Background Angiography shows that stereotactic radiosurgery obliterates most cerebral arteriovenous malformations after a latency period of a few years. However, the effect of this procedure on the risk of hemorrhage is poorly understood.

Methods We performed a retrospective observational study of 500 patients with malformations who were treated with radiosurgery with use of a gamma knife. The rates of hemorrhage were assessed during three periods: before radiosurgery, between radiosurgery and the angiographic documentation of obliteration of the malformation (latency period), and after angiographic obliteration.

Results Forty-two hemorrhages were documented before radiosurgery (median follow-up, 0.4 year), 23 during the latency period (median follow-up, 2.0 years), and 6 after obliteration (median follow-up, 5.4 years). As compared with the period between diagnosis and radiosurgery, the risk of hemorrhage decreased by 54 percent during the latency period and by 88 percent after obliteration. The risk was significantly reduced during the period after obliteration, as compared with the latency period (hazard ratio, 0.26; 95 percent confidence interval, 0.10 to 0.68; P=0.006). The reduction was greater among patients who presented with hemorrhage than among those without hemorrhage at presentation and similar in analyses that took into account the delay in confirming obliteration by means of angiography and analyses that excluded data obtained during the first year after diagnosis.

Conclusions Radiosurgery significantly decreases the risk of hemorrhage in patients with cerebral arteriovenous malformations, even before there is angiographic evidence of obliteration. The risk of hemorrhage is further reduced, although not eliminated, after obliteration.

Discussion

We found that the risk of hemorrhage from cerebral arteriovenous malformations was significantly decreased after radiosurgery, both during the latency period (between radiosurgery and angiographic obliteration) and after angiographic obliteration. Previous studies have reported that the risk of hemorrhage during the latency period decreases, remains unchanged, or even increases, as compared with the natural course of the disease. These studies tended to compare the risk of hemorrhage among selected patients who underwent radiosurgery with patients who did not undergo radiosurgery, whereas we analyzed changes in the rate of hemorrhage relative to the timing of radiosurgery in a large cohort of consecutive patients.

Most previous studies assumed that angiographic obliteration was the ultimate goal of radiosurgery, because hemorrhage was rare once obliteration was confirmed. Although recanalization of malformations can lead to hemorrhages after obliteration, this phenomenon was not observed in the six patients who had hemorrhage after obliteration in our study. We found that a small risk of hemorrhage remained after obliteration, although it was markedly lower than that before radiosurgery.

We did not address the mechanisms by which the risk of hemorrhage may be reduced. However, histopathological studies of arteriovenous malformations after radiosurgery suggest potential mechanisms. Progressive thickening of the intimal layer,which begins as early as three months after radiosurgery, appears to decrease the stress to the vessel walls. In addition, partial or complete thrombosis of the irradiated vessels may decrease the number of patent vessels in the malformation. In vessels with a decreased diameter, thickening of the endothelium may cause occlusion at a relatively early stage. When blood flow declines below the threshold of detection by angiography, malformations, in effect, become invisible (angiographic obliteration), although they may still be evident histologically.

Our study has some limitations. Because we did not include a control group of patients who did not undergo radiosurgery, one concern is whether the decrease in the risk of hemorrhage after radiosurgery reflects, at least in part, the natural history of malformations, rather than effects of the procedure itself. A natural decline in the rate of recurrent bleeding has been reported within one year after the rupture of arteriovenous malformations. Because the criteria for conservative management were not well described in previous reports of the natural history of ruptured malformations, it has remained unclear whether small malformations that can be effectively treated with radiosurgery have a similar natural decline in the rate of repeated hemorrhage. However, the Cox models we used accounted for the time since diagnosis. In addition, hemorrhage rates before radiosurgery in our cohort appeared stable over a period of more than three years after diagnosis, although the number of patients observed for longer periods before radiosurgery was limited. In addition, our results did not materially change in an analysis that excluded data obtained during the first year after diagnosis.

Another potential problem is the delay in confirming angiographic obliteration. The exact time of obliteration was not known but, instead, was inferred on the basis of findings on consecutive imaging studies. Angiography was initially carried out at six-month intervals; after 1993, less invasive imaging was performed every six months.  However, our results were materially unchanged after adjustment for a potential delay of six months in identifying obliteration. Although some patients had prior treatments, these treatments are not expected to have a delayed effect, and the results were more conservative when the period before these treatments was excluded. Because our clinical practice incorporates close follow-up of our patients according to standard schedules, the retrospective nature of our analysis should not pose a problem. The lack of blinding among those reviewing studies and judging outcomes is also acceptable, since obliteration and hemorrhage were diagnosed separately. There was some loss to follow-up, but the assignment of extreme outcomes to these patients also did not substantively affect the results of the analyses.

The gold standard for evaluating the effect of radiosurgery on the risk of hemorrhage would be a randomized trial comparing a group undergoing radiosurgery with a group receiving no treatment. However, this approach is not possible, because the beneficial effects of radiosurgery in terms of angiographic cure are well recognized and hemorrhage is rare after complete obliteration. The large size and close follow-up of our cohort made it well suited to an assessment of the outcomes of radiosurgery.

In conclusion, we found that the risk of hemorrhage from cerebral arteriovenous malformations was significantly reduced after stereotactic radiosurgery during the latency period (after radiosurgery and before angiographic obliteration) and that it was reduced even further after obliteration. However, a risk of hemorrhage remained even after malformations were no longer visible on imaging studies.