in the training dataset using convolutional neural networks, and its performance was compared with that of manual and semiautomated segmentation methods in the test dataset. Results- The mean volumetric dice similarity coefficients for the fully automated segmentation algorithm were 0.838±0.294 and 0.843±0.293 with manual and semiautomated segmentation methods as reference standards, respectively. PHE volumes derived from the fully automated versus manual (r=0.959; P<0.0001), fully automated versus semiautomated (r=0.960; P<0.0001), and semiautomated versus manual (r=0.961; P<0.0001) segmentation methods had strong between-group correlations. The fully automated segmentation algorithm (mean 18.0±1.8 seconds/scan) quantified PHE volumes at a significantly faster rate than both of the manual (mean 316.4±168.8 seconds/scan; P<0.0001) and semiautomated (mean 480.5±295.3 seconds/scan; P<0.0001) segmentation methods. Conclusions- The fully automated segmentation algorithm accurately quantified PHE volumes from computed tomography scans of supratentorial intracerebral hemorrhage patients with high fidelity and greater efficiency compared with manual and semiautomated segmentation methods. External validation of fully automated segmentation for assessment of PHE is warranted.

Onyx embolization of skull base paragangliomas: a single-center experience.

BACKGROUND: Skull base paragangliomas are highly vascular tumors that are often embolized before surgical resection; however, the safety and efficacy of preoperative embolization using an ethylene vinyl alcohol copolymer (Onyx; Medtronic, Dublin, Republic of Ireland) in these tumors is unknown. This retrospective cohort study evaluated patient outcomes after preoperative embolization of skull base paragangliomas using Onyx. METHODS: We retrospectively analyzed data from all patients with skull base paragangliomas who underwent preoperative Onyx embolization at our institution (January 01, 2005-December 31, 2017). Patient, tumor, embolization, and outcomes data were extracted by reviewing inpatient and outpatient clinical and imaging records. RESULTS: Seven patients were studied (5/7 [71%] female), 6 with glomus jugulares and 1 with a glomus vagale. The median age was 52 years, and the most common presenting symptom was cranial neuropathy (6/7 [86%]). The tumor vascular supply was from the ascending pharyngeal artery in all 7 cases (100%) with additional feeders including the occipital artery in 5 (71%); internal carotid artery in 3 (43%); middle meningeal, vertebral, and internal maxillary artery each in 2 (29%); and posterior auricular artery in 1 (14%). The median postembolization tumor devascularization was 80% (range, 64-95%). The only postembolization complication was a facial palsy in 1 patient. CONCLUSION: Preoperative embolization with Onyx affords excellent devascularization for the majority of skull base paragangliomas, and it may facilitate resection of these hypervascular lesions. The advantages provided by Onyx with respect to penetration of intratumoral vessels must be weighed against the risk of cranial neuropathy.

Fully Automated Segmentation Algorithm for Hematoma Volumetric Analysis in Spontaneous Intracerebral Hemorrhage.

Background and Purpose- Hematoma volume measurements influence prognosis and treatment decisions in patients with spontaneous intracerebral hemorrhage (ICH). The aims of this study are to derive and validate a fully automated segmentation algorithm for ICH volumetric analysis using deep learning methods. Methods- In-patient computed tomography scans of 300 consecutive adults (age ≥18 years) with spontaneous, supratentorial ICH who were enrolled in the ICHOP (Intracerebral Hemorrhage Outcomes Project; 2009-2018) were separated into training (n=260) and test (n=40) datasets. A fully automated segmentation algorithm was derived using convolutional neural networks, and it was trained on manual segmentations from the training dataset. The algorithm's performance was assessed against manual and semiautomated segmentation methods in the test dataset. Results- The mean volumetric Dice similarity coefficients for the fully automated segmentation algorithm when tested against manual and semiautomated segmentation methods were 0.894±0.264 and 0.905±0.254, respectively. ICH volumes derived from fully automated versus manual (R2=0.981; P<0.0001), fully automated versus semiautomated (R2=0.978; P<0.0001), and semiautomated versus manual (R2=0.990; P<0001) segmentation methods had strong between-group correlations. The fully automated segmentation algorithm (mean 12.0±2.7 s/scan) was significantly faster than both of the manual (mean 201.5±92.2 s/scan; P<0.001) and semiautomated (mean 288.58±160.3 s/scan; P<0.001) segmentation methods. Conclusions- The fully automated segmentation algorithm quantified hematoma volumes from computed tomography scans of supratentorial ICH patients with similar accuracy and substantially greater efficiency compared with manual and semiautomated segmentation methods. External validation of the fully automated segmentation algorithm is warranted.

Cigarette Smoking History and Functional Outcomes After Spontaneous Intracerebral Hemorrhage.

Background and Purpose- Although cigarette use may be a risk for intracerebral hemorrhage (ICH), animal models suggest that nicotine has a potential neuroprotective effect. The aim of this multicenter study is to determine the effect of smoking history on outcome in ICH patients. Methods- We analyzed prospectively collected data from the Ethnic/Racial Variations of Intracerebral Hemorrhage study and included patients with smoking status data in the analysis. Patients were dichotomized into nonsmokers versus ever-smokers, and the latter group was further categorized as former (>30 days before ICH) or current (≤30 days before ICH) smokers. The primary outcome was 90-day modified Rankin Scale score shift analysis. Secondary outcomes were in-hospital mortality and mortality, Barthel Index, and self-reported health status measures at 90 days. Results- The overall study cohort comprised 1509 nonsmokers and 1423 ever-smokers (841 former, 577 current, 5 unknown). No difference in primary outcome was observed between nonsmokers versus ever-smokers (adjusted odds ratio [aOR], 1.041; 95% CI, 0.904-1.199; P=0.577). No differences in primary outcome were observed between former (aOR, 0.932; 95% CI, 0.791-1.178; P=0.399) or current smokers (aOR, 1.178; 95% CI, 0.970-1.431; P=0.098) versus nonsmokers. Subgroup analyses by race/ethnicity demonstrated no differences in primary outcome when former and current smokers were compared with nonsmokers. Former, but not current, smokers had a lower in-hospital mortality rate (aOR, 0.695; 95% CI, 0.500-0.968; P=0.031), which was only observed in Hispanics (aOR, 0.533; 95% CI, 0.309-0.921; P=0.024). Differences in self-reported health status measures were only observed in whites. Conclusions- Cigarette smoking history does not seem to provide a beneficial effect on 90-day functional outcome in patients with ICH.

Risk of Brain Arteriovenous Malformation Hemorrhage Before and After Stereotactic Radiosurgery.

Background and Purpose- Understanding the hemorrhage risks associated with brain arteriovenous malformations (AVMs) before and after stereotactic radiosurgery (SRS) is important. The aims of this multicenter, retrospective cohort study are to evaluate and compare the rates of pre- and post-SRS AVM hemorrhage and identify risk factors. Methods- We pooled AVM SRS data from 8 institutions participating in the International Radiosurgery Research Foundation. Predictors of post-SRS hemorrhage were determined using a multivariate logistic regression model. Pre- and post-SRS hemorrhage rates were compared using Fisher exact test. Ruptured and unruptured AVMs were matched in a 1:1 ratio using propensity scores, and their outcomes were compared. Results- The study cohort comprised 2320 AVM patients who underwent SRS. Deep AVM location (odds ratio, 1.86; 95% CI, 1.19-2.92; P=0.007), the presence of an AVM-associated arterial aneurysm (odds ratio, 2.44; 95% CI, 1.63-3.66; P<0.001), and lower SRS margin dose (odds ratio, 0.93; 95% CI, 0.88-0.98; P=0.005) were independent predictors of post-SRS hemorrhage. The post-SRS hemorrhage rate was lower for obliterated versus patent AVMs (6.0 versus 22.3 hemorrhages/1000 person-years; P<0.001). The AVM hemorrhage rate decreased from 15.4 hemorrhages/1000 person-years before SRS to 11.9 after SRS ( P=0.001). The outcomes of the matched ruptured versus unruptured AVM cohorts were similar. Conclusions- SRS appears to reduce the risk of AVM hemorrhage, although this effect is predominantly driven by obliteration. Deep-seated AVMs are more likely to rupture during the latency period after SRS. AVM-associated aneurysms should be considered for selective occlusion before SRS of the nidus to ameliorate the post-SRS hemorrhage rate of these lesions.

Stereotactic Radiosurgery for Unruptured Versus Ruptured Pediatric Brain Arteriovenous Malformations.

Background and Purpose- The effects of prior hemorrhage on stereotactic radiosurgery (SRS) outcomes for pediatric arteriovenous malformations (AVMs) are not well defined. The aim of this multicenter, retrospective cohort study is to compare the SRS outcomes for unruptured versus ruptured pediatric AVMs. Methods- The International Radiosurgery Research Foundation pediatric AVM database from 1987 to 2018 was reviewed retrospectively. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes. Associations between prior hemorrhage and outcomes were adjusted for baseline differences, inverse probability weights, and competing risks. Results- The study cohort comprised 153 unruptured and 386 ruptured AVMs. Favorable outcome was achieved in 48.4% and 60.4% of unruptured and ruptured AVMs, respectively (adjusted odds ratio, 1.353; P=0.190). Cumulative AVM obliteration probabilities were 51.2%, 59.4%, 64.2%, and 70.0% for unruptured and 61.0%, 69.3%, 74.0%, and 79.3% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.311; P=0.020). Cumulative post-SRS hemorrhage probabilities were 4.5%, 5.6%, 5.6%, and 9.8% for unruptured and 4.7%, 6.1%, 6.1%, and 10.6% for ruptured AVMs at 4, 6, 8, and 10 years, respectively (subhazard ratio, 1.086; P=0.825). Probabilities of AVM obliteration (adjusted subhazard ratio, 0.968; P=0.850) and post-SRS hemorrhage (adjusted subhazard ratio, 1.663; P=0.251) were comparable between the 2 cohorts after inverse probability weight adjustments. Symptomatic (15.8% versus 8.1%; adjusted odds ratio, 0.400; P=0.008) and permanent (9.2% versus 5.0%; adjusted odds ratio, 0.441; P=0.045) radiation-induced change were more common in unruptured AVMs. Conclusions- The overall outcomes after SRS for unruptured versus ruptured pediatric AVMs are comparable. However, symptomatic and permanent radiation-induced change occur more frequently in pediatric patients with unruptured AVMs.

Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

OBJECTIVE: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture. APPROACH AND RESULTS: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1ß, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs. CONCLUSIONS: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies.

National trends in cerebral bypass for unruptured intracranial aneurysms: a National (Nationwide) Inpatient Sample analysis of 1998-2015.

OBJECTIVEThe development and recent widespread dissemination of flow diverters may have reduced the utilization of surgical bypass procedures to treat complex or giant unruptured intracranial aneurysms (UIAs). The aim of this retrospective cohort study was to observe trends in cerebral revascularization procedures for UIAs in the United States before and after the introduction of flow diverters by using the National (Nationwide) Inpatient Sample (NIS).METHODSThe authors extracted data from the NIS database for the years 1998-2015 using the ICD-9/10 diagnostic and procedure codes. Patients with a primary diagnosis of UIA with a concurrent bypass procedure were included in the study. Outcomes and hospital charges were analyzed.RESULTSA total of 216,212 patients had a primary diagnosis of UIA during the study period. The number of patients diagnosed with a UIA increased by 128% from 1998 (n = 7718) to 2015 (n = 17,600). Only 1328 of the UIA patients (0.6%) underwent cerebral bypass. The percentage of patients who underwent bypass in the flow diverter era (2010-2015) remained stable at 0.4%. Most patients who underwent bypass were white (51%), were female (62%), had a median household income in the 3rd or 4th quartiles (57%), and had private insurance (51%). The West (33%) and Midwest/North Central regions (30%) had the highest volume of bypasses, whereas the Northeast region had the lowest (15%). Compared to the period 1998-2011, bypass procedures for UIAs in 2012-2015 shifted entirely to urban teaching hospitals (100%) and to an elective basis (77%). The median hospital stay (9 vs 3 days, p < 0.0001), median hospital charges ($186,746 vs $66,361, p < 0.0001), and rate of any complication (51% vs 17%, p < 0.0001) were approximately threefold higher for the UIA patients with bypass than for those without bypass.CONCLUSIONSDespite a significant increase in the diagnosis of UIAs over the 17-year study period, the proportion of bypass procedures performed as part of their treatment has remained stable. Therefore, advances in endovascular aneurysm therapy do not appear to have affected the volume of bypass procedures performed in the UIA population. The authors' findings suggest a potentially ongoing niche for bypass procedures in the contemporary treatment of UIAs.

Stereotactic Radiosurgery for Pediatric Versus Adult Brain Arteriovenous Malformations.

Background and Purpose- The aim of this international, multicenter, retrospective matched cohort study is to directly compare the outcomes after stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVM) in pediatric versus adult patients. Methods- We performed a retrospective review of patients with AVM who underwent SRS at 8 institutions participating in the International Gamma Knife Research Foundation from 1987 to 2014. Patients were categorized into pediatric (<18 years of age) and adult (≥18 years of age) cohorts and matched in a 1:1 ratio using propensity scores. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes. Results- From a total of 2191 patients who were eligible for inclusion in the overall study cohort, 315 were selected for each of the matched cohorts. There were no significant differences between matched pediatric versus adult cohorts with respect to the rates of favorable outcome (59% versus 58%; P=0.936), AVM obliteration (62% versus 63%; P=0.934), post-SRS hemorrhage (9% versus 7%; P=0.298), radiological radiation-induced changes (26% versus 26%; P=0.837), symptomatic radiation-induced changes (7% versus 9%; P=0.383), or permanent radiation-induced changes (2% versus 3%; P=0.589). The all-cause mortality rate was significantly lower in the matched pediatric cohort (3% versus 10%; P=0.003). Conclusions- The outcomes after SRS for comparable AVMs in pediatric versus adult patients were not found to be appreciably different. SRS remains a reasonable treatment option for appropriately selected pediatric patients with AVM, who harbor a high cumulative lifetime hemorrhage risk. Age seems to be a poor predictor of AVM outcomes after SRS.

Repeat stereotactic radiosurgery for Cushing's disease: outcomes of an international, multicenter study.

Stereotactic radiosurgery (SRS) is frequently used for Cushing's disease (CD) after failed pituitary surgery. Management of patients with persistent CD after failed SRS is complex, as the alternative therapeutic options harbor significant risks. The outcomes of repeat pituitary radiosurgery, however, have not been described. We sought to determine the outcomes of repeat SRS in patients with CD. We pooled data from five institutions participating in the International Gamma Knife Research Foundation for patients with recurrent or persistent CD ≥ 12 months after initial SRS. Patients were included in the study if they had ≥ 6 months endocrine follow-up after repeat SRS. Twenty patients were included in the study. Repeat single-session SRS was performed 1.3-9.7 years after initial SRS. Median endocrine follow-up was 6.6 years (1.4-19.1 years). Median margin dose was 20 Gy (range 10.8-35 Gy). Endocrine remission after second SRS was noted in 12 patients (60%), with a median time to remission of 6 months (range 2-64 months). Biochemical recurrence occurred in two patients (17%) after initial remission. Overall, the cumulative rates of durable endocrine remission at 5 and 10 years were 47 and 53%, respectively. Two patients (10%) experienced adverse radiation effects, including transient visual loss and permanent diplopia. Repeat SRS achieves lasting biochemical remission in approximately half of patients with CD refractory to both prior microsurgery and SRS. Because of the morbidity of refractory or recurrent CD, repeat SRS should be considered for carefully selected patients with hypercortisolism confirmed one or more years after initial SRS.

Transvenous embolization of brain arteriovenous malformations: a review of techniques, indications, and outcomes.

Endovascular embolization of brain arteriovenous malformations (AVMs) is conventionally performed from a transarterial approach. Transarterial AVM embolization can be a standalone treatment or, more commonly, used as a neoadjuvant therapy prior to microsurgery or stereotactic radiosurgery. In contrast to the transarterial approach, curative embolization of AVMs may be more readily achieved from a transvenous approach. Transvenous embolization is considered a salvage therapy in contemporary AVM management. Proposed indications for this approach include a small (diameter < 3 cm) and compact AVM nidus, deep AVM location, hemorrhagic presentation, single draining vein, lack of an accessible arterial pedicle, exclusive arterial supply by perforators, and en passage feeding arteries. Available studies of transvenous AVM embolization in the literature have reported high complete obliteration rates, with reasonably low complication rates. However, evaluating the efficacy and safety of this approach is challenging due to the limited number of published cases. In this review the authors describe the technical considerations, indications, and outcomes of transvenous AVM embolization.

Magnetic resonance-guided, high-intensity focused ultrasound sonolysis: potential applications for stroke.

Stroke is one of the leading causes of death worldwide and a significant source of long-term morbidity. Unfortunately, a substantial number of stroke patients either are ineligible or do not significantly benefit from contemporary medical and interventional therapies. To address this void, investigators recently made technological advances to render transcranial MR-guided, high-intensity focused ultrasound (MRg-HIFU) sonolysis a potential therapeutic option for both acute ischemic stroke (AIS)-as an alternative for patients with emergent large-vessel occlusion (ELVO) who are ineligible for endovascular mechanical thrombectomy (EMT) or as salvage therapy for patients in whom EMT fails-and intracerebral hemorrhage (ICH)-as a neoadjuvant means of clot lysis prior to surgical evacuation. Herein, the authors review the technological principles behind MRg-HIFU sonolysis, its results in in vitro and in vivo stroke models, and its potential clinical applications. As a noninvasive transcranial technique that affords rapid clot lysis, MRg-HIFU thrombolysis may develop into a therapeutic option for patients with AIS or ICH. However, additional studies of transcranial MRg-HIFU are necessary to ascertain the merit of this treatment approach for thrombolysis in both AIS and ICH, as well as its technical limitations and risks.