Publications by authors named "William L Young"

199 Publications

Integrin β8 Deletion Enhances Vascular Dysplasia and Hemorrhage in the Brain of Adult Alk1 Heterozygous Mice.

Transl Stroke Res 2016 12 29;7(6):488-496. Epub 2016 Jun 29.

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, 1001 Potrero Avenue, Box 1363, San Francisco, CA, 94143, USA.

Brain arteriovenous malformation (bAVM), characterized by tangled dysplastic vessels, is an important cause of intracranial hemorrhage in young adults, and its pathogenesis and progression are not fully understood. Patients with haploinsufficiency of transforming growth factor-β (TGF-β) receptors, activin receptor-like kinase 1 (ALK1) or endoglin (ENG) have a higher incidence of bAVM than the general population. However, bAVM does not develop effectively in mice with the same haploinsufficiency. The expression of integrin β8 subunit (ITGB8), another member in the TGF-β superfamily, is reduced in sporadic human bAVM. Brain angiogenic stimulation results at the capillary level of vascular malformation in adult Alk1 haploinsufficient (Alk1 ) mice. We hypothesized that deletion of Itgb8 enhances bAVM development in adult Alk1 mice. An adenoviral vector expressing Cre recombinase (Ad-Cre) was co-injected with an adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) into the brain of Alk1 ;Itgb8-floxed mice to induce focal Itgb8 gene deletion and angiogenesis. We showed that compared with Alk mice (4.75 ± 1.38/mm), the Alk1 ;Itgb8-deficient mice had more dysplastic vessels in the angiogenic foci (7.14 ± 0.68/mm, P = 0.003). More severe hemorrhage was associated with dysplastic vessels in the brain of Itgb8-deleted Alk1 , as evidenced by larger Prussian blue-positive areas (1278 ± 373 pixels/mm vs. Alk1  : 320 ± 104 pixels/mm; P = 0.028). These data indicate that both Itgb8 and Alk1 are important in maintaining normal cerebral angiogenesis in response to VEGF. Itgb8 deficiency enhances the formation of dysplastic vessels and hemorrhage in Alk1 mice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065781PMC
http://dx.doi.org/10.1007/s12975-016-0478-2DOI Listing
December 2016

Morphometric characterization of brain arteriovenous malformations for clinical and radiological studies to identify silent intralesional microhemorrhages.

Clin Neuropathol 2016 May-Jun;35(3):114-21

Brain arteriovenous malformations (bAVMs) are vascular lesions that can cause significant morbidity and mortality, particularly when they bleed, i.e., rupture. Determining the risk of rupture for bAVMs is a crucial task to determine the most appropriate approach to patients with bAVM. Furthermore, patients who present with a hemorrhagic event also have a higher risk of subsequent hemorrhage. Determination of the hemorrhage risk and management strategy for incidentally discovered bAVMs still remains a controversial subject. In recent years, we have identified silent intralesional microhemorrhages (SIMs) as a possible risk factor for subsequent hemorrhage in patients with bAVMs. The principal aim of this study was to determine critical histological features that can be correlated with preoperative radioimaging findings, and allow better identification of patients with greater risk of adverse outcome. Here we provide a detailed descriptive analysis of the morphometric assessment of bAVMs in order to provide reproducible methodology that will aid in correlating preoperative radioimaging findings with histological features that may be significantly associated with increased risk of hemorrhage/rupture.
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http://dx.doi.org/10.5414/NP300937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910647PMC
March 2017

Genome-wide association study of sporadic brain arteriovenous malformations.

J Neurol Neurosurg Psychiatry 2016 09 27;87(9):916-23. Epub 2016 Jan 27.

Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California, USA Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA Institute for Human Genetics, University of California, San Francisco, California, USA.

Background: The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium.

Methods: The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls.

Results: The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort.

Conclusions: We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution.
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http://dx.doi.org/10.1136/jnnp-2015-312272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963303PMC
September 2016

Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia.

Stroke 2015 May 9;46(5):1362-4. Epub 2015 Apr 9.

From the Departments of Anesthesia and Perioperative Care (H.K., J.N., W.L.Y.), Epidemiology and Biostatistics (H.K., C.E.M.), and Neurological Surgery (M.T.L., W.L.Y.), University of California, San Francisco; Division of Neuroradiology, Department of Medical Imaging (T.K., K.G.T.), Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada; and Division of Respirology, Keenan Research Centre, and Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada (M.E.F.).

Background And Purpose: Hereditary hemorrhagic telangiectasia (HHT) is a systemic disease characterized by mucocutaneous telangiectasias, epistaxis, and arteriovenous malformations (AVMs). Intracranial hemorrhage (ICH) rates in this population are not well described. We report ICH rates and characteristics in HHT patients with brain AVMs (HHT-BAVMs).

Methods: We studied the first 153 HHT-BAVM patients with follow-up data enrolled in the Brain Vascular Malformation Consortium HHT Project. We estimated ICH rates after BAVM diagnosis.

Results: The majority of patients were women (58%) and white (98%). The mean age at BAVM diagnosis was 31±19 years (range, 0-70), with 61% of cases diagnosed on asymptomatic screening. Overall, 14% presented with ICH; among symptomatic cases, 37% presented ruptured. During 493 patient-years of follow-up, 5 ICH events occurred yielding a rate of 1.02% per year (95% confidence interval, 0.42-2.44%). ICH-free survival differed significantly by ICH presentation (P=0.003); ruptured cases had a higher ICH rate (10.07%; 95% confidence interval, 3.25-31.21%) than unruptured cases (0.43%; 95% confidence interval, 0.11-1.73%).

Conclusions: Patients with HHT-BAVM who present with hemorrhage are at a higher risk for rehemorrhage compared with patients with BAVM detected presymptomatically.
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http://dx.doi.org/10.1161/STROKEAHA.114.007367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415515PMC
May 2015

The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations.

Am J Med Genet A 2015 Jun 2;167(6):1262-7. Epub 2015 Apr 2.

Division of Respirology, Department of Medicine and Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vascular malformations (VMs) and caused by mutations in TGFβ/BMP9 pathway genes, most commonly ENG or ACVRL1. Patients with HHT have diverse manifestations related to skin and mucosal telangiectases and organ VMs, including arteriovenous malformations (AVM). The clinical heterogeneity of HHT suggests a role for genetic modifiers. We hypothesized that the ACVRL1 c.314-35A>G and ENG c.207G>A polymorphisms, previously associated with sporadic brain AVM, are associated with organ VM in HHT. We genotyped these variants in 716 patients with HHT and evaluated association of genotype with presence of any organ VM, and specifically with brain VM, liver VM and pulmonary AVM, by multivariate logistic regression analyses stratified by HHT mutation. Among all patients with HHT, neither polymorphism was significantly associated with presence of any organ VM; ACVRL1 c.314-35A>G showed a trend toward association with pulmonary AVM (OR = 1.48, P = 0.062). ACVRL1 c.314-35A>G was significantly associated with any VM among patients with HHT with ENG (OR = 2.66, P = 0.022), but not ACVRL1 (OR = 0.79, P = 0.52) mutations. ACVRL1 c.314-35A>G was also associated with pulmonary AVM and liver VM among ENG mutation heterozygotes. There were no significant associations between ENG c.207G>A and any VM phenotype. These results suggest that common polymorphisms in HHT genes other than the mutated gene modulate phenotype severity of HHT disease, specifically presence of organ VM.
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http://dx.doi.org/10.1002/ajmg.a.36936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449292PMC
June 2015

Current surgical results with low-grade brain arteriovenous malformations.

J Neurosurg 2015 Apr 6;122(4):912-20. Epub 2015 Feb 6.

Departments of 1 Neurological Surgery.

Object: Resection is an appealing therapy for brain arteriovenous malformations (AVMs) because of its high cure rate, low complication rate, and immediacy, and has become the first-line therapy for many AVMs. To clarify safety, efficacy, and outcomes associated with AVM resection in the aftermath of A Randomized Trial of Unruptured Brain AVMs (ARUBA), the authors reviewed their experience with low-grade AVMs-the most favorable AVMs for surgery and the ones most likely to have been selected for treatment outside of ARUBA's randomization process.

Methods: A prospective AVM registry was searched to identify patients with Spetzler-Martin Grade I and II AVMs treated using resection during a 16-year period.

Results: Of the 232 surgical patients included, 120 (52%) presented with hemorrhage, 33% had Spetzler-Martin Grade I, and 67% had Grade II AVMs. Overall, 99 patients (43%) underwent preoperative embolization, with unruptured AVMs embolized more often than ruptured AVMs. AVM resection was accomplished in all patients and confirmed angiographically in 218 patients (94%). There were no deaths among patients with unruptured AVMs. Good outcomes (modified Rankin Scale [mRS] score 0-1) were found in 78% of patients, with 97% improved or unchanged from their preoperative mRS scores. Patients with unruptured AVMs had better functional outcomes (91% good outcome vs 65% in the ruptured group, p = 0.0008), while relative outcomes were equivalent (98% improved/unchanged in patients with ruptured AVMs vs 96% in patients with unruptured AVMs).

Conclusions: Surgery should be regarded as the "gold standard" therapy for the majority of low-grade AVMs, utilizing conservative embolization as a preoperative adjunct. High surgical cure rates and excellent functional outcomes in patients with both ruptured and unruptured AVMs support a dominant surgical posture for low-grade AVMS, with radiosurgery reserved for risky AVMs in deep, inaccessible, and highly eloquent locations. Despite the technological advances in endovascular and radiosurgical therapy, surgery still offers the best cure rate, lowest risk profile, and greatest protection against hemorrhage for low-grade AVMs. ARUBA results are influenced by a low randomization rate, bias toward nonsurgical therapies, a shortage of surgical expertise, a lower rate of complete AVM obliteration, a higher rate of delayed hemorrhage, and short study duration. Another randomized trial is needed to reestablish the role of surgery in unruptured AVM management.
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http://dx.doi.org/10.3171/2014.12.JNS14938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422639PMC
April 2015

Adult mouse venous hypertension model: common carotid artery to external jugular vein anastomosis.

J Vis Exp 2015 Jan 27(95):50472. Epub 2015 Jan 27.

Department of Neurological Surgery, University of California, San Francisco;

The understanding of the pathophysiology of brain arteriovenous malformations and arteriovenous fistulas has improved thanks to animal models. A rat model creating an artificial fistula between the common carotid artery (CCA) and the external jugular vein (EJV) has been widely described and proved technically feasible. This construct provokes a consistent cerebral venous hypertension (CVH), and therefore has helped studying the contribution of venous hypertension to formation, clinical symptoms, and prognosis of brain AVMs and dural AVFs. Equivalent mice models have been only scarcely described and have shown trouble with stenosis of the fistula. An established murine model would allow the study of not only pathophysiology but also potential genetic therapies for these cerebrovascular diseases. We present a model of arteriovenous fistula that produces a durable intracranial venous hypertension in the mouse. Microsurgical anastomosis of the murine CCA and EJV can be difficult due to diminutive anatomy and frequently result in a non-patent fistula. In this step-by-step protocol we address all the important challenges encountered during this procedure. Avoiding excessive retraction of the vein during the exposure, using 11-0 sutures instead of 10-0, and making a carefully planned end-to-side anastomosis are some of the critical steps. Although this method requires advanced microsurgical skills and a longer learning curve that the equivalent in the rat, it can be consistently developed. This novel model has been designed to integrate transgenic mouse techniques with a previously well-established experimental system that has proved useful to study brain AVMs and dural AVFs. By opening the possibility of using transgenic mice, a broader spectrum of valid models can be achieved and genetic treatments can also be tested. The experimental construct could also be further adapted to the study of other cerebrovascular diseases related with venous hypertension such as migraine, transient global amnesia, transient monocular blindness, etc.
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http://dx.doi.org/10.3791/50472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354570PMC
January 2015

Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation.

Neuroimmunol Neuroinflamm 2014 ;1(3):147-152

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.

Aim: To test the hypothesis that lymphocyte infiltration in brain arteriovenous malformation (bAVM) is not associated with iron deposition (indicator of microhemorrhage).

Methods: Sections of unruptured, previously untreated bAVM specimens (n=19) were stained immunohistochemically for T-lymphocytes (CD3), B-lymphocytes (CD20), plasma cells (CD138) and macrophages (CD68). Iron deposition was assessed by hematoxylin and eosin and Prussian blue stains. Superficial temporal arteries (STA) were used as control.

Results: Both T lymphocytes and macrophages were present in unruptured, previously untreated bAVM specimens, whereas few B cells and plasma cells were detected. Iron deposition was detected in 8 specimens (42%; 95% confidence interval =20-67%). The samples with iron deposition tended to have more macrophages than those without (666±313 vs 478±174 cells/mm; P=0.11). T-cells were clustered on the luminal side of the endothelial surface, on the vessel-wall, and in the perivascular regions. There was no correlation between T lymphocyte load and iron deposition (P=0.88). No macrophages and lymphocytes were detected in STA controls.

Conclusions: T-lymphocytes were present in bAVM specimens. Unlike macrophages, the load and location of T-lymphocytes were not associated with iron deposition, suggesting the possibility of an independent cell-mediated immunological mechanism in bAVM pathogenesis.
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http://dx.doi.org/10.4103/2347-8659.143674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283567PMC
January 2014

The natural history of AVM hemorrhage in the posterior fossa: comparison of hematoma volumes and neurological outcomes in patients with ruptured infra- and supratentorial AVMs.

Neurosurg Focus 2014 Sep;37(3):E6

Department of Neurological Surgery, University of California, San Francisco, California.

Object: Patients with posterior fossa arteriovenous malformations (AVMs) are more likely to present with hemorrhage than those with supratentorial AVMs. Observed patients subject to the AVM natural history should be informed of the individualized effects of AVM characteristics on the clinical course following a new, first-time hemorrhage. The authors hypothesize that the debilitating effects of first-time bleeding from an AVM in a previously intact patient with an unruptured AVM are more pronounced when AVMs are located in the posterior fossa.

Methods: The University of California, San Francisco prospective registry of brain AVMs was searched for patients with a ruptured AVM who had a pre-hemorrhage modified Rankin Scale (mRS) score of 0 and a post-hemorrhage mRS score obtained within 2 days of the hemorrhagic event. A total of 154 patients met the inclusion criteria for this study. Immediate post-hemorrhage presentation mRS scores were dichotomized into nonsevere outcome (mRS ≤ 3) and severe outcome (mRS > 3). There were 77 patients in each group. Univariate and multivariate logistic regression analyses using severe outcome as the binary response were run. The authors also performed a logistic regression analysis to measure the effects of hematoma volume and AVM location on severe outcome.

Results: Posterior fossa location was a significant predictor of severe outcome (OR 2.60, 95% CI 1.20-5.67, p = 0.016) and the results were strengthened in a multivariate model (OR 4.96, 95% CI 1.73-14.17, p = 0.003). Eloquent location (OR 3.47, 95% CI 1.37-8.80, p = 0.009) and associated arterial aneurysms (OR 2.58, 95% CI 1.09, 6.10; p = 0.031) were also significant predictors of poor outcome. Hematoma volume for patients with a posterior fossa AVM was 10.1 ± 10.1 cm(3) compared with 25.6 ±28.0 cm(3) in supratentorial locations (p = 0.003). A logistic analysis (based on imputed hemorrhage volume values) found that posterior fossa location was a significant predictor of severe outcome (OR 8.03, 95% CI 1.20-53.77, p = 0.033) and logarithmic hematoma volume showed a positive, but not statistically significant, association in the model (p = 0.079).

Conclusions: Patients with posterior fossa AVMs are more likely to have severe outcomes than those with supratentorial AVMs based on this natural history study. Age, sex, and ethnicity were not associated with an increased risk of severe outcome after AVM rupture, but posterior fossa location, associated aneurysms, and eloquent location were associated with poor post-hemorrhage mRS scores. Posterior fossa hematomas are poorly tolerated, with severe outcomes observed even with smaller hematoma volumes. These findings support an aggressive surgical posture with respect to posterior fossa AVMs, both before and after rupture.
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http://dx.doi.org/10.3171/2014.7.FOCUS14211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425310PMC
September 2014

Activation of α-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress.

PLoS One 2014 26;9(8):e105711. Epub 2014 Aug 26.

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.

Activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) has a neuro-protective effect on ischemic and hemorrhagic stroke. However, the underlying mechanism is not completely understood. We hypothesized that α-7 nAchR agonist protects brain injury after ischemic stroke through reduction of pro-inflammatory macrophages (M1) and oxidative stress. C57BL/6 mice were treated with PHA568487 (PHA, α-7 nAchR agonist), methyllycaconitine (MLA, nAchR antagonist), or saline immediately and 24 hours after permanent occlusion of the distal middle cerebral artery (pMCAO). Behavior test, lesion volume, CD68(+), M1 (CD11b(+)/Iba1(+)) and M2 (CD206/Iba1+) microglia/macrophages, and phosphorylated p65 component of NF-kB in microglia/macrophages were quantified using histological stained sections. The expression of M1 and M2 marker genes, anti-oxidant genes and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were quantified using real-time RT-PCR. Compared to the saline-treated mice, PHA mice had fewer behavior deficits 3 and 7 days after pMCAO, and smaller lesion volume, fewer CD68(+) and M1 macrophages, and more M2 macrophages 3 and 14 days after pMCAO, whereas MLA's effects were mostly the opposite in several analyses. PHA increased anti-oxidant genes and NADPH oxidase expression associated with decreased phosphorylation of NF-kB p65 in microglia/macrophages. Thus, reduction of inflammatory response and oxidative stress play roles in α-7 nAchR neuro-protective effect.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105711PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144901PMC
December 2015

Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors.

Neurology 2014 Aug 11;83(7):590-7. Epub 2014 Jul 11.

From the Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care (H.K., W.L.Y.), and Departments of Epidemiology and Biostatistics (H.K., C.E.M.), Neurological Surgery (W.L.Y.), and Neurology (W.L.Y.), University of California, San Francisco; Division of Clinical Neurosciences (R.A.-S.S.), Centre for Clinical Brain Sciences, University of Edinburgh, UK; and Neurovasc-Paris Sorbonne (C.S.), Univ Paris Diderot-Sorbonne Paris Cité, and Department of Neurology, APHP-Hôpital Lariboisière, Paris, France.

Objective: To identify risk factors for intracranial hemorrhage in the natural history course of brain arteriovenous malformations (AVMs) using individual patient data meta-analysis of 4 existing cohorts.

Methods: We harmonized data from Kaiser Permanente of Northern California (n = 856), University of California San Francisco (n = 787), Columbia University (n = 672), and the Scottish Intracranial Vascular Malformation Study (n = 210). We censored patients at first treatment, death, last visit, or 10-year follow-up, and performed stratified Cox regression analysis of time-to-hemorrhage after evaluating hemorrhagic presentation, sex, age at diagnosis, deep venous drainage, and AVM size as predictors. Multiple imputation was performed to assess impact of missing data.

Results: A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation. Hemorrhagic presentation (hazard ratio 3.86, 95% CI 2.42-6.14) and increasing age (1.34 per decade, 1.17-1.53) independently predicted hemorrhage and remained significant predictors in the imputed dataset. Female sex (1.49, 95% CI 0.96-2.30) and exclusively deep venous drainage (1.60, 0.95-2.68, p = 0.02 in imputed dataset) may be additional predictors. AVM size was not associated with intracerebral hemorrhage in multivariable models (p > 0.5).

Conclusion: This large, individual patient data meta-analysis identified hemorrhagic presentation and increasing age as independent predictors of hemorrhage during follow-up. Additional AVM cohort data may further improve precision of estimates, identify new risk factors, and allow validation of prediction models.
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http://dx.doi.org/10.1212/WNL.0000000000000688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141996PMC
August 2014

Endoglin deficiency impairs stroke recovery.

Stroke 2014 Jul 29;45(7):2101-6. Epub 2014 May 29.

From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (F.S., V.D., Z.H., E.M.W., E.-J.C., H.K., M.M., W.L.Y., H.S.) and Departments of Neurological Surgery (M.T.L., W.L.Y.) and Neurology (W.L.Y.), University of California, San Francisco; Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China (F.S.); Department of Anesthesia and Intensive Care, INSERM, U676, Hôpital Robert Debré, Paris, France (V.D.); and Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC (P.-L.C., D.M.).

Background And Purpose: Endoglin deficiency causes hereditary hemorrhagic telangiectasia-1 and impairs myocardial repair. Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia-1 are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that endoglin deficiency impairs stroke recovery.

Methods: Eng heterozygous (Eng+/-) and wild-type mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Pial collateral vessels were quantified before pMCAO. Infarct/atrophic volume, vascular density, and macrophages were quantified in various days after pMCAO, and behavioral function was assessed using corner and adhesive removal tests on days 3, 15, 30, and 60 after pMCAO. The association between ENG 207G>A polymorphism and brain arteriovenous malformation rupture and surgery outcome was analyzed using logistic regression analysis in 256 ruptured and 157 unruptured patients.

Results: After pMCAO, Eng+/- mice showed larger infarct/atrophic volumes at all time points (P<0.05) and showed worse behavior performance (P<0.05) at 15, 30, and 60 days when compared with wild-type mice. Eng+/- mice had fewer macrophages on day 3 (P=0.009) and more macrophages on day 60 (P=0.02) in the peri-infarct region. Although Eng+/- and wild-type mice had similar numbers of pial collateral vessels before pMCAO, Eng+/- mice had lower vascular density in the peri-infarct region (P=0.05) on day 60 after pMCAO. In humans, ENG 207A allele has been associated with worse outcomes after arteriovenous malformation rupture or surgery of patients with unruptured arteriovenous malformation.

Conclusions: Endoglin deficiency impairs brain injury recovery. Reduced angiogenesis, impaired macrophage homing, and delayed inflammation resolution could be the underlying mechanism.
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http://dx.doi.org/10.1161/STROKEAHA.114.005115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118747PMC
July 2014

Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms.

J Neurol Neurosurg Psychiatry 2014 Nov 28;85(11):1280-3. Epub 2014 Apr 28.

Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, California, USA Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA Institute for Human Genetics, University of California, San Francisco, California, USA.

Objective: To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVM), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040).

Methods: We used data from 338 BAVM cases participating in the University of California, San Francisco (UCSF)-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R(2)>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: 74 BAVM with aneurysm versus 504 controls and 131 BAVM without aneurysm versus 504 controls.

Results: We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI 0.99 to 1.53, p=0.064) and rs1333040-T (OR=1.27, 95% CI 1.01 to 1.58, p=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI 1.03 to 2.22, p=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI 0.72 to 1.34, p=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r(2)>0.8) with rs10757278.

Conclusions: Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM-associated aneurysms share similar vascular pathology mechanisms with other aneurysm types.
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http://dx.doi.org/10.1136/jnnp-2013-306461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201968PMC
November 2014

Stereotactic radiosurgery at a low marginal dose for the treatment of pediatric arteriovenous malformations: obliteration, complications, and functional outcomes.

J Neurosurg Pediatr 2014 Jul 25;14(1):1-11. Epub 2014 Apr 25.

Departments of Neurological Surgery.

Unlabelled: OBJECT.: Stereotactic radiosurgery (SRS) is an established treatment modality for brain arteriovenous malformations (AVMs) in children, but the optimal treatment parameters and associated treatment-related complications are not fully understood. The authors present their single-institution experience of using SRS, at a relatively low marginal dose, to treat AVMs in children for nearly 20 years; they report angiographic outcomes, posttreatment hemorrhage rates, adverse treatment-related events, and functional outcomes.

Methods: The authors conducted a retrospective review of 2 cohorts of children (18 years of age or younger) with AVMs treated from 1991 to 1998 and from 2000 to 2010.

Results: A total of 80 patients with follow-up data after SRS were identified. Mean age at SRS was 12.7 years, and 56% of patients had hemorrhage at the time of presentation. Median target volume was 3.1 cm(3) (range 0.09-62.3 cm(3)), and median prescription marginal dose used was 17.5 Gy (range 12-20 Gy). Angiograms acquired 3 years after treatment were available for 47% of patients; AVM obliteration was achieved in 52% of patients who received a dose of 18-20 Gy and in 16% who received less than 18 Gy. At 5 years after SRS, the cumulative incidence of hemorrhage was 25% (95% CI 16%-37%). No permanent neurological deficits occurred in patients who did not experience posttreatment hemorrhage. Overall, good functional outcomes (modified Rankin Scale Scores 0-2) were observed for 78% of patients; for 66% of patients, functional status improved or remained the same as before treatment.

Conclusions: A low marginal dose minimizes SRS-related neurological deficits but leads to low rates of obliteration and high rates of hemorrhage. To maximize AVM obliteration and minimize posttreatment hemorrhage, the authors recommend a prescription marginal dose of 18 Gy or more. In addition, SRS-related symptoms such as headache and seizures should be considered when discussing risks and benefits of SRS for treating AVMs in children.
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http://dx.doi.org/10.3171/2014.3.PEDS13381DOI Listing
July 2014

Deep arteriovenous malformations in the basal ganglia, thalamus, and insula: multimodality management, patient selection, and results.

World Neurosurg 2014 Sep-Oct;82(3-4):386-94. Epub 2014 Mar 19.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA; Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, California, USA. Electronic address:

Objective: This study sought to describe a single institution's experience treating arteriovenous malformations (AVMs) of the basal ganglia, thalamus, and insula in a multimodal fashion.

Methods: We conducted a retrospective review of all deep AVMs treated at our institution between 1997 and 2011 with attention to patient selection, treatment strategies, and radiographic and functional outcomes.

Results: A total of 97 patients underwent initial treatment at our institution. 64% presented with hemorrhage with 29% located in the basal ganglia, 41% in the thalamus, and 30% in the insula. 80% were Spetzler-Martin grade III-IV. Initial treatment was microsurgical resection in 42%, stereotactic radiosurgery (SRS) in 45%, and observation in 12%. Radiographic cure was achieved in 54% after initial surgical or SRS treatment (71% and 23%, respectively) and in 63% after subsequent treatments, with good functional outcomes in 78% (median follow-up 2.2 years). Multivariate logistic regression analysis revealed treatment group and age as factors associated with radiographic cure, whereas Spetzler-Martin score and time to follow-up were significantly associated with improved/unchanged functional status at time of last follow-up. Posttreatment hemorrhage occurred in 11% (7% of surgical and 18% of SRS patients).

Conclusions: Modern treatment of deep AVMs includes a multidisciplinary approach utilizing microsurgery, SRS, embolization, and observation. Supplementary grading adds meaningfully to traditional Spetzler-Martin grading to guide patient selection. Surgical resection is more likely to result in obliteration compared with SRS, and is associated with satisfactory results in carefully selected patients.
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http://dx.doi.org/10.1016/j.wneu.2014.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169357PMC
March 2015

Novel brain arteriovenous malformation mouse models for type 1 hereditary hemorrhagic telangiectasia.

PLoS One 2014 10;9(2):e88511. Epub 2014 Feb 10.

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.

Endoglin (ENG) is a causative gene of type 1 hereditary hemorrhagic telangiectasia (HHT1). HHT1 patients have a higher prevalence of brain arteriovenous malformation (AVM) than the general population and patients with other HHT subtypes. The pathogenesis of brain AVM in HHT1 patients is currently unknown and no specific medical therapy is available to treat patients. Proper animal models are crucial for identifying the underlying mechanisms for brain AVM development and for testing new therapies. However, creating HHT1 brain AVM models has been quite challenging because of difficulties related to deleting Eng-floxed sequence in Eng(2fl/2fl) mice. To create an HHT1 brain AVM mouse model, we used several Cre transgenic mouse lines to delete Eng in different cell-types in Eng(2fl/2fl) mice: R26CreER (all cell types after tamoxifen treatment), SM22α-Cre (smooth muscle and endothelial cell) and LysM-Cre (lysozyme M-positive macrophage). An adeno-associated viral vector expressing vascular endothelial growth factor (AAV-VEGF) was injected into the brain to induce focal angiogenesis. We found that SM22α-Cre-mediated Eng deletion in the embryo caused AVMs in the postnatal brain, spinal cord, and intestines. Induction of Eng deletion in adult mice using R26CreER plus local VEGF stimulation induced the brain AVM phenotype. In both models, Eng-null endothelial cells were detected in the brain AVM lesions, and formed mosaicism with wildtype endothelial cells. However, LysM-Cre-mediated Eng deletion in the embryo did not cause AVM in the postnatal brain even after VEGF stimulation. In this study, we report two novel HHT1 brain AVM models that mimic many phenotypes of human brain AVM and can thus be used for studying brain AVM pathogenesis and testing new therapies. Further, our data indicate that macrophage Eng deletion is insufficient and that endothelial Eng homozygous deletion is required for HHT1 brain AVM development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088511PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919779PMC
October 2014

Induction of brain arteriovenous malformation in the adult mouse.

Methods Mol Biol 2014 ;1135:309-16

Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, USA.

Brain arteriovenous malformations (bAVM) are tangles of abnormal, dilated vessels that directly shunt blood between the arteries and veins. The pathogenesis of bAVM is currently unknown. Patients with hereditary hemorrhagic telangiectasia (HHT) have a higher prevalence of bAVM than the general population. Animal models are important tools for dissecting the disease etiopathogenesis and for testing new therapies. Here, we introduce a method that induces the bAVM phenotype through regional deletion of activin-like kinase 1 (Alk1, the causal gene for HHT2) and vascular endothelial growth factor (VEGF) stimulation.
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http://dx.doi.org/10.1007/978-1-4939-0320-7_25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988785PMC
September 2014

De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation.

Stroke 2014 Mar 23;45(3):900-2. Epub 2014 Jan 23.

From the Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research (W.C., Z.H., K.J., M.C., M.W., L.M., W.L.Y., H.S.), Departments of Radiology (Z.S.), Pediatrics (T.A.), Neurological Surgery (W.L.Y.), and Neurology (W.L.Y.), University of California, San Francisco.

Background And Purpose: In humans, activin receptor-like kinase 1 (Alk1) deficiency causes arteriovenous malformations (AVMs) in multiple organs, including the brain. Focal Alk1 pan-cellular deletion plus vascular endothelial growth factor stimulation induces brain AVMs in the adult mouse. We hypothesized that deletion of Alk1 in endothelial cell (EC) alone plus focal vascular endothelial growth factor stimulation is sufficient to induce brain AVM in the adult mouse.

Methods: Focal angiogenesis was induced in the brain of 8-week-old Pdgfb-iCreER;Alk1(2f/2f) mice by injection of adeno-associated viral vectors expressing vascular endothelial growth factor. Two weeks later, EC-Alk1 deletion was induced by tamoxifen treatment. Vascular morphology was analyzed, and EC proliferation and dysplasia index (number of vessels with diameter>15 μm per 200 vessels) were quantified 10 days after tamoxifen administration.

Results: Tangles of enlarged vessels resembling AVMs were present in the brain angiogenic region of tamoxifen-treated Pdgfb-iCreER;Alk1(2f/2f) mice. Induced brain AVMs were marked by increased dysplasia index (P<0.001) and EC proliferation clustered within the dysplastic vessels. AVMs were also detected around the ear tag-wound and in other organs.

Conclusions: Deletion of Alk1 in EC in adult mice leads to an increased local EC proliferation during brain angiogenesis and de novo brain AVM.
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http://dx.doi.org/10.1161/STROKEAHA.113.003655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117234PMC
March 2014

Endovascular biopsy: evaluating the feasibility of harvesting endothelial cells using detachable coils.

Interv Neuroradiol 2013 Dec 18;19(4):399-408. Epub 2013 Dec 18.

Department of Radiology and Biomedical Imaging; University of California; San Francisco, CA, USA -

The absence of safe and reliable methods to harvest vascular tissue in situ limits the discovery of the underlying genetic and pathophysiological mechanisms of many vascular disorders such as aneurysms. We investigated the feasibility and comparable efficacy of endothelial cell collection using a spectrum of endovascular coils. Nine detachable coils ranging in k coefficient (0.15-0.24), diameter (4.0 mm-16.0 mm), and length (8.0 cm-47.0 cm) were tested in pigs. All coils were deployed and retrieved within the iliac artery of pigs (three coils/pig). Collected coils were evaluated under light microscopy. The total and endothelial cells collected by each coil were quantified. The nucleated cells were identified by Wright-Giemsa and DAPI stains. Endothelial and smooth muscle cells were identified by CD31 and α-smooth muscle actin antibody staining. Coils were deployed and retrieved without technical difficulty. Light microscopy demonstrated sheets of cellular material concentrated within the coil winds. All coils collected cellular material while five of nine (55.6%) coils retrieved endothelial cells. Coils collected mean endothelial cell counts of 89.0±101.6. Regression analysis demonstrated a positive correlation between increasing coil diameter and endothelial cell counts (R(2)=0.52, p = 0.029). Conventional detachable coils can be used to harvest endothelial cells. The number of endothelial cells collected by a coil positively correlated with its diameter. Given the widespread use of coils and their well-described safety profile their potential as an endovascular biopsy device would expand the availability of tissue for cellular and molecular analysis.
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http://dx.doi.org/10.1177/159101991301900401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902737PMC
December 2013

MRI blood-brain barrier permeability measurements to predict hemorrhagic transformation in a rat model of ischemic stroke.

Transl Stroke Res 2012 Dec 16;3(4):508-16. Epub 2012 Sep 16.

Department of Radiology, Neuroradiology Division, University of Virginia, Box 800170, Charlottesville, VA, 22908, USA.

Permeability imaging might add valuable information in the risk assessment of hemorrhagic transformation. This study evaluates the predictive value of blood-brain barrier permeability (BBBP) measurements extracted from dynamic contrast-enhanced MRI for hemorrhagic transformation in ischemic stroke. Spontaneously hypertensive and Wistar rats with 2 h filament occlusion of the right MCA underwent MRI during occlusion, at 4 and 24 h post reperfusion. BBBP was imaged by DCE imaging and quantified by Patlak analysis. Cresyl-violet staining was used to characterize hemorrhage in sacrificed rats at 24 h, immediately following the last imaging study. BBBP changes were evaluated at baseline, 4 and 24 h after reperfusion. Receiver-operating characteristic (ROC) analysis was performed to determine the most accurate BBBP threshold to predict hemorrhagic transformation. In animals showing macroscopic hemorrhage at 24 h, 95th BBBP percentile values ipsilateral were 0.323 [0.260, 0.387], 0.685 [0.385, 0.985], and 0.412 [0.210, 0.613] ml/min·100 g (marginal mean [95%CI]) during occlusion, at 4 and 24 h post reperfusion, respectively. The BBBP values on the infarcted and contralateral side were significantly different at 4 (p = 0.034) and 24 h post reperfusion (p = 0.031). The predictive value of BBBP in terms of macroscopic hemorrhage was highest 4 h after reperfusion (ROC area under the curve = 84 %) with a high negative predictive value (98.3 %) and limited positive predictive value (14.9 %) for a threshold of 0.35 ml/min·100g. Altered BBBP is a necessary but not sufficient condition to cause hemorrhagic transformation in rats with an infarct. Further research is needed to identify those additional risk factors that are required for hemorrhagic transformation to develop in the setting of ischemic stroke.
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http://dx.doi.org/10.1007/s12975-012-0212-7DOI Listing
December 2012

Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial.

Lancet 2014 Feb 20;383(9917):614-21. Epub 2013 Nov 20.

International Center for Health Outcomes and Innovation Research, Department of Health Evidence and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: The clinical benefit of preventive eradication of unruptured brain arteriovenous malformations remains uncertain. A Randomised trial of Unruptured Brain Arteriovenous malformations (ARUBA) aims to compare the risk of death and symptomatic stroke in patients with an unruptured brain arteriovenous malformation who are allocated to either medical management alone or medical management with interventional therapy.

Methods: Adult patients (≥18 years) with an unruptured brain arteriovenous malformation were enrolled into this trial at 39 clinical sites in nine countries. Patients were randomised (by web-based system, in a 1:1 ratio, with random permuted block design [block size 2, 4, or 6], stratified by clinical site) to medical management with interventional therapy (ie, neurosurgery, embolisation, or stereotactic radiotherapy, alone or in combination) or medical management alone (ie, pharmacological therapy for neurological symptoms as needed). Patients, clinicians, and investigators are aware of treatment assignment. The primary outcome is time to the composite endpoint of death or symptomatic stroke; the primary analysis is by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389181.

Findings: Randomisation was started on April 4, 2007, and was stopped on April 15, 2013, when a data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health recommended halting randomisation because of superiority of the medical management group (log-rank Z statistic of 4·10, exceeding the prespecified stopping boundary value of 2·87). At this point, outcome data were available for 223 patients (mean follow-up 33·3 months [SD 19·7]), 114 assigned to interventional therapy and 109 to medical management. The primary endpoint had been reached by 11 (10·1%) patients in the medical management group compared with 35 (30·7%) in the interventional therapy group. The risk of death or stroke was significantly lower in the medical management group than in the interventional therapy group (hazard ratio 0·27, 95% CI 0·14-0·54). No harms were identified, other than a higher number of strokes (45 vs 12, p<0·0001) and neurological deficits unrelated to stroke (14 vs 1, p=0·0008) in patients allocated to interventional therapy compared with medical management.

Interpretation: The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain arteriovenous malformations followed up for 33 months. The trial is continuing its observational phase to establish whether the disparities will persist over an additional 5 years of follow-up.

Funding: National Institutes of Health, National Institute of Neurological Disorders and Stroke.
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http://dx.doi.org/10.1016/S0140-6736(13)62302-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119885PMC
February 2014

A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation.

PLoS One 2013 3;8(10):e71434. Epub 2013 Oct 3.

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.

Background: Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFβ) signaling pathway.

Methods: To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM.

Results: A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10(-9)); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM.

Conclusion: We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071434PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789669PMC
June 2014

Angiographic features help predict outcome after stereotactic radiosurgery for the treatment of pediatric arteriovenous malformations.

Childs Nerv Syst 2014 Feb 27;30(2):241-7. Epub 2013 Jul 27.

Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Purpose: Arteriovenous malformations (AVMs) are a frequent cause of hemorrhagic stroke in children. Stereotactic radiosurgery (SRS) is an established treatment for these lesions, particularly those that are surgically inaccessible. Because only complete AVM obliteration is believed to protect against the future risk of hemorrhage, identifying lesion characteristics that predict response to therapy is an important objective. The goal of this study is to evaluate the influence of angiographic features of AVMs on the rate of obliteration following treatment with SRS.

Methods: This is a retrospective cohort study of pediatric patients (age ≤18 years) treated with Gamma Knife SRS for cerebral AVMs between 2000 and 2012. Detailed angiographic data at the time of initial angiographic evaluation were prospectively recorded by experienced neurointerventional radiologists. The primary outcome was the rate of obliteration on a 3-year follow-up angiogram.

Results: We identified 42 pediatric patients treated with SRS for cerebral AVMs. Twenty-seven patients completed 3-year angiographic follow-ups. Complete obliteration was seen in 30%, partial response in 67%, and no response in 4%. Higher SRS dose was associated with complete obliteration. Larger AVM diameter, presence of multiple draining veins, and presence of multiple draining veins reaching a sinus were associated with partial response. In this small cohort, diffuse AVM borders, presence of aneurysm, and pre-SRS embolization were not associated with obliteration.

Conclusions: Our study identifies AVMs in the pediatric population with a nidus diameter of <2.5 cm and a solitary draining vein as the most likely to undergo complete obliteration after SRS treatment.
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http://dx.doi.org/10.1007/s00381-013-2231-4DOI Listing
February 2014

Temporal lobe arteriovenous malformations: anatomical subtypes, surgical strategy, and outcomes.

J Neurosurg 2013 Sep 12;119(3):616-28. Epub 2013 Jul 12.

Department of Neurological Surgery, University of California, San Francisco, California 94143-0112, USA.

Object: Descriptions of temporal lobe arteriovenous malformations (AVMs) are inconsistent. To standardize reporting, the authors blended existing descriptions in the literature into an intuitive classification with 5 anatomical subtypes: lateral, medial, basal, sylvian, and ventricular. The authors' surgical experience with temporal lobe AVMs was reviewed according to these subtypes.

Methods: Eighty-eight patients with temporal lobe AVMs were treated surgically.

Results: Lateral temporal lobe AVMs were the most common (58 AVMs, 66%). Thirteen AVMs (15%) were medial, 9 (10%) were basal, and 5 (6%) were sylvian. Ventricular AVMs were least common (3 AVMs, 3%). A temporal craniotomy based over the ear was used in 64%. Complete AVM resection was achieved in 82 patients (93%). Four patients (5%) died in the perioperative period (6 in all were lost to follow-up); 71 (87%) of the remaining 82 patients had good outcomes (modified Rankin Scale scores 0-2); and 68 (83%) were unchanged or improved after surgery.

Conclusions: Categorization of temporal AVMs into subtypes can assist with surgical planning and also standardize reporting. Lateral AVMs are the easiest to expose surgically, with circumferential access to feeding arteries and draining veins at the AVM margins. Basal AVMs require a subtemporal approach, often with some transcortical dissection through the inferior temporal gyrus. Medial AVMs are exposed tangentially with an orbitozygomatic craniotomy and transsylvian dissection of anterior choroidal artery and posterior cerebral artery feeders in the medial cisterns. Medial AVMs posterior to the cerebral peduncle require transcortical approaches through the temporo-occipital gyrus. Sylvian AVMs require a wide sylvian fissure split and differentiation of normal arteries, terminal feeding arteries, and transit arteries. Ventricular AVMs require a transcortical approach through the inferior temporal gyrus that avoids the Meyer loop. Surgical results with temporal lobe AVMs are generally good, and classifying them does not offer any prediction of surgical risk.
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http://dx.doi.org/10.3171/2013.6.JNS122333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159961PMC
September 2013

Deep arteriovenous malformations in the Basal Ganglia, thalamus, and insula: microsurgical management, techniques, and results.

Neurosurgery 2013 Sep;73(3):417-29

Department of Neurological Surgery, University of California, San Francisco, CA 94143-0112, USA.

Background: Arteriovenous malformations (AVMs) in the basal ganglia, thalamus, and insula are considered inoperable given their depth, eloquence, and limited surgical exposure. Although many neurosurgeons opt for radiosurgery or observation, others have challenged the belief that deep AVMs are inoperable. Further discussion of patient selection, technique, and multimodality management is needed.

Objective: To describe and discuss the technical considerations of microsurgical resection for deep-seated AVMs.

Methods: Patients with deep AVMs who underwent surgery during a 14-year period were reviewed through the use of a prospective AVM registry.

Results: Microsurgery was performed in 48 patients with AVMs in the basal ganglia (n=10), thalamus (n=13), or insula (n=25). The most common Spetzler-Martin grade was III- (68%). Surgical approaches included transsylvian (67%), transcallosal (19%), and transcortical (15%). Complete resection was achieved in 34 patients (71%), and patients with incomplete resection were treated with radiosurgery. Forty-five patients (94%) were improved or unchanged (mean follow-up, 1.6 years).

Conclusion: This experience advances the notion that select deep AVMs may be operable lesions. Patients were highly selected for small size, hemorrhagic presentation, young age, and compactness-factors embodied in the Spetzler-Martin and Supplementary grading systems. Overall, 10 different approaches were used, exploiting direct, transcortical corridors created by hemorrhage or maximizing anatomic corridors through subarachnoid spaces and ventricles that minimize brain transgression. The same cautious attitude exercised in selecting patients for surgery was also exercised in deciding extent of resection, opting for incomplete resection and radiosurgery more than with other AVMs to prioritize neurological outcomes.
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http://dx.doi.org/10.1227/NEU.0000000000000004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123817PMC
September 2013

Perioperative management of coagulation in nontraumatic intracerebral hemorrhage.

Anesthesiology 2013 Jul;119(1):218-27

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California.

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http://dx.doi.org/10.1097/ALN.0b013e318297c18aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815673PMC
July 2013

Brain Vascular Malformation Consortium: Overview, Progress and Future Directions.

J Rare Disord 2013 Apr;1(1)

Center for Cerebrovascular Research, Departments of Anesthesia and Perioperative Care, Neurological Surgery, Neurology, and Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA.

Brain vascular malformations are resource-intensive to manage effectively, are associated with serious neurological morbidity, lack specific medical therapies, and have no validated biomarkers for disease severity and progression. Investigators have tended to work in "research silos" with suboptimal cross-communication. We present here a paradigm for interdisciplinary collaboration to facilitate rare disease research. The Brain Vascular Malformation Consortium (BVMC) is a multidisciplinary, inter-institutional group of investigators, one of 17 consortia in the Office of Rare Disease Research (RDCRN). The diseases under study are: familial Cerebral Cavernous Malformations type 1, common Hispanic mutation (CCM1-CHM); Sturge-Weber Syndrome (SWS); and brain arteriovenous malformation in hereditary hemorrhagic telangiectasia (HHT). Each project is developing biomarkers for disease progression and severity, and has established scalable, relational databases for observational and longitudinal studies that are stored centrally by the RDCRN Data Management and Coordinating Center. Patient Support Organizations (PSOs) are a key RDCRN component in the recruitment and support of participants. The BVMC PSOs include , and . Our networks of clinical centers of excellence in SWS and HHT, as well as our PSOs, have enhanced BVMC patient recruitment. The BVMC provides unique and valuable resources to the clinical neurovascular community, and recently reported findings are reviewed. Future planned studies will apply successful approaches and insights across the three projects to leverage the combined resources of the BVMC and RDCRN in advancing new biomarkers and treatment strategies for patients with vascular malformations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160161PMC
April 2013

Evidence that acetylsalicylic acid attenuates inflammation in the walls of human cerebral aneurysms: preliminary results.

J Am Heart Assoc 2013 Feb 22;2(1):e000019. Epub 2013 Feb 22.

Department of Neurosurgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.

Background: Inflammatory cells and molecules may play a critical role in formation and rupture of cerebral aneurysms. Recently, an epidemiologic study reported that acetylsalicylic acid (ASA) decreases the risk of aneurysm rupture. The goal of this study was to determine the effects of ASA on inflammatory cells and molecules in the walls of human cerebral aneurysms, using radiographic and histological techniques.

Methods And Results: Eleven prospectively enrolled patients harboring unruptured intracranial aneurysms were randomized into an ASA-treated (81 mg daily) group (n=6) and an untreated (control) group (n=5). Aneurysms were imaged at baseline using ferumoxytol-enhanced MRI to estimate uptake by macrophages. After 3 months, patients were reimaged before undergoing microsurgical clipping. Aneurysm tissues were collected for immunostaining with monoclonal antibodies for cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), microsomal prostaglandin E2 synthase-1 (mPGES-1), and macrophages. A decrease in signal intensity on ferumoxytol-enhanced MRI was observed after 3 months of ASA treatment. Expression of COX-2 (but not COX-1), mPGES-1, and macrophages was lower in the ASA group than in the control group.

Conclusions: This study provides preliminary radiographical and histological evidence that ASA may attenuate the inflammatory process in the walls of human cerebral aneurysms.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01710072.
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http://dx.doi.org/10.1161/JAHA.112.000019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603234PMC
February 2013

Bone fracture exacerbates murine ischemic cerebral injury.

Anesthesiology 2013 Jun;118(6):1362-72

Center for Cerebrovascular Research and Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California 94110, USA.

Background: Bone fracture increases alarmins and proinflammatory cytokines in the blood, and provokes macrophage infiltration and proinflammatory cytokine expression in the hippocampus. We recently reported that stroke is an independent risk factor after bone surgery for adverse outcome; however, the impact of bone fracture on stroke outcome remains unknown. We tested the hypothesis that bone fracture, shortly after ischemic stroke, enhances stroke-related injuries by augmenting the neuroinflammatory response.

Methods: Tibia fracture (bone fracture) was induced in mice one day after permanent occlusion of the distal middle cerebral artery (stroke). High-mobility-group box chromosomal protein-1 (HMGB1) was tested to mimic the bone fracture effects. HMGB1 neutralizing antibody and clodrolip (macrophage depletion) were tested to attenuate the bone fracture effects. Neurobehavioral function (n = 10), infarct volume, neuronal death, and macrophages/microglia infiltration (n = 6-7) were analyzed after 3 days.

Results: We found that mice with both stroke and bone fracture had larger infarct volumes (mean percentage of ipsilateral hemisphere ± SD: 30 ± 7% vs.12 ± 3%, n = 6, P < 0.001), more severe neurobehavioral dysfunction, and more macrophages/microglia in the periinfarct region than mice with stroke only. Intraperitoneal injection of HMGB1 mimicked, whereas neutralizing HMGB1 attenuated, the bone fracture effects and the macrophage/microglia infiltration. Depleting macrophages with clodrolip also attenuated the aggravating effects of bone fracture on stroke lesion and behavioral dysfunction.

Conclusions: These novel findings suggest that bone fracture shortly after stroke enhances stroke injury via augmented inflammation through HMGB1 and macrophage/microglia infiltration. Interventions to modulate early macrophage/microglia activation could be therapeutic goals to limit the adverse consequences of bone fracture after stroke.
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http://dx.doi.org/10.1097/ALN.0b013e31828c23f8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987811PMC
June 2013
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