Radiosurgical Treatment for Epilepsy

Dose

The targets in functional radiosurgery (capsulotomy, thalamotomy of ventral intermediate [VIM] or the centromedian nuclei, pallidotomy) were treated using a high dose (300–150 Gy nuclei) delivered in very small volumes (3–5 mm in diameter). Barcia-Salorio et al. reported a small and heterogeneous group of patients treated with different types of radiosurgery and variable dosimetry plans according to the patient. Some of these patients were treated with very large volumes and very low dosage (10 Gy). These results led several other investigators to consider using very low doses, as low as 10 to 20 Gy at the margin, but to expect the same efficacy as the 24-Gy protocol (at the margin). This was the dose that was used for first series of patients with MTLE in Marseille. However, the real rate of seizure cessation and control was only 36% (4 of 11) among the 11 patients reported by Barcia-Salorio et al., and this was much lower than what we would expect with resection in MTLE. ^{, ,}

In another publication, Yang et al. confirmed that only a very low rate of seizure cessation is achieved when low doses (9–13 Gy at the margin) are used, based on the results in a heterogeneous group of 176 patients. Again, a deescalation study has demonstrated poorer results in patients receiving doses of 18 to 20 Gy at the margin compared with 24 Gy. ^, This finding is significant because any radiosurgical management strategy associated with a much lower rate of seizure control in MTLE is unacceptable because of the high rate of seizure freedom achievable by surgical resection. Fractionated stereotactically guided radiotherapy was used by Grabenbauer et al. in 12 patients; none of these patients become seizure free, and only seizure reduction has been obtained in this series. ^,

Efforts to use lower doses to reduce radiographic changes consistent with tissue damage and edema have shown that there seems to be an effective dose threshold at or greater than 20 Gy. Recent dose studies have also suggested that a dose of 20 Gy or less at the margins may be less effective than higher marginal doses in reducing seizure activity. Cmelak and colleagues reported unsuccessful reduction of seizures with a 15-Gy marginal radiosurgery dose. Similarly, Kawai and colleagues reported two cases of radiosurgery with an unsuccessful antiepileptic effect at a marginal radiosurgery dose of 18 Gy. 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. Chang and colleagues showed that a significant radiographic change was correlated with a better seizure-free outcome, further corroborating these data.

Target

When the target volume is a lesion, then it can be precisely defined radiologically and the question of the selection of the marginal dose can be easily addressed by correlating safety and efficacy with individual outcome to the marginal dose and can be refined based on stratification according to volume, location, age, and so on. However, this is not the case in patients with MTLE for two main reasons: there is no consensus regarding the required extent of mesial temporal lobe resection for optimum seizure control, and the concept of MTLE syndrome with a stable extent of the epileptogenic zone that can be defined as surgical target is controversial. ^, The volume, in association with marginal dose, is well known to be a major determinant of the tissue effect in radiosurgery, as shown in integrated risk/dose volume formulas. Therefore target volume definition and determination are crucial in the effectiveness of GKRS in patients with MTLE. In the first series of patients treated in Marseille, the marginal isodose volume was approximately 7 mL (range, 5–8.5 mL). In a published study, authors tried to correlate dose and volume, degree of MRI changes, and seizure control rates. In this study it was found that the higher the dose and the volume were, the higher the risk was of having more severe MRI changes, as well as the higher the chance was of achieving seizure control and cessation.

It is clear that effective dose planning with smaller prescription isodose volumes needs more precise definition of the essential targets in the mesial temporal lobe. This is a difficult main task, however. There is growing evidence in the current literature that defines the organization of the epileptogenic zone as a network. According to this hypothesis, the epileptogenic zone includes several different and possibly distant structures that discharge simultaneously at the onset of the electroclinical seizures. This perspective helps to explain the high failure risk in a simple lesionectomy without preoperative investigations in the management of severe drug-resistant epilepsies associated with a benign lesion. ^, This has been also reported in MTLE cases. ^, Therefore, precise definition of the target in radiosurgery is very critical. Wieser et al. analyzed postoperative MR images of patients who were operated on by Yasargil and underwent amygdalohippocampectomy. In this study they were able to correlate the degree of the resection of each substructure of the mesial temporal lobe and correlate the result with the seizure outcome cessation. The authors reported that only the resection amount of the anterior parahippocampal cortex was correlated strongly with a higher chance of seizure control and cessation. We in the Marseille group also tried to perform a similar study in patients treated with GKRS.

Patient Selection

Whang and Kwon reported seizure cessation and control in 39% (12/31) of the patients who were treated with radiosurgery for epilepsy associated with slowly growing lesions. This observation as well as the arguments we summarized previously emphasize the importance of preoperative clear definition of the epileptic zone and network and its relationship with the target lesion. ^, Therefore the optimum philosophy is to choose appropriate preoperative investigations and management strategies in each case individually. In some patients the electroclinical information, structural and functional imaging, and neuropsychological examination may be sufficiently concordant, and surgery of the temporal lobe is proposed without depth electrode recording. In other cases preoperative assessment results may be discordant to define MTLE reliably, and a stereo-electroencephalographic (stereo-EEG) study is performed. Stereo-EEG implantation is used to assess the reliability of the primary hypothesis (mesial epileptogenic zone) or alternative hypothesis (early involvement of the temporal pole, lateral cortex, basal cortex, insular cortex, or other cortical areas). The aim is to record the patient’s seizures to define the temporospatial pattern of cortical involvement during these seizures. In these patients, depth electrode recording allows precise tailoring of the extent of surgical resection according to the temporospatial course of the seizures. Furthermore, if depth electrode investigation enables us to define a particular subtype of MTLE, then further tailoring of the treatment target volume, even reducing it, becomes feasible. Because the main limitation of radiosurgery is the size of the target (prescription isodose volume), the requirement for precision and accuracy to define the epileptogenic zone and network is higher in this technique. Although this requirement makes the GKRS planning for MTLE very challenging, it also makes it the most selective surgical modality for this group.

One of the difficulties in applying radiosurgery broadly as an application for intractable MTLE is the definition of the radiosurgical target because of a lack of clear boundaries of MTS ( Fig. 97.1 ). For example, Régis and colleagues radiosurgically targeted the mesial temporal lobe structures in their series, whereas Kawai and colleagues restricted their treatment to the amygdala or hippocampus structures, and each series reported varying rates of successful amelioration of MTLE. ^{, , ,} Although target definition can 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.

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 because of ineffective seizure control after radiosurgery. ^{, ,} Histopathologic studies after subtherapeutic doses of 15 and 18 Gy found one of three patients with a necrotic focus with some prominent vascular changes consisting of vessel wall thickening and fibrinoid and hyaline degeneration. ^, When treated with a larger but 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.

Currently the radiobiology of radiosurgery in the setting of MTS-associated MTLE is not completely understood. Although some preclinical studies have suggested an antiepileptic effect of radiation with subnecrotic doses, 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.

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 can 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. Elomaa theorized that the antiepileptic effect of radiation is further mediated through the effects of somatostatin. 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. Among patients who underwent open resection after radiosurgery, Kawai and colleagues and Srikijvilaikul and colleagues found necrotic foci with vessel wall thickening and fibrinoid and hyaline degeneration, perivascular sclerosis, and macrophage infiltration on resection on histopathologic analysis in two patients treated with 18 and 20 Gy, although no radiation-induced histopathologic changes were found in tissues treated with 15 Gy of radiosurgery, suggesting that some histologic damage may be needed for effective seizure control. ^a

aReferences 39, 44, 45, 48, 94, 109.

Animal studies have shown mixed results regarding this hypothesis, with some animal studies demonstrating improvement in seizures without evidence of necrosis, whereas others have shown direct structural, destructive lesions in the tissue zone to correlate with seizure remission. The mechanisms may be some combination of neuromodulation and neuronal destruction, with ischemic factors likely playing a role.

Surrogate markers of radiation effect and radiobiology, such as changes on MRI, are also showing some promising results. Radiation-induced edema typically becomes evident in most patients 9 to 15 months after radiosurgery ( Fig. 97.2 ). T2 hyperintensity volumes of edema were found to be closely related to seizure remission such that no seizure remission was found between 24 and 36 months in patients who had volumes of edema less than 200 mL at 12 months. These imaging findings, however, are usually time limited and are often followed by focal atrophic changes. Thus changes on MRI might 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 posttreatment 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, ^, recent case reports also demonstrate the failure of low-dose radiosurgery to control seizures. ^{, ,} Although failure of seizure control is easy to identify, it is a much more difficult task to determine that a 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. Furthermore, radiosurgery patients with 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. ^{, ,} Thus the best evidence 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 evidence suggests that the radiosurgery dose required to reduce seizures is close to the absolute tolerability threshold of human brain tissue.

Current Indications

Radiosurgery for MTLE is still an investigational option. The advantages are the comfort and no-invasiveness of the technique; avoiding general anesthesia and severe surgical complications, including mortality; the very short hospital stay; and finally the immediate return to the previous function level, activity, and employment. Whether or not radiosurgery provides a better result in sparing memory function is still a matter of debate and needs to be confirmed with further comparative analysis and studies. Long-term efficacy and safety of radiosurgery also need to be established. Microsurgery of MTLE provides very satisfactory results because of the rarity of surgical complications and the high rate of seizure control. Therefore the most appropriate treatment strategy should be chosen carefully, and the patient should clearly understand the advantages, disadvantages, and potential limitations of both strategies. The patient should be able to understand the limits and constraints of radiosurgery very well. In our opinion, the most important selection parameter is the demonstration of the purely mesial location of the epileptogenic zone.

Another good candidate for GKRS is the patient with proven MTLE who has had a surgical failure because of insufficient extent of resection. Overall, the best candidates are young patients with moderately severe epilepsy and socially well-adapted people with a high functioning level and quite a high risk of memory deficit with open surgery techniques (such as MTLE on the dominant side with a subtle hippocampal atrophy and slight preoperative deficit in verbal memory). Postoperative memory deficit exposes these patients to potentially huge social and professional consequences; therefore GKRS constitutes a very good alternative strategy for this patient group.