- Email: [email protected]
Radiation Therapy of Epilepsy
CHAPTER 106
Radiation Therapy of Epilepsy ELLEN AIR • NICHOLAS BARBARO
History Experience with stereotactic radiosurgery (SRS) over the 60 years since its development by Lars Leksell1 has demonstrated its efficacy in the treatment of various central nervous system conditions. Although Leksell initially developed this technique to treat functional disorders such as pain and movement disorders, the earliest widespread uses of SRS focused on deep-seated tumors or arteriovenous malformations (AVMs) located in eloquent regions of the brain, using it as a means of treating these lesions while avoiding the risks associated with surgical resection.2 Within these contexts, seizures were treated as secondary manifestations of the primary disorder, rather than as specific conditions. Subsequent to radiosurgical treatment, significant reduction, or even resolution, of the associated seizures has been documented. The efficacy of SRS in secondary epilepsy has been most evident following the treatment of AVMs.3-9 Several large series of patients with AVMs have found complete seizure remission in 50% to 80% of patients following SRS.5,7-9 Small lesion size,7 shorter duration of epilepsy,5 and absence of prior hemorrhage9 were associated with higher seizure-free outcomes. In contrast, seizure outcome appears to be independent of AVM obliteration.3,4,6,8 Steiner et al. found 3 of 11 patients who became seizure free following SRS did so despite persistence of the AVM,8 while Lim et al. found 40% of patients with partial AVM obliteration to be seizure free.6 A similar phenomenon was described by Schrottner et al. in the treatment of 24 patients with tumor-related intractable epilepsy. Prolonged seizure control was achieved in 54% of patients in a dose-dependent manner, while tumor control was achieved in all patients.10 These studies indicate that radiosurgery exerts an independent antiepileptic effect. Animal studies have provided additional support for the use of radiosurgery in the treatment of seizures, as well as insight into the potential mechanism underlying its antiepileptic effect. One hypothesis has been that radiation causes destruction of epileptogenic tissue. Dose-dependent cell death and radiation necrosis develop in both normal and epileptic rat models in response to increasing doses of radiation.11-15 Similarly, a dose-dependent effect of radiation on seizure control has been demonstrated in several rat models of epilepsy. However, seizure reduction occurred in the absence of necrosis,11,13,14,16 suggesting necrosis may not be required for antiepileptic effects.
Another hypothesis has been that radiation inhibits seizure-induced neurogenesis and mitosis. In electrically kindled rats, radiation prevented kindling-associated neuroblast proliferation.17,18 Similarly, radiation halted seizureinduced mitosis in flurothyl-kindled mice.19 Despite the clear effect on neurogenesis and mitosis in these models, radiation did not inhibit mossy fiber synaptic reorganization,20 kindling progression, or seizure threshold.17,19 Alternatively, radiation may induce vascular and inflammatory changes that lead to seizure reduction.21 Further animal studies will be critical to understanding the mechanisms underlying radiation-induced seizure control.
Modern Indications HYPOTHALAMIC HAMARTOMAS Hypothalamic hamartomas (HHs), though rare, are an important cause of debilitating epilepsy in childhood. HHs can cause a progressive epileptic encephalopathy characterized by seizures, endocrine dysfunction, cognitive and behavioral impairment, and developmental delay. Classically, HHs are associated with gelastic seizures, which appear as recurrent bouts of emotionless laughter or grimacing. In addition, most patients develop multiple seizure types, including tonic–clonic, partial complex, and drop attacks.22,23 As devastating is the progressive cognitive decline that accompanies the medically refractory epilepsy.24 These heterotopic masses of mixed neuronal and glial cells arise from the floor of the third ventricle or mammillary bodies and present a significant therapeutic challenge due to their deep location and critical surrounding structures. Both open and endoscopic surgical approaches have been used in the resection of these lesions. While good seizure outcomes have been achieved, resection is associated with high morbidity and mortality.25-27 SRS has therefore emerged as a primary treatment for HHs due to its ability to precisely target and treat HHs without the morbidity of surgical resection. Arita et al. first applied gamma knife radiosurgery (GKS) to the treatment of a 25-year-old male with HH-a ssociated epilepsy who remained seizure free 21 months after treatment.28 Regis et al. have the largest experience with GKS treatment of HH. They reported seizure cessation in 40% of patients, with an additional 20% experiencing only
1235
Radiation Therapy of Epilepsy ELLEN AIR • NICHOLAS BARBARO
History Experience with stereotactic radiosurgery (SRS) over the 60 years since its development by Lars Leksell1 has demonstrated its efficacy in the treatment of various central nervous system conditions. Although Leksell initially developed this technique to treat functional disorders such as pain and movement disorders, the earliest widespread uses of SRS focused on deep-seated tumors or arteriovenous malformations (AVMs) located in eloquent regions of the brain, using it as a means of treating these lesions while avoiding the risks associated with surgical resection.2 Within these contexts, seizures were treated as secondary manifestations of the primary disorder, rather than as specific conditions. Subsequent to radiosurgical treatment, significant reduction, or even resolution, of the associated seizures has been documented. The efficacy of SRS in secondary epilepsy has been most evident following the treatment of AVMs.3-9 Several large series of patients with AVMs have found complete seizure remission in 50% to 80% of patients following SRS.5,7-9 Small lesion size,7 shorter duration of epilepsy,5 and absence of prior hemorrhage9 were associated with higher seizure-free outcomes. In contrast, seizure outcome appears to be independent of AVM obliteration.3,4,6,8 Steiner et al. found 3 of 11 patients who became seizure free following SRS did so despite persistence of the AVM,8 while Lim et al. found 40% of patients with partial AVM obliteration to be seizure free.6 A similar phenomenon was described by Schrottner et al. in the treatment of 24 patients with tumor-related intractable epilepsy. Prolonged seizure control was achieved in 54% of patients in a dose-dependent manner, while tumor control was achieved in all patients.10 These studies indicate that radiosurgery exerts an independent antiepileptic effect. Animal studies have provided additional support for the use of radiosurgery in the treatment of seizures, as well as insight into the potential mechanism underlying its antiepileptic effect. One hypothesis has been that radiation causes destruction of epileptogenic tissue. Dose-dependent cell death and radiation necrosis develop in both normal and epileptic rat models in response to increasing doses of radiation.11-15 Similarly, a dose-dependent effect of radiation on seizure control has been demonstrated in several rat models of epilepsy. However, seizure reduction occurred in the absence of necrosis,11,13,14,16 suggesting necrosis may not be required for antiepileptic effects.
Another hypothesis has been that radiation inhibits seizure-induced neurogenesis and mitosis. In electrically kindled rats, radiation prevented kindling-associated neuroblast proliferation.17,18 Similarly, radiation halted seizureinduced mitosis in flurothyl-kindled mice.19 Despite the clear effect on neurogenesis and mitosis in these models, radiation did not inhibit mossy fiber synaptic reorganization,20 kindling progression, or seizure threshold.17,19 Alternatively, radiation may induce vascular and inflammatory changes that lead to seizure reduction.21 Further animal studies will be critical to understanding the mechanisms underlying radiation-induced seizure control.
Modern Indications HYPOTHALAMIC HAMARTOMAS Hypothalamic hamartomas (HHs), though rare, are an important cause of debilitating epilepsy in childhood. HHs can cause a progressive epileptic encephalopathy characterized by seizures, endocrine dysfunction, cognitive and behavioral impairment, and developmental delay. Classically, HHs are associated with gelastic seizures, which appear as recurrent bouts of emotionless laughter or grimacing. In addition, most patients develop multiple seizure types, including tonic–clonic, partial complex, and drop attacks.22,23 As devastating is the progressive cognitive decline that accompanies the medically refractory epilepsy.24 These heterotopic masses of mixed neuronal and glial cells arise from the floor of the third ventricle or mammillary bodies and present a significant therapeutic challenge due to their deep location and critical surrounding structures. Both open and endoscopic surgical approaches have been used in the resection of these lesions. While good seizure outcomes have been achieved, resection is associated with high morbidity and mortality.25-27 SRS has therefore emerged as a primary treatment for HHs due to its ability to precisely target and treat HHs without the morbidity of surgical resection. Arita et al. first applied gamma knife radiosurgery (GKS) to the treatment of a 25-year-old male with HH-a ssociated epilepsy who remained seizure free 21 months after treatment.28 Regis et al. have the largest experience with GKS treatment of HH. They reported seizure cessation in 40% of patients, with an additional 20% experiencing only
1235