The Role of the Gamma Knife in the Treatment of Seizures
Hans G. Eder, MD†
Robert S. Fisher, MD, PhD
Department of Neurology, Barrow Neurological Institute, Mercy Healthcare Arizona, Phoenix, Arizona
†Department of Neurosurgery, Karl – Franzens University, Graz, Austria
A few early studies suggest that Gamma Knife radiosurgery appears to have a beneficial effect on seizures and to be well-tolerated by patients. Seizures associated with brain arteriovenous malformations (AVMs) often improve when the AVM is irradiated. Experience with the treatment of idiopathic mesial temporal epilepsy by radiosurgery is limited but favorable. The mechanisms of this benefit are unknown, but neurotoxic doses of radiation may not be required for efficacy. Much more experience and longer follow-ups, however, are needed to evaluate the true potential of this technique for the treatment of epilepsy.
Key Words : arteriovenous malformations, epilepsy, Gamma Knife, radiosurgery, seizures
Surgery is an effective treatment for some patients with intractable epilepsy.7,8,10 Because the underlying pathology in about 30% of patients with partial epilepsy is a foreign-tissue lesion,1, 23 partial or focal epilepsies have been treated successfully by surgical resection of the lesion itself (“lesionectomy”).5 A significant fraction of the remaining patients demonstrates mesial temporal sclerosis.9 In some patients with medically intractable epilepsy who are not candidates for focal resections, corpus callosotomy can decrease the frequency and severity of their seizures, particularly those severe enough to cause falls and trauma. However, surgery for epilepsy is associated with costs and risks, especially when lesions are located in deep or eloquent areas of the brain. One review has suggested that the associated mortality rate is approximately 1% and the morbidity rate is 10 to 20%.16
Alternative treatments with lower rates of morbidity and higher rates of efficacy are needed. One such treatment alternative is cerebral irradiation to eliminate the epileptogenic focus or to interrupt the propagation pathways of the epileptic discharges by means of the Gamma Knife or other focused beam radiation methods. The Gamma Knife was designed by Dr. Lars Leksell in the early 1950s for functional neurosurgery. He recognized that deep epileptic foci could become targets for irradiation.11 This article evaluates the current status of Gamma Knife radiosurgical therapy for seizures associated with arteriovenous malformations (AVMs) and epilepsy.
Seizures and AVMs
Considerable experience has accrued with the use of the Gamma Knife in the treatment of AVMs.13,19,20 When seizures are associated with AVMs, Gamma Knife treatment seems to be effective in reducing seizure activity.13,18-20 For example, Steiner et al.19 reported the results of Gamma Knife therapy in 228 patients with AVMs, 59 (25.9%) of whom had seizures as their presenting symptom. All 59 patients had evidence of prior intracerebral hemorrhage. After these 59 patients underwent radiosurgery, the seizures ceased in 41 (69.5%) patients, 11 (18.6%) of whom were able to stop taking their anticonvulsant drugs. In three of these 11 cases, the benefit occurred without obliteration of the AVM. Seizure activity was uninfluenced by radiosurgery in 18 (30.5%) patients. Moreover, 11 of the overall group of 228 (4.8%) AVM patients developed new seizures after Gamma Knife treatment.
Lunsford and colleagues13 treated 227 patients with AVMs with the Gamma Knife. Of these 227 patients, 70 (30.8%) had seizures before radiosurgery: 47 patients with generalized, 8 with complex partial, and 15 with simple partial seizures. According to a 1- to 3-year follow-up of 43 of these 70 patients, 22 (51%) improved, 20 (47%) had no changes in their epilepsy, and 1 (2%) became worse. No patients developed new types of seizures after radiosurgery. Reduction or elimination of seizures after radiosurgery was linked to reduced AVM flow, which was confirmed by neuroimaging. Unfortunately, no details were given about antiepileptic medications the patients may have taken before and after treatment or about the radiosurgical effect on different types of seizures.
Sutcliffe and coworkers20 reviewed 160 patients with intracranial AVMs treated by radiosurgery with a follow-up of at least 2 years. They delivered 25 Gy to the AVM margin (50% isodose curve). Forty-eight patients had epilepsy on presentation. The epilepsy improved in 29 (60%) patients, 18 of whom were seizure-free. The epilepsy worsened in three (6%) patients. Again, neither type and frequencies of seizures nor medication regimens were specified.
These studies suggest that Gamma Knife treatment may have a beneficial effect on seizures associated with AVMs in 50 to 70% of the cases. In some patients, however, this effect could be related to optimized anticonvulsant regimens around the time of radiosurgery or to other confounding factors rather than to obliteration of the AVM itself. Only in one study19 have a few patients (19%) been free of seizures for the duration of the follow-up interval.
Patients with Epilepsy
Gamma Knife radiosurgery has been used to treat only a small number of patients with idiopathic epilepsy. For example, Barcia-Salorio and associates2,3 treated 11 patients with idiopathic seizures with stereotactic radiosurgery. Nine patients received gamma irradiation at a dose of 10 to 20 Gy to the presumed seizure focus, and two received betatron irradiation. The seizure focus was localized by electroencephalography (EEG) and invasive monitoring with deep and/or cortical electrodes. In six cases the focus was localized to the mesial temporal lobe, in one to the lateral temporal lobe, in three to the occipital lobe, and in one to the parietal lobe. Patients with an estimated epileptic focus that was 15-mm diameter or less were treated with the Gamma Knife using 10-mm collimators and a dose of 10 Gy. One patient received bilateral irradiation for a bitemporal focus. Two patients with a cortical epileptic area estimated at 4 cm in diameter or more were irradiated with 10 to 15 MeV from a 45 MeV betatron. Patients continued their antiepileptic drugs for 1 year after radiosurgery, after which attempts were made to taper their medication. Seizures began to improve 2 to 12 months after treatment. Two of the six patients with mesial temporal epilepsy became free of seizures and were able to discontinue their antiepileptic drugs. The frequency of seizures was reduced at least 75% in three patients, and one experienced no change. Of the five patients with a focus outside the mesial temporal area, seizures remitted in two (medication free) and improved more than 75% in another two. In this study, follow-up ranged between 28 and 127 months, with a mean of 75 months.
Whang and Kim25 reported nine patients with intractable seizures and nonprogressive focal cerebral lesions. The location of only one lesion was specified (i.e., left mesial temporal lobe). Seizures were the only neurological symptoms in these patients and consisted of partial attacks with secondary generalized tonic-clonic seizures, complex partial seizures, and simple partial seizures. The seizure focus was localized by magnetic resonance (MR) imaging, scalp and nasopharyngeal EEG, and prolonged video EEG monitoring. The mean marginal dose delivered to the lesion was 26.7 Gy (range, 20 to 50 Gy) using the 45 to 70% isodose curves. The aim was stereotactic lesionectomy of the seizure focus. At follow-up at least 1 year after treatment, eight patients had excellent outcomes (i.e., seizure free, single seizures, or auras only), and two were able to discontinue their antiepileptic drugs. Only one patient failed to improve. Except for transient perilesional edema, which was asymptomatic, no complications were reported.
Regis and associates17 described the first selective amygdalohippocampal radiosurgery for mesial temporal lobe epilepsy. The patient’s seizure focus was delineated by MR imaging and electrical recordings from the scalp or bilateral foramen ovale electrodes. The target included the head and the anterior part of the hippocampal body, the amygdalofugal part of the amygdala, and the entorhinal area. A marginal dose of 25 Gy at the 50% isodose curve was used. After treatment the patient was free of seizures for the 16 months of follow-up but was still taking antiepileptic drugs. The first changes on MR imaging appeared 10 months after treatment in the form of contrast enhancement corresponding to the 50% isodose curve, a low signal intensity on T1-weighted images and a high signal intensity on T2-weighted images inside the target volume, and edema outside the target volume. Positron emission tomography showed a corresponding region of glucose hypometabolism.
Lindquist and coworkers12 reported six patients with complex partial seizures who underwent Gamma Knife treatment. Seizures were localized with EEG, magnetoencephalography, and MR imaging. During the observation period of 1 to 2 years, seizure activity decreased in all patients. No details, however, were given regarding the frequency of seizures, medications, or dose planning.
Irradiation also can be used to interrupt the propagation pathways of epileptiform discharges. Preliminary results of corpus callosotomy performed with the Gamma Knife in three patients have been reported.6 All three patients suffered from intractable epilepsy, classified in two as the Lennox-Gastaut syndrome and in one as multifocal epilepsy with atonic, tonic-clonic, and atypical absence seizures. Stereotactic radiosurgery was performed using a 4-mm collimator targeted to the rostrum, genu, and anterior half of the body of the corpus callosum. The patients were treated with a maximum dose of 150 to 170 Gy, using four isocenters in two patients and three isocenters in one patient. All three patients improved significantly with at least a 50% reduction in the overall frequency of their seizures. The improvement began 4 to 9 weeks after radiosurgery and continued throughout the mean follow-up period of 15 months. No new neurological deficit or disconnection syndrome was recorded during this period.
The concept of treating epilepsy by radiotherapy is not new. As early as 1905, Tracy22 described the use of x-radiation in conjunction with bromide medication. In 1939, Wieser24 treated 70 patients with epilepsy with external beam irradiation, the details of which were not described. Between 1959 and 1973, Talairach and Bancaud21 treated 44 seizure patients by stereotactic implantation of yttrium 90 with the aim of destroying the amygdala and the hippocampus. They reported short-term success in 11 of 15 cases of temporal lobe epilepsy. Since 1982 Gamma Knife radiosurgery has been used to replace surgical resection of epileptic foci and interruption of bilateral synchronous epileptiform discharges in a small number of selected patients with intractable epilepsy.2,3,6,17,25
The mechanisms by which irradiation reduces seizure activity are still unknown, and the optimal dose of radiation is not yet clear. Complete destruction of neural tissues may be unnecessary. Elimination or inactivation of certain “pacemaker” neurons of the seizure focus might, in theory, suffice. Barcia-Salorio et al.4 observed attenuation of chronic focal epileptiform activity in a cat-cobalt model of epilepsy after low-dose Gamma Knife radiation.4 They hypothesized that irradiation induces the formation of new synapses and changes in synaptic plasticity. Malis et al.14 observed the proliferation of dendrites after producing laminar lesions in rabbit cerebral cortex with deuteron irradiation. Monnier and Krupp15 reported that low-dose radiation (10 Gy) diminished cortical activity.
Vascular and glial tissue cannot in themselves generate epileptiform discharges. Therefore, the antiepileptic effect of irradiation on AVMs must be caused by some changes in the neuronal network in the vicinity of the lesion. Furthermore, the antiepileptic effect does not seem to depend upon the obliteration of an AVM.
Gamma Knife treatment of epilepsy remains experimental for several reasons. First, the number of treated patients remains very small. Studies have not yet randomized candidates to treatment arms such as an anterior-mesial temporal lobectomy performed by the Gamma Knife or conventional surgery. The duration of available follow-up also is too brief to evaluate long-term outcome. In this regard, the efficacy and safety of modern temporal lobectomies will be difficult to surpass. Can Gamma Knife treatment provide the “complete” removal of a mesial temporal seizure focus known to be needed for remission of temporal lobe epilepsy? Will Gamma Knife therapy also deliver significant radiation to the healthy margins of the target zone? Since most people with epilepsy will live for decades after therapy, the long-term consequences of such irradiation must be understood. In other settings, for example, brain irradiation has led to accelerated cerebrovascular disease, white matter changes, and dementia.
Radiation therapy to the brain is most often employed as a palliative therapy for cancer. Will the Gamma Knife also have a role in the palliation of intractable and unresectable epileptic foci? The answer to this question will depend upon whether radiation can attenuate seizure activity without causing necrosis of normal brain tissue. One case report2 of bitemporal radiosurgery for epilepsy, which did not mention a subsequent Kluver-Bucy syndrome, suggests that sometimes Gamma Knife treatment may be better tolerated (at least in the short-term) than surgical ablation. Definitive answers, however, will depend upon controlled clinical trials with careful delineation of the epileptic syndromes under treatment and long-term follow-up periods to evaluate the efficacy and safety of radiosurgical treatment of seizures.
- Awad IA, Rosenfeld J, Ahl J, et al: Intractable epilepsy and structural lesions of the brain: Mapping, resection strategies, and seizure outcome. Epilepsia 32:179-186, 1991
- Barcia-Salorio JL, Barcia JA, Hernandez G, et al: Radiosurgery of epilepsy. Long-term results. Acta Neurochir (Wien) 62:111-113, 1994
- Barcia-Salorio JL, Barcia JA, Roldan P, et al: Radiosurgery of epilepsy. Acta Neurochir (Wien) 58:195-197, 1993
- Barcia-Salorio JL, Vanaclocha V, Cerda M, et al: Response of experimental epileptic focus to focal ionizing radiation. Appl Neurophysiol 50:359-364, 1987
- Cascino GD, Kelly PJ, Sharbrough FW, et al: Long-term follow-up of stereotactic lesionectomy in partial epilepsy: Predictive factors and electroencephalographic results. Epilepsia 33:639-644, 1992
- Eder HG, Schröttner O, Pendl G: Radiochirurgische Kallosotomie bei Epilepsie. Zentralbl Neurochir Suppl:16, 1996
- Engel J, Jr: Alternate treatment, in Engel J, Jr. (ed): Seizures and Epilepsy. Philadelphia: F.A.Davis, 1989, pp 443-474
- Engel JE, Jr., Shewmon DA: Overview. Who should be considered a surgical candidate? in Engel J, Jr. (ed): Surgical Treatment of the Epilepsies. New York: Raven, 1993, pp 23-34
- Falconer MA: Mesial temporal (Ammon’s horn) sclerosis as a common cause of epilepsy. Aetiology, treatment, and prevention.Lancet 2:767-770, 1974
- Jensen I: High-level drug therapy versus surgical treatment: Long-term outcome, in Wieser HG, Elger CE (eds): Presurgical Evaluation of Epileptics: Basics, Techniques, Implications. Berlin: Springer-Verlag, 1987, pp 337-343
- Leksell L: Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 46:797-803, 1983
- Lindquist C, Kihlström L, Hellstrand E, et al: Stereotactic radiosurgery instead of conventional epilepsy surgery. Acta Neurochir (Wien) 122:179, 1993
- Lunsford LD, Kondziolka D, Flickinger JC, et al: Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg 75:512-524, 1991
- Malis LI, Rose JE, Kruger L, et al: Production of laminar lesions in the cerebral cortex by deuteron irradiation, in Haley TJ, Snider RS (eds): Response of the Nervous System to Ionizing Radiation. New York: Academic, 1962, pp 359-368
- Monnier M, Krupp P: Action of gamma irradiation on electrical brain activity, in Haley TJ, Snider RS (eds): Response of the Nervous System to Ionizing Radiation. New York: Academic, 1962, pp 604-620
- Pilcher WH, Roberts DW, Flanigin HF, et al: Complications of epilepsy surgery, in Engel J, Jr. (ed): Surgical Treatment of the Epilepsies. New York: Raven, 1993, pp 565-581
- Regis J, Peragui JC, Rey M, et al: First selective amygdalohippocampal radiosurgery for ‘mesial temporal lobe epilepsy’.Stereotact Funct Neurosurg 64:193-201, 1995
- Steinberg GK, Fabrikant JI, Marks MP, et al: Stereotactic heavy-charged-particle Bragg-peak radiation for intracranial arteriovenous malformations. N Engl J Med 323:96-101, 1990
- Steiner L, Lindquist C, Adler JR, et al: Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg 77:1-8, 1992
- Sutcliffe JC, Forster DMC, Walton L, et al: Untoward clinical effects after stereotactic radiosurgery for intracranial arteriovenous malformations. Br J Neurosurg 6:177-185, 1992
- Talairach J, Bancaud J: Stereotaxic approach to epilepsy. Progr Neurol Surg 5:297-354, 1973
- Tracy SG: High frequency, high potential currents, and X radiations in the treatment of epilepsy. N Y Med J 422-424, 1905
- Vinters HV, Armstrong DL, Babb TL, et al: The neuropathology of human symptomatic epilepsy, in Engel J, Jr. (ed): Surgical Treatment of the Epilepsies. New York: Raven, 1993, pp 593-608
- von Wieser W: Die Röntgentherapie der traumatischen Epilepsie. Monatsschr Psychiatr Neurol 1-11:171-179, 1939
- Whang CJ, Kim CJ: Short-term follow-up of stereotactic Gamma Knife radiosurgery in epilepsy. Stereotact Funct Neurosurg 64:202-208, 1995