Object

Management of unruptured arteriovenous malformations (AVMs) is controversial. In the first randomized trial of unruptured AVMs (A Randomized Trial of Unruptured Brain Arteriovenous Malformations [ARUBA]), medically managed patients had a significantly lower risk of death or stroke and had better outcomes. The University of California, San Francisco (UCSF) was one of the participating ARUBA sites. While 473 patients were screened for eligibility, only 4 patients were enrolled in ARUBA. The purpose of this study is to report the treatment and outcomes of all ARUBA-eligible patients at UCSF.

Methods

The authors compared the treatment and outcomes of ARUBA-eligible patients using prospectively collected data from the UCSF brain AVM registry. Similar to ARUBA, they compared the rate of stroke or death in observed and treated patients and used the modified Rankin Scale to grade outcomes.

Results

Of 74 patients, 61 received an intervention and 13 were observed. Most treated patients had resection with or without preoperative embolization (43 [70.5%] of 61 patients). One of the 13 observed patients died after AVM hemorrhage. Nine of the 61 treated patients had a stroke or died. There was no significant difference in the rate of stroke or death (HR 1.34, 95% CI 0.12-14.53, p = 0.81) or clinical impairment (Fisher's exact test, p > 0.99) between observed and treated patients.

Conclusions

The risk of stroke or death and degree of clinical impairment among treated patients was lower than reported in ARUBA. The authors found no significant difference in outcomes between observed and treated ARUBA-eligible patients at UCSF. Results in ARUBA-eligible patients managed outside that trial led to an entirely different conclusion about AVM intervention, due to the primary role of surgery, judicious surgical selection with established outcome predictors, and technical expertise developed at high-volume AVM centers.

Brain arteriovenous malformations (AVMs) are abnormal connections of arteries and veins, resulting in arteriovenous shunting of blood. Primary medical therapy is lacking; treatment options include surgery, radiosurgery, and embolization, often in combination. Judicious selection of AVM patients for treatment requires balancing risk of treatment complications against the risk of hemorrhage in the natural history course. This review focuses on the epidemiology, hemorrhage risk, and factors influencing risk of hemorrhage in the untreated natural course associated with sporadic brain AVM.

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.

Mutations in the smooth muscle-specific isoform of alpha actin (ACTA2) cause smooth muscle dysfunction in arteries. This rare loss-of-function mutation may cause a diffuse occlusive cerebral arteriopathy, resulting in stroke. While ACTA2 arteriopathy is often described as moyamoya-like, it has a distinct phenotype characterized by dilation of the proximal internal carotid artery (ICA) and occlusion of the terminal ICA and proximal middle cerebral artery. Intracranial arteries have an abnormally straight course, often with small aneurysms. There is limited experience with revascularization procedures for ACTA2 arteriopathy, and the safety and efficacy of these procedures are unknown. In this paper the authors present a symptomatic 6-year-old patient with ACTA2 cerebral arteriopathy who underwent both indirect revascularization and direct cerebrovascular bypass. Postoperatively, the patient suffered an ischemic infarct in a neighboring vascular territory. While direct cerebrovascular bypass is technically feasible, patients with ACTA2 arteriopathy may be at increased risk for perioperative stroke compared with patients with moyamoya disease.

Background

The treatment of dolichoectatic basilar trunk aneurysms has been ineffectual or morbid due to nonsaccular morphology, deep location, and involvement of brainstem perforators. Treatment with bypass surgery has been advocated to eliminate malignant hemodynamics and to stabilize aneurysm growth.

Objective

To validate that flow alteration with bypass and parent artery occlusion favorably impacts aneurysm progression.

Methods

Surgical management evolved in 3 phases, each with different hemodynamic alterations.

Results

During a 17-year period, 37 patients with dolichoectatic basilar trunk aneurysms were retrospectively identified, of whom 21 patients were observed, 12 treated immediately, and 4 selected for treatment after clinical progression. In phase 1, flow reversal was overly thrombogenic, despite heparin (N = 5, final mortality, 100%). In phase 2, flow reduction with intracranial-to-intracranial bypass was safer than flow reversal, but did not prevent progressive aneurysm enlargement (N = 3, final mortality 67%). In phase 3, distal clip occlusion of the basilar trunk aneurysm preserved anterograde flow in the aneurysm without rupture, but reduced flow threatened perforator patency, despite treatment with clopidogrel (N = 8, final mortality 62%).

Conclusion

Shifting treatment strategy for dolichoectatic basilar trunk aneurysms improved surgical (80% to 50%) and final mortalities (100% to 62%), with stabilization of aneurysms in the phase 3 survivors. Good outcomes are determined by perforator preservation and mitigating aneurysm thrombosis. Occlusion techniques with increased distal run-off seem to benefit perforators. The treatment of dolichoectatic basilar trunk aneurysms can advance through concentrated management in dedicated centers, concerted efforts to study morphology and hemodynamics with computational methods, and widespread collection of registry data.

Abbreviations

4D PC-MRI, time-resolved phase-contrast MRIAICA, anterior inferior cerebellar arteryCE-MRA, high-resolution contrast-enhanced MR angiographyEC-IC, extracranial-to-intracranial bypassMCA, middle cerebral arteryMR, magnetic resonancemRS, modified Rankin ScalePCA, posterior cerebral arteryPICA, posterior inferior cerebellar arterySCA, superior cerebellar arterySTA, superficial temporal arteryVA, vertebral artery.

Background

The effect of timing of initiation of concurrent radiation and chemotherapy after surgery on outcome of patients with glioblastoma (GBM) remains unclear.

Objective

To further explore this issue, we analyzed 4 clinical trials for patients newly diagnosed with GBM receiving concurrent and adjuvant temozolomide.

Methods

The cohort study included 198 adult patients with newly diagnosed supratentorial GBM who were enrolled from 2004 to 2010 in 4 clinical trials consisting of radiation plus temozolomide and an experimental agent. The interval to initiation of therapy was determined from the time of surgical resection. The partitioning deletion/substitution/addition algorithm was used to determine the cutoff points for timing of chemoradiation at which there was a significant difference in overall survival (OS) and progression-free survival (PFS).

Results

The median wait time between surgery and initiation of concurrent chemoradiation was 29.5 days (range, 7-56 days). A short delay in chemoradiation administration (at 30-34 days) was predictive of prolonged OS (hazard ratio [HR]: 0.63, P = .03) and prolonged PFS (HR: 0.68, P = .06) compared with early initiation of concurrent chemoradiation (<30 days), after adjusting for protocol and baseline prognostic variables including extent of resection by multivariate analysis. A longer delay to chemoradiation beyond 34 days was not associated with improved OS or PFS compared with early initiation (HR: 0.94, P = .77 and HR: 0.91, P = .63, respectively).

Conclusion

A short delay in the start of concurrent chemoradiation is beyond the classic paradigm of 4 weeks post-resection and may be associated with prolonged OS and PFS.

Background

Currently, most basilar artery aneurysms (BAAs) are treated endovascularly. Surgery remains an appropriate therapy for a subset of all intracranial aneurysms. Whether open microsurgery would be required or utilized, and to what extent, for BAAs treated by a surgeon who performs both endovascular and open procedures has not been reported.

Methods

Retrospective analysis of prospectively maintained, single-surgeon series of BAAs treated with endovascular or open surgery from the first 5 years of practice.

Results

Forty-two procedures were performed in 34 patients to treat BAAs-including aneurysms arising from basilar artery apex, trunk, and perforators. Unruptured BAAs accounted for 35/42 cases (83.3%), and the mean aneurysm diameter was 8.4 ± 5.4 mm. Endovascular coiling-including stent-assisted coiling-accounted for 26/42 (61.9%) treatments and led to complete obliteration in 76.9% of cases. Four patients in the endovascular cohort required re-treatment. Surgical clip reconstruction accounted for 16/42 (38.1%) treatments and led to complete obliteration in 88.5% of cases. Good neurologic outcome (mRS ≤ 2) was achieved in 88.5% and 75.0% of patients in endovascular and open surgical cohorts, respectively (p = 0.40). Univariate logistic regression analysis demonstrated that advanced age (OR 1.11[95% CI 1.01-1.23]) or peri-procedural adverse event (OR 85.0 [95% CI 6.5-118.9]), but not treatment modality (OR 0.39[95% CI 0.08-2.04]), was the predictor of poor neurologic outcome.

Conclusions

Complementary implementation of both endovascular and open surgery facilitates individualized treatment planning of BAAs. By leveraging strengths of both techniques, equivalent clinical outcomes and technical proficiency may be achieved with both modalities.

OBJECTIVEBrain arteriovenous malformations (bAVMs) are rupture-prone tangles of blood vessels with direct shunting of blood flow between arterial and venous circulations. The molecular and/or cellular mechanisms contributing to bAVM pathogenesis and/or destabilization in sporadic lesions have remained elusive. Initial insights into AVM formation have been gained through models of genetic AVM syndromes. And while many studies have focused on endothelial cells, the contributions of other vascular cell types have yet to be systematically studied. Pericytes are multifunctional mural cells that regulate brain angiogenesis, blood-brain barrier integrity, and vascular stability. Here, the authors analyze the abundance of brain pericytes and their association with vascular changes in sporadic human AVMs.METHODSTissues from bAVMs and from temporal lobe specimens from patients with medically intractable epilepsy (nonvascular lesion controls [NVLCs]) were resected. Immunofluorescent staining with confocal microscopy was performed to quantify pericytes (platelet-derived growth factor receptor-beta [PDGFRβ] and aminopeptidase N [CD13]) and extravascular hemoglobin. Iron-positive hemosiderin deposits were quantified with Prussian blue staining. Syngo iFlow post-image processing was used to measure nidal blood flow on preintervention angiograms.RESULTSQuantitative immunofluorescent analysis demonstrated a 68% reduction in the vascular pericyte number in bAVMs compared with the number in NVLCs (p < 0.01). Additional analysis demonstrated 52% and 50% reductions in the vascular surface area covered by CD13- and PDGFRβ-positive pericyte cell processes, respectively, in bAVMs (p < 0.01). Reductions in pericyte coverage were statistically significantly greater in bAVMs with prior rupture (p < 0.05). Unruptured bAVMs had increased microhemorrhage, as evidenced by a 15.5-fold increase in extravascular hemoglobin compared with levels in NVLCs (p < 0.01). Within unruptured bAVM specimens, extravascular hemoglobin correlated negatively with pericyte coverage (CD13: r = -0.93, p < 0.01; PDGFRβ: r = -0.87, p < 0.01). A similar negative correlation was observed with pericyte coverage and Prussian blue-positive hemosiderin deposits (CD13: r = -0.90, p < 0.01; PDGFRβ: r = -0.86, p < 0.01). Pericyte coverage positively correlated with the mean transit time of blood flow or the time that circulating blood spends within the bAVM nidus (CD13: r = 0.60, p < 0.05; PDGFRβ: r = 0.63, p < 0.05). A greater reduction in pericyte coverage is therefore associated with a reduced mean transit time or faster rate of blood flow through the bAVM nidus. No correlations were observed with time to peak flow within feeding arteries or draining veins.CONCLUSIONSBrain pericyte number and coverage are reduced in sporadic bAVMs and are lowest in cases with prior rupture. In unruptured bAVMs, pericyte reductions correlate with the severity of microhemorrhage. A loss of pericytes also correlates with a faster rate of blood flow through the bAVM nidus. This suggests that pericytes are associated with and may contribute to vascular fragility and hemodynamic changes in bAVMs. Future studies in animal models are needed to better characterize the role of pericytes in AVM pathogenesis.

Objective

Brain arteriovenous malformations (AVMs) consist of dysplastic blood vessels with direct arteriovenous shunts that can hemorrhage spontaneously. In children, a higher lifetime hemorrhage risk must be balanced with treatment-related morbidity. The authors describe a collaborative, multimodal strategy resulting in effective and safe treatment of pediatric AVMs.

Methods

A retrospective analysis of a prospectively maintained database was performed in children with treated and nontreated pediatric AVMs at the University of California, San Francisco, from 1998 to 2017. Inclusion criteria were age ≤ 18 years at time of diagnosis and an AVM confirmed by a catheter angiogram.

Results

The authors evaluated 189 pediatric patients with AVMs over the study period, including 119 ruptured (63%) and 70 unruptured (37%) AVMs. The mean age at diagnosis was 11.6 ± 4.3 years. With respect to Spetzler-Martin (SM) grade, there were 38 (20.1%) grade I, 40 (21.2%) grade II, 62 (32.8%) grade III, 40 (21.2%) grade IV, and 9 (4.8%) grade V lesions. Six patients were managed conservatively, and 183 patients underwent treatment, including 120 resections, 82 stereotactic radiosurgery (SRS), and 37 endovascular embolizations. Forty-four of 49 (89.8%) high-grade AVMs (SM grade IV or V) were treated. Multiple treatment modalities were used in 29.5% of low-grade and 27.3% of high-grade AVMs. Complete angiographic obliteration was obtained in 73.4% of low-grade lesions (SM grade I-III) and in 45.2% of high-grade lesions. A periprocedural stroke occurred in a single patient (0.5%), and there was 1 treatment-related death. The mean clinical follow-up for the cohort was 4.1 ± 4.6 years, and 96.6% and 84.3% of patients neurologically improved or remained unchanged in the ruptured and unruptured AVM groups following treatment, respectively. There were 16 bleeding events following initiation of AVM treatment (annual rate: 0.02 events per person-year).

Conclusions

Coordinated multidisciplinary evaluation and individualized planning can result in safe and effective treatment of children with AVMs. In particular, it is possible to treat the majority of high-grade AVMs with an acceptable safety profile. Judicious use of multimodality therapy should be limited to appropriately selected patients after thorough team-based discussions to avoid additive morbidity. Future multicenter studies are required to better design predictive models to aid with patient selection for multimodal pediatric care, especially with high-grade AVMs.