Introduction
The most devastating presentation associated with arteriovenous malformations (AVMs) of the brain is intracerebral hemorrhage. Numerous natural history studies have demonstrated a substantial (3% to 4% per year) risk of hemorrhage in patients harboring AVMs [1-5]. Several treatment modalities (microsurgery, radiosurgery, or endovascular therapy) are available that may eliminate the lesion before a hemorrhage can occur—or recur, in the case of a hemorrhagic presentation. When an AVM is amenable to safe micro-surgical resection, this therapy is preferred because it offers immediate cure and elimination of hemorrhage risk. When the surgical morbidity is judged to be excessive, radiosurgery offers a reasonable expectation of delayed cure.
When an AVM is treated with radiosurgery a pathologic process appears to be induced that is similar to the response-to-injury model of atherosclerosis. Radiation injury to the vascular endothelium is believed to induce the proliferation of smooth-muscle cells and the elaboration of extracellular collagen. This leads to progressive stenosis and obliteration of the AVM nidus (Fig. 1) [6-10], thereby eliminating the risk of hemorrhage.
The advantages of radiosurgery—compared to microsurgical and en-dovascular treatments—are that it is noninvasive, has minimal risk of acute complications, and is performed as an outpatient procedure requiring no recovery time for the patient. The primary disadvantage of radiosurgery is that cure is not immediate. Thrombosis of the lesion is achieved in the majority of cases, but it commonly does not occur until 2 or 3 years after treatment. During the interval between radiosurgical treatment and AVM thrombosis, the risk of hemorrhage remains. Another potential disadvantage of radiosurgery is possible long-term adverse effects of radiation. Finally, radiosurgery has been shown to be much less effective for lesions over 10 cc in volume. For these reasons, selection of an appropriate treatment modality depends on multiple variables, including perceived risks of surgery and predicted lielihood of hemorrhage for a given patient.
Figure 1 Before and after radiosurgery for arteriovenous malformation (AVM). A, This patient received 17.5 Gy to the margin of the nidus of this left frontotemporal AVM. B, On follow-up angiography 3 years later, the lesion has been completely obliterated.
AVM RADIOSURGERY TECHNIQUE
The technical methods of radiosurgery have been described at length in other publications [11], but a brief description of radiosurgical techniques that apply specifically to AVM treatment is in order. The fundamental elements of any successful radiosurgical treatment include the following: patient selection, head ring application, stereotactic image acquisition, treatment planning, dose selection, radiation delivery and follow-up. All of these elements are critical, and poor performance of any step will result in suboptimal results.
Patient Selection
Open surgery is generally favored if an AVM is amenable to low-risk resection (e.g., low Spetzler-Martin grade, young healthy patient) or is felt to be at high risk for hemorrhage during the latency period between radiosurg-ical treatment and AVM obliteration (e.g., associated aneurysm, prior hemorrhage, large AVM with diffuse morphology, venous outflow obstruction).
Radiosurgery is favored when the AVM nidus is small (<3 cm) and compact, when surgery is judged to carry a high risk or is refused by the patient, or when the risk of hemorrhage is not felt to be extraordinarily high.
Endovascular treatment, although rarely curative alone, may be useful as a preoperative adjunct to either microsurgery or radiosurgery.
The history, physical examination, and diagnostic imaging of each patient are evaluated, and the various factors outlined above are weighed in combination to determine the best treatment approach for a given case.
Head Ring Application
The techniques for optimal head ring application for AVM radiosurgery are no different from those for other target lesions, and are described in detail elsewhere [11].
Stereotactic Image Acquisition
The most problematic aspect of AVM radiosurgery is target identification. In some series (see below), targeting error is listed as the most frequent cause of radiosurgical failure. The problem lies with imaging. Angiography very effectively defines blood flow (feeding arteries, nidus, and draining veins), however, it does so in only two dimensions. Using the two-dimensional data from stereotactic angiography to represent the three-dimensional target results in significant errors of both overestimation and underestimation of AVM nidus dimensions [12,13]. Underestimation of the nidus size may result in treatment failure, whereas overestimation results in the inclusion of normal brain within the treatment volume. This can cause radiation damage to normal brain, which, when affecting an eloquent area, may result in a neurological deficit. To avoid such targeting errors, a true three-dimensional image database is required. Both contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used for this purpose.
Diagnostic (nonstereotactic) angiography is used to characterize the AVM, but because of its inherent inadequacies as a treatment planning database, stereotactic angiography has been largely abandoned at our institution. We use contrast-enhanced stereotactic CT as a targeting image database for the vast majority of AVMs. Our CT technique uses rapid infusion (1 cc/ sec) of contrast while scanning through the AVM nidus with 1-mm slices. The head ring is bolted to a bracket at the head of the CT table, assuring that the head/ring/localizer complex remains immobile during the scan. This technique yields a very clear three-dimensional picture of the nidus. Alternative approaches use MRI/MRA, as opposed to CT. Attention to optimal image sequences in both CT and MRI is essential for effective AVM radio-surgical targeting.
Treatment Planning
The primary goal of AVM radiosurgery treatment planning is to develop a plan with a target volume that conforms closely to the surface of the AVM nidus while maintaining a steep dose gradient (the rate of change in dose relative to position) away from the nidal surface to minimize the radiation dose to surrounding brain. A number of treatment planning tools can be used to tailor the shape of the target volume to fit even highly irregular nidus shapes. Regardless of its shape, the entire nidus, not including the feeding arteries and draining veins, must lie within the target volume (the ”prescription isodose shell”), with as little normal brain included as possible (Fig. 2).
Another goal of dose planning is to manipulate the dose gradient so that critical brain structures receive the lowest possible dose of radiation, to avoid disabling complications. In addition, many radiosurgeons strive to produce a treatment dose distribution that maximizes uniformity (homogeneity) of dose throughout the entire target volume. A detailed discussion of the methodology of dose planning is beyond the scope of this topic, but can be found elsewhere [11].
Dose Selection
Various analyses of AVM radiosurgery outcomes (described below) have elucidated an appropriate range of doses for the treatment of AVMs. Minimum nidal doses lower than 15 Gy have been associated with a significantly lower rate of AVM obliteration, whereas doses above 20 Gy have been associated with a higher rate of permanent neurological complications. We prescribe doses ranging from 15 Gy to as high as 22.5 Gy to the margin of the AVM nidus, nearly always at the 70% or 80% isodose line. The selection of a dose within this range is made based on the volume of the nidus, as well as the eloquence and radiosensitivity of surrounding brain structures. Lower doses are prescribed for larger lesions and lesions in eloquent areas.
Radiation Delivery
The process of radiation delivery is the same for any radiosurgical target, but careful attention to detail and the execution of various safety checks and redundancies are necessary to ensure that the prescribed treatment plan is accurately and safely delivered [11]. When radiation delivery has been completed, the head ring is removed, the patient is observed for approximately 30 minutes, and then discharged to resume her/his normal activities.
Follow-up
Standard follow-up after AVM radiosurgery typically consists of annual clinic visits with MRI/MRA to evaluate the effect of the procedure and monitor for neurological complications. If the patient’s clinical status changes, she/he is followed more closely at clinically appropriate intervals.
Each patient is scheduled to undergo cerebral angiography at three years postradiosurgery, and a definitive assessment of the success or failure of treatment is made based on the results of angiography (see below). If no flow is observed through the AVM nidus, the patient is pronounced cured and is discharged from follow-up. If the AVM nidus is incompletely obliterated, appropriate further therapy (most commonly repeat radiosurgery on the day of angiography) is prescribed, and the treatment/follow-up cycle is repeated.
REPORTED EFFICACY OF AVM RADIOSURGERY
Many series have evaluated rates of AVM thrombosis after radiosurgery [10,14-29]. Overall reported rates of successful angiographic AVM obliteration range from 56% to 92% (Table 1). The rate of obliteration is strongly correlated with AVM size. For example, among the 153 AVM radiosurgery patients who have undergone 3-year follow-up angiography at the University of Florida, rates of angiographic cure according to AVM volume were as follows: < 1 cc—82%; 1-4 cc—81%; 4-10 cc—73%; > 10 cc—42%. Similar trends have been reported by most groups [14,15,20,24].
Figure 2 Treatment plan, contrast-enhanced computed tomography (CT). This 43-year-old male presented with seizures and refused surgical intervention in favor of radiosurgery. His treatment plan, based on a contrast-enhanced CT database, is shown here (A, Axial; B, Sagittal; C, Coronal). Note the conformality of the innermost (70%) isodose line to the arteriovenous malformation (AVM) nidus in all planes. The 35% and 14% isodose lines are also shown. This 7-isocenter plan delivered 15.0 Gy to the 70% isodose shell. The total AVM nidus volume treated was 12 cc.
WHY DOES RADIOSURGERY FAIL?
Synthesis of the published studies addressing etiologies of AVM radiosurg-ical failure [17,21,30-33] leads to several useful conclusions. The dose delivered to the periphery of the AVM (Dmin) is the most significant predictor of successful obliteration, provided that the nidus is completely encompassed by the prescription isodose shell (targeting error is an important cause of failure and is commonly caused by inadequate imaging/angiography). Large lesion volume and high Spetzler-Martin grade are also predictors of failure, although less significant than Dmin. The importance of AVM location and patient age are unclear. Based on our experience [30], lower rates of AVM obliteration can be expected at peripheral doses below 15 Gy and for lesion volumes greater than 10 cc.
Figure 2 Treatment plan, contrast-enhanced computed tomography (CT). This 43-year-old male presented with seizures and refused surgical intervention in favor of radiosurgery. His treatment plan, based on a contrast-enhanced CT database, is shown here (A, Axial; B, Sagittal; C, Coronal). Note the conformality of the innermost (70%) isodose line to the arteriovenous malformation (AVM) nidus in all planes. The 35% and 14% isodose lines are also shown. This 7-isocenter plan delivered 15.0 Gy to the 70% isodose shell. The total AVM nidus volume treated was 12 cc.
Table 1 Major AVM Radiosurgery Series
|
First author |
Yamamoto (28) |
Pollock (21) |
Karlsson (17) |
Steinberg (24) |
Colombo (16) |
Friedman |
|
Radiosurgical device |
Gamma Knife |
Gamma Knife |
Gamma Knife |
Proton beam |
LINAC |
LINAC |
|
Number of patients |
40 |
313 |
945 |
86 |
180 |
407 |
|
Angiographic cure rate |
65% |
61% |
56% |
92% |
80% |
65% |
|
Complications Permanent radiation induced |
3 patients (7.5%) |
30 patients (9%) |
5% |
11% |
4 patients (2%) |
7 patients (2%) |
|
Hemorrhage |
None |
8 fatal |
55 patients |
10 patients |
15 patients, 5 fatal |
26 patients, 5 fatal |
When a group had multiple reports, the most recent results are listed. AVM, Arteriovenous malformation.
Complications
Hemorrhage after Radiosurgery
The issue of AVM hemorrhage after radiosurgical treatment has been examined by several groups [14,16,20,22,24,34-38]. It has been reported that radiosurgery decreases the risk of hemorrhage even with incomplete AVM obliteration [34]; however, most reports have shown no postradiosurgical alteration in bleeding risk [39,40] from the 3% to 4% per year expected based on natural history [1-5]. This suggests that radiosurgery offers no protective effect unless complete obliteration is achieved.
Several groups have reported an increased risk of AVM hemorrhage with increasing AVM size or subtotal irradiation [16,34,39]. In our series [39], a strong correlation between AVM volume and the risk of hemorrhage was also found. Ten of the 12 AVMs that bled were more than 10 cc in volume. It is also noteworthy that in this study, neither age nor history of prior hemorrhage correlated with the incidence of hemorrhage.
Ten of the 12 AVMs that bled also had associated "angiographic risk factors” for bleeding, including arterial aneurysms, venous aneurysms, venous outlet obstruction, and periventricular location. Pollock et al. [40] found a significant correlation between the incidence of postradiosurgical hemorrhage and presence of an unsecured proximal aneurysm and recommended that such aneurysms be obliterated before radiosurgery.
The Pittsburgh group [41] also recently studied factors associated with bleeding risk of AVMs and found three AVM characteristics to be predictive of greater hemorrhage risk: (1) history of prior bleed, (2) presence of a single draining vein, and (3) diffuse AVM morphology. Based on the presence or absence of these risk factors, they stratified AVM patients into hemorrhage risk groups and recommended that predicted hemorrhage risk be used to help determine appropriate management of patients with AVMs. For example, patients with a high predicted hemorrhage risk would be considered less attractive candidates for radiosurgery because of their greater risk during the latency period between treatment and cure.
Radiation-Induced Complications
Acute complications are rare after AVM radiosurgery. Several authors have previously reported that radiosurgery can acutely exacerbate seizure activity. Others have reported nausea, vomiting, and headache occasionally occurring after radiosurgical treatment [42].
Delayed radiation-induced complications have been reported by all groups performing radiosurgery. Observed rates of permanent postradiosurg-ical neurological deficit range from 2% to 4%, and transient deficits have been observed in 3% to 9% of patients [20,25,43,44]. Symptoms are location dependent and generally develop between 3 and 18 months after treatment. Symptomatic patients are commonly treated with a several-week course of oral steroids, and nearly all improve. The use of peripheral doses greater than 20 Gy have been associated with a higher frequency of permanent neurological deficits [43].
In addition to the well-established correlation between increasing ra-diosurgical target volume and increasing incidence of radiation necrosis [36,45-47], the most important predictors of symptomatic radiation injury are lesion location and dose [24,43,48]. Radiation induced changes appear frequently (20% in the Pittsburgh series) on postradiosurgery MR images [49-51]. These changes tend to be asymptomatic if the lesion is located in a relatively "silent” brain area and symptomatic if the lesion is located in an "eloquent" brain area. This is further evidence that lesion location is an important consideration in radiosurgical treatment planning and dose selection [45].
CONCLUSIONS
Many reports indicate that approximately 80% of arteriovenous malformations in the "radiosurgery size range” will be angiographically obliterated 2 to 3 years after radiosurgical treatment. The likelihood of successful AVM obliteration decreases with increasing lesion volume and decreasing peripheral target dose. Accurate targeting is critical to successful AVM radiosur-gery, and a three-dimensional image database (e.g., CT or MRI) is an indispensable element in the treatment planning process. Stereotactic angiography alone is inadequate.
The major drawback of this treatment method is that patients are unprotected against hemorrhage during the 2- to 3-year latent period after treatment. Radiosurgery does not significantly alter the natural rate of AVM hemorrhage until the lesion has completely thrombosed. Increasing AVM volume appears to be associated with a higher risk for hemorrhage, as are certain angiographic findings such as proximal aneurysms, venous outflow restriction, and periventricular location.
Radiation-induced neurological symptoms occur in 5% to 10% of patients, but the majority of these are transient, responding to steroid therapy. Permanent complications are rare (2% to 4%). The most significant predictors of radiation-induced complications are AVM volume, lesion location, and dose. Asymptomatic MRI changes are not uncommon.
