Pathogenesis and Radiobiology of Brain Arteriovenous Malformations: Implications for Risk Stratification in Natural History and Post-treatment Course

Achal S. Achrol, B.S.; Raphael Guzman, M.D.; Monika Varga, B.S.; John R. Adler, M.D.; Gary K. Steinberg, M.D.; Ph.D.; Steven D. Chang, M.D.


Neurosurg Focus. 2009;26(5):E9 

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Stereotactic Radiosurgery and Radiobiology of BAVMs

Current treatment options for BAVM focus on removal or obliteration of the lesion in an attempt to protect against future ICH risk. These options include microsurgical resection, endovascular embolization, and SRS. While microsurgical resection physically removes the nidus and endovascular embolization selectively occludes feeding arteries, neither treatment is mediated by the intrinsic vascular biology of the patient in its therapeutic effect. As such, SRS represents the only biological therapy for BAVM that avoids the need for invasive treatment. Obliteration is the hallmark of successful radiosurgical treatment of BAVM, and is defined by "complete absence of pathological vessels forming the AVM nidus, disappearance or normalization of veins draining the AVM, appearance of normal circulatory kinetics, and absence of visible arteriovenous shunt."[61]

Despite the widespread use of SRS in the management of BAVMs, the exact mechanism of radiosurgical obliteration remains poorly understood.[58] Available data regarding the biology of radiation-induced vascular obliteration result from observations in BAVM tissue resected after radiosurgical treatment[14,82] and in irradiated arteries in animal models.[8,49,70,77]

Observations from BAVM tissue[14,82] have suggested that damaged endothelial cells shrink, detach from neighboring endothelial cells and basement membrane, and permit platelet infiltration with deposition of fibrin and hyaline. As these endothelial cells slough off over time, inhibition of smooth muscle cell proliferation is lost, and smooth muscle cell migration into the subintimal layer results in collagen deposition that thickens the subintima and adventitia, progressively narrowing the lumen and eventually occluding it.

Study of irradiated arteries in animal models has suggested that the radiosensitivity of BAVMs originates in endothelial cells.[8,49,58,70,77] Failed mitosis of irradiated endothelial cells, damaged by direct interactions with irradiating electrons and indirect free-radical byproducts, results in eventual apoptosis[26] and initiation of radiationinduced arteriopathy. As such, it is believed that the latency period of BAVM obliteration after SRS is dependent on the turnover rate of endothelial cells, which typically ranges on the order of a couple of months to a couple of years, since initiation of the arteriopathy only manifests once endothelial cells attempt mitosis.[26,49,58] Currently, the major disadvantage of SRS is the latency period before a BAVM might successfully become obliterated, during which time the patient remains unprotected against risk of new ICH.[91] Widespread variation in patient response to SRS treatment of BAVMs may be the result of varying degrees of endothelial cell turnover, which is known to be abnormal in BAVMs.[38]

Important progress has recently been made in animal models of SRS-induced arteriopathy,[58] and it provides the basis for future studies in transgenic mice as to the role of genetic variation in modulating response to SRS. Future studies in patients with BAVMs will include proteomic analyses and gene expression profiling of peripheral blood cell populations, which may reflect indirect interactions from circulating through diseased tissue[84] as well as direct interactions in the pathophysiology of BAVM.[15,16,17,33,71] These peripheral blood cells could provide important biofeedback as to progression toward successful BAVM obliteration following initiation of SRS treatment. Such biomarkers of BAVM response to SRS could not only guide treatment planning but could identify novel targets for adjuvant therapies designed to promote obliteration after SRS.


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