Stereotactic Radiosurgery for Epilepsy

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Stereotactic Radiosurgery for Epilepsy

Mark Quigg and Nicholas M. Barbaro

In association with epilepsy, radiosurgery is most often used in the treatment of symptomatic lesions, such as tumors or vascular malformations; epilepsy in these cases is often one of several presenting symptoms and often improves as a benefit of the treatment of the lesion. Recently, the use of radiosurgery has expanded to the treatment of physiologic lesions, such as those seen in mesial temporal lobe epilepsy, and previously inoperable epileptic lesions, such as hypothalamic hamartomas. This review will outline the radiosurgical treatment of epilepsy with special attention to mesial temporal lobe epilepsy.

Experimental Models for and Effects of Radiation on Epilepsy

Investigations on the effects of focal irradiation on epileptic lesions in experimental animal models of partial epilepsy carry some common findings that are important when evaluating trials of radiosurgery in human epilepsy. First, experimental models of focal epilepsy demonstrate that destruction of neuronal tissue through radionecrosis is not required. Instead, application of sufficient radiation to the epileptogenic penumbra surrounding a lesion appears to be the critical variable. Second, seizure response, either in successful remission or in a paradoxical worsening, varies with target, dose, and postoperative duration. Third, the treatment target, dose, and volume remain empirically determined, and scaling up from experimental models to humans is not straightforward.

It is not known how radiation produces an antiepileptic effect. Sensitivity to ionizing radiation is largely dependent on mitotic rate; therefore, neurons are relatively radioresistant. In kindled mice, although total brain radiation terminates seizure-induced mitotic activity in hippocampal dentate gyri, treated mice have no changes in seizure threshold or clinical seizure phenotype. Therefore, radiation-induced changes in mitotic activity may not underlie the antiepileptic effect.1 Tissue necrosis is not necessary.^2–5 Histology of radiosurgery-treated rat hippocampi shows changes of experimental hippocampal sclerosis rather than changes typical of acute or chronic severe radiation injury.^2–5 Similarly, after radiosurgery of human hippocampi, histopathology of resected tissue following “rescue” temporal lobectomy reveals hippocampal cell loss and fibrillary astrocytosis consistent with epilepsy-related sclerosis. No radiation-induced histopathologic changes are seen.⁶

Although neurons are resistant to radionecrosis, mitotically active structures–vasculature and glia–are not. One hypothesis, therefore, is that neuronal damage results from ischemia caused by radiation vasculitis. Accordingly, the major pathologic findings following focal radiation consist of endothelial damage.⁷ Other hypotheses suggest that radiated neuronal circuits undergo neuromodulation that renders an anticonvulsant (or, sometimes, a paradoxically proconvulsant) effect. Differential susceptibility to irradiation or ischemia among different neuronal populations within epileptogenic circuits may account for this phenomenon.⁸

Given these possible mechanisms, studies with the use of models of partial epilepsy address some of the questions regarding target, administration, time course, and clinical sequelae. These models include electrically kindled rats^2,9 studied through seizure surrogates of afterdischarge threshold or severity as well as rat models that experience spontaneous seizures.^3–5 The earliest of these series established that there might be a pro- or anticonvulsant effect of radiosurgery that varies with postoperative duration or dose. Kindled rats with doses ≤ 25 Gy to the amygdala experience clinically more intense seizures.⁹ Kindled rats treated with 40 Gy to the hippocampus initially experience a transient decrease in seizure threshold that later increases.²

Other experiments established relationships between dose and latency with experimental limbic seizures. In animals monitored for 6 weeks, doses of 80 and 100 Gy cause seizure reductions within 2 to 4 weeks postoperatively, whereas lesser doses cause reductions of slower onset. Increasing doses of radiosurgery correlate with higher percentages of rats that became seizure free.5 Other studies indicate that there is a threshold effect, with single treatments of 30 Gy being equally effective as 60 Gy.⁴ Therefore, “overdosing” beyond a tissue-damaging level carries little advantage. Long-term electroencephalogram (EEG) monitoring for periods of up to 10 months in epileptic rats establishes that the anticonvulsant effects of radiosurgery are durable.³

In summary, preclinical literature suggests that single-fraction focal radiosurgery has a dose-dependent effect on epileptic lesions. These experiments help define a therapeutic window of treatment dose bounded by ineffectiveness, paradoxical exacerbation, or delayed remission at the lower doses and by tissue necrosis at higher doses. Evaluation of human studies, therefore, requires particular attention to treatment dose, volume, and target.

Treatment of Lesional Epilepsy

Epileptogenic Tumors

Given the variety of types, pathology, and locations of central nervous system (CNS) tumors, the studies on the effects of radiosurgery on tumor-associated epilepsy are few. Schrottner et al, however, concentrated on the dose absorbed by tissue in tumor penumbra, dividing patients in two groups according to the volume of tissue outside the tumor that had received 10 Gy or more.10 Outcome was retrospectively ranked at mean duration of ~2 years as “excellent” (Engel class I and II) or not. High-volume patients achieved a 66% improvement rate compared with 42% for the low-volume group. Because all patients achieved tumor control with radiosurgery (thus removing tumor response as a confounder), the differing rates of seizure improvement suggest that higher radiosurgery volumes delivered to tumor penumbra are important in modifying tumor-associated epilepsy.

Arteriovenous Malformations

The potential efficacy of radiosurgery in the treatment of symptomatic localization-related epilepsies is most evident in the treatment of arteriovenous malformations (AVMs), with an across-study mean seizure-remission rate of 70%.11–15 Representative is the large series accumulated by Steiner et al, who reported that seizures remit after radiosurgery in 69% of patients with AVMs and epilepsy.¹² A later study¹⁵ described dose-volume effects on epileptogenic AVMs opposite that reported for epileptogenic tumors, in that seizure remission is better with smaller AVMs.¹⁵ The amount of radiation to the margin had no clear effect. Neither study found a relationship between obliteration of the AVM and seizure remission.^12,15

Cavernous Malformations

Rebleeding 16 and epilepsy,¹⁷ with independent incidences of ~2.5% per patient per year for either, form the bulk of morbidity associated with cavernous malformations (CMs). The across-study proportion of seizure remission reported in retrospective case series is 50%,^18–22 but the radiation dose may account for the broad range of remission, with greater doses associated with increased remission. For example, representing the two extremes in efficacy, Kim et al¹⁹ used a mean marginal dose of 15 Gy and a center dose of 26 Gy for a remission rate of 70%, whereas Shih and Pan²² reported mean doses of 13 Gy marginal and 21 Gy central for a remission rate of 25%. The volume or marginal dose applied to the brain surrounding CMs, thought important in epileptogenic tumors¹⁰ and possibly AVMs,¹² has not been systematically studied in terms of seizure control. Retrospective studies of open resection suggest that removal of the hemosiderin-stained tissue surrounding CMs is associated with better outcomes;²³ therefore, variable outcomes following radiosurgery may also stem from targeting of epileptogenic tissue surrounding CMs.

Unfortunately, excess morbidity in terms of radiotoxicity with higher doses and postoperative hemorrhage with lower doses remains a concern. For example, the early Swedish experience determined that radiosurgery did not appreciably alter the natural course of CMs while exposing patients to radiation-induced complications that exceeded by 7 times those expected for the same dose for AVMs.²⁴ A case of a patient treated with radiosurgery for a bilateral CM and intractable epilepsy reported delayed (>2 years postoperative) radionecrosis and intractable edema, requiring craniotomy and hyperbaric oxygen treatments.²⁵ A more recent retrospective comparison concluded that open resection resulted in better seizure control and rebleeding avoidance than radiosurgery.²² This study, as well as comparisons to the ~70 to 80% seizure remission rate seen after open surgery for CMs,^26,27 suggests that any benefits of noninvasive radiosurgery over open surgery for CMs must be weighed against risks of less efficacy and possibly increased toxicities. From the viewpoint of an epileptologist, the thorough presurgical localization of the epileptic network in the region of CMs should guide resection, whether performed with open surgery or radiosurgery.

Hypothalamic Hamartomas

Hypothalamic hamartomas are an important cause of an epileptic encephalopathy marked by medically intractable gelastic and other seizures usually accompanied by behavioral and cognitive decline. Although hypothalamic hamartomas are difficult to excise with the use of standard surgical techniques, radiosurgery has the advantage of noninvasive access. Series of radiosurgery treatment of hypothalamic hamartomas 28–33 demonstrate a seizure remission rate of 27% across studies. Although this rate appears low, seizure remission alone underestimates the benefits on morbidity and custodial care required in these cases of severe epilepsy. Behavioral outcomes have not been rigorously quantified, but most reports cited above note that the majority of patients undergoes anecdotal improvements in behavior, sleep quality, and learning.

A European multicenter, prospective trial of radiosurgery for hypothalamic hamartomas has enrolled 60 patients, 27 of whom exceeded 3 years follow-up.32 This study emphasizes the evolution of seizure changes during the postoperative period. Within the first 2 months a slight improvement in seizure rate typically occurs. Seizures transiently worsen in frequency before reduction and remission occur. Behavioral improvements, along with EEG normalization, tend to occur in a more linear fashion. Morbidity is low, with no ill effects except for one instance of poikilothermia noted among the above reports. Some data emphasize the importance of the marginal dose of radiation³² as noted in tumors and AVMs. Patients treated with doses >17 Gy to the margin of hypothalamic hamartomas have greater rates of seizure remission than those receiving <13 Gy.²⁸ Radiosurgery may be one of several nontraditional surgical approaches that can improve what is otherwise a devastating epileptic encephalopathy.