Radiosurgical Treatment of Epilepsy

Published on 13/03/2015 by admin

Filed under Neurosurgery

Last modified 13/03/2015

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 942 times

CHAPTER 68 Radiosurgical Treatment of Epilepsy

Radiosurgical Therapy for Temporal Lobe Epilepsy

Radiosurgery is the precise application of focused radiation under stereotactic guidance to a targeted volume area within the brain identified on magnetic resonance imaging (MRI).1 Conceptualized by Lars Leksell for use in functional neurosurgery, radiosurgical treatment of neurological disorders has progressively widened its utility234 and is now also a treatment modality option for several neoplastic3584 and vascular indications.62,85118 Unlike standard-dose fractionated radiotherapy, radiosurgery allows the neurosurgeon to deliver effective, precise, and accurate doses of radiation to a smaller volume without affecting large portions of normal parenchyma, thereby allowing a powerful radiobiologic effect on the chosen targeted volume.1,119121

Epilepsy is one of the most common serious neurological diseases and has a prevalence of 0.5% to 1.0% in the U.S. population.122,123 Approximately, 20% of patients with epilepsy have seizures that are medically refractory (i.e., failing to respond to medications). Despite modern advances in new antiepileptic medications, the percentage of patients with medically refractory epilepsy has not significantly improved. Patients with medically refractory seizures may be referred for possible surgical management, and approximately half of them are found to be suitable candidates for open surgical resection of a seizure focus.124 Focal partial epilepsies such as temporal lobe epilepsy are typically responsive to open surgical resection and are increasingly being treated with “structural” treatment modalities.117,125

The most common type of open surgery performed for temporal lobe epilepsy is anterior temporal lobectomy, which is resection of a portion of the temporal lobe.123,125127 With modern advances in surgical and anesthetic techniques, microsurgical resection of mesial temporal lobe structures can be performed with low morbidity and even lower mortality.121 Open invasive surgical procedures, however, have inherent risks, including damage to the brain (either directly or indirectly by injury to important blood vessels), bleeding (which can require reoperation), blood loss (which can require transfusion), infection, and general anesthetic risks.128131 In addition, significant postoperative pain can result from surgical incisions and scars. Several clinical studies evaluating the morbidity and mortality associated with open microsurgery for temporal lobe epilepsy have reported that approximately 5% to 23% of patients undergoing open microsurgery experience a symptomatic neurological deficit postoperatively.126,128,129,132,133 Furthermore, open surgical procedures require several days of care in the hospital, typically including one night in the intensive care unit, which contributes to the economic costs of open microsurgical treatment.117 There is also a significant population of patients with medically intractable epilepsy who are unsuitable for conventional open microsurgery.117 These patients may have their epileptic focus in regions that are difficult to access or in eloquent functional regions of the brain where surgical resection could result in irreversible language, motor, or visual impairment.117,118

Radiosurgery is now being evaluated as an alternative treatment modality to open resective microsurgery for intractable temporal lobe epilepsy. High-dose radiation is toxic to all living cells, but the highly focused nature of radiosurgery allows stereotactic guidance and sparing of adjacent tissues from the damaging effects of radiation. Although performed in a hospital setting, radiosurgery is relatively noninvasive, with frame-based radiosurgery using just frame pins that penetrate only the skin to firmly fix the stereotactic frame to the skull. Typically, patients can return to full activity within 1 to 2 days after treatment. Currently, radiosurgery is under investigations as a treatment modality for epilepsy associated with vascular malformations, hypothalamic hamartomas, and medial temporal lobe epilepsy (MTLE) associated with mesial temporal sclerosis (MTS).*

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.117,118,144,153156 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.117,123,125,127,157162 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

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

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.

Radiosurgical Treatment of Epilepsy Associated with Hypothalamic Hamartomas and Cavernomas

Radiosurgery is, by definition, a neurosurgical procedure that uses stereotactically focused, converging narrow ionizing beams to induce a desired biologic effect in a predetermined target with minimal radiation delivered to surrounding tissues and without opening the skull. Lars Leksell, a Swedish neurosurgeon, was the first to introduce the concept of radiosurgery in 1951.166 His goal in performing stereotactic procedures was to avoid the risk associated with craniectomy, notably bleeding and infection. The increased worldwide use of GKRS to treat various pathologies has shown the side-effect profile of radiosurgery to be rare, generally transient, and quite easily predictable.57 Once it is established that resection of a small, deeply seated lesion is associated with a significant risk for surgical complications or functional worsening (or both), GKRS must be discussed as an alternative. For these indications, GKRS frequently compares favorably with microsurgical removal in terms of safety, efficacy, and cost-effectiveness.

The first radiosurgical treatments in epilepsy surgery were performed by Talairach in the 1950s.167 Unlike Leksell, he already had expertise in epilepsy surgery and led one of the first large comprehensive programs for epilepsy surgery. As early as 1974, Talairach reported on the use of radioactive yttrium implants in patients with MTLE without space-occupying lesions and showed a high rate of seizure control in patients with epilepsies confined to the mesial structures of the temporal lobe.167 In 1980, Elomaa165 promoted the idea of the use of focal irradiation for the treatment of temporal lobe epilepsy based on the preliminary reports of Tracy, Von Wieser, and Baudouin.168,169 Furthermore, clinical experience with the use of GKRS and LINAC-based radiosurgery for arteriovenous malformations and cortical-subcortical tumors (mostly metastases and low-grade glial tumors) revealed an anticonvulsive effect of radiosurgery in the absence of tissue necrosis.138,170,171 A series of experimental studies in small animals confirmed this effect134,172 and emphasized a relationship to the dose delivered.153,154 Barcia Salorio and colleagues and later Lindquist and coauthors reported on a small and heterogeneous group of patients treated by radiosurgery for the purpose of alleviating seizures. However, their data were poor173175 and unfortunately were never published in peer-reviewed papers, so precise data are unavailable.

The Department of Functional Surgery in Marseille is a major referral center for epilepsy surgery and radiosurgery and has reported the first comprehensively evaluated series of MTLE successfully treated by GKRS. The first use of GKRS for MTLE took place in 1993 and was reported in 1995 by this group.145 Several prospective trials by this group have demonstrated (1) the safety and efficacy of this approach,121,146 (2) a very specific timetable for the clinical and radiologic events,146,176 (3) the importance of the anterior parahippocampal cortex for seizure cessation,177,178 (4) the importance of the marginal dose (24 Gy) for efficacy,178 (5) sparing of verbal memory in dominant-side epilepsy,121 and (6) the nonlesional mechanism of action of radiosurgery.179 Recently, all these findings have been confirmed by a prospective trial in the United States.180 Since 1993, among a total of 8590 GKRS procedures, the Marseille group performed GKRS for epilepsy in 155 patients. The majority of these patients had MTLE (56 patients) or hypothalamic hamartoma (HH, 55 patients). The rest of the patients suffered from severe epilepsy associated with small benign lesions such as cavernous malformations (CMs), for which the epileptic zone was considered to be confined to the surrounding cortex.181

Cessation of seizures may be generated by a specific neuromodulatory effect of radiosurgery, without induction of a significant amount of histologic necrosis.145,176,179,182,183 Selection of the appropriate technical parameters (e.g., dose, volume target) that allow us to accurately achieve the desired functional effect without histologic damage remains an important challenge. A review of these cases, as well as other clinical and experimental data, suggests that the use of radiosurgery is beneficial only in patients in whom a strict preoperative definition of the extent of the epileptogenic network has been achieved184 and in whom strict rules of dose planning have been followed.178 The strategy is to identify patients in whom the safety-to-efficacy ratio makes radiosurgery advantageous or at least comparable to craniotomy and cortectomy.

In patients with HH, GKRS offers very low morbidity with efficacy similar to that of microsurgical alternatives.148,185 This has led us to systematically consider radiosurgery as the first-line treatment in patients with limited type I, II, and III and possibly type IV HH.185

Patients with CMs and a longer duration of epilepsy are thought to have a more widespread epileptogenic zone involving distant cortical structures.186188 In patients with seizures arising from eloquent cortex surrounding the lesion, GKRS appears to be a suitable alternative. It is essential that electroclinical correlation be established for this strategy to work. Microsurgical excision remains the preferred approach for cortical-subcortical epileptogenic CMs that are not located in functional cortex.

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,191193 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 studies198200 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).

Surgical Approach

Even though the first successful and safe removal of an HH was reported by Paillas and coauthors in 1969,189 interest in surgical cure of this specific group of patients developed only in the 1990s. According to Valdueza and colleagues, epilepsy-related HH is observed only with medium/large sessile HHs broadly attached to tuber cinereum or mammillary body.204 Microsurgical resection in this critical area is associated with a significant risk for oculomotor palsy, hemiparesis, and visual field deficits.205,206 The first clinical series evaluating microsurgical resection via pterional and midline frontal approaches did not emphasize complications.204,207210 However, in 2002, Palmini and coworkers observed severe complications after microsurgical resection in 7 of 13 patients by analyzing patients treated in several of the best centers for epilepsy surgery around the world.211 These complications included thalamocapsular infarcts with contralateral hemiplegia in 4 patients (with subtotal recovery), a transient third nerve paresis in 4 patients, central diabetes insipidus, and nonreversible hyperphagia.211 Nonetheless, they confirmed the efficacy of surgery for this kind of pathologic condition. More specifically, 3 patients showed complete seizure cessation and the remaining 10 patients had a greater than 90% reduction in the frequency of their seizures.

The rationale for surgical disconnection treatment of HH is that the lesion is not a neoplasm and removal of it is therefore not mandatory. A further factor favoring a disconnection technique is the possibility of avoiding the complications that may occur during dissection in the cisterns, a maneuver necessary for microsurgical resection. Delalande and associates actually stressed this point as favoring the simple disconnection of an HH versus complete excision of it because of the occurrence of severe complications in their first patient.205 When the clinical result is not satisfactory and the upper part of the lesion is mainly in the third ventricle, Delalande and colleagues proposed a second step via an endoscopic approach to the third ventricle. In 2003, Delalande and Fohlen published a series of 17 patients with a follow-up of between 1 month and 5.4 years.205a A second intervention (usually endoscopic) was necessary in 8 patients. In this excellent series, 47% of the patients (8 of 17) were seizure free, including 3 patients operated on twice. The authors reported some permanent severe complications, namely, 1 patient with hemiplegia, 1 with hemiparesis, 2 with hyperphagia, 1 with panhypopituitarism, 1 with hypothyroidism, and 1 with growth hormone deficiency. Transient morbidity included one case of meningitis and two cases of diabetes insipidus. In addition, the authors reported a postoperative frontal lobe ischemic complication that was apparently asymptomatic. In conclusion, only 6 patients (35%) were seizure free with no permanent toxicity. In contrast to reports of the use of a transcallosal approach, Delalande and Fohlen did not observe any memory deficit. Finally, the authors found a correlation between the completeness of exclusion and control of the seizures.