Natural History

The natural history of AVMs is summarized in this section. For a comprehensive review of the natural history of AVMs, the reader is referred to Chapter 384.

Large, prospective population-based studies have determined the incidence of newly diagnosed AVM to range from 1.12 to 1.34 per 100,000 person-years.^2,3 The number of incidentally discovered intracranial AVMs continues to rise as more patients undergo magnetic resonance imaging (MRI) of the head. The annual risk for ICH from AVMs has been reported to be 2% to 4%^4–11; the combined annual morbidity plus mortality from intracranial AVMs is approximately 1%.⁹ The majority of AVMs are diagnosed at a point when patients’ life expectancy is long, so the cumulative risk for hemorrhage is often significant. The factor associated with the greatest increased risk for bleeding is previous hemorrhage.^10,11 The estimated risk for rebleeding from intracranial AVMs is thought to be elevated in the first months after an ICH. Additional factors that have been correlated with AVM hemorrhage include increasing age,¹² single or deep draining veins,^10,11 associated arterial aneurysm,¹³ and diffuse AVM morphology.¹¹ Pediatric patients,¹⁴ patients with deeply located AVMs (basal ganglia, thalamus, brainstem, cerebellum),^10,11 and patients with small AVMs¹⁵ are more frequently first seen after an ICH. It remains unclear whether these patients truly have an increased annual risk for hemorrhage or whether they are just unlikely to have other symptoms that would permit the diagnosis.

Management of Arteriovenous Malformations

The definitive treatment options available for patients with intracranial AVMs are surgical resection and stereotactic radiosurgery. Patients with a large ICH require urgent surgical evacuation to eliminate the mass effect. Once the blood clot has been removed, cerebral angiography can be performed to determine a best plan for the residual nidus. Surgical resection is the preferred treatment of patients after a recent ICH if the nidus is accessible.^16–22 The benefit of surgical resection versus radiosurgery is the immediate elimination of future hemorrhage risk. Embolization of AVMs is frequently performed in conjunction with either surgical resection or radiosurgery, but it is rarely curative by itself. Alternatively, fractionated radiation therapy is rarely performed because it results in a low AVM cure rate²³ and the optimal dose fraction schedule has not been determined.²⁴

In 1972, Ladislau Steiner and colleagues recognized that single-fraction, high-dose irradiation causes progressive obliteration of AVMs and subsequent cure from the risk for later hemorrhage.²⁵ Based on the fact that AVMs could be visualized with angiography before the development of axial imaging, AVMs were a common early indication for radiosurgery: 27% (n = 204) of the first 762 patients who underwent Gamma Knife radiosurgery at the Karolinska Institute had AVMs.²⁶ Concurrent with findings from the Karolinska Institute, Kjellberg and Fabrikant were using heavy charged particles instead of photons to irradiate AVMs.^27,28 These pioneers also noted that focused radiation techniques could obliterate a high percentage of irradiated AVMs. Later studies showed that AVM radiosurgery could be performed successfully with modified linear accelerators (LINACs).^29–31

If the risk associated with treatment is determined to be greater than the lifetime risk based on the natural history of untreated AVMs, observation alone is a reasonable management option. This is especially applicable for older patients with incidentally discovered AVMs. Despite technologic advances, it is recognized that the risk related to treatment in patients with Spetzler-Martin grade IV and V AVMs is substantial, so observation of large AVMs is often recommended unless the patient has bled or is suffering from a progressive neurological deficit.³² Recently, recognition of two factors has led to a re-examination of observation for patients discovered to have smaller, unruptured brain AVMs.³³ First, the morbidity associated with AVM bleeding may be less than previously thought. Hartmann and colleagues reviewed 119 AVM patients and found that 47% suffered no disability related to their first ICH and an additional 37% remained independent in activities of daily living.³⁴ Second, the incidence of neurological injury related to surgical resection of AVMs may be greater than previously described. A prospective observation study of 124 AVM patients noted that at last follow-up, 38% had new postoperative neurological deficits.³⁵ Of these patients, 6% were disabled after surgery. Likewise, Lawton and associates found that patients with unruptured AVMs were 2.3 times more likely to experience a decline in their modified Rankin scale score than were patients with ruptured AVMs.³⁶ Future studies on AVM management must carefully consider the risk-benefit ratio associated with the treatment of patents with unruptured AVMs.

Patient Selection

Proper patient selection is essential for successful AVM radiosurgery. In particular, a number of factors must be considered when discussing radiosurgery for AVM, including age, signs and symptoms, AVM size, and AVM location. As mentioned before, patients with a recent ICH and a surgically accessible AVM are best managed by surgical resection. However, patients with a recent hemorrhage and a surgically inaccessible AVM are generally good candidates for radiosurgery, assuming that the AVM is not too large. Moreover, patients with a distant hemorrhage should be considered for radiosurgery because they have passed the time when rehemorrhage is most likely to occur. For individual patients, a comparison of the chance of surgical resection or radiosurgery eliminating AVMs without risk for new deficits should be undertaken. Standardized scales such as the Spetzler-Martin grade¹⁶ and the Pollock-Flickinger score³⁷ can be used to estimate the efficacy of surgical resection and radiosurgery, respectively, for individual AVM patients.

A previous history of seizures can also affect management decisions for patients with AVMs. Although between 15% and 20% of AVM patients will have a seizure,^3,26,38 few patients have medically resistant epilepsy. In addition, few AVM studies have used standardized scales in reporting epilepsy outcomes. Piepgras and coworkers studied seizure outcomes after AVM surgery.³⁹ In the low-seizure group (less than four seizures before surgery) with a follow-up longer than 2 years, 93% were seizure free, 2% improved but continued to have seizures, and 5% had worsening of their seizures. In comparison, 76% of patients with more than four seizures preoperatively were without seizures 2 or more years after surgery, 21% were improved, and 3% remained unchanged. Overall, 83% of patients remained seizure free at last follow-up in this study. Schäuble and coauthors retrospectively reviewed 65 AVM patients with one or more seizures who underwent radiosurgery between 1990 and 1998.⁴⁰ Forty patients (78%) had an excellent outcome (nondisabling simple partial seizures only) at 3-year follow-up; 26 patients (51%) were seizure free. Factors associated with seizure-free outcomes included a low seizure frequency score (<4) before radiosurgery and smaller AVM size. Eleven of 18 (61%) patients with medically intractable partial epilepsy had excellent outcomes 3 years after radiosurgery. Hoh and colleagues reviewed 110 patients with seizures who underwent AVM treatment.⁴¹ Patients with a short seizure history, seizures related to an ICH, surgical resection, and complete AVM obliteration were more likely to have Engel class I outcomes. However, selection bias with regard to the different treatments prevents any meaningful conclusion whether surgical resection or radiosurgery correlates with improved seizure outcomes.

Technique of Radiosurgery for Arteriovenous Malformations

The goal of stereotactic radiosurgery is to accurately deliver a high dose of radiation to an imaging-defined target. To accomplish this goal in a single fraction, placement of a stereotactic head frame is needed to ensure rigid fixation and minimize patient movement during imaging and delivery of radiation. Head frame placement for adults is performed under local anesthesia supplemented with a low dose of a benzodiazepine. General anesthesia is typically required for patients younger than 16 years. After the head frame has been placed, patients undergo either gadolinium-enhanced MRI or contrast-enhanced computed tomography in addition to cerebral angiography. Reliance on angiography alone for radiosurgical dose planning increases the chance of treating too much adjacent normal brain tissue because of the often irregular shape of AVMs.^42,43 In addition, AVMs in selected locations (posterior fossa, lateral temporal regions) are difficult to clearly visualize on angiography, so the chance of not including a portion of the nidus in the prescription isodose volume (PIV) is increased. More recently, we have become increasingly confident in excluding cerebral angiography for AVM dose planning. Ideal patients for this approach have small, compact, hemispheric AVMs with simple venous drainage. In our current practice, approximately 20% of AVM patients undergo radiosurgery based on MRI alone. However, we continue to perform complete diagnostic angiography, including appropriate external carotid injections, before any decision is made about the feasibility of radiosurgery and to determine whether the patient has any associated aneurysms.

The goal of dose planning is to completely cover the three-dimensional shape of the nidus and exclude adjacent brain parenchyma. Feeding arteries and draining veins are not included in the dose plan if possible. Inclusion of these vessels increases the PIV and may result in a lower radiation dose. Dose prescription must take into account two conflicting considerations: the chance of obliteration versus the chance of radiation-related complications. Higher radiation doses directly correlate with the chance of obliteration. Assuming that the nidus is completely covered, the chance of AVM cure is approximately 70%, 80%, and 90% for radiation doses of 16, 18, and 20 Gy, respectively.^44,45 However, the likelihood of radiation-related complications after AVM radiosurgery increases at higher radiation doses and with larger AVM volumes. Dose prescription for AVM radiosurgery has traditionally followed either Kjellberg’s 3% isodose line²⁷ or Flickinger’s integrated logistic formula⁴⁶ to predict the probability of radiation-related complications. Recent studies have correlated the chance of radiation-related complications after AVM radiosurgery to some measure (10-Gy volume, 12-Gy volume) of irradiation of the surrounding brain.^47–49 Patients with deeply located AVMs are more likely to exhibit neurological deficits as a result of the changes noted on MRI.⁴⁷ The prescribed radiation dose is typically reduced for patients undergoing AVM radiosurgery to minimize the chance for radiation-related complications.

Patients undergo radiation therapy after the dose plan is reviewed by all members of the radiosurgical team. After radiation delivery, patients are discharged home either the day of the procedure or after an overnight observation period. Immediate complications are rare, but some patients complain of pin site discomfort, neck pain, or headache. Such symptoms are usually temporary and can be managed with over-the-counter medications. Follow-up after radiosurgery consists of clinical examination and MRI at 1, 2, and 3 years after radiosurgery. If MRI suggests that the AVM has been completely obliterated, follow-up angiography is recommended 3 or more years after radiosurgery to definitively determine the status of the AVM.⁵⁰ Patients with residual AVM on follow-up angiography are evaluated for repeat radiosurgery or surgical resection based on their age, clinical condition, and response of the AVM to the first radiosurgical procedure.

Obliteration of Arteriovenous Malformations after Radiosurgery

The goal of AVM radiosurgery is complete nidus obliteration to eliminate a patient’s risk for future hemorrhage. Generally, AVM obliteration after radiosurgery requires between 1 and 5 years. Histopathologic changes after AVM radiosurgery include damage to endothelial cells, progressive thickening of the intimal layer secondary to proliferation of smooth muscle cells (which produces an extracellular matrix containing type IV collagen), and then cellular degeneration and hyaline transformation.⁵¹ Electron microscopic studies of seven AVMs resected after bleeding 10 to 52 months after radiosurgery revealed spindle cell proliferation in the connective tissue stroma and subendothelial region of irradiated vessels.⁵² The characteristics of the spindle cells were similar to those of myofibroblasts noted during wound healing, and these cells probably contributed to the occlusive process and obliteration of AVMs after radiosurgery.

The AVM margin dose is the most important factor associated with obliteration after radiosurgery.^{44,45,53–55} Several models have been developed to predict the chance for cure of AVMs after radiosurgery. Karlsson and coauthors reported the K index as a method to predict obliteration after AVM radiosurgery.⁴⁵ Analysis of 945 AVM patients who underwent radiosurgery from 1970 to 1990 showed a logarithmic relationship between minimum dose and AVM obliteration: the product minimum dose (AVM volume) × was termed the K index, and it increased to a maximum of 87%. The obliteration rate increased linearly with the K index up to a value of approximately 27, and for higher K index values, the obliteration rate had a constant value of approximately 80%. For the group of patients receiving an AVM margin dose of 25 Gy or greater, the obliteration rate at 2 years was 80%. Higher average doses also shortened the latency to AVM obliteration. Schwartz and colleagues developed the obliteration prediction index as a method to predict success or failure after AVM radiosurgery.⁵⁶ By analyzing patients who underwent either Gamma Knife or LINAC-based radiosurgery, a relationship was noted between the obliteration prediction index (AVM margin dose, Gy per lesion diameter in centimeters) and AVM obliteration. A number of papers have analyzed factors associated with incomplete AVM obliteration after radiosurgery.^57–60 Common reasons for incomplete obliteration of the nidus are targeting errors, recanalization of a portion of the AVM that was previously embolized, reexpansion of the nidus after hemorrhage, and low radiation dose. These studies have emphasized the need for complete nidus coverage at the time of radiosurgery. Nonetheless, part of the problem in AVM radiosurgery is defining the nidus accurately. Buis and coworkers had six independent clinicians contour the nidus of AVMs based on digital subtraction angiography.⁶¹ They noted significant interobserver variation when outlining the nidus and concluded that such variation may contribute to failure in some AVM radiosurgical cases. Yu and associates compared AVM dose plans based on a combination of angiography and MRI with those based on MRI alone.⁶² They concluded that AVM dose planning without angiography should be limited to patients with smaller AVMs and compact niduses. A recent study from the University of Florida suggested that AVM morphology is also an important factor associated with obliteration.⁶³ Specifically, they noted that patients with a diffuse nidus structure and associated neovascularity were at a higher risk for incomplete nidus obliteration than were patients with compact AVMs.

Bleeding of Arteriovenous Malformations after Radiosurgery

The primary drawback of AVM radiosurgery is that patients remain at risk for hemorrhage until the AVM has eventually been completely obliterated. Despite early papers on AVM radiosurgery suggesting increased risk for bleeding before documented obliteration of AVMs,^30,64 later, more detailed analyses of this topic have concluded that the risk for AVM bleeding is either unchanged or reduced during this latency interval.^65–69 Karlsson and colleagues analyzed the large AVM experience at the Karolinska Institute and found that some measure of protection occurred as early as 6 months after radiosurgery for patients receiving an AVM margin dose of 25 Gy.⁶⁶ Maruyama and associates performed a retrospective observational study of 500 AVM patients who underwent radiosurgery.⁶⁷ In comparing the risk for bleeding before and after radiosurgery, they found a 54% reduction in bleeding risk during the latency interval. The reduction in risk was greatest in patients initially seen with hemorrhage. Despite the general contention that the risk for bleeding after angiographically confirmed obliteration is zero, episodes of bleeding after AVM obliteration have been reported.^70,71 Pediatric AVM patients appear to have an increased chance of this delayed complication. Consequently, follow-up angiography is indicated for these patients when they reach adulthood to ensure that they do not have any residual nidus. Moreover, if bleeding does occur after angiographically documented AVM obliteration, the clinical sequelae are generally minimal, with the hemorrhages behaving more like bleeding from CMs than AVMs.

Radiation-Related Complications after Radiosurgery for Arteriovenous Malformations

Advances in radiosurgical technique have significantly improved patient outcomes after stereotactic radiosurgery. Nonetheless, the tissue adjacent to a radiosurgical target does receive a dose of radiation. Provided that the dose plan conforms to the three-dimensional shape of the target, the major factors that determine the amount of radiation delivered to nearby structures are the PIV and the prescribed radiation dose. As the PIV increases, exposure of adjacent brain to radiation increases because the dose gradient is less steep when large volumes are covered. It is this general concept that limits the size of intracranial radiosurgical targets to approximately 3 cm or less in average diameter. Similarly, there is direct correlation between higher radiosurgical doses and the dose received by nearby tissues. For example, an AVM dose plan that covers the nidus at the 50% isodose line would result in the optic nerve receiving 8 Gy if the maximum dose was 40 Gy and the 20% isodose line was in contact with the optic nerve. Increasing the maximum dose to 50 Gy exposes the optic nerve to a maximum dose of 10 Gy if no other adjustments are made to the dose plan.

It has been demonstrated that various measures of radiation exposure correlate with the chance of areas of increased signal developing on long-TR sequences after AVM radiosurgery. The most commonly used measure is the 12-Gy volume (V12)⁴⁷; other studies have shown the 10-Gy volume (V10)⁴⁹ and the mean dose received by 20 cc surrounding the maximum radiation point (Dmean20)⁴⁸ to also correlate with changes on MRI after AVM radiosurgery. Such imaging changes are noted in approximately 30% to 50% of AVM patients within the first year after radiosurgery, but the majority remain asymptomatic (Fig. 260-1). Comparison of AVM patients with non-AVM patients has demonstrated that the incidence of these imaging changes is greater in AVM patients. Thus, it is probable that many “radiation-associated” imaging changes relate not to radiation damage to adjacent brain but rather to alterations in regional blood flow in brain tissue adjacent to the AVM. Patients with AVMs in the thalamus, basal ganglia, and brainstem are more likely to have neurological deficits as a result of the changes noted on MRI.⁴⁷ Levegrun and coworkers studied the correlation of radiation-induced imaging changes and dose distribution parameters in 73 patients who underwent AVM radiosurgery.⁷² They concluded that all three measures studied (V10, V12, Dmean20) yielded similar results and that no parameter was favored over the others in predicting these abnormalities on MRI. Occlusive hyperemia from early closure of draining veins before nidus obliteration may be a significant factor contributing to the development of such imaging changes.^73,74

FIGURE 260-1 Axial long-TR magnetic resonance imaging (MRI) in an 11-year-old boy with a right frontoparietal arteriovenous malformation (AVM). Left, MRI before radiosurgery. Right, MRI 9 months after radiosurgery. The nidus has decreased in size, and there are extensive areas of increased signal surrounding the irradiated AVM.

Despite the fact that most imaging changes detected on MRI after AVM radiosurgery resolve over time, radiation necrosis will develop in a small percentage of patients. MRI findings consistent with radiation necrosis are persistent enhancement at the irradiated site with associated edema and mass effect. In addition to radiation necrosis, other late complications have been noted after AVM radiosurgery, including cyst formation and diffuse white matter changes.^75–78 The development of radiation-induced tumors after radiosurgery is exceedingly rare.^79,80 Although the true incidence of this complication will not be known for many years, it is clear that the risk for a radiation-induced tumor after radiosurgery is significantly less than the incidence after fractionated radiation therapy.

Repeat Radiosurgery for Arteriovenous Malformations

Patients with incomplete obliteration after AVM radiosurgery remain at risk for ICH. Repeat AVM radiosurgery has proved to be a safe and effective option for the majority of patients with subtotal AVM obliteration after their initial radiosurgical procedure.^81–84 Karlsson and coauthors reviewed 112 patients who underwent repeat AVM radiosurgery and compared complication rates after the first procedure with complication rates after repeat AVM radiosurgery.⁸² Sixty-two of 101 patients with angiographic follow-up exhibited complete obliteration; 14 patients had radiation-related complications after a second radiosurgical procedure. They concluded that the obliteration rate after repeat radiosurgery is similar to that after primary procedures but that the complication rate increases with the overall amount of radiation given. Maesawa and associates noted complete obliteration in 21 of 30 patients (70%) on angiographic follow-up after repeat AVM radiosurgery.⁸³ Permanent radiation-related complications were noted in 2 of 41 patients (5%); the annual risk for hemorrhage after repeat AVM radiosurgery was 1.6%. Foote and colleagues analyzed 52 patients who underwent repeat LINAC-based AVM radiosurgery between 1991 and 1998.⁸¹ The mean volume of the AVMs was 66% smaller at the time of repeat radiosurgery. The cure rate after repeat radiosurgery was 60%. Schlienger and coworkers also noted complete obliteration in 19 of 32 patients (59%) who underwent repeat LINAC-based AVM radiosurgery.⁸⁴

Radiosurgery for Large Intracranial Arteriovenous Malformations

Studies on the dose-volume relationship of AVM radiation-related complications have demonstrated an unacceptable rate of complications for large AVMs after radiosurgery. Miyawaki and coauthors reported that radiation necrosis developed in 22% of patients after LINAC-based radiosurgery for AVMs greater than 14 cc.⁸⁵ Alternative strategies that use radiation for the management of large AVMs include embolization followed by radiosurgery, fractionated radiation techniques, and staged-volume radiosurgery. Planned embolization plus radiosurgery has been used for many years to manage patients with large AVMs.^86–90 Unlike presurgical embolization, where reduction in flow is the goal, embolization before radiosurgery must achieve a permanent reduction in volume with minimal morbidity to be a useful adjunct. Gobin and colleagues published the results of 125 patients who underwent acrylate embolization followed by radiosurgery.⁸⁶ Although complete AVM obliteration was noted in 53 of 90 evaluable patients (59%), 16 patients (13%) had complications from the embolization procedures, and 2 died of intracerebral hemorrhage before undergoing radiosurgery. In addition, nidus recanalization was seen in 14% of patients. Wikholm and coauthors reported the complications associated with AVM embolization as primary treatment or in preparation for either surgical resection or radiosurgery.^89,90 The overall procedural complication rate was 40%, but only 7% were considered severe. The procedural mortality rate was 1.3%. Based on such studies, planned embolization before radiosurgery is rarely used to manage patients with large AVMs.

Fractionated radiation therapy has also been used to treat patients with large AVMs.^23,24,91,92 Karlsson and associates reviewed 28 AVM patients who underwent fractionated radiation therapy between 1980 and 1985.²³ The median volume treated was 78 cc. Only 2 patients (7%) achieved angiographically confirmed cure with a fractionation scheme of 42 Gy in 12 fractions. They concluded that conventional radiation therapy provides little protection against future bleeding. A number of centers have more recently examined the efficacy of hypofractionated radiation schedules in which higher radiation doses per fraction are used to treat patients with intracranial AVMs.^24,91,92 Lindvall and coworkers used hypofractionated radiation therapy to treat 36 AVM patients.⁹² Two-year follow-up angiography showed that 48% of the patients were cured; angiographically corroborated obliteration rates rose to 76% at the 5-year follow-up. Veznedaroglu and colleagues managed 30 patients with large AVMs from 1995 to 1998 with a combination of preradiation embolization and hypofractionated radiation therapy.²⁴ The radiation schedules were either 42 Gy in six fractions (n = 7) or 30 Gy in six fractions (n = 23). Obliteration was confirmed on 5-year follow-up angiography in 83% of patients in the 42-Gy group (5 of 6 patients) versus only 22% of patients in the 30-Gy group (4 of 18 patients). However, the morbidity rate in patients receiving 42 Gy was 43%, and the most effective hypofractionated dosing schedule to achieve AVM obliteration with an acceptable rate of radiation-related morbidity remains unclear.

Staged-volume radiosurgery has emerged as an option for patients with large-volume AVMs.^93–96 Volume staging of large AVMs consists of performing multiple radiosurgical procedures separated by several months with each procedure covering a different portion of the nidus. This strategy permits a higher radiation dose to be delivered to the entire AVM volume while reducing radiation exposure to adjacent brain tissue. We compared the dosimetry of our first 10 patients who underwent staged-volume AVM radiosurgery with hypothetical single-session procedures covering the same volume and using the same margin and maximum radiation doses.⁹⁴ Staged-volume radiosurgery decreased V12 by an average of 11.1%, and the non-AVM V12 was reduced by an average of 27.2%. Sirin and coauthors reported 28 patients who underwent staged-volume AVM radiosurgery at the University of Pittsburgh.⁹⁵ The median AVM volume was 22.2 cc, and the median AVM margin dose used at each procedure was 16 Gy. Seven of 21 patients (33%) with follow-up beyond 36 months achieved AVM obliteration. Four patients (14%) had bleeding after radiosurgery, 2 patients died, and 2 had new neurological deficits. In 4 patients (14%), areas of increased signal on MRI developed and they required corticosteroid medications; no patient had a permanent new radiation-related deficit. To date, we have completed staged-volume radiosurgery in 25 patients with large AVMs. The treatment was completed in two procedures for 22 patients, three procedures for 2 patients, and four procedures for 1 patient. The median AVM volume was 16.2 cc; the median AVM margin dose was 16 Gy. Obliteration was noted in 6 of 18 patients (33%) with imaging performed 3 or more years after completion of staged-volume radiosurgery. Four patients (16%) sustained eight hemorrhages after staged-volume radiosurgery. Three patients suffered neurological deficits from the bleeding, and 1 patient died. In no patient did a radiation-related complication develop. More information is needed, however, to determine whether staged-volume AVM radiosurgery will be a useful technique in patients with large AVMs.

Radiosurgery-Based Arteriovenous Malformation Grading System

The Spetzler-Martin grading system is the most widely used system for grading intracranial AVMs.¹⁶ Consisting of three components (AVM size, location, and pattern of venous drainage), this system has been validated prospectively¹⁸ and by other cerebrovascular centers of excellence.^19–22 Unfortunately, this grading scale is insensitive to factors associated with successful AVM radiosurgery, such as volume and location.⁹⁷