Gamma Knife Surgery for Cerebral Vascular Malformations and Tumors

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Chapter 5 Gamma Knife Surgery for Cerebral Vascular Malformations and Tumors

The gamma knife is a neurosurgical tool used either as a primary or adjuvant procedure for intracranial pathologies. It was developed in the late 1960s as an alternative to open stereotactic lesioning for functional disorders. Variations in anatomy and needs for physiologic confirmation of the target limited its usefulness for these indications at that time. However, the technology was found to be efficacious in the management of structural disorders later on. The limited scope of the pathologies treated with the gamma knife (intracranial) and unique technology make the gamma knife an extension of the neurosurgeons’ therapeutic armamentarium and not a separate specialty. It should not be mistaken for a form of radiation therapy, for it differs in concept from the radiation oncologists’ idea of tumor treatment that is based on variable tissue response to fractionated radiation. It is a single session, stereotactically guided procedure for various neurosurgical pathologic processes limiting exposure to radiation as much as possible to the lesion only.

Recently it has been shown that the gamma knife can palliate some ocular tumors. In a more limited application of the concept, the treatment of extracranial tumors in abdominal and thoracic locations has evolved with the use of the various stereotactic body radiation therapy machines.14 Obviously, lesions that lie outside the central nervous system will not be treated by a neurosurgeon. However, when it is used for neurosurgical pathology, no one is more qualified to apply it. It is the operator and the pathology that define the use of a technology. When Walter Dandy placed a cystoscope in a ventricle for the first time, he was not performing a urologic procedure.5 The microscope when used by the neurosurgeon, ophthalmologist, or otolaryngologist is a neurosurgical, ophthalmologic, or otolaryngologic instrument, respectively.

It is remarkable how difficult it was, and still is for some neurosurgeons, to accept the use of gamma knife as a neurosurgical tool. Some of the causes of this reticence can be identified:

1. Lack of historic perspective makes it difficult for some neurosurgeons to realize that Leksell’s concept was rooted in the philosophy of the founders of neurosurgery, that is, recognition of technological advances and their application to neurosurgical practice. The early adoption by Cushing of the x-ray machine, his use of the “radium bomb” in glioma treatment,6 and the introduction, also by Cushing, of radiofrequency treatment of lesions are just a few examples of “technology transfer.”

2. The difficulty of accepting a neurosurgical procedure without opening the skull, despite the fact that every neurosurgeon knows that trephination is itself a minor part of the neurosurgical act. The laser beam, the bipolar coagulator, and the ultrasound probe are accepted without resistance because they are used after trephining the skull. The recently introduced “photon radiosurgery” with its limited scope compared to gamma surgery is accepted widely as “neurosurgery” because it reaches the target through a small burr hole.

3. The loss of the thrill and glamor provided by open surgery.

4. The deeply rooted acceptance of the dogma that where ionizing beams are involved a radiotherapist is needed. The last 40 years have demonstrated that a neurosurgeon can acquire the necessary knowledge of radiophysics and radiobiology to handle ionizing beams. This is much easier than for a radiation oncologist to master neuroanatomy and management of neurosurgical lesions, and thus to exclude bias when deciding whether to use the microscope or the gamma knife in each particular case.

The trend in cranial as well as spinal neurosurgery has been minimally invasive approaches. These may be achieved with the increasing skill of the operators and by new technology. If the result of these changes in the procedure, aspects are modified or even eliminated, the procedure is still neurosurgical. To relegate less-invasive procedures to non-surgeons is to argue that the only aspect of a patient’s care that is unique to a surgeon is purely technical. This is patently untrue; it is the surgeon’s responsibility to maintain surgical care standards by adapting to new technologies.

There is no substitute at this time for the physical extirpation of a mass lesion in terms of cure or control of either vascular or oncologic pathologies. The attractiveness of radiosurgery is not that it supplants open neurosurgical procedures, but that it allows treatment of pathologies only treated earlier with unacceptable morbidity or mortality. There is, and likely always will be a gray area where the benefits of various modalities are debated. It will only be through evaluation of long-term results of these various therapies as well as their availability, cost, experience of the operators and individual patient preferences that the “best” therapy in any given case is decided.

In this chapter we describe the results of our experience with the gamma knife as well as published results of other centers where required.

Table 5-1 lists all the cases treated with the gamma knife worldwide through 2006. It should be kept in mind that many of the indications listed are not universally accepted as appropriate for gamma surgery. In this chapter we will give our version of the facts for each indication.

TABLE 5-1 Cases Treated with Gamma Knife Worldwide through December 2008

Diagnosis n Percentage
Vascular 65,084 12.95
Arteriovenous malformation 57,136 11.37
Cavernous angioma 3,258 0.65
Other vascular 4690 0.93
Tumor 397,215 79.01
Benign 176,319 35.07
Vestibular schwannoma 46,835 9.32
Trigeminal schwannoma 2,822 0.56
Other schwannoma 1,590 0.32
Meningioma 64,115 12.75
Pituitary tumor 38,553 7.67
Pineal tumor 3,540 0.70
Craniopharyngioma 4,053 0.81
Hemangioblastoma 2,056 0.41
Chordoma 1,911 0.38
Hemaniopericytoma 1,151 0.23
Benign glial tumors 3,594 0.71
Other benign tumors 6,099 1.21
Malignant 220,896 43.94
Metastasis 185,070 36.81
Malignant glial tumors 26,437 5.26
Chondrosarcoma 775 0.15
Nasopharyngeal carcinoma 1,454 0.29
Other malignant tumors 7,160 1.42
Ocular Disorder 1,966 0.39
Functional 38,461 7.65
Intractable pain targets 622 0.12
Trigeminal neuralgia 32,798 6.52
Parkinson’s disease 1,473 0.29
Obsessive compulsive disorder 154 0.03
Epilepsy 2,399 0.48
Other functional targets 1,015 0.20
Total indications 502,726 100.0

Note: These figures include cases treated at gamma knife sites throughout the world from 1968 through December 2008.

Source: Elekta Radiosurgery Inc.

History

Clarke and Horsley developed the first stereotactic system,7 and the method was first applied clinically by Spiegel et al.8 This system allowed for the localization of intracranial structures by their spatial relationship to Cartesian coordinates relative to a ring rigidly affixed to the skull. This was a prerequisite to the development of radiosurgery by Lars Leksell. His ambition was to develop a method of destroying localized structures deep within the brain without the degree of coincident brain trauma associated with open procedures. The convergence of multiple ionizing beams at one stereotactically defined point was the result. A nominal dose is delivered to the paths of each incident beam. However, at the point of intersection of the beams, a dose proportional to the number of individual beams is delivered. The physical specifications of the device would be designed to ensure steep drop-off of delivered radiation at the edge of the intersection point. This would allow precise selection of the targeted lesion and minimization of trauma to surrounding tissue. He named this concept radiosurgery in 1951.9

Various sources of ionizing radiation were tried. Leksell first used an orthovoltage x-ray tube coupled to a stereotactic frame in the treatment of trigeminal neuralgia and for cingulotomy in obsessive compulsive disorders.9 A cyclotron was then used as an accelerated proton source and used to treat various pathologies.10,11 The cyclotron was too cumbersome and expensive for widespread application. A linear accelerator was evaluated but found at that time to lack the inherent precision necessary for this work. Fixed gamma sources of cobalt-60 and a fixed stereotactic target fulfilled the requirements of precision and compactness. The first gamma knife was built between 1965 and 1968.

The use of a single high dose of ionizing beams to treat neurosurgical problems was a novel and creative concept 40 years ago, which changed the direction of development in many fields of neurosurgery. However, a creative innovation is not perfect in its inception. The gamma knife was not an exception. Contributions of excellence by numerous neurosurgeons and physicists, and utilizing advances in computer technology to improve the software used in planning have over the years defined the present use of the tool. For instance improvements in the planning system now allow for systematic shielding of the optic apparatus from exposure during treatment of parasellar masses. In lesions only 2 to 5 mm away, the dose to sensitive structures can be limited to less than 2% to 7% of the maximum dose. However, in spite of all the changes in application of gamma surgery the underlying concepts behind it have not changed since its inception. This speaks for the sagacity of Lars Leksell and his invention.

Doses delivered and indications for the various pathologies treated were all empiric initially. In the subsequent discussions this should be considered when doses, both minimal and maximal are discussed, as well as results.

Pathophysiology

The effects of single high-dose gamma radiation on pathologic and normal tissue have been studied on clinical human and experimental animal tissue. These studies are incomplete because the human material tends to come from treatment failures and the experimental material is from normal animals. However some conclusions as to the method of effectiveness and of tissue tolerances can be drawn.

Normal Tissue

The relative radioresistance of normal brain relates to its low mitotic activity. Also, the rate at which a total dose of radiation is applied affects the damage caused by the dose. This is due to the ability of the cell to effect repairs during the actual time of irradiation. A higher dose rate (same total dose applied over a shorter period of time) consequently increases the lethality of the dose. The normal tissue surrounding the stereotactically targeted pathologic tissue receives a markedly lower dose but over the same time. Therefore, not only is the total dose lower, but the dose rate is lower as well. The radiation effect is seen most clearly at doses above and below 1 Gy/min.12 This radiobiological phenomenon explains part of the relative safety of single dose radiation with steep gradients at the edge of targeted tissue on the surrounding structures. There are likely additional mechanisms of such sparing.

The steep gradient of dose and consequently dose rate described above does not exist in conventional radiotherapy. When treating tumors the radiation oncologist uses “fractionation” or dividing the total dose into smaller portions, which allows repair of normal tissue as well as transition of dormant cells within the target to cells in division (at which time they are more sensitive to radiation). Creating a dose gradient at the lesion’s margin not only eliminates the need for fractionation but also improves the effectiveness of the delivered dose within the target (high-dose rate zone) 2.5 to 3 times that of the same dose delivered in a fractionated manner. The gamma knife stereotactically excludes normal tissue from the high-dose rate zone as much as possible. It may also take advantage of the natural difference in susceptibility of pathologic versus normal tissue.

In order to understand the radiobiology of a single high-dose of radiation on normal brain the parietal lobe of rats treated by a gamma knife was studied at our center. It was found that a dose of 50 Gy caused astrocytic swelling without changes in neuronal morphology or breakdown of the blood–brain barrier at 12 months. There was fibrin deposition in the walls of capillaries. At 75 Gy, necrosis was seen at 4 months as was breakdown of the blood–brain barrier. More vigorous morphological changes were seen in astrocytes and hemispheric swelling coincident with the necrosis occurred at 4 months. With the dose increased to 120 Gy, necrosis was seen at 4 weeks but not associated with hemispheric swelling. Astrocytic swelling occurred at only 1 week postirradiation.13 These findings are consistent with earlier reports on the effective dose to produce well-defined lesions in the thalamus in patients treated with the gamma knife.14,15

Tumor Response

Little is known about the pathophysiologic changes induced by gamma surgery at the cellular level in tumors. Division of tumor cells is presumably inhibited by radiation induced damage to DNA. Also it has been shown that the microvascular supply to tumors is inhibited by changes resulting from gamma surgery. In meningiomas studied after this treatment there was reduction of blood flow over time.16 Tumors responding early showed the greatest reduction in blood flow. Other authors have proposed that the induction of apoptosis by gamma radiation to proliferating cells may be responsible for at least a portion of the effect of gamma surgery on tumors.17,18 Although such contentions may be premature they may point the direction to future research.

Thus the pathophysiologic effect of gamma surgery seems not to be tumor necrosis. For this, higher doses than typically used would be required. Necrotic doses are rarely used for gamma surgery (e.g., in functional cases). Ideally following gamma surgery, tumors begin to shrink without changes in the normal tissue. The rate of shrinkage in general is slower in more benign tumors.

The effectiveness of the therapy is most dependent on the ability to define and treat the entire lesion. However, the result can also be obtained at times by treating the nutrient or feeding vessels of tumors (e.g., meningiomas). Malignant gliomas do poorly with any surgical technique, including gamma surgery because of the inability to include all of the microscopic disease within the treated area. Individual metastatic deposits and small benign tumors are adequately handled with both open resection and with the gamma knife because the tumor margin can be well-defined intraoperatively or on neuroimaging studies.

In order to conformally cover the target more than one isocenter is nearly always utilized. When multiple radiation fields are made to overlap the radiation dose distribution becomes inhomogeneous. The resulting areas of local maxima are called “hot spots.” Controversy exists as to whether the presence of “hot spots” in gamma surgery is beneficial or detrimental. An even dose distribution is an essential and basic concept in radiotherapy. There is some evidence that these areas may be of benefit in gamma surgery. The factors to keep in mind to understand this line of reasoning are as follows: due to radiation geometry hot spots are usually located in the deep portions of the target. In tumors this is usually the area that receives the poorest blood supply and is therefore relatively hypoxic and radioresistant. Furthermore the ability of a cell to respond to otherwise sublethal dosages of radiation can be affected by its own condition as well as the state of the cells near it. Cells that are sublethally injured and are in the vicinity of similar cells recover more often than cells that are in the vicinity of lethally injured cells. The hot spots therefore create islands of lethally injured cells that will enhance the cell kill in the sublethal injury zone.19 Oxygen is a radiosensitizer, and the relatively high-dose rate of the hot spots will act to offset any loss of efficacy in the hypoxic core of the target. This position is supported by the work of other authors.20

Cranial Nerves

The susceptibility of cranial nerves to injury from gamma surgery is of great interest. Tolerance is dependent on the particular nerve and the individual nerves involvement by the pathologic process requiring treatment. Because of these it is difficult to extrapolate exact numbers in many instances. Some statements can be made with some certainty.

The optic and acoustic nerves are the most sensitive to radiation of the cranial nerves. Being central nervous system tracts, containing oligodendrocytes, and carrying complex information is thought to be the source of their vulnerability. These tracts are unable to regenerate following injury. Optic neuropathy has been reported as a complication following single doses greater than 8 Gy.21 The tolerable level of radiation to the optic apparatus is still a subject of debate. Some advocate that the optic apparatus can tolerate doses as high as 12 to 14 Gy.2224 Others recommend an upper limit of 8 Gy.21,25 Small volumes of the optic apparatus exposed to doses of 10 Gy or less may be acceptable in some cases.26,27 Both the tolerable absolute dose and volume undoubtedly vary from patient to patient. This degree of variability likely depends upon the extent of damage to the optic apparatus by pituitary adenoma compression, ischemic changes, type and timing of previous interventions (e.g., fractionated radiation therapy and surgery), the patient’s age, and the presence or absence of other co-morbidities (e.g., diabetes).

On the other hand the trigeminal and facial nerves are significantly more resilient. Few developed profound hypoesthesia in trigeminal neuralgia patients treated with gamma knife using doses of 80 to 90 Gy. Vey few facial pareses were reported in several large groups of vestibular schwannomas treated with radiosurgery.

The cranial nerves in the cavernous sinus are relatively robust. Low incidence of neuropathies has been reported with doses up to 40 Gy.21 We have not observed any neuropathies of CN IX through XII in the treatment of glomus jugulare tumors.

Normal Cerebral Vasculature

There is both clinical and experimental data regarding the effect of single high-dose gamma irradiation of normal cerebral vasculature. In treating 1,917 arteriovenous malformations we have seen only two incidences of clinical syndromes possibly associated with the stenosis of normal vessels. This low incidence has occurred even though occasionally normal vessels are included in the treatment field. One case was reported after treating a glioma with 90 Gy gamma surgery followed by 40 Gy of fractionated whole brain irradiation of a middle cerebral artery occlusion. Steiner et al. described two cases in which disproportionate white matter changes might have been ascribed to venous stenosis and occlusion.28 Another case, of a diencephalic AVM, demonstrated marked edema associated with venous outflow occlusion. This patient suffered visual and cognitive deficits but over the course of months his neurologic status returned to baseline (Fig. 5-1).

In our treatment of pituitary adenomas with cavernous sinus extension or parasellar meningiomas, we have not observed occlusion of normal vasculature. This absence of stenosis is noted even though the internal carotid artery or portions of the circle of Willis, or its proximal branches, are often included in the treatment field. The only incidence of treating an intracranial aneurysm by us with a gamma knife did lead to narrowing and eventual occlusion of the adjacent small posterior communicating artery segment.29 Whether this was associated with the obliteration of the aneurysm neck or primary changes in the artery is unknown. It is possible that the incidence of occlusion of smaller vessels is more common than recognized as the occlusion would occur slowly and compensatory changes could take place preventing clinical syndromes from occurring. Regardless, the clinical impact is minimal. Others have noted injury to the cavernous segment of the carotid artery following radiosurgery for pituitary adenomas. A total of four cases have been reported and in only two of these cases were the patients symptomatic from carotid artery stenosis.3032 Pollock et al. have recommended that the prescription dose should be limited to less than 50% of the intracavernous carotid artery vessel diameter.32 Shin et al. recommended restricting the dose to the internal carotid artery to less than 30 Gy.33

Experimental studies done on normal vasculature in the brains of rats and cats showed similar findings.34,35 The primary injury was endothelial necrosis and desquamation, muscular coat hypertrophy and fibrosis at lower doses (25 to 100 Gy). At doses up to 300 Gy necrosis of the muscular layer was seen in cats. In only one instance, a rat anterior cerebral artery treated with 100 Gy was occlusion of a vessel seen. Similar studies on hypercholesterolemic rabbits treated with 10 to 100 Gy showed no histologic changes in the basilar arteries and no instances of occlusion after 2 to 24 months.36

Arteriovenous Malformations

The minimal clinical and only moderate histologic change in the normal cerebral vasculature after high doses of gamma radiation is in sharp contrast to the response of the vessels of an arteriovenous malformation (AVM). Complete radiographic obliteration can be achieved after appropriate gamma surgery. The effects of ionizing radiation and a role in the management of AVMs was first reported in 1928 by Cushing and Bailey.37 During craniotomy for an AVM he had to interrupt surgery due to major hemorrhage from the lesion. He then treated the patient with fractionated radiation. At reoperation 5 years later only an obliterated avascular mass was discovered. This early success was overshadowed by numerous series of failures.3840 In this early period, Johnson was the only one to report reasonable results with a 45% angiographic obliteration.41 The introduction of the gamma knife rekindled interest in the treatment of AVMs with radiation.42

The pathologic changes in AVMs treated with the gamma knife have been described by several authors.4345 The earliest change is damage to the endothelium with swelling of the endothelial cells and subsequent denudation or separation of the endothelium from the underlying vessel wall. The most important changes are seen later in the intima with the appearance of loosely organized spindle cells (myofibroblasts) and an extracellular matrix containing collagen type IV, not seen in the intima of untreated vessels. Expansion of the extracellular matrix and cellular degeneration define the final stage prior to luminal obliteration. The occlusion of the vessels is not a thrombotic process but rather the culmination of concentric narrowing of the vessel by an expanding vessel wall.

Gamma Surgery Procedure

Imaging and Dose Planning

The accuracy of a gamma surgery is ultimately dependent on the neurosurgeon’s ability to visualize the intended target. Thus, the technique would be impossible without imaging studies that allow three-dimensional views of anatomic structures in the brain. Magnetic resonance image (MRI) is the most used imaging modality because of its superior visualization of soft tissue structures and solid tumors. Typical MRI protocols include T1-weighted pre- and postcontrast (Gadolinium-enhanced) images through the entire volume of the head. Sequences may be a collection of 2D image slices, or a true 3D acquisition such as the MP-RAGE or its successors. Specialized sequences such as constructive interference in steady state (CISS) protocols may be used for circumstances such as visualization of the internal auditory canals, the cerebellopontine angle, and parasellar regions.

In planning the treatment of an AVM, digital subtraction angiography remains the imaging modality of choice. As with the MRI and computed tomography (CT), images are acquired using a fiducial system. However the digital subtraction angiography is based on projections rather than tomographic information. Images need to be geometrically corrected to account for the curvature of the image intensifier screen before importing the images into the treatment planning system. Gadolinium-enhanced MRI is currently often used to correlate the extent of the AVM nidus with angiography. It helps to define the shape of the AVM and confirms angiographically obtained information. However, it is sometimes difficult to differentiate the nidus from the feeding arteries and draining veins so the MRI tends to overestimate the size of the AVM. The capability to incorporate CTA and MRA data into the planning process is under investigation.

The Gamma Knife

The gamma knife assembly is comprised of unit that contains the radiation source and treatment couch that delivers the patient into the unit. Within the unit are 201 cobalt-60 source capsules aligned with two internal collimators that direct the gamma radiation toward the center of the unit. A third external collimator helmet is attached to the treatment couch. Four external collimator helmets are provided, and they have fixed diameter apertures that create a 4-, 8-, 14-, or 18-mm diameter isocenter. By changing external collimator helmets, the diameter of the roughly spherical isocenter can be varied. The 201 individual collimators within the helmet are machined to exact standards to direct the 201 beams of gamma radiation to a common point where they intersect, creating the isocenter. The frame attached to the patient’s head is adjusted within the collimator helmet so that the area to be treated is at that point of intersection.

In the new gamma knife model, Perfexion, the central body contains 192 cobalt-60 sources that are grouped into eight independent source sectors and collimators are entirely internal to the radiation body. Each source sector is housed in an aluminum frame that is attached to sector drive motors at the rear of the radiation body via linear graphite bushings. There are 576 collimators machined into 12 cm-thick tungsten in five concentric rings to align with the source assembly configurations. Each source has three available collimators (4, 8, and 16 mm) as well as shielded positions (‘‘blocked’’) to shield a critical structure. To achieve a particular collimation, the sector drive motors move the sources along their bushings to the correct position over the appropriate collimator opening. These changes allow a single isocenter composed of different beam diameters to optimize dose distribution shape for each individual shot.

Treatment Execution

After the treatment plan has been made the patient is moved on to the gamma knife couch and the y and z coordinates for the first exposure are set on the frame attached to the patient’s head. The patient’s head is then placed within the collimator helmet and secured on either side by trunions and the x coordinate is set. The head at this point is suspended by the frame within the helmet. The exposure time of the corresponding isocenter is entered at the control panel twice for confirmation and the session then commences with the entire couch being mechanically pulled into the body of the unit. The external collimator helmet locks into place with the internal collimators. After each exposure the patient is withdrawn from the collimator helmet and the process is repeated. Necessary changes of the collimator helmet are made as needed according to the plan. The introduction of the Automatic Positioning System (APS), a system that sets the coordinates by six independent motors just outside the irradiation field, has led to shorter treatment times, enhanced selectivity, and better physician work-flow. In the gamma knife Perfexion, the treatment table itself acts as a positioning device (the Patient Position System, or PPS). The stereotactic frame is attached to the treatment table via a removable frame adapter that attaches to the frame and acts as an interface with the treatment table. Treatment execution with Perfexion is a fully automated process including set up of the stereotactic coordinates, alignment of different sector positions and set up of exposure times. Obviously these changes will not affect the efficacy of the treatment but will make the process simpler for the operator.

At the end of the treatment the frame is removed from the head within the suite. There is usually a sensation of tightening and discomfort reported by the patient during removal. At least two pairs of hands should be available to steady the frame and prevent injury by a pin as they are removed. Venous bleeding when it occurs can be controlled with hand held pressure for a few minutes. The occasional arterial bleeder might require a suture. After frame removal the pin sites are dressed in a sterile fashion, steri-strips are used to oppose the skin edges for optimal cosmesis, and a modest head wrap applied.

Indications

Vascular Malformation

Arteriovenous Malformations

The indications for gamma surgery of arteriovenous malformations (AVMs) versus other treatment options are in many cases unclear at best. Small asymptomatic inoperable AVMs are clearly best treated with the gamma knife while AVMs with a large symptomatic hemorrhage in noneloquent superficial brain are best treated with open surgery. The reason for this is that the risk-benefit value is clear in both of these situations. In other situations it is more ambiguous. Knowledge of the capabilities of various treatments to effect cure, the associated morbidity and mortality associated with the treatment and the natural history of the disease following various treatments must be known to accurately prescribe the most efficacious treatment plan. Unfortunately these are in most instances not known. The natural history of AVMs is not fully understood. Some authors believe that size matters, with smaller AVMs bleeding at a higher rate than larger ones or at a lower rate.4649 There is also evidence that size is independent of the hemorrhage rate.5052 Similarly the rate of hemorrhage of an AVM following a previous hemorrhage is thought to be higher than the rate in unruptured AVMs by some authors46,52,53 but not by others.47,54,55 The effects of age, gender, pregnancy and AVM location also confound the question of risk of rupture.5052,5658

The results of microsurgery published in the literature tend to come from centers of excellence and the patients they treat with open surgery are, by definition more amenable to this treatment. The effectiveness of the treatment by this manner and its co-morbid results are known shortly after surgery. The short-term morbidity of treatment with the gamma knife approaches zero but because the benefit and potential complications require time to become apparent follow-up of these patients is problematic. The quality of the AVMs treated with the gamma knife also varies in large series with those treated by microsurgery. All of these make comparison of the modalities difficult. Add to that the additional risks and benefits of preoperative embolization and the matter is that much less clear. It is paramount to the physician treating a patient harboring an AVM to be aware, as much as possible, of the options that are available and the magnitude of the risks and benefits associated with each.

Early Experience

Since the first AVM case treated by Steiner et al. in 1972,42 we have treated over 2500 AVMs with the gamma knife. As experience with this tool grows the capabilities and limitations of the gamma knife are being defined.

Serendipitously the first AVM was treated by prescribing a 25 Gy peripheral dose. Subsequent changes in protocol showed a significant decrease in success with doses less than 23 Gy and small improvements in obliteration rates but with significantly more radiation associated complications with higher doses. Optimally, therefore, we treat most AVMs with 23 to 25 Gy at the margin. While more patients with relatively large AVMs were treated, dose lower than 23 Gy was quite often used in hopes of achieving a total obliteration with reasonable risk of complications.

As in microsurgery, also when performing gamma surgery, feeding arteries or draining veins should be left alone and only the nidus should be treated. In very large AVMs, only partially treated due to the excessive dose necessary to treat optimally, occasional cures have been achieved. This is thought to be due to fortuitous inclusion of all the pathologic shunts within the higher dose treatment field. Targeting only the feeding vessels to the AVM have had very limited success because of recruitment of small angiographically occult feeding arteries. Interestingly, the first patient ever treated had only the feeding vessels targeted and a cure was obtained.42 The early success with this strategy has not been reproduced.

The results of gamma surgery on AVMs is affected by the minimum dose applied to the AVM and the size of the AVM. These two factors are interdependent. It has been shown that the limitation of the allowed margin dose by the size of the malformation decreases the rate of obliteration. There are reports contending that low-dose gamma surgery with large malformations results in obliteration rates that are comparable to smaller lesions treated with a larger margin dose. It is doubtful that these results will hold up with larger series. Thus far at our center, larger AVMs have had a lower obliteration rate.

Between 1970 and 1990, 880 AVM patients were optimally treated. Optimally is defined as at least 25 Gy at the margin of the entire nidus of the AVM. Of these patients the age range was 3 to 76 years. Approximately 15% were pediatric patients (<18 years old). The presenting symptoms were hemorrhage (70%), seizures (16%), headache (5%), neurologic deficits not associated with acute hemorrhage (4%), and other symptoms (5%). The majority of referrals were for AVMs deemed operable only with unacceptable morbidity explaining the fact that 73% of the AVMs were located in deep areas of the brain or within eloquent cortex. Patients treated earlier were subjected to a vigorous protocol of repeated angiograms. Later with the introduction of CT and then MRI, angiography was not performed until nidus was no longer evident on these screening examinations. The angiogram should be complete, of high quality, and should be reviewed by an experienced and interested neuroradiologist or neurosurgeon.

Imaging Outcomes

Following gamma surgery, angiography reveals hemodynamic changes occur before changes in the size and shape of an AVM.59 First, the flow rate decreases progressively. This may be related to the changes in the sizes of the feeding arteries and outflow veins. The outcome of an AVM following radiosurgery may be a total, subtotal, or partial obliteration of the nidus.

Total obliteration of the AVM after radiosurgery was defined as “complete absence of former nidus, normalization of afferent and efferent vessels, and a normal circulation time on high-quality rapid serial subtracted angiography”59 (Fig. 5-2). Any remaining nidus, regardless of its size, is considered partial obliteration (Fig. 5-3). Subtotal obliteration of an AVM means the angiographic persistence of an early filling draining veins without demonstrable nidus (Fig. 5-4).60

Of the 880 patients treated 461 had adequate angiographic follow-up. Of these 461 patients, 80% were found to be cured within 2 years. At the time of the last evaluation of the results only 5% of patients had no change in the status of their AVMs. Ten percent had subtotal obliteration and 5% were partially obliterated. In this group of patients obliteration rates were affected by the size of the nidus. The rate for AVMs less than 1 cm3 in volume was 88%. For 1 to 3 cm3 it was 78% and for greater than 3 cm3 it was 50%.

No patient that was harboring an angiographically proven obliterated AVM has ever hemorrhaged in our experience. Nor has a patient with a subtotally obliterated AVM sustained a postradiosurgery hemorrhage. Regardless of this we do not consider a patient cured until he has total obliteration of the AVM. The early draining vein represents persistence of the shunt.

Outcomes of Gamma Surgery for Arteriovenous Malformations after 1989

Since 1989, a total of 1350 AVM patients were treated with gamma surgery at the Lars Leksell center for Gamma Surgery, University of Virginia, Charlottesville. Excluding 82 patients completely lost to follow-up, 139 patients with follow-up of less than 2 years and additional 106 patients with large AVMs undergoing only partial treatment, we analyze the outcome of 1023 AVMs. There were 523 males and 500 females with a mean age of 34 years (range 4–82 years). The presenting symptoms leading to the diagnosis of AVMs was hemorrhage in 529 (52%), seizure in 237 (23%), headache in 133 (13%), and neurologic deficits in 94 (9%). In 30 patients (3%), the AVMs were incidental findings. The locations of the AVMs were in the cerebral hemispheres in 630 (62%), basal ganglion in 96 (9%), thalamus in 82 (8%), corpus callosum in 38 (4%), brain stem in 84 (8%), cerebellum in 68 (7%), and insula in 25 patients (2%). The Spetzler-Martin grading of the AVMs were Grade I in 174 (17%) patients, grade II in 328 (32.1%), Grade III in 440 (43%), Grade IV in 78 (7.6%) and grade V in three (0.3%). One hundred and twenty-two patients (12%) had previous partial resection of the nidi, and 244 patients (24%) underwent preradiosurgical embolization. The nidus volume ranged from 0.1 to 33 cm3 (mean 3.5 cm3). The mean prescription dose was 21.1 Gy (range 5–36 Gy), and the mean maximum dose was 39.0 Gy (range 10–60 Gy). The mean number of isocenters was 2.7 (range 1–22).

The mean follow-up was 80 months. Gamma surgery yielded a total angiographic obliteration in 552 (54%) and subtotal obliteration in 42 (4%) patients. In 290 (28%) patients, the AVMs remained patent and in 139 patients (14%) no flow voids were observed on the MRI. The angiographic total obliteration was achieved in 66% of patients with nidus less than 3 cm3; 44% between 3 and 8 cm3, and 28% with nidus volume larger than 8 cm3. Small nidus volume, high prescription dose, and low number of isocenters are predictive of obliteration. Preradiosurgical embolization has a negative effect on obliteration.

The reported obliteration rate following radiosurgery varied greatly.6265 One should be cautious when interpreting the results owning to the biases injected from different cut-off time and imaging modality used to conclude total obliteration. Studies only including patients with long follow-up, reporting only patients undergoing angiography or including MRI as imaging study to conclude obliteration tend to overestimate the success rate of radiosurgery.63,66,67

Gamma Surgery for AVMs in Pediatric Patients

Between 1989 and 2007, we treated 200 AVM patients less than 18 years of age. Fourteen cases with follow-up less than 2 years were excluded, leaving 186 patients for analysis. There were 98 males and 88 females with a mean age of 12.7 years (range 4–18 years). The presenting symptoms leading to the diagnosis of AVMs were hemorrhage in 133 (72%) patients, seizure in 29 (16%), headache in 11 (6%), and neurologic deficits in 8 (4%). Five (3%) patients were asymptomatic. Thirty-eight patients underwent embolization prior to gamma surgery. Incomplete surgical resection was carried out in 24 patients. Five patients had partial resection and embolization before undergoing gamma surgery.

The locations of the AVMs were hemispheric in 101 (54%) patients, thalamus in 24 (13%), basal ganglia in 23 (12%), corpus callosum in 9 (5%), brain stem in 18 (10%), insula/sylvian fissure in 5 (3%), and cerebellum in 6 (3%). The nidus volumes ranged from 0.1 to 24 cm3 (mean 3.2 cm3). The treatment parameters were: mean prescription dose 21.9 Gy (range 7.5–35 Gy); mean maximum dose 40.1 Gy (range 20–50 Gy).

Following gamma surgery, a total obliteration was confirmed in 109 (59%) and subtotal obliteration in 9 (5%). Forty-nine (26%) patients still had patent residual nidus. In 19 (10%) patients, obliteration was confirmed on MRI only. The actuarial angiographic obliteration rate was 34% at 2 years, 46% at 3 years, and 51% at 5 years. In general, the imaging outcome of pediatric patients is similar to that observed in adult population. A negative history of preradiosurgical embolization and a high prescription dose were significantly associated with increased rate of obliteration.

Only a small series of children went through a systemic psychological test analyzing the cognitive deficits after gamma surgery. However, yearly follow-ups including questioning the parents, the patients, and the referring doctors about the intellectual development and possible cognitive or endocrinologic deficits were conducted. According to this information, 95% of the children had normal intellectual development after radiosurgery with satisfactory or good school performance. As adults, they performed from average to excellent and were socially well-adjusted.

Some studies had proposed that in pediatric patients the response to radiosurgery seems to be less favorable.66 Hypotheses such as the immature vessels in pediatric cases more likely to recover from radiation induced damage and neovascularization in response to radiation have been proposed. Our experience show comparable result in children compared to adults. Additionally, we observe that adverse radiation induced damage seems to be more tolerable for kids, which proves that radiosurgery has a favorable benefit risk profile in the management of pediatric AVMs. However, the risk of hemorrhage remained in pediatric patients and the development of secondary tumor cannot be overlooked.

Gamma Surgery following Embolization of Arteriovenous Malformations

The effectiveness of partial embolization followed by gamma surgery in the management of relatively large AVMs still remains controversial. When comparing the outcome in patients treated with gamma knife alone to those with combined embolization and gamma knife treatment, recent studies reported less favorable outcome in patients with preradiosurgical embolization.65,68

Between 1989 and 2007, a total number of 217 AVMs with prior partial embolization were treated with gamma surgery at the Lars Leksell center. There were 107 males (49%) and 110 females (51%) with a mean age of 32.8 years. Most of the AVMs were embolized with liquid embolics such as NBCA or ethanol. In 167 patients the nidus was compact after the embolization, whereas the angiogram of 50 cases revealed that the nidus was broken apart after the endovascular procedures. The mean volume of the nidus at the time of GKS was 5.1 cm3 (range 0.02–24.9 cm3). The mean prescription dose was 19.6 Gy (range 10–28.0 Gy) and the mean maximum dose was 37.2 Gy (range 20–50 Gy).

After gamma surgery an angiographically confirmed total obliteration of the AVMs was achieved in 71 patients (27%) (Fig. 5-5). A total obliteration on MRI was observed in 26 patients (10%). In 157 patients (60%) only a partial obliteration could be obtained after a follow-up period of at least 2 years. Eight patients (3%) presented with a subtotal obliteration. The outcome after gamma surgery in embolized AVMs (obliteration rate 27%) is much less favorable than AVMs treated with gamma knife only (obliteration rate 72%).

Recanalization of previously embolized parts of the nidus,69 difficulty in nidus delineation following previous embolization,65 and attenuation of radiation dose by embolization materials70 have been proposed to explain the less favorable outcome in patients with preradiosurgical embolization. Theoretically, volume reduction following embolization affords a lower chance of radiosurgery-related adverse effect; however, our data do not show this. Additionally, the complications from embolization are not negligible. Therefore, the use of embolization before gamma knife treatment remains problematic and awaits further investigation.

Gamma Surgery for Large Arteriovenous Malformations

Recently, there has been much discussion of gamma surgery for large AVMs. The main problem with large AVMs is due to the dependence of the obliteration response on dose and volume; this dependency requires a delicate balance in deciding an efficient dose but low enough to avoid adverse neurologic deficits.

The following strategies are currently available to treat large AVMs with radiosurgery.

1. Embolization of a portion of the AVMs then performing radiosurgery if the nidus shrinks to a size manageable with radiosurgery. However, embolization should effectively shrink the nidus for radiosurgery to achieve good results; otherwise fragmentation of the nidus into a number of segments will make the radiosurgical planning difficult and increasing the probability of radiosurgery failure.

2. Staged radiosurgery to selected volumes of the AVMs. Sirin et al.71 used staged volumetric radiosurgery in 28 large AVMs. Out of the 21 patients, seven underwent repeat radiosurgery and were eliminated from outcome analysis. Of the remaining 14 patients, three had total obliteration on angiograms, and 4 had no flow voids on MRI but had no follow-up angiography. Four patients had hemorrhages after radiosurgery resulting in two deaths. Worsened neurologic deficits occurred in one patient.

3. Treating the whole nidus in one session with low-dose radiosurgery. Pan et al.72 reported an obliteration rate of 25% for AVMs with volume larger than 15 cm3. The obliteration rate increased to 50% at 50 months follow-up. The morbidity was 3.3%. Post-treatment hemorrhage occurred in 9.2% of cases.

4. At Lars Leksell center, we evaluated a protocol using combined radiosurgery and microsurgery for the management of large AVMs. Gamma surgery was performed for the deep medullary portion of the AVMs as a first step. The second step was planned as microsurgical extirpation of the superficial segment if the goal of the first step, obliteration of the deep segment of the AVM, was achieved. However, in less than 5% of the patients, this goal was achieved.

The management of large AVMs demonstrates that every treatment has its limitations. In an effort to solve the problems of the management of large AVMs, a cautious approach is warranted pending the development of new techniques and agents for embolization.

Hemorrhage Risk in the Treatment–Response Interval

Whether gamma surgery without obliteration of the nidus provides partial protection from hemorrhage is still controversial. It has been demonstrated by some authors that there may be some degree of protective effect.7375 Because the incidence of hemorrhage in a matched group of untreated patients will likely never be known and the timing of obliteration is not known except as being between diagnostic scans, it is a difficult position to support.

The incidence of hemorrhage following gamma surgery during the first 2 years was studied in 1604 of our patients and reported by Karlsson et al.76 There were 49 hemorrhages for an annual incidence of 1.4%. This is slightly lower than the generally accepted rate of 2% to 4% per year but includes all 1604 patients, consisting of those known and not known to have obliterated AVMs. Of these hemorrhages, 14 were fatal (annual rate of 0.4%) and 9 had permanent neurologic deficits (annual rate of 0.3%).

Repeat Gamma Surgery for Incompletely Obliterated Arteriovenous Malformations

In general, the risk of hemorrhage persists as long as the AVM nidus is still patent. This provided the rationale for retreatment of still patent AVMs following the initial gamma surgery.

In our experience, 74 males and 66 females with a mean age of 33 years underwent repeat gamma surgery for still-patent AVMs following initial gamma surgery from 1989 to 2007. Causes of initial treatment failure included inaccurate nidus definition in 14, failure to fill part of the nidus due to hemodynamic factors in 16, recanalization of embolized AVM compartments in 6, and suboptimal dose (<20 Gy) in 23 patients. Nineteen patients had repeat gamma surgery for subtotal obliteration of AVMs. In 62 patients, the AVMs failed to obliterate in spite of correct target definition and adequate dose. At the time of retreatment, the nidus volume ranged from 0.1 to 6.9 cm3 (mean 1.4 cm3) and the mean prescription dose was 20.3 Gy. Clinical follow-up ranged from 15 to 220 months with a mean of 84.2 months after repeat gamma surgery.

Repeat treatment yielded a total angiographic obliteration in 77 (55%) (Fig. 5-6) and subtotal obliteration in 9 (6.4%) patients. In 38 (27.1%) patients, the AVMs remained patent. In 16 patients (11.4%) no flow voids were observed on the MRI. High prescription dose, small nidus volume, nidi with only superficial venous drainage, and a negative history of prior embolization were significantly associated with increased rate of AVM obliteration. Clinically, 126 patients improved or remained stable and 14 experienced deterioration (8 due to a rebleed, 2 caused by persistent arteriovenous shunting, and 4 related to radiation induced changes).

We advise repeat gamma surgery in cases with still patent nidi 3 to 4 years after initial gamma surgery when open surgery or endovascular procedures were expected to yield higher risk of complications than gamma surgery. Our experience showed that when repeating gamma knife treatment a dose of at least 20 Gy led to a higher chance of subsequent nidus obliteration (77% vs. 47% with prescription dose less than 20 Gy).

Hemorrhage from Angiographically Confirmed Obliterated Arteriovenous Malformations

Some studies have noted AVM reappearance after apparent gamma knife surgery obliteration.77 In our histopathologic analysis, gamma surgery of AVMs caused endothelial damage, proliferation of smooth muscle cells, and the elaboration of extracellular collagen by these cells, which led to progressive stenosis and obliteration of the AVM nidus.43 In this same report, there was evidence of small trapped vessels that would have very little blood flow. It is unclear what histopathologic process would permit the formation of new vessels following radiosurgical-induced obliteration of the AVM nidus. However, it is clear that the infrequent and small trapped vessels observed by Schneider et al.43 could not explain the angiographic findings reported by Linqvist et al.78 Such inconsistent findings following radiosurgical treatment of AVMs suggest the need for further clinical and histopathologic investigation and the continued follow-up of patients, particularly pediatric ones, following gamma surgery.

In our series of AVMs treated with gamma surgery, we observed no recurrent hemorrhage after angiographically confirmed obliteration of the AVMs. In one case reported by Guo et al., a rebleed occurred after angiographic documentation of nidus obliteration.79 The MRI findings suggested that hemorrhage possibly resulted from radiation-induced tissue damage. Furthermore, the histologic examination of the suspected recanalized AVM revealed channels that were one-fiftieth the size of the smallest vascular channels in AVMs, making it unlikely that these were vessels with significant blood flow. This view has been further confirmed by the fact that a repeat angiogram revealed no evidence of residual malformation or recanalization. Rebleeding, in spite of post-treatment angiograms interpreted as normal, may be explained by unsatisfactory quality of the neuroimaging studies or inadequate interpretation leading to the misdiagnosis of angiographic cure.

Subtotal Obliteration of Arteriovenous Malformations
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