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  • By Author: Lawton, Michael T. x
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Ethan A. Winkler, Harjus Birk, Jan-Karl Burkhardt, Xiaolin Chen, John K. Yue, Diana Guo, W. Caleb Rutledge, George F. Lasker, Carlene Partow, Tarik Tihan, Edward F. Chang, Hua Su, Helen Kim, Brian P. Walcott and Michael T. Lawton

OBJECTIVE

Brain 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.

METHODS

Tissues 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.

RESULTS

Quantitative 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.

CONCLUSIONS

Brain 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.

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Brian P. Walcott, Jae Seung Bang, Omar Choudhri, Sirin Gandhi, Halima Tabani, Arnau Benet and Michael T. Lawton

A 46-year-old male presented with an incidentally discovered left ventricular body arteriovenous malformation (AVM). It measured 2 cm in diameter and had drainage via an atrial vein into the internal cerebral vein (Spetzler-Martin Grade III, Supplementary Grade 4). Preoperative embolization of the posterior medial choroidal artery reduced nidus size by 50%. Subsequently, he underwent a right-sided craniotomy for a contralateral transcallosal approach to resect the AVM. This case demonstrates strategic circumferential disconnection of feeding arteries (FAs) to the nidus, the use of aneurysm clips to control large FAs, and the use of dynamic retraction and importance of a generous callosotomy. Postoperatively, he was neurologically intact, and angiogram confirmed complete resection.

The video can be found here: https://youtu.be/j0778LfS3MI.

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W. Caleb Rutledge, Omar Choudhri, Brian P. Walcott, Arnau Benet, Christine K. Fox, Nalin Gupta and Michael T. Lawton

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.