**Advanced Gamma Knife Treatment Planning of Epilepsy**

Andrew Hwang and Lijun Ma *University of California San Francisco, California, USA* 

## **1. Introduction**

122 Gamma Knife Radiosurgery

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radiosurgery for treatment of trigeminal neuralgia: idiopathic and tumor related.

Gamma knife radiosurgery for multiple sclerosis-related trigeminal neuralgia.

## **1.1 Background**

Epilepsy is not a single disease, but a broad group of conditions characterized by recurrent seizures resulting from the abnormal firing of cerebral neurons (1). Both medical and surgical treatments have been available for over a century, but there has been recent interest in radiosurgery as an alternative to open surgery for patients with medically intractable epilepsy.

Mesial temporal lobe epilepsy (MTLE) specifically consists of atrophy and gliosis within the limbic system and is the most frequent cause of medically intractable epilepsy in adults (2). Currently, the standard treatment for epilepsy is the use of anticonvulsants. Medically intractable cases may be treated with temporal lobectomy, consisting of removal of parts of the superior temporal gyrus, temporal portion of the amygdala, and the hippocampus.

Other causes of epilepsy include hypothalamic hamartomas (HH) and vascular malformations. Hypothalamic hamartomas are benign lesions composed of varying amounts of glia, neurons, and myelinated fibers. These tumors are often associated with gelastic seizures, precocious puberty, and behavioral problems (3) and often do not respond well to anticonvulsant therapy. As a result, surgical resection and stereotactic radiofrequency thermocoagulation have been used to treat HH (4). Epilepsy is also a symptom of cerebral vascular malformations. In particular, patients with cavernous malformations (CM) frequently present with drug-resistant epilepsy (5).

Given the toxicity of open surgery and poor quality of life for patients with medically intractable epilepsy, stereotactic radiosurgery (SRS) with the Gamma Knife has been proposed as a viable alternative to open surgery for treating these patients. Preliminary data have shown that Gamma Knife radiosurgery is highly promising in terms of safety and efficacy for the treatment of MTLE (6-8). Potential advantages of Gamma Knife radiosurgery include lower morbidity and lower cost with equal effectiveness. One potential disadvantage of radiosurgery is the latency of response, which may be up to two years (9). Although much of the data are promising, the results of Vojtĕch et al suggest that more study is needed (10). Based on these data, an international clinical trial is currently being conducted for determining the role of radiosurgery for managing MTLE.

Advanced Gamma Knife Treatment Planning of Epilepsy 125

of HH (18). A good summary of the various treatment options for HH including SRS has been published by Régis *et al* (20). This report also includes the results of a prospective study of Gamma Knife SRS for hypothalamic hamartomas. At the time of publication, the authors had sufficient (3 years) follow-up to report results for 27 patients and found that a very good result

Data have also been published regarding the use of radiosurgery for treatment of epilepsy associated with cavernous malformations (23-28). In 1999, Bartolomei *et al* reported the results of a retrospective study to evaluate the feasibility of using radiosurgery to treat epilepsy associated with cavernous malformations (23, 29). Data from forty nine patients were included in this study, with over 70% either seizure-free or with a significant reduction

**Findings**

**Patients**

Régis *et al* (15) 2000 10 40% patients were seizure free.

Matthieu *et al* (19) 2006 4 75% of patients showed improvement Régis *et al* (20) 2006 27 Very good result in 60% of patients. Abla *et al* (21) 2010 10 40% were seizure free after SRS.

Mathieu *et al* (22) 2010 9 4/6 patients with smaller tumors seizure

Hsu *et al* (28) 2007 14 64% seizure free. Linac based radiosurgery.

achieved.

at 24 months.

Bartolomei *et al* (23) 1999 49 53% of patients seizure free. Kim *et al* (24) 2005 12 75% of patients seizure free Liscák *et al* (25) 2005 44 45% improved after radiosurgery Liu *et al* (26) 2005 28 53% reported good seizure control

Shih and Pan (27) 2005 16 25% remained seizure free.

Régis *et al* (6) 2004 20 65% were seizure free.

Régis *et al* (7) 1999 7 83% of patients were seizure free.

Vojtech *et al* (10) 2009 14 18, 20, or 25 Gy. No seizure control

Quigg *et al* (8) 2011 26 Patients received 20 or 24 Gy. No

Table 1. Published Studies for Radiosurgical Treatment of Epilepsy Due to Various Causes.

free. 0/3 with larger tumors seizure free.

neuropsychological changes from baseline

Unger *et al* (16) 2002 4 No patients seizure free Barajas *et al* (17) 2005 3 No patients seizure free

Selch *et al* (18) 2005 3 67% seizure free

was obtained in 60% of the patients.

*Hypothalamic Hamartomas* 

*Cavernous Malformations* 

*Mesial Temporal Lobe Epilepsy*

**Study Year No. of** 

## **1.2 Radiosurgery for MTLE**

Because radiosurgery for MTLE is still an experimental procedure, a multi-center Phase III clinical trial known as the ROSE trial (Radiosurgery or Open Surgery for Epilepsy) was initiated in 2009 to investigate the use of Gamma Knife radiosurgery as an alternative to open surgery for the treatment of medically intractable mesial temporal lobe epilepsy (11, 12). The primary objective of this study is to demonstrate the equivalence of radiosurgery with temporal lobectomy in terms of freedom from seizures. Other endpoints include quality of life, neuropsychological outcomes, and cost-effectiveness.

Due to the location of the target volume and proximity of critical structures, Gamma Knife radiosurgery for mesial temporal lobe epilepsy (MTLE) is technically challenging. In this chapter we will discuss the methods used for planning Gamma Knife radiosurgery treatments for epilepsy, the equipment used for delivering these treatments, and challenges specific to the treatment of MTLE and other causes of epilepsy.

Similar to the traditional surgical approach to treatment of MTLE with temporal lobectomy, the proposed radiosurgical treatment target is comprised of the amygdala, anterior 2 cm of the hippocampus, and the parahippocampal gyrus. Images of a representative target volume are shown in FIG. 1. The current target prescription dose is 24 Gy, which is based on the results of an earlier study in which lower doses were shown to result in reduced efficacy (13). The total irradiated volume is maintained to be less than 7.5 mL in order to minimize late radiation sequelae such as festering radiation necrosis.

Fig. 1. (left) MR image showing target volume (red), brainstem (pink), and optical chiasm (blue). The target volume consists of the amygdala, anterior hippocampus, and parahippocampal gyrus. (right) A typical dose distribution is shown with the prescription (24 Gy) isodose line shown in yellow and the 8 Gy isodose line in green.

## **1.3 Radiosurgery for hypothalamic harmatomas and cavernous malformations**

Studies have demonstrated that the use of stereotactic radiosurgery for treatment of epilepsy associated with hypothalamic hamartomas is safe and effective (14-22). In 2000, Régis *et al* reported the results of a multi-center study that involved ten patients treated at seven sites with Gamma Knife SRS (15). The median follow-up was 28 months and the results demonstrated a clear relationship between dose and efficacy and the authors recommended a margin dose of 18 Gy or more. Selch *et al* described the use of linac based SRS for the treatment

Because radiosurgery for MTLE is still an experimental procedure, a multi-center Phase III clinical trial known as the ROSE trial (Radiosurgery or Open Surgery for Epilepsy) was initiated in 2009 to investigate the use of Gamma Knife radiosurgery as an alternative to open surgery for the treatment of medically intractable mesial temporal lobe epilepsy (11, 12). The primary objective of this study is to demonstrate the equivalence of radiosurgery with temporal lobectomy in terms of freedom from seizures. Other endpoints include

Due to the location of the target volume and proximity of critical structures, Gamma Knife radiosurgery for mesial temporal lobe epilepsy (MTLE) is technically challenging. In this chapter we will discuss the methods used for planning Gamma Knife radiosurgery treatments for epilepsy, the equipment used for delivering these treatments, and challenges

Similar to the traditional surgical approach to treatment of MTLE with temporal lobectomy, the proposed radiosurgical treatment target is comprised of the amygdala, anterior 2 cm of the hippocampus, and the parahippocampal gyrus. Images of a representative target volume are shown in FIG. 1. The current target prescription dose is 24 Gy, which is based on the results of an earlier study in which lower doses were shown to result in reduced efficacy (13). The total irradiated volume is maintained to be less than 7.5 mL in order to minimize

Fig. 1. (left) MR image showing target volume (red), brainstem (pink), and optical chiasm

parahippocampal gyrus. (right) A typical dose distribution is shown with the prescription

Studies have demonstrated that the use of stereotactic radiosurgery for treatment of epilepsy associated with hypothalamic hamartomas is safe and effective (14-22). In 2000, Régis *et al* reported the results of a multi-center study that involved ten patients treated at seven sites with Gamma Knife SRS (15). The median follow-up was 28 months and the results demonstrated a clear relationship between dose and efficacy and the authors recommended a margin dose of 18 Gy or more. Selch *et al* described the use of linac based SRS for the treatment

**1.3 Radiosurgery for hypothalamic harmatomas and cavernous malformations** 

(blue). The target volume consists of the amygdala, anterior hippocampus, and

(24 Gy) isodose line shown in yellow and the 8 Gy isodose line in green.

quality of life, neuropsychological outcomes, and cost-effectiveness.

specific to the treatment of MTLE and other causes of epilepsy.

late radiation sequelae such as festering radiation necrosis.

**1.2 Radiosurgery for MTLE** 

of HH (18). A good summary of the various treatment options for HH including SRS has been published by Régis *et al* (20). This report also includes the results of a prospective study of Gamma Knife SRS for hypothalamic hamartomas. At the time of publication, the authors had sufficient (3 years) follow-up to report results for 27 patients and found that a very good result was obtained in 60% of the patients.

Data have also been published regarding the use of radiosurgery for treatment of epilepsy associated with cavernous malformations (23-28). In 1999, Bartolomei *et al* reported the results of a retrospective study to evaluate the feasibility of using radiosurgery to treat epilepsy associated with cavernous malformations (23, 29). Data from forty nine patients were included in this study, with over 70% either seizure-free or with a significant reduction


Table 1. Published Studies for Radiosurgical Treatment of Epilepsy Due to Various Causes.

Advanced Gamma Knife Treatment Planning of Epilepsy 127

Due to the critical location of these lesions, special radiosurgical treatment planning techniques are applied to minimize the dose to the surrounding normal brain and functional structures. In order to achieve optimal dose fall-off outside of the target, it is preferable to use small collimators (i.e., 4-mm diameter) for treating such lesions. Selective blocking of individual beamlets is a must for enhancing the dose gradient toward a nearby critical structure. However, selective blocking and planning techniques are known to vary significantly among different Gamma Knife models and individual users. To benchmark such differences, a pre-clinical trial quality assurance procedure was developed. The results

**3. Comparison among present gamma knife models for treating MTLE** 

There are multiple models of the Leksell Gamma Knife currently in use. The newest is the Perfexion model introduced in 2006 (5-7). The Perfexion uses 192 Cobalt-60 sources (versus 201 Cobalt-60 sources of prior Gamma Knife models) focused on a single point, the isocenter. The sources are arranged and divided conically into 8 sectors each containing 24 sources. The sources can be collimated to form circular beams with a 4-mm, 8-mm, or 16 mm diameter respectively or blocked entirely, with each sector being independently

By contrast, the previous model Gamma Knife (Model 4C) uses 201 Cobalt-60 sources. The sources are collimated to form circular beams with 4 mm, 8 mm, 14 mm, or 18 mm diameters. The collimator size is selected by switching helmets. All beams have the same diameter, but individual beams can be blocked by "plugging" the helmets. However, switching helmets and changing plugging patterns can be time consuming, so in reality only a limited number of plugging patterns are used. Despite these differences, the mechanical accuracy of all Gamma Knife models has been consistently maintained to be better than 0.4 mm. As a result, Gamma Knife has so far been the only radiosurgical modality reported for

As part of the physics review process for the ROSE trial, each center was required to submit a treatment plan based on a sample data set for the purpose of quality assurance. Image data for this sample patient were transferred to participating institutions. The target volume was then delineated and a treatment plan was created to satisfy the previously described dosimetric constraints. The plans were then transferred to the review center for a centralized review by the trial director. Plans that did not satisfy the dosimetric constraints were revised and resubmitted. Plans were submitted for the Gamma Knife Perfexion and C/4C models, depending on the device used at the individual centers. These data were analyzed to look

A total of 13 plans from 8 institutions satisfied the dosimetric constraints and were included in the data analysis. This included seven plans for the Model 4/4C and six plans for the

Parameters studied included beam-on time, number of shots, volume receiving 24 Gy (V-24Gy), minimum dose to the delineated target, and the gradient index. Beam-on time was

**2.3 Benchmarking treatment planning practices** 

of such a study are summarized in the following section.

controlled, which is fundamentally different from previous models.

for potential differences between the Perfexion and C/4C models.

Perfexion. Details of the individual plans are shown in TABLE 2.

managing intractable mesial temporal lobe epilepsy.

in the number of seizures. Shih and Pan reported on 46 patients treated with surgery or radiosurgery for supratentorial cavernous malformations (27). Of this group, 24 of 46 patients presented with seizures. The results suggested that patients undergoing craniotomy had better bleeding and seizure control than those receiving Gamma Knife radiosurgery.

A brief summary of the literature regarding radiosurgical treatment of epilepsy due to various causes can be found in TABLE 1. We also refer the reader to the literature reviews on this topic by Quigg and Barbaro (2) and Romanelli *et al* (30).

## **2. Methods and techniques**

## **2.1 Mesial temporal lobe epilepsy**

The dosimetric criteria for the ROSE trial included: 1) prescription dose of 24 Gy to the 50% isodose line (*i.e.*, maximum dose of 48 Gy), 2) total volume receiving 24 Gy (V-24 Gy) within the range of 5.5-7.5 cm3, 3) maximum brainstem dose of 10 Gy, and 4) maximum dose of 8 Gy to the optical apparatus.

## **2.2 Hypothalamic hamartomas**

Planning for hypothalamic hamartomas is challenging due to the proximity of the brainstem and the optical apparatus (FIG. 2). However, compared to MTLE, planning for HH is less challenging due to lower doses and smaller target volumes for hypothalamic hamartomas. In our institution, target doses range from 15-18 Gy. Target volumes have ranged from 0.3 to 2.1 cm3, with a mean volume of 0.81 cm3 (N=4).

Fig. 2. Radiosurgery treatment for hypothalamic hamartoma. Note the proximity of the brainstem and the optical chiasm to the target volume. The prescription isodose line is shown in yellow and the 12 Gy isodose line in green.

in the number of seizures. Shih and Pan reported on 46 patients treated with surgery or radiosurgery for supratentorial cavernous malformations (27). Of this group, 24 of 46 patients presented with seizures. The results suggested that patients undergoing craniotomy had better bleeding and seizure control than those receiving Gamma Knife radiosurgery.

A brief summary of the literature regarding radiosurgical treatment of epilepsy due to various causes can be found in TABLE 1. We also refer the reader to the literature reviews

The dosimetric criteria for the ROSE trial included: 1) prescription dose of 24 Gy to the 50% isodose line (*i.e.*, maximum dose of 48 Gy), 2) total volume receiving 24 Gy (V-24 Gy) within the range of 5.5-7.5 cm3, 3) maximum brainstem dose of 10 Gy, and 4) maximum dose of 8

Planning for hypothalamic hamartomas is challenging due to the proximity of the brainstem and the optical apparatus (FIG. 2). However, compared to MTLE, planning for HH is less challenging due to lower doses and smaller target volumes for hypothalamic hamartomas. In our institution, target doses range from 15-18 Gy. Target volumes have ranged from 0.3 to

Fig. 2. Radiosurgery treatment for hypothalamic hamartoma. Note the proximity of the brainstem and the optical chiasm to the target volume. The prescription isodose line is

on this topic by Quigg and Barbaro (2) and Romanelli *et al* (30).

**2. Methods and techniques 2.1 Mesial temporal lobe epilepsy** 

Gy to the optical apparatus.

**2.2 Hypothalamic hamartomas** 

2.1 cm3, with a mean volume of 0.81 cm3 (N=4).

shown in yellow and the 12 Gy isodose line in green.

## **2.3 Benchmarking treatment planning practices**

Due to the critical location of these lesions, special radiosurgical treatment planning techniques are applied to minimize the dose to the surrounding normal brain and functional structures. In order to achieve optimal dose fall-off outside of the target, it is preferable to use small collimators (i.e., 4-mm diameter) for treating such lesions. Selective blocking of individual beamlets is a must for enhancing the dose gradient toward a nearby critical structure. However, selective blocking and planning techniques are known to vary significantly among different Gamma Knife models and individual users. To benchmark such differences, a pre-clinical trial quality assurance procedure was developed. The results of such a study are summarized in the following section.

## **3. Comparison among present gamma knife models for treating MTLE**

There are multiple models of the Leksell Gamma Knife currently in use. The newest is the Perfexion model introduced in 2006 (5-7). The Perfexion uses 192 Cobalt-60 sources (versus 201 Cobalt-60 sources of prior Gamma Knife models) focused on a single point, the isocenter. The sources are arranged and divided conically into 8 sectors each containing 24 sources. The sources can be collimated to form circular beams with a 4-mm, 8-mm, or 16 mm diameter respectively or blocked entirely, with each sector being independently controlled, which is fundamentally different from previous models.

By contrast, the previous model Gamma Knife (Model 4C) uses 201 Cobalt-60 sources. The sources are collimated to form circular beams with 4 mm, 8 mm, 14 mm, or 18 mm diameters. The collimator size is selected by switching helmets. All beams have the same diameter, but individual beams can be blocked by "plugging" the helmets. However, switching helmets and changing plugging patterns can be time consuming, so in reality only a limited number of plugging patterns are used. Despite these differences, the mechanical accuracy of all Gamma Knife models has been consistently maintained to be better than 0.4 mm. As a result, Gamma Knife has so far been the only radiosurgical modality reported for managing intractable mesial temporal lobe epilepsy.

As part of the physics review process for the ROSE trial, each center was required to submit a treatment plan based on a sample data set for the purpose of quality assurance. Image data for this sample patient were transferred to participating institutions. The target volume was then delineated and a treatment plan was created to satisfy the previously described dosimetric constraints. The plans were then transferred to the review center for a centralized review by the trial director. Plans that did not satisfy the dosimetric constraints were revised and resubmitted. Plans were submitted for the Gamma Knife Perfexion and C/4C models, depending on the device used at the individual centers. These data were analyzed to look for potential differences between the Perfexion and C/4C models.

A total of 13 plans from 8 institutions satisfied the dosimetric constraints and were included in the data analysis. This included seven plans for the Model 4/4C and six plans for the Perfexion. Details of the individual plans are shown in TABLE 2.

Parameters studied included beam-on time, number of shots, volume receiving 24 Gy (V-24Gy), minimum dose to the delineated target, and the gradient index. Beam-on time was

Advanced Gamma Knife Treatment Planning of Epilepsy 129

Fig. 3. Boxplots showing the total volume receiving the prescription dose and the minimum dose received by the target. Differences were not statistically significant, although the results suggest that plans generated for the Perfexion provide better target

Fig. 4. Comparison of the number of shots and beam-on time of treatment plans for the Gamma Knife Perfexion and Model 4C. Due to high variability in the results, differences are not statistically significant. However, the mean number of shots and mean beam-on time are

coverage.

lower for the Perfexion.


Table 2. Summary of Treatment Planning Results of a Single MLTE Case by 8 Individual Institutions.

calculated assuming a dose rate of 3.0 Gy/minute. The gradient index was defined as the volume receiving the prescription dose (24 Gy) divided by the volume receiving half the prescription dose (12 Gy).(31) The Wilcoxon rank-sum test was employed to check for statistical significance.

The average 24-Gy volume was larger for Perfexion plans as compared with Model 4/4C plans, suggesting more aggressive targeting of the treatment area while satisfying normal tissue constraints due to the added flexibility of the Perfexion. Plans created for the Perfexion tended to have a higher minimum dose to the target volume (FIG. 3), which is consistent with the above result. In addition, the results showed that the plans for the Perfexion tended to have shorter beam-on times (155±58 vs. 163±62**)** and used fewer shots (19±5 vs. 20±10). However the differences were not statistically significant due to the small sample size (FIG. 4). In particular, Plan 7 (for the 4C) used only four shots and had an extremely short beam-on time. After excluding Plan 7, the beam-on time and number of shots for the Model 4C increase to 182±41 minutes and 23±8 shots, respectively. The mean gradient index was 3.0 for both the Perfexion and the Model 4C.

1 1 4C 5.6 6.7 128 17 3.16 2 2 4C 5.7 7.2 209 37 2.90 3 2 4C 5.6 6.0 209 26 2.95 4 3 4C 5.5 6.9 228 20 3.47 5 4 4C 6.2 3.2 180 22 2.86 6 4 4C 5.5 3.8 138 17 3.09 7 5 4C 6.2 9.9 51 4 2.71 **All 4C 4C 5.8**±**0.3 6.2**±**2.2 163**±**62 20.4**±**10.0 3.0**±**0.2**  8 2 Pfxn 6.7 7.1 197 23 3.02 9 6 Pfxn 7.5 5.2 158 17 2.93 10 7 Pfxn 5.6 6.4 120 17 3.02 11 2 Pfxn 5.5 7.0 246 26 2.96 12 8 Pfxn 7.5 7.2 123 19 2.87 13 8 Pfxn 7.4 8.7 88 12 2.95 **All Pfxn Pfxn 6.7**±**0.9 6.9**±**1.1 155**±**58 19.0**±**4.9 3.0**±**0.1** 

Table 2. Summary of Treatment Planning Results of a Single MLTE Case by 8 Individual

calculated assuming a dose rate of 3.0 Gy/minute. The gradient index was defined as the volume receiving the prescription dose (24 Gy) divided by the volume receiving half the prescription dose (12 Gy).(31) The Wilcoxon rank-sum test was employed to check for

The average 24-Gy volume was larger for Perfexion plans as compared with Model 4/4C plans, suggesting more aggressive targeting of the treatment area while satisfying normal tissue constraints due to the added flexibility of the Perfexion. Plans created for the Perfexion tended to have a higher minimum dose to the target volume (FIG. 3), which is consistent with the above result. In addition, the results showed that the plans for the Perfexion tended to have shorter beam-on times (155±58 vs. 163±62**)** and used fewer shots (19±5 vs. 20±10). However the differences were not statistically significant due to the small sample size (FIG. 4). In particular, Plan 7 (for the 4C) used only four shots and had an extremely short beam-on time. After excluding Plan 7, the beam-on time and number of shots for the Model 4C increase to 182±41 minutes and 23±8 shots, respectively. The mean

gradient index was 3.0 for both the Perfexion and the Model 4C.

Minimum dose (Gy)

Beam-on Time (min) No. of Shots

Gradient Index

(cm3)

Plan Institution Machine V-24Gy

Institutions.

statistical significance.

Fig. 3. Boxplots showing the total volume receiving the prescription dose and the minimum dose received by the target. Differences were not statistically significant, although the results suggest that plans generated for the Perfexion provide better target coverage.

Fig. 4. Comparison of the number of shots and beam-on time of treatment plans for the Gamma Knife Perfexion and Model 4C. Due to high variability in the results, differences are not statistically significant. However, the mean number of shots and mean beam-on time are lower for the Perfexion.

Advanced Gamma Knife Treatment Planning of Epilepsy 131

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### **4. Summary**

Gamma Knife radiosurgery is being actively investigated as an alternative to open surgery for the treatment of MTLE and other forms of medically intractable epilepsy. Despite notable efficiency and practice differences between the various Gamma Knife models, consistent treatment planning practices and dosimetric parameters are demonstrated for a multi-institutional international trial setting. The final clinical results of such a trial for treating MTLE are forthcoming.

## **5. References**


Gamma Knife radiosurgery is being actively investigated as an alternative to open surgery for the treatment of MTLE and other forms of medically intractable epilepsy. Despite notable efficiency and practice differences between the various Gamma Knife models, consistent treatment planning practices and dosimetric parameters are demonstrated for a multi-institutional international trial setting. The final clinical results of such a trial for

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adverse events, and verbal memory. *Ann Neurol* 2009; 65:167-75.

gamma knife radiosurgery for mesial temporal lobe epilepsy: seizure response,

hamartomas in gelastic epilepsy. *Annals of Neurology* 1997; 42:60-7.

Epilepsy: A comprehensive textbook. Philadelphia: Lippincott-Raven Publishers;

application to hypothalamic hamartoma. In: Wylie EG, Ajay, Lachhwani DK, eds. The treatment of epilepsy:principles and practice 4th ed. Philadelphia: Lippincott

Epileptic Seizures: Preoperative Course and Postoperative Outcome. *Neurosurgery*

Knife radiosurgery for mesial temporal lobe epilepsy: A prospective multicenter

**4. Summary** 

**5. References** 

treating MTLE are forthcoming.

1997:1-7.

2008; 65:177-83.

1996; 39:26-34.

6:39.

Williams & Wilkins; 2006:1169-74.

Epilepsy. *Epilepsia* 1999; 40:1551-6.

study. *Epilepsia* 2011; 52:909-16.

epilepsy. *Journal of Neurosurgery* 2000; 93:141-6.


**8** 

*USA* 

**Hemorrhage from Arteriovenous Malformation** 

Arteriovenous malformations (AVM) are uncommon congenital abnormalities with a prevalence of 10-18 per 100, 000 adults (Al-Shahi et al. 2002; Berman et al. 2000) and an incidence of 1. 3 per 100, 000 person-years. (Stapf et al. 2003) Arteriovenous malformations typically present with hemorrhage, seizure, or focal neurological deficit. Intracranial hemorrhage is the most common clinical presentation of an AVM, resulting in significant morbidity and mortality. The natural risk of primary hemorrhage in untreated AVMs is 2% to 4% per year. (Barrow and Reisner 1993; Brown et al. 1988; Crawford et al. 1986; Davis and Symon 1985; Forster, Steiner, and Hakanson 1972; Fults and Kelly 1984; Graf, Perret, and Torner 1983; Mast et al. 1997; Ondra et al. 1990; Pollock et al. 1996) The primary goal of AVM treatment is elimination of the risk of hemorrhage by removal of the bleeding potential of the abnormal vasculature. Currently, the therapeutic options for AVM treatment include microsurgical resection, stereotactic radiosurgery (SRS), and endovascular embolization, alone or in combination. Small AVMs or those that are surgically inaccessible in deep brain or eloquent cortex are typically amenable to

Complete obliteration of the vascular malformation and concomitant elimination of the risk of hemorrhage are the goals of radiosurgical treatment for AVM. There is generally a latency period of 2 to 3 years to achieve the vessel obliteration that results from radiationinduced changes to the abnormal vasculature, and 80%-95% of patients will achieve angiographic obliteration by 5 years. (Colombo et al. 1994; Friedman, Bova, and Mendenhall 1995; Karlsson, Lindquist, and Steiner 1997; Lindqvist et al. 2000) During the interval from treatment to AVM obliteration, a risk of rupture persists, but there is debate as to the direction and magnitude of the influence of radiosurgery on the risk of AVM hemorrhage during the latency period. Conflicting reports in the literature provide evidence for a decreased risk of hemorrhage, (Karlsson, Lax, and Soderman 2001; Karlsson, Lindquist, and Steiner 1996; Kjellberg et al. 1983; Levy et al. 1989; Maruyama et al. 2005; Maruyama et al. 2007; Yen et al. 2007) an unchanged risk of hemorrhage, (Friedman et al. 1996; Kjellberg 1986; Lunsford et al. 1991; Maesawa et al. 2000; Nataf et al.

**1. Introduction** 

stereotactic radiosurgery.

**Following Gamma Knife Radiosurgery:** 

**Pathophysiology of Rupture Early** 

Juanita M. Celix, James G. Douglas and Robert Goodkin

**in the Latency Period** 

*University of Washington* 

