Preclinical Evidence

Preclinical studies investigating focused high-dose radiosurgery in animal models of epilepsy have demonstrated the potential utility of radiosurgical treatment applied to nonhuman epilepsy models. Early animal experiments indicated the efficacy of focused irradiation in a feline model of epilepsy in reducing seizure activity.^117,134,135 At doses between 10 and 20 Gy (1 Gy is equivalent to 1 J of energy per kilogram of tissue), cats with epileptic foci treated with an implanted cobalt radiation source had reduced seizure activity. Histologic analysis of these radiosurgically treated animal specimens revealed “neuronal reafferentation” as a proposed potential mechanism for amelioration of seizures with focused irradiation.^134,135

Recently, Sun and colleagues reported that radiosurgery successfully reduced seizure activity and raised seizure thresholds in a nonhuman epilepsy model.¹¹⁸ In this preclinical investigation, a linear accelerator (LINAC) was used to deliver radiosurgery doses of 10 or 40 Gy at the 90% isodose line. These investigators reported that seizure thresholds in these radiosurgically treated rats were significantly increased and that the length of afterdischarges was significantly decreased in the group treated with 40 Gy. These antiepileptic effects were observed 1 week after radiosurgical treatment, and the antiseizure effects persisted at the 3-month follow-up period.¹¹⁸

In animal studies from the University of Virginia, the effects of radiosurgery on a chronic spontaneous epilepsy model in rodents were reported.¹⁵³ In this preclinical investigation, hippocampal electrodes were implanted to produce a rodent temporal lobe epilepsy model. Ten weeks later, Gamma Knife radiosurgery (GKRS) with radiation doses between 10 and 40 Gy was applied as the therapeutic modality. Although the group receiving the lowest dose (10 Gy) showed no improvement in seizure activity, the 20-Gy group did exhibit a gradual and progressive reduction in seizures 2 to 6 months after radiosurgery. Also reported in this animal study, the 40-Gy group displayed a more dramatic and earlier reduction in seizures by the second month of follow-up. On histologic analysis of temporal lobe regions treated by radiosurgery in this rodent study, no necrosis in the tissue specimens was reported. Synaptically driven neuronal firing was reported to be intact in these radiosurgically treated rodent brain slices, thus suggesting that functional neuronal death was not responsible for the identified reduction in seizures.¹⁵³

Recent preclinical experiments from the University of Pittsburgh were designed to estimate the radiation dose in radiosurgery that was needed to reduce seizure activity in a rat kainic acid–induced epilepsy model.¹⁴⁴ In this animal investigation, rats underwent stereotactic injection of kainic acid into the hippocampus to induce seizures. Ten days after the injections, the focal epileptic injection site was treated by GKRS at a dose range of 20 to 100 Gy. Even animals treated with the lowest dose of 20 Gy in this study were reported to demonstrate a progressive reduction in the number of daily seizures during each week of observation after radiosurgery. Furthermore, 3 weeks after radiosurgery, all treated rats in this study at each radiosurgery dose—20, 40, 60, and 100 Gy—showed a statistically significant reduction in seizure activity. The authors reported that histologic evaluation revealed radiation-induced necrosis only at the highest 100-Gy radiosurgery dose. However, injection of kainic acid induces a loss of CA3 neurons in all animals, and for this reason, interpretation of the histologic findings, especially for radiation-induced necrosis, is extremely difficult and problematic in this kainic acid–based epilepsy model. Small areas of kainic acid–induced necrosis were, however, reported in 2 of 20 control animals and in 14 of 37 radiosurgically treated animals, but only in the animals treated with 100 Gy of radiosurgery did the observed histologic necrosis match the collimator size.¹⁴⁴

A second preclinical study using the same kainic acid–induced epilepsy model was undertaken to further evaluate the histopathologic and behavioral effects of “subnecrotic” radiosurgery doses.¹⁵⁴ Stereotactic hippocampal kainic acid injections were subsequently followed by GKRS at doses of either 30 or 60 Gy. A statistically significant reduction in seizures was reported in all radiosurgically treated animals, and this antiepileptic effect was observed earlier in the animals treated with the higher radiosurgery dose (weeks 5 to 9 versus weeks 7 to 9). Furthermore, in this preclinical investigation, no animals treated with radiosurgery were reported to demonstrate a deficit in new memory attainment tasks on water maze testing in comparison to control animals only injected with kainic acid, but both groups showed “cognitive” impairment when compared with rats that did not receive any kainic acid injection or radiosurgical treatment. For the histopathologic analysis in this study, two blinded observers evaluated the specimens from all animals at 13 weeks after radiosurgery. Typical changes with kainic acid injections were seen in all injected animals. Furthermore, in 25 of 46 injected animals, unilateral hippocampal atrophy was also observed. Again as noted earlier, histopathologic assessment is difficult given the use of kainic acid, but radiation-induced necrosis matching the target volume of radiation was not reported in any of the animals treated with radiosurgery.¹⁵⁴ These preclinical animal findings suggest that reduction of seizure activity after radiosurgery does not require necrosis or concomitant functional loss of treated neurons.¹⁵⁴

With the suggestion that necrosis is not necessary for reduction of seizures, the radiosurgery group in Prague reported on their preclinical characterization of a “subnecrotic” dose of radiosurgery in a rat model.^155,156 This preclinical investigation evaluated radiosurgery doses of 25, 50, 75, or 100 Gy delivered bilaterally to the rat hippocampus and then assessed the rats with cognitive tests, MRI, and histopathologic examinations at 1, 3, 6, and 12 months after radiosurgery. A progressive time- and dose-dependent response curve was observed in cognitive memory function, edema on MRI, and necrotic histopathology. All animals radiosurgically treated with the 100-Gy dose died by 6 months after radiation therapy, and all histopathology specimens from these rats had radiation-induced necrotic lesions. All animals treated with 75 Gy displayed cognitive memory functional impairments, edema on MRI, and radiation-induced necrotic lesions, whereas only one of the animals treated with the 50-Gy radiosurgery dose had observable edema and necrosis. Animals treated with radiosurgery doses of 25 and 50 Gy were not reported to demonstrate any functional or structural impairments after radiosurgery.¹⁵⁵ This observation of a potential subnecrotic radiosurgery dose that could improve seizure activity prompted a second follow-up preclinical study in which a 35-Gy radiosurgery dose was used with a long-term follow-up period of 16 months.¹⁵⁶ In this study, 6 months after radiosurgical treatment, edema was observed on MRI, and this edema was most pronounced at 9 months after radiosurgery. After 16 months, two of six treated animals were reported to have radiation-induced necrotic cavities after treatment with a 35-Gy dose of radiosurgery. The four treated animals without frankly necrotic cavities had other notable histopathologic findings such as severe atrophy of the corpus callosum, loss of thickness of the somatosensory cortex, and damage to the stratum oriens hippocampi.¹⁵⁶ These preclinical animal studies suggest that the full radiobiologic and histopathologic effect of radiosurgery may be manifested only several months after radiosurgery.

These preclinical studies reported amelioration of seizures, as well as histologic neuronal changes associated with radiosurgical treatment in different animal epilepsy models. These animal studies suggested that the antiepileptic efficacy of radiosurgery is dose dependent.^{121,144,153,154} Most of these studies suggest that a radiosurgery dose of approximately 25 Gy is required to induce a therapeutic antiepileptic effect and that the full histologic and other toxicity may require several months to fully develop.^{117,118,144,153–156} Animal models, however, may be poor predictors of radiation effects for translation to human biologic responses.

Clinical Evidence

The first application of radiosurgery for epilepsy surgery is attributed to Talairach in the 1950s, who implanted radioactive yttrium in patients with temporal lobe epilepsy without a lesion.^117,118,121 Further clinical experiences with GKRS and LINAC-based radiosurgery for the treatment of arteriovenous malformations and low-grade tumors also reported the incidental antiseizure effects of radiosurgery.* Although it is not clear whether lesion resolution itself may contribute to the reduction in seizure activity, these clinical reports of improvement in seizures with radiosurgery provided the impetus for investigating radiosurgery as a potentially effective treatment of medically intractable epilepsy.

Medial Temporal Lobe Epilepsy

MTLE associated with MTS is perhaps the most well defined epilepsy syndrome responsive to structural intervention. MTS is an idiopathic process associated with extensive loss of neurons and an increase in astrocytes in the mesial temporal structures, which include the amygdala and hippocampus in the temporal lobe. When temporal lobe epilepsy is due to underlying MTS, improvements in seizures with open microsurgical structural resections can be expected in between 65% and 90% of patients.^{117,123,125,127,157–162} This form of temporal lobe epilepsy is particularly amenable to structural interventions such as radiosurgery because 80% to 90% of these patients show detectable changes on MRI.^120,159

Radiosurgery has also been explored as an alternative to open microsurgery for MTS-associated MTLE. In a small series of patients with MTLE treated with GKRS, Régis and coauthors reported clinical and effective amelioration of seizures with minimal morbidity.^145,146 A recent, prospective, multicenter European study evaluating GKRS for MTS showed comparable efficacy rates (65%) for reduction of seizures by conventional microsurgery and radiosurgery after 2 years of follow-up.¹²¹ Using a marginal dose of 24 Gy, Régis and colleagues reported that radiosurgery can be used as an alternative to conventional open microsurgery to effectively treat MTLE associated with MTS and improve quality of life with comparable rates of morbidity and mortality.¹²¹ In the United States, a multicenter pilot trial is currently being conducted, and the initial results show that 85% of patients treated with 24 Gy (to the 50% isodose line) delivered to the medial temporal lobe, including the amygdala, anterior hippocampus, and nearby cortex, are seizure free at 2 years of follow-up with minimal morbidity (Barbaro and coworkers, unpublished). This study group is also planning a follow-up, phase III multicenter trial to compare open microsurgery with radiosurgery for patients with clinically and radiographically defined MTS-associated MTLE.

Although radiosurgery has proved effective and safe in improving MTLE-associated seizures, the beneficial effects of radiosurgery are not demonstrated immediately. Typically, patients with MTLE treated by radiosurgery can achieve improvement in seizures between 9 and 12 months and dramatic improvement in seizures between 18 and 24 months after treatment. A transient increase in partial seizures (auras) has been reported at approximately the same time that the complex seizures decrease.¹²¹ Most patients require a temporary course of corticosteroids to treat the delayed radiation-induced edema associated with the initial radiosurgical effect, commonly 10 to 15 months after treatment (Fig. 68-1) (Barbaro, personal observation).¹²¹

FIGURE 68-1 Changes on magnetic resonance imaging at 12 months and 24 months after radiosurgery.

One of the difficulties in applying radiosurgery broadly as an application for intractable MTLE is the definition of the radiosurgical target (Fig. 68-2). Because the MTS associated with MTLE is not clearly defined anatomically, the precise boundaries and structures for radiosurgical treatment are yet not well characterized. Hence, standardization among different academic and community treatment centers has not been implemented and is difficult to achieve thus far, and consensus on treatment targets remains elusive. Successful radiosurgical treatment, however, is correlated with the targets treated with radiosurgery. For example, in recent reports, Régis and colleagues radiosurgically targeted the mesial temporal lobe structures in their series, whereas Kawai and associates restricted their treatment to the amygdala or hippocampus structures, and each series reported varying rates of successful amelioration of MTLE.^{121,140,145,146} Although target definition may vary among different neurosurgeons, radiosurgery for MTS-associated MTLE remains an attractive therapeutic option because of its effectiveness, low morbidity and mortality, and the consistent manifestations of this disease with identifiable imaging characteristics on MRI. Moreover, conventional open microsurgical temporal lobectomy is still possible if the initial radiosurgical treatment is ineffective after sufficient time has elapsed for the delayed radiosurgical antiepileptic effect.¹²¹

FIGURE 68-2 Treatment planning session for Gamma Knife radiosurgery.

Furthermore, recent dose studies have also suggested that a lower dose of 20 Gy at the margins may be less effective than higher marginal doses in reducing seizure activity. Cmelak and coauthors reported unsuccessful reduction of seizures with a 15-Gy marginal radiosurgery dose.¹⁶³ Similarly, Kawai and coworkers reported two cases of radiosurgery with an unsuccessful antiepileptic effect at a marginal radiosurgery dose of 18 Gy.¹⁴⁰ Finally, Srikijvilaikul and colleagues from the Cleveland Clinic also reported their series of ineffective radiosurgical treatment for seizure control with a 20-Gy marginal dose.¹⁶⁴

Histologic Evaluation after Radiosurgical Treatment of Medial Temporal Lobe Epilepsy

Histologic examination of radiosurgically treated human mesial temporal tissue for MTLE has been limited because of the efficacy of radiosurgery for MTS-associated MTLE. However, histologic analysis of radiation-treated tissues has been reported in patients who underwent resection as a result of ineffective seizure control after radiosurgery.^140,163,164 Using a subtherapeutic dose, Cmelak and coauthors reported no radiation-induced histopathologic changes in tissues treated with radiosurgery at 15 Gy.¹⁶³ In another series in which two patients were treated with 18 Gy, one patient was noted to have a necrotic focus with some prominent vascular changes consisting of vessel wall thickening and fibrinoid and hyaline degeneration, whereas the other patient treated with this subtherapeutic dose showed no necrosis or vascular histopathologic changes.¹⁴⁰ When treated with a higher, yet subtherapeutic dose of 20 Gy, all five patients from a series reported from the Cleveland Clinic demonstrated histopathologic necrosis, perivascular sclerosis, and macrophage infiltration on resection and evaluation.¹⁶⁴ These reports suggest that in the clinical use of radiosurgery, significant identifiable histologic changes may be observed only with radiosurgical doses of 20 Gy or greater. These radiobiologic and histologic markers such as necrosis and vascular changes may be required for an effective antiseizure effect to become manifested. Thus, a dose that produces some tissue necrosis and histopathologic effects without inducing an excessive biologic response (e.g., edema), such as 24 Gy, may be the optimal effective dose for the radiosurgical treatment of MTLE.^121,145,146

Currently, the radiobiology of radiosurgery in the setting of MTS-associated MTLE is not yet completely understood. Although some preclinical studies have suggested an antiepileptic effect of radiation with subnecrotic doses,¹⁵⁴ human clinical studies have suggested that a certain amount of tissue necrosis and histopathologic changes may be required to produce significant amelioration of MTS-associated seizures. The importance of this issue on biologic effect is that radiosurgical treatment of eloquent brain regions would be possible if an effective subnecrotic dose could be found.

The Antiepileptic Radiosurgery Mechanism

Although radiosurgery has been shown to reduce seizures in various forms of medically intractable epilepsy, the mechanism by which this abatement occurs is not well understood. It has been suggested that radiation itself has a direct antiepileptic effect that may operate through several mechanisms. Because glial cells are more radiosensitive than neurons, Barcia-Salorio proposed that low-dose radiosurgery may reduce glial scar formation, allowing increased dendritic sprouting and improved cortical reorganization that results in fewer seizures.¹³⁷ Elomaa theorized that the antiepileptic effect of radiation is further mediated through the effects of somatostatin.¹⁶⁵ Although the clinical results of the most recent human studies suggest that the therapeutic efficacy of radiosurgery is linked to histopathologic changes and identifiable necrosis of mesial temporal structures, proof of this theory would need to come from direct observation and histologic evaluation of tissue samples from patients in whom radiosurgery has effectively controlled the seizures. This is unlikely to occur because only patients with persistent seizures after radiosurgery are likely to undergo further open resective microsurgery.

Surrogate markers of radiation effect and radiobiology such as changes on MRI have thus far shown variable results. Radiation-induced edema typically becomes evident in most patients 9 to 15 months after radiosurgery (see Fig. 68-1). These imaging findings, however, are usually time-limited and are often followed by focal atrophic changes. Thus, changes on MRI may not be diagnostic or indicative of true radiation necrosis. Furthermore, our pilot clinical trials have shown that MRI changes and peak MRI effects are poorly correlated with post-treatment symptoms. The actual biomechanism by which high-dose radiation and radiosurgery reduce neuronal hyperexcitability to ameliorate seizures will probably not be found or elucidated from human studies.

Although preclinical evidence and the results from early clinical human trials suggest that control of seizures might be possible with doses of radiosurgery that are lower than those typically applied to tumors,^136,139 recent case reports also demonstrate the failure of low-dose radiosurgery to control seizures.^140,163,164 Although failure of seizure control is easy to identify, it is a much more difficult task to determine that lack of seizure control is caused by an insufficient radiation dose. The time dependence of radiosurgical effects is also a confounding factor that has not been fully elucidated, and a consensus among different treating radiosurgical centers of when radiosurgical treatment has “failed” has not yet been reached.¹⁴⁹ Furthermore, radiosurgery patients reported to have inadequate reduction of seizures commonly received radiation doses of 20 Gy or less, and these patients showed little evidence of radiation-induced necrosis or histopathologic changes in their tissue specimens.^140,163,164 Thus, the best evidence to date from human and animal preclinical experiments suggests that there is a steep dose-response curve for seizure reduction and that some neuronal necrosis is required to produce abatement of seizures. This suggests that the radiosurgery dose required to reduce seizures is very close to the absolute tolerability threshold of human brain tissue.

Summary

Recent data suggest that radiosurgery is an effective and safe alternative treatment modality for reducing epileptiform activity and seizures in patients with medically intractable temporal lobe epilepsy. In preclinical studies, the low doses of radiation required to be therapeutic have not been shown to cause histologic changes or significant learning deficits. When animals are observed over longer periods, the patterns of changes seen on MRI closely mimic those observed in human trials, and associated histologic analysis indicates that structural lesions are created. Animal studies have not yet proved whether the antiepileptic effects of radiosurgery are due to tissue necrosis and functional ablation or whether the seizure activity has been eliminated in still functional parenchyma. However, the available clinical human data suggest that it is necessary to produce changes on MRI consistent with tissue necrosis and histopathologic changes to eliminate seizures.

Recent prospective trials suggest that radiosurgery may be an effective and safe treatment modality for medically intractable epilepsy associated with MTS. Prospective trials with larger numbers of patients in multicenter studies will be required to establish radiosurgery as a standard alternative therapy for MTLE. Radiosurgery may prove to be especially appealing in treating lesions near functional cortex or deep-seated lesions when open microsurgical resection may not be feasible without significant morbidity.

Hypothalamic Hamartomas

HHs are rare congenital heterotopic lesions that are intrinsically epileptogenic when closely connected to the mammillary bodies.^185,189 Patients classically experience gelastic seizures during the first years of life.¹⁹⁰ In more severe forms of the disease, an epileptic encephalopathy characterized by drug resistance, various types of seizures with generalization (including drop attacks),¹⁹⁰ cognitive decline,^191–193 and severe psychiatric comorbidity develops in affected patients during the following years.¹⁹⁴ Usually, the seizures begin early in life and are often particularly drug resistant from the onset. Commonly, the seizure semiology suggests the involvement of temporal or frontal lobe regions and a phenomenon of secondary epileptogenesis. HHs may also be asymptomatic or be associated with precocious puberty, neurological disorders (including epilepsy, behavior disturbances, and cognitive impairment), or both.

In 1969, Paillas and coworkers first showed that the epilepsy associated with HH can be alleviated by surgical resection of the HH lesion itself.¹⁸⁹ Direct proof of the role of HH in generating seizure activity was provided by Munari and associates,¹⁹⁵ who relied on data obtained from stereo encephalographic recordings from implanted depth electrodes.^196,197 This evidence was reinforced by ictal single-photon emission computed tomographic studies^198–200 and by other studies using depth electrodes.^201,202

The natural history is unfavorable in the majority of patients because of behavioral symptoms (particularly aggressive behavior) and mental decline, which occur as a direct effect of the seizures.²⁰³ Interestingly, in our experience, reversal of these behavioral symptoms after radiosurgery seems to begin even before complete cessation of the seizures and appears to be correlated to the improvement in background electroencephalographic (EEG) activity. It is the authors’ speculation that these continuous discharges lead to the disorganization of several systems, including the limbic system, and that their disappearance accounts for the improvement seen in attention, memory, cognitive performance, and impulsive behavior. In these cases, radiosurgery’s role in reversal of the behavioral symptoms may be as or more important than its effect on decreasing seizure occurrence. Consequently, we consider it essential to operate on these young patients as early as possible, whatever the surgical approach being considered (resection or radiosurgery).