Xiaolin Chen

Morbidity after Hemorrhage in Children with Untreated Brain Arteriovenous Malformation

Background: Children with untreated brain arteriovenous malformations (bAVM) are at risk of encountering life-threatening hemorrhage very early in their lives. The primary aim of invasive treatment is to reduce unfavorable outcome associated with a bAVM rupture. A better understanding of the morbidity of bAVM hemorrhage might be helpful for weighing the risks of untreated bAVM and invasive treatment. Our aim was to assess the clinical outcome after bAVM rupture and identify features to predict severe hemorrhage in children. Methods: We identified all consecutive children admitted to our institution for bAVMs between July 2009 and December 2014. Clinical outcome after hemorrhagic presentation and subsequent hemorrhage was evaluated using the modified Rankin Scale (mRS) for children. The association of demographic characteristics and bAVM morphology with severe hemorrhage (mRS >3 or requiring emergency hematoma evacuation) was studied using univariate and multivariable regression analyses. A nomogram based on multivariable analysis was formulated to predict severe hemorrhage risk for individual patients. Results: A total of 134 patients were identified with a mean treatment-free follow-up period of 2.1 years. bAVM ruptured in 83 (62%) children: 82 had a hemorrhage at presentation and 6 of them experienced a recurrent hemorrhage during follow-up; 1 patient had other diagnostic symptoms but bled during follow-up. Among them, 49% (41/83) had a severe hemorrhage; emergency hematoma evacuation was required in 28% of them (23/83), and 24% (20/83) remained as disabled (mRS ≥3) at last follow-up. Forty-six percent (38/82) of children with hemorrhagic presentation were severely disabled (mRS >3). Forty-three percent (3/7) were severely disabled after subsequent hemorrhage. The annual rate of severe subsequent hemorrhage was 1% in the overall cohort and 3.3% in children with ruptured presentation. All the subsequent severe hemorrhage events occurred in children with severe hemorrhage history (7%, 3/41). Periventricular location, non-temporal lobe location, and long draining vein were predictors for severe hemorrhage in pediatric untreated bAVMs. A nomogram based on bAVM morphology was contracted to predict severe hemorrhage risk for individual patients, which was well calibrated and had a good discriminative ability (adjusted C-statistic, 0.72). Conclusions: Evaluating bAVM morbidity and morphology might be helpful for weighing the risks of untreated bAVM in pediatric patients.

Reductions in brain pericytes are associated with arteriovenous malformation vascular instability

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.

Higher Flow Is Present in Unruptured Arteriovenous Malformations With Silent Intralesional Microhemorrhages

Background and Purpose— Silent microhemorrhage (hemosiderin) has been observed in resected brain arteriovenous malformations (bAVM) tissue and may represent a subgroup at increased risk for clinical hemorrhage. Previous studies suggest that ruptured bAVMs have faster flow and shorter mean transit time of contrast in blood vessels than unruptured bAVMs. We hypothesized that flow would be faster in unruptured AVMs with hemosiderin compared with those without hemosiderin. Methods— We selected unruptured, supratentorial bAVMs >3.5 cc with pathology specimens. Hemodynamic features were evaluated using color-coding angiography, including contrast mean transit time of AVM nidus, time to peak (TTP) of feeding artery (FA) and draining vein (DV), and the ratio (TTP DV/FA). Characteristics of 9 cases with hemosiderin and 16 without hemosiderin were compared using 2-sample t tests and Fisher exact tests. Results— No difference in FA TTP and DV TTP was observed between groups. However, cases with hemosiderin had significantly shorter mean transit time compared with those without hemosiderin (1.11±0.28 versus 1.64±0.55 seconds; P=0.013) and a lower ratio of DV TTP/FA TTP (1.48±0.32 versus 1.94±0.61; P=0.045). Presence of venous varix was significantly associated with hemosiderin (P=0.003). No other clinical or angioarchitectural factors were associated with hemosiderin. Conclusions— Shorter mean transit time through the AVM nidus, lower DV TTP/FA TTP, and the high prevalence of venous varices suggests that high flow is an important feature of unruptured bAVMs with hemosiderin.

Three-dimensional intracranial middle cerebral artery aneurysm models for aneurysm surgery and training.

To develop a realistic model of middle cerebral artery (MCA) aneurysms using three-dimensional (3D) printing for surgical planning, research, and training of neurosurgical residents. This study included eight MCA aneurysm cases. The aneurysm together with the adjacent arteries and skull base were printed based on raw computed tomography angiography (CTA) data using a 3D printer with acrylonitrile-butadiene-styrene as the model material. The aneurysm models were used for surgical planning, and craniotomy and clipping practice by neurosurgical residents. Feedback was obtained using a survey. 3D aneurysm models were created for all seven MCA aneurysm patients. There was good agreement in the model aneurysm diameter, width, and neck and the CTA data, with no significant difference (p > 0.05) among the groups. The simulator was useful for choosing the clips to use before surgery. The average response to each of the survey questions was greater than 3.85 (range 3.0-5.0) on a five-point scale. The 3D printed MCA aneurysm models were accurate. Simulation and practice using the 3D models was useful for understanding the aneurysm structure and choosing the clips to use before surgery, especially for junior neurosurgeons.

Procedure for the Isolation of Endothelial Cells from Human Cerebral Arteriovenous Malformation (cAVM) Tissues

In this study, we successfully established a stable method for the isolation of endothelial cells (ECs) from human cerebral arteriovenous malformation (cAVM) tissues. Despite human cAVM tissues having a minor population of ECs, they play an important role in the manifestation and development of cAVM as well as in hemorrhagic stroke and thrombogenesis. To characterize and understand the biology of ECs in human cAVM (cAVM-ECs), methods for the isolation and purification of these cells are necessary. We have developed this method to reliably obtain pure populations of ECs from cAVMs. To obtain pure cell populations, cAVM tissues were mechanically and enzymatically digested and the resulting single cAVM-ECs suspensions were then labeled with antibodies of specific cell antigens and selected by flow cytometry. Purified ECs were detected using specific makers of ECs by immunostaining and used to study different cellular mechanisms. Compared to the different methods of isolating ECs from tissues, we could isolate ECs from cAVMs confidently, and the numbers of cAVM-ECs harvested were almost similar to the amounts present in vessel components. In addition to optimizing the protocol for isolation of ECs from human cAVM tissues, the protocol could also be applied to isolate ECs from other human neurovascular-diseased tissues. Depending on the tissues, the whole procedure could be completed in about 20 days.