Radiosurgery for epilepsy: clinical experience and potential antiepileptic mechanisms

Keywords: radiosurgery, mesial temporal lobe epilepsy, epilepsy surgery, Gamma Knife, partial seizure

Proton beam accelerator

A proton beam accelerator strips protons of their electrons and aims them at a target. An advantage of the proton beam accelerator is that protons, having mass, scatter less when entering tissue. Furthermore, the most intense radiation concentrates at the end of the proton’s trajectory, a phenomenon known as the Bragg peak (Haffty and Wilson 2009). Despite these advantages, the limited availability of proton beam accelerators, their high costs (Mehta 1995), and relative difficulties in constructing complexly shaped targets limit widespread use.

Photon/linear accelerators

The other carriers of ionizing radiation, photons, are easier to generate. The tradeoff is that photons, being massless, tend to scatter more readily than protons and are therefore more complicated to aim (Haffty & Wilson 2009, Khan 2010, Mehta 1995). Rather than the aiming of a single proton beam, photons are best aimed by concentrating multiple weak sources to a single intense focus point. The Novalis Tx (Varian Medical Systems, Palo Alto, CA) and CyberKnife (Accuray, Inc.; Sunnyvale, California, USA) are linear accelerators that are steered about to direct many single beams at a common aiming point. The Gamma Knife (GK) (Elekta Ab; Stockholm, Sweden) consists of ~200 separate radioactive cobalt-60 sources housed inside a hemispheric chamber and focused to a single target. The target, in turn, is determined and maintained with the patient installed into a stereotactic frame. Except where noted, the studies cited below used GK radiosurgery.

Seizure Remission

The first use of focal radiation to treat “lesionless” epilepsy in a systematic fashion was reported by Talairach (Talairach, et al. 1974) who treated 44 patients between 1959–1973 with the use of implanted yttrium⁹⁰. Although ~5 year outcomes of 75% seizure remission were reported, early attempts with other forms of RS were not encouraging (Barcia, et al. 1994, Linquist, et al. 1991).

Régis et al. resurrected the GK technique for treatment of MTLE in 1995 (Régis, et al. 1995), and then conducted a subsequent trial of 7 MTLE patients (Régis, et al. 1999). In this series, a target comprising the parahippocampal gyrus, head and anterior body of the hippocampus, and amygdala, comprising a ~6.5ml 50% isodose volume, was treated with 25 Gy.

A variety of single-center case reports and case series followed (Cmelak, et al. 2001, Hoggard, et al. 2008, Kawai, et al. 2001, Prayson and Yoder 2007, Srikijvilaikul, et al. 2004). With one exception (Hoggard, et al. 2008), these series used doses smaller than 25Gy, and rates of seizure remission were low or nil.

Two larger, prospective, multicenter trials followed, one European (Régis, et al. 2004) and one US (Barbaro, et al. 2009). The European trial demonstrated a 2 year postoperative seizure remission rate of 62% with the use of a treatment protocol identical to the group’s earlier studies. Barbaro et al. in the US Multicenter Pilot Study randomized 30 patients to a high (24 Gy, n = 13) or low dose (20 Gy, n = 17) delivered to the target as specified by Régis et al (Régis, et al. 2004) with the added specification that 50% isodose volumes were restricted to 5.5–7.0 ml attained with 2–6 isodoses. Ten patients in each group were seizure free at 36 months of follow-up, resulting in a remission rate of 77% in the high dose and 59% in the low dose group.

Vojtĕch et al. released a retrospective analysis of 14 patients with markedly different results (Vojtĕch, et al. 2009). Initial doses were identical to that reported by Régis, and in fact, 6 of the patients overlap with the European multicenter trial (Régis, et al. 2004). Doses decreased with accumulated experience; of the 14 patients in the report, the last 6 were treated with 18 Gy because of clinically significant “prominent radiosurgical responses” associated with 25 Gy. None of the 14 patients were seizure free after 39 months.

Finally, seizure remission rates were reported for a 15 patients with follow-up durations >5 years (Bartolomei, et al. 2008). Nine of 15 (60%) remained seizure free.

Secondary outcomes

Neurocognitive and psychological outcomes have been measured at different points of the post-surgical follow-up period. McDonald et al evaluated three patients treated on the language dominant side during the period of development of the radiosurgical lesion and found a significant impairment in at least one measure of verbal memory with sparing of IQ, visual memory, and language (McDonald, et al. 2004). Measurements of cognitive function at 12 postoperatively (again corresponding to the period of maximum radiosurgical edema (Chang, et al. 2010)) found that verbal memory have no consistent impairments, but that tests of cognitive processing speed demonstrate trends of worsening in a dose-dependent fashion (Quigg, et al. 2011); impairment, however, is not reliably proportional to the volume of edema (Chang, et al. 2010).

At 24 months postoperatively (when edema resolves in most patients, leaving atrophic residual tissue (Chang, et al. 2010)), Régis et al. in the European multicenter trial noted no significant cognitive deficits (Régis, et al. 2004). In fact, 20% experienced some degree of cognitive improvement, and only one patient a decline to a degree under that considered significant for that trial. Similar findings were seen in the US Multicenter Pilot Study (Barbaro, et al. 2009, Quigg, et al. 2011), Impairment occurred in one measure of verbal memory (Wechsler Memory Scale or the California Verbal Learning Test) in 25% of patients treated on the language-dominant side when testing was measured in terms of relative change indices (significant score changes beyond that expected from test-retest variability). Conversely, 16% of language dominant RS patients experienced improvements in the same measures. These proportions compare favorably against findings after open anterior temporal lobectomy (Stroup, et al. 2003). Comparison of mean scores obtained from patients at 24 months after RS, using the tests of verbal memory above, as a well as the Boston Naming Test, Trail Making Test, and Beck Depression Inventory, revealed no overall neuropsychological changes in the patients between their preoperative baseline and post-treatment states. Importantly, quality of life scores were significantly improved in those patients attaining seizure freedom. The long-term follow-up study reported by Bartolomei et al (Bartolomei, et al. 2008) shows that neuropsychological results are stable (although the exact timing of testing in relationship to follow-up course was not reported).

Safety and development of the RS lesion

Since RS is a surgical technique, some side effects of RS are similar to those of standard surgery. For example, typical “temporal lobe” homonymous visual field defects as seen after anterior temporal lobectomy (Engel, et al. 1993) occur in 43% (Régis, et al. 2004) – 50% of patients (Barbaro, et al. 2009). Although verbal memory impairments are seen after dominant hemisphere surgery either by RS or open surgery, the focused nature of RS targeting induces a “superselective” lesion, analogous to the putative advantages of selective amygdalohippocampectomy over anterior temporal lobectomy (Clusmann, et al. 2002, Helmstaedter, et al. 2003, Jones-Gotman, et al. 1997, Wyler, et al. 1995). Formal comparison is pending a randomized study (see below).

Some side effects, especially during development of the radiosurgical lesion, are unique to RS. The time course of the RS lesion and associated symptoms has been well documented (Régis, et al. 2004). Most studies find a dramatic increase in the number of auras, starting ~6–8 months and peaking between 9–12 months after RS. In studies with higher doses and greater proportions of seizure remission (Régis, et al. 2004), the number of complex partial seizures simultaneously drops with the increase in auras; often, subjects have no complex partial seizures from the time they notice the increase in auras. Barbaro et al (Barbaro, et al. 2009) documented a dose-dependent pattern of earlier onset of remission of complex partial seizures and reduced aura production with higher doses. Vojtĕch et al (Vojtĕch, et al. 2009) described an exacerbation of both auras and complex partial seizures, with complex partial seizures during peak event expression predominating in high dose protocols and auras in low dose protocols.

New-onset headaches (occurring in 14% (Régis, et al. 2004) to 70% of patients (Barbaro, et al. 2009)) do not have predictable timing and can precede or follow changes in aura and seizure frequencies or MRI. In contrast, the time course of MRI changes is predictable (with the limitation that no study thus far has systematically obtained MRI from all patients at fixed intervals shorter than one year postoperatively; interim neuroimaging is obtained to evaluate patient complaints). The most striking effects are the development of a dose-dependent T2 hyperintensity, contrast enhancement, and vasogenic edema with mass effect beginning 9 months postoperatively and peaking at 12 months. These changes correspond to declines in complex partial seizures and to transient increases in the number of auras (Chang, et al. 2010). At 24 months, the mass effects resolve to mild atrophy of the mesial temporal lobe.

Serious adverse events have also been reported with the use of RS for MTLE (Barbaro, et al. 2009, Prayson & Yoder 2007, Srikijvilaikul, et al. 2004). One death reported by Prayson et al occurred two weeks post-radiation, due to “persistent seizure complications.” Because radiographic changes occur on the order of months, rather than days, it is unlikely that RS contributed to this patient’s outcome. An autopsy showing mesial temporal sclerosis, but no radiation-induced pathology, supports this interpretation (Prayson & Yoder 2007). Additional mortality was reported by Srikijvilaikul et al., who described one death at 1 month and another at 1 year following RS (Srikijvilaikul, et al. 2004). Both were attributed to complications of seizures, consistent with sudden unexplained death in epilepsy (SUDEP). A protocol-defined severe event was reported by Barbaro et al (Barbaro, et al. 2009). Between 12–15 months after RS at 24Gy, one patient exhibited signs of increasing intracranial pressure (headaches, visual changes, and papilledema). Anterior temporal lobectomy was performed at 15 months leading to seizure freedom and resolution of symptoms.

While side effects and adverse events of RS are clearly important, they should be viewed in the light of the complications occurring with open surgery. For example, mortality and visual field changes have been reported in open surgery (Engel, et al. 1993). Complications of open surgery include permanent hemiparesis (2%), bleeding requiring transfusion (2.3%), and infection (0.8%) (Engel 1993; McClelland 2011). These side effects have, as of yet, not been observed in RS.

Target

All studies of MTLE cited above, despite minor variations in description, target essentially the same anatomy: the amygdala, anterior hippocampus, and the parahippocampal gyrus, regions corresponding to anatomical structures found most important in seizure remission following standard surgery (Seigel, et al. 1990). However, those patients with “epileptogenic zones” that extend beyond those traditionally attributed to MTLE may not be good RS candidates; long term seizure remission is less likely in these cases because of the highly restricted field of RS (Rheims, et al. 2008).

Isodose centers

No data is available in determining the number of isodose centers (“shots”) that are optimal to distribute and shape the radiation dose within a particular isodose volume for MTLE. Based on Régis’ preliminary studies (Régis, et al. 1995) (all of which were limited to 2 shots), Barbaro et al specified a range of 2–6 shots in the US Multicenter Pilot Study. In general, neurosurgeons recommend “conformal” RS with multiple isodose centers to tailor dose to anatomy and to protect bystander tissue (such as the brainstem and optic nerve in the case of RS of MTLE).

Volume

When reported, the 50% isodose volumes (the volume into which 50% of the total radiation dose is delivered) typically range in the 6.0–8.5ml range. Régis et al in preliminary studies (Figure 1) determined that there was a narrow window of ineffective anticonvulsant effect versus excessive toxicity in terms of volume of maximum radiation edema at 12 months postoperatively. On this basis, Barbaro et al specified treatment volumes limited to 5.5–7.5ml in their studies (Barbaro, et al. 2009).

Dose

Of the various parameters, dose appears to be best correlated to outcome (Figure 2), and is the only variable rigorously studied; in the US Multicenter Pilot Study, the group randomized to 24Gy had a higher proportion seizure remission than those to 20Gy (a finding tempered by lack of statistical power) (Barbaro, et al. 2009). As Figure 2 suggests, 20Gy appears to serve as a threshold at or over which seizure remission occurs.

Mechanisms

Radiation dose stands at the center of the controversy of mechanisms of the anticonvulsant effects of RS. Fundamental to RS is ionization - the stripping of electrons resulting in the alteration of chemical bonds or the production of free radicals (Haffty and Wilson 2009, Khan 2010). Susceptibility to ionizing radiation is proportional to DNA synthesis. Differentiated neurons are relatively radio-resistant; actively proliferating tissue, like vasculature, is radiosensitive. Furthermore, although animal models of epilepsy – usually rats - are helpful in evaluating mechanisms of anticonvulsant effects of radiation, rat brains are remarkably radio-resistant and “scaling up” directly to humans to predict anticonvulsant dosing is not applicable.

Studies with rat models of limbic epilepsy that followed the first reports of RS for MTLE emphasize that destruction of the epileptic focus is not necessary for an anticonvulsant effect. For example, a dose-dependent reduction in spontaneous seizures was shown in kainic-acid treated epileptic rats (Maesawa, et al. 1999, Maesawa, et al. 2000) and in electrical-stimulation epileptic rats (Chen, et al. 2001) despite the lack of evidence of gross neuronal injury. Cognitive functions were spared; for example, water maze performance was unimpaired after treatment (Maesawa, et al. 1999, Maesawa, et al. 2000).

These nondestructive “neuromodulatory effects” (Régis, et al. 2002, Regis, et al.) were further evaluated with RS of normal rats. A 50 Gy isodose induced different amplitudes and timing of changes in neuronal enzymes, raising the possibility that different neuronal systems vary in susceptibility to radiation (Régis, et al. 1996). Tsuchitani et al (Tsuchitani, et al. 2003) report in an abstract that hippocampi of normal rats were treated with 40 Gy. Whereas the numbers of nonspecific neurons of the hippocampus remained unchanged, both calbindin-staining interneurons (excitatory) and GAD-staining interneurons (inhibitory) were substantially decreased. Physiologic changes resulting from these selective interneuronal losses were not measured.

Kindling experiments demonstrate that RS may have different effects depending on whether normal or kindled circuitry is involved (Jenrow, et al. 2006). Three groups of rats were treated with hippocampal RS at different time points of an electrical stimulation kindling protocol to observe which experienced the most severe seizures. Relative to controls, the occurrence of stage 6 seizures is significantly increased by irradiation before kindling, but is unaffected by irradiation at kindling stage 3, and significantly is reduced by irradiation at kindling stage 5. Thus, epileptic tissue exposed to radiation may undergo different changes than normal tissue, or, perhaps more likely, lack processes of plasticity and repair enjoyed by normal tissue. Other experiments with the use of more widespread radiation doses (analogous to traditional fractionated radiotherapy) support the hypothesis of alterations in neurogenesis and plasticity in irradiated tissue. For example, Tan et al demonstrated that low doses of brain irradiation (0.5–6Gy) in normal rats induce an 80% decrement in neuronal precursor cells in the dentate gyrus. Whereas lower doses allow a compensatory proliferation of neuronal precursors during recovery, higher doses completely block compensatory proliferation (Tan, et al. 2011).

Neuromodulatory effects, however, may not be entirely beneficial, as demonstrated by proconvulsant effects outlined in above animal experiments(Jenrow, et al. 2006). This point is emphasized by results of low-dose human protocols - perhaps designed to emulate nondestructive doses in animal models - in which paradoxical exacerbation in auras or sometimes complex partial seizures are seen in parallel with development of the RS lesion (Chang, et al. 2010, Vojtĕch, et al. 2009). In contrast, neuromodulatory effects may account for findings of a case series of treatment of temporal lobe epilepsy (hippocampal sclerosis not specified) with fractionated stereotactic RS (Grabenbauer, et al. 2002) (as opposed to single-dose schemes discussed so far). In this protocol, doses of 21 Gy (7 × 3 Gy, 6 patients) or 30 Gy (15 × 2 Gy, 6 patients) were administered and follow-up performed for 24 months. Although no patients achieved seizure remission, seizure reduction occurred at mean 46% with no patients experiencing seizure exacerbation. A limitation is that postoperative imaging was not reported.

In contrast to neuromodulatory mechanisms, other findings in both animal models and human epilepsy suggest that gross structural changes in the target zone, more akin to the use of RS as a destructive surgical tool, better account for the anticonvulsant effects seen in more successful protocols. MRI and mass spectroscopy (Chang, et al. 2010) data from the US Multicenter Pilot Study (Barbaro, et al. 2009) show that the volume of contrast enhancement and T2 hyperintensity seen on MRIs obtained 12 months after RS correlate strongly with outcome (Figure 3). No patients with T2-weighted volumes of edema < 200ml at 12 months went on to experience seizure remission between 24–36 months (Chang, et al. 2010). Furthermore, magnetic resonance spectroscopy (MRS) within RS target zone show evidence of frank ischemia; one year after RS, lactate (evidence of anerobic metabolism) appears, and choline, creatine, and NAA levels (evidence of normal neuronal activity) are largely absent (Chang, et al. 2010). Similar findings of decreased markers of neuronal activity were observed with MRS > 1 year after RS in a trial of 6 patients (without seizure responses results reported) (Hajek, et al. 2003).

Although animal models of epilepsy cited above do not demonstrate necrosis of tissue, one possible confounder may be an insufficient duration of observation following irradiation. Hippocampi irradiated >50Gy in normal rats and followed for >6m (longer than durations of Maesawa (Maesawa, et al. 1999, Maesawa, et al. 2000) or Chen (Chen, et al. 2001)) show evidence of neuronal destruction (Liscak, et al. 2002).

Analogous to findings of ischemia via MRS in humans, irradiation can cause ischemic changes by affecting vasculature as seen in animal models. Kamiryo et al (Kamiryo, et al. 2001) showed that rat brains treated with RS at 75 Gy and examined 3 months later have, through the method of vascular casting, a markedly decreased vascular density. Electron microscopy demonstrates thickening of the vascular basement membrane. These vascular changes precede development of necrosis within the radiosurgical target.

Supporting data from treated human tissue (as opposed to MRS data) is difficult to interpret because tissue may be obtained from failed rather than successful RS. For example, patients who underwent open surgery after failed RS demonstrated hippocampal sclerosis and “radiational changes” in operative samples (Srikijvilaikul, et al. 2004). In the US Multicenter Pilot Study, the patient who underwent anterior temporal lobectomy for steroid-dependent symptoms (and who was seizure-free for ~3 months before open surgery) was found to have hippocampal sclerosis as well as evidence of chronic infarcts with prominent hyalinization, thickening, and closure of small vessels (Figure 4). Therefore, limited data from human histopathology show, in the RS target in a patient with decreased seizure frequency, ischemic changes arising from radiation-induced damage to vasculature.

Clinical data suggests that the two mechanisms discussed above – neuromodulation and neuronal destruction – may not mutually exclusive. For example, patients in the US Multicenter Pilot Study were asked to describe the symptoms of their typical auras, which in turn were classified as originating from “mesial” or “nonmesial” structures as validated by previous studies of auras recorded with intracranial monitoring (Bancaud, et al. 1994, Binder, et al. 2009, Fried, et al. 1995, Maillard, et al. 2004, Palmini and Gloor 1992, Penfield & Perot 1963, Vignal, et al. 2007) (Figure 5). At baseline, 76% of patients had auras, with 69% consisting of “mesial” symptoms. During the peak RS effect at 12 months, corresponding to development of ischemia within the target zone and surrounding edema, mesial auras increased in relative proportion (79%) of all aura types. After resolution of the RS lesion and simultaneous decrease in complex partial seizures, the number of patients with auras decreased to 54% with the proportion attributable to mesial auras decreased to 30%. The inversion of proportion with mesial versus nonmesial auras along with the decrease in complex partial seizures suggests that successful RS of the limbic system for MTLE causes an heterogeneous lesion: a core within the RS target that includes destructive ischemia, and a penumbra of tissue exposed to less intense radiation that may include a time-dependent expression of neuromodulatory proconvulsant and anticonvulsant effects. The “cockade” theory (after the concentric rosettes once fastened upon military hats), originally proposed by Régis (Regis, et al. 2010) may be further characterized in ongoing trials of RS.

1. Anschel DJ, Romanelli P. Epilepsy and radiosurgery. Arch Neurol. 2008;65:1136–1137. doi: 10.1001/archneur.65.8.1136-b. author reply 1137. [DOI] [PubMed] [Google Scholar]
2. Bancaud J, Brunet-Bourgin F, Chauvel P, Halgren E. Anatomical origin of deja vu and vivid ‘memories’ in human temporal lobe epilepsy. Brain. 1994;117:71–90. doi: 10.1093/brain/117.1.71. [DOI] [PubMed] [Google Scholar]
3. Barbaro NM, Quigg M, Broshek DK, Ward MM, Lamborn KR, Laxer KD, Larson DA, Dillon W, Verhey L, Garcia P, Steiner L, Heck C, Kondziolka D, Beach R, Olivero W, Witt TC, Salanova V, Goodman R. A multicenter, prospective pilot study of gamma knife radiosurgery for mesial temporal lobe epilepsy: seizure response, adverse events, and verbal memory. Ann Neurol. 2009;65:167–175. doi: 10.1002/ana.21558. [DOI] [PubMed] [Google Scholar]
4. Barcia JA, Barcia-Salorio JL, Lopez-Gomez L, Hernandez G. Stereotactic radiosurgery may be effective in the treatment of idiopathic epilepsy: report on the methods and results in a series of eleven cases. Stereotact Funct Neurosurg. 1994;63:271–279. doi: 10.1159/000100331. [DOI] [PubMed] [Google Scholar]
5. Bartolomei F, Hayashi M, Tamura M, Rey M, Fischer C, Chauvel P, Régis J. Long-term efficacy of gamma knife radiosurgery in mesial temporal lobe epilepsy. Neurology. 2008 doi: 10.1212/01.wnl.0000294326.05118.d8. [DOI] [PubMed] [Google Scholar]
6. Binder DK, Garcia PA, Elangovan GK, Barbaro NM. Characteristics of auras in patients undergoing temporal lobectomy. J Neurosurg. 2009;111:1283–1289. doi: 10.3171/2009.3.JNS081366. [DOI] [PubMed] [Google Scholar]
7. Chang EF, Quigg M, Oh MC, Dillon WP, Ward MM, Laxer KD, Broshek DK, Barbaro NM. Predictors of efficacy after stereotactic radiosurgery for medial temporal lobe epilepsy. Neurology. 2010;74:165–172. doi: 10.1212/WNL.0b013e3181c9185d. [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Chen ZF, Kamiryo T, Henson SL, Yamamoto H, Bertram EH, Schottler F, Patel F, Steiner L, Prasad D, Kassell NF, Shareghis S, Lee KS. Anticonvulsant effects of gamma surgery in a model of chronic spontaneous limbic epilepsy in rats. J Neurosurgery. 2001;94:270–280. doi: 10.3171/jns.2001.94.2.0270. [DOI] [PubMed] [Google Scholar]
9. Clusmann H, Schramm J, Kral T, Helmstaedter C, Ostertun B, Fimmers R, Haun D, Elger CE. Prognostic factors and outcome after different types of resection for temporal lobe epilepsy. J Neurosurg. 2002;97:1131–1141. doi: 10.3171/jns.2002.97.5.1131. [DOI] [PubMed] [Google Scholar]
10. Cmelak AJ, Abou-Khalil B, Konrad PE, Duggan D, Maciunas RJ. Low-dose stereotactic radiosurgery is inadequate for medically intractable mesial temporal lobe epilepsy: a case report. Seizure. 2001;10:442–446. doi: 10.1053/seiz.2001.0519. [DOI] [PubMed] [Google Scholar]
11. Engel JJ, Van Ness P, Rasmussen T. Outcome with respect to epileptic seizures. In: Engel JJ, editor. Surgical treatment of the epilepsies. Raven Press; New York: 1993. pp. 609–621. [Google Scholar]
12. Frazier JL, Goodwin CR, Ahn ES, Jallo GI. A review on the management of epilepsy associated with hypothalamic hamartomas. Childs Nerv Syst. 2009;25:423–432. doi: 10.1007/s00381-008-0798-y. [DOI] [PubMed] [Google Scholar]
13. Fried I, Spencer DD, Spencer SS. The anatomy of epileptic auras: focal pathology and surgical outcome. J Neurosurg. 1995;83:60–66. doi: 10.3171/jns.1995.83.1.0060. [DOI] [PubMed] [Google Scholar]
14. Gerszten PC, Adelson PD, Kondziolka D, Flickinger JC, Lunsford LD. Seizure outcome in children treated for arteriovenous malformations using gamma knife radiosurgery. Pediatr Neurosurg. 1996;24:139–144. doi: 10.1159/000121030. [DOI] [PubMed] [Google Scholar]
15. Grabenbauer GG, Reinhold C, Kerling F, Muller RG, Lambrecht U, Pauli E, Ganslandt O, Sauer R, Stefan H. Fractionated stereotactically guided radiotherapy of pharmacoresistant temporal lobe epilepsy. Acta Neurochir Suppl. 2002;84:65–70. doi: 10.1007/978-3-7091-6117-3_7. [DOI] [PubMed] [Google Scholar]
16. Haffty BG, Wilson LD. Handbook of radiation oncology: basic principles and clinical protocols. Jones and Bartlett; Sudbury, MA: 2009. [Google Scholar]
17. Hajek M, Dezortova M, Liscak R, Vymazal J, Vladyka V. 1H MR spectroscopy of mesial temporal lobe epilepsies treated with Gamma knife. Eur Radiol. 2003;13:994–1000. doi: 10.1007/s00330-002-1723-5. [DOI] [PubMed] [Google Scholar]
18. Hayashi M, Bartolomei F, Rey M, Farnarier P, Chauvel P, Régis J. MR changes after gamma knife radiosurgery for mesial temporal lobe epilepsy: evidence for the efficacy of subnecrotic doses. In: Kondziolka D, editor. Radiosurgery. Kargel; Basel: 2002. pp. 192–202. [Google Scholar]
19. Heikkinen ER, Konnov B, Melnikov L, Yalynych N, Zubkov Yu N, Garmashov Yu A, Pak VA. Relief of epilepsy by radiosurgery of cerebral arteriovenous malformations. Stereotact Funct Neurosurg. 1989;53:157–166. doi: 10.1159/000099532. [DOI] [PubMed] [Google Scholar]
20. Helmstaedter C, Kurthen M, Lux S, Reuber M, Elger CE. Chronic epilepsy and cognition: a longitudinal study in temporal lobe epilepsy. Ann Neurol. 2003;54:425–432. doi: 10.1002/ana.10692. [DOI] [PubMed] [Google Scholar]
21. Hoggard N, Wilkinson ID, Griffiths PD, Vaughan P, Kemeny AA, Rowe JG. The clinical course after stereotactic radiosurgical amygdalohippocampectomy with neuroradiological correlates. Neurosurgery. 2008;62:336–344. doi: 10.1227/01.neu.0000316000.96140.12. discussion 344–336. [DOI] [PubMed] [Google Scholar]
22. Jenrow KA, Ratkewicz AE, Zalinski DN, Roszka KM, Lemke NW, Elisevich KV. Influence of ionizing radiation on the course of kindled epileptogenesis. Brain Res. 2006;1094:207–216. doi: 10.1016/j.brainres.2006.03.096. [DOI] [PubMed] [Google Scholar]
23. Jones-Gotman M, Zatorre RJ, Olivier A, Andermann F, Cendes F, Staunton H, McMackin D, Siegel AM, Wieser HG. Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures. Neuropsychologia. 1997;35:963–973. doi: 10.1016/s0028-3932(97)00024-9. [DOI] [PubMed] [Google Scholar]
24. Kamiryo T, Lopes B, Kassell NF, Steiner L, Lee KS. Radiosurgery-induced Microvascular Alterations Precede Necrosis of the Brain Neuropil. Neurosurgery. 2001;49:409–415. doi: 10.1097/00006123-200108000-00026. [DOI] [PubMed] [Google Scholar]
25. Kawai K, Suzuki I, Kurita H, Shin M, Arai N, Kirino T. Failure of low-dose radiosurgery to control temporal lobe epilepsy. J Neurosurg. 2001;95:883–887. doi: 10.3171/jns.2001.95.5.0883. [DOI] [PubMed] [Google Scholar]
26. Khan FM. The physics of radiation therapy. Lippincott Williams & Wilkins; Philadelphia: 2010. [Google Scholar]
27. Kim W, Stramotas S, Choy W, Dye J, Nagasawa D, Yang I. Prognostic factors for post-operative seizure outcomes after cavernous malformation treatment. J Clin Neurosci. 2011;18:877–880. doi: 10.1016/j.jocn.2010.12.008. [DOI] [PubMed] [Google Scholar]
28. Kurita H, Kawamoto S, Suzuki I, Sasaki T, Tago M, Terahara A, Kirino T. Control of epilepsy associated with cerebral arteriovenous malformations after radiosurgery. J Neurol Neurosurg Psychiatry. 1998;65:648–655. doi: 10.1136/jnnp.65.5.648. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Linquist C, Kilstrom L, Hellestrand E. Functional neurosurgery-a future for the gamma knife? Stereotact Funct Neurosurg. 1991;57:72–81. doi: 10.1159/000099557. [DOI] [PubMed] [Google Scholar]
30. Liscak R, Vladyka V, Novotny J, Jr, Brozek G, Namestkova K, Mares V, Herynek V, Jirak D, Hajek M, Sykova E. Leksell gamma knife lesioning of the rat hippocampus: the relationship between radiation dose and functional and structural damage. J Neurosurg. 2002;97:666–673. doi: 10.3171/jns.2002.97.supplement. [DOI] [PubMed] [Google Scholar]
31. Maesawa S, Kondziolka D, Balzer J, Fellows W, Dixon E, Lunsford LD. The behavioral and electroencephalographic effects of stereotactic radiosurgery for the treatment of epilepsy evaluated in the rat kainic acid model. Stereotact Funct Neurosurg. 1999;73:115. doi: 10.1159/000029766. [DOI] [PubMed] [Google Scholar]
32. Maesawa S, Kondziolka D, Dixon CE, Balzer J, Fellows W, Lunsford LD. Subnecrotic stereotactic radiosurgery controlling epilepsy produced by kainic acid injection in rats. J Neurosurg. 2000;93:1033–1040. doi: 10.3171/jns.2000.93.6.1033. [DOI] [PubMed] [Google Scholar]
33. Maillard L, Vignal JP, Gavaret M, Guye M, Biraben A, McGonigal A, Chauvel P, Bartolomei F. Semiologic and electrophysiologic correlations in temporal lobe seizure subtypes. Epilepsia. 2004;45:1590–1599. doi: 10.1111/j.0013-9580.2004.09704.x. [DOI] [PubMed] [Google Scholar]
34. McDonald CR, Norman MA, Tecoma E, Alksne J, Iragui V. Neuropsychological change following gamma knife surgery in patients with left temporal lobe epilepsy: a review of three cases. Epilepsy Behav. 2004;5:949–957. doi: 10.1016/j.yebeh.2004.08.014. [DOI] [PubMed] [Google Scholar]
35. Mehta MP. The physical, biologic, and clinical basis of radiosurgery. Curr Probl Cancer. 1995;19:265–329. [PubMed] [Google Scholar]
36. Ng YT, Rekate HL. Endoscopic resection of hypothalamic hamartoma for refractory epilepsy: preliminary report. Semin Pediatr Neurol. 2007;14:99–105. doi: 10.1016/j.spen.2007.03.008. [DOI] [PubMed] [Google Scholar]
37. Ng YT, Rekate HL, Prenger EC, Chung SS, Feiz-Erfan I, Wang NC, Varland MR, Kerrigan JF. Transcallosal resection of hypothalamic hamartoma for intractable epilepsy. Epilepsia. 2006;47:1192–1202. doi: 10.1111/j.1528-1167.2006.00516.x. [DOI] [PubMed] [Google Scholar]
38. Palmini A, Gloor P. The localizing value of auras in partial seizures: a prospective and retrospective study. Neurology. 1992;42:801–808. doi: 10.1212/wnl.42.4.801. [DOI] [PubMed] [Google Scholar]
39. Penfield W, Perot P. The brain’s record of auditory and visual experience: a final summary and discussion. Brain. 1963;86:595–696. doi: 10.1093/brain/86.4.595. [DOI] [PubMed] [Google Scholar]
40. Prayson RA, Yoder BJ. Clinicopathologic findings in mesial temporal sclerosis treated with gamma knife radiotherapy. Ann Diagn Pathol. 2007;11:22–26. doi: 10.1016/j.anndiagpath.2006.03.004. [DOI] [PubMed] [Google Scholar]
41. Quigg M, Broshek DK, Barbaro NM, Ward MM, Laxer KD, Yan G, Lamborn K. Neuropsychological outcomes after Gamma Knife radiosurgery for mesial temporal lobe epilepsy: A prospective multicenter study. Epilepsia. 2011;52:909–916. doi: 10.1111/j.1528-1167.2011.02987.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Régis J, Bartolomei F, de Toffol B, Genton P, Kobayashi T, Mori Y, Takakura K, Hori T, Inoue H, Schrottner O, Pendl G, Wolf A, Arita K, Chauvel P. Gamma knife surgery for epilepsy related to hypothalamic hamartomas. Neurosurgery. 2000a;47:1343–1351. [PubMed] [Google Scholar]
43. Régis J, Bartolomei F, Kida Y, Kobayashi T, Vladyka V, Liscak R, Forster D, Kemeny A, Schrottner O, Pendl G. Radiosurgery for epilepsy associated with cavernous malformation: retrospective study in 49 patients. Neurosurgery. 2000b;47:1091–1097. doi: 10.1097/00006123-200011000-00013. [DOI] [PubMed] [Google Scholar]
44. Régis J, Bartolomei F, Rey M, Genton P, Dravet C, Semah F, Gastaut JL, Chauvel P, Peragut JC. Gamma knife surgery for mesial temporal lobe epilepsy. Epilepsia. 1999;40:1551–1556. doi: 10.1111/j.1528-1157.1999.tb02039.x. [DOI] [PubMed] [Google Scholar]
45. Regis J, Carron R, Park M. Is radiosurgery a neuromodulation therapy?: A 2009 Fabrikant award lecture. J Neurooncol. 2010;98:155–162. doi: 10.1007/s11060-010-0226-5. [DOI] [PubMed] [Google Scholar]
46. Régis J, Kerkerian-Legoff L, Rey M, Vial M, Porcheron D, Nieoullon A, Peragut JC. First biochemical evidence of differential functional effects following Gamma Knife surgery. Stereotact Funct Neurosurg. 1996;66(Suppl 1):29–38. doi: 10.1159/000099698. [DOI] [PubMed] [Google Scholar]
47. Régis J, Peragui J, Rey M, Samson Y, Levrier O, Porcheron D, Régis H, Sedan R. First selective amygdalohippocampal radiosurgery for ‘mesial temporal lobe epilepsy’. Stereotactic & Functional Neurosurgery. 1995;64(Suppl 1):193–201. doi: 10.1159/000098779. [DOI] [PubMed] [Google Scholar]
48. Régis J, Rey M, Bartolomei F, Vladyka V, Liscak R, Schrottner O, Pendl G. Gamma knife surgery in mesial temporal lobe epilepsy: a prospective multicenter study. Epilepsia. 2004;45:504–515. doi: 10.1111/j.0013-9580.2004.07903.x. [DOI] [PubMed] [Google Scholar]
49. Rheims S, Fischer C, Ryvlin P, Isnard J, Guenot M, Tamura M, Régis J, Mauguiere F. Long-term outcome of gamma-knife surgery in temporal lobe epilepsy. Epilepsy Res. 2008;80:23–29. doi: 10.1016/j.eplepsyres.2008.03.003. [DOI] [PubMed] [Google Scholar]
50. Schauble B, Cascino GD, Pollock BE, Gorman DA, Weigand S, Cohen-Gadol AA, McClelland RL. Seizure outcomes after stereotactic radiosurgery for cerebral arteriovenous malformations. Neurology. 2004;63:683–687. doi: 10.1212/01.wnl.0000134659.95217.6e. [DOI] [PubMed] [Google Scholar]
51. Schrottner O, Eder HG, Unger F, Feichtinger K, Pendl G. Radiosurgery in lesional epilepsy: brain tumors. Stereotact Funct Neurosurg. 1998;70(Suppl 1):50–56. doi: 10.1159/000056406. [DOI] [PubMed] [Google Scholar]
52. Seigel A, Wieser H, Wichmann W, Yasargil G. Relationships between MR-imaged total amount of tissure removed, resection scores of specific mediobasal limbic subcampoartments and clinical outcome following selective amygdalohippocampectomy. Epilepsy Res. 1990;6:56–65. doi: 10.1016/0920-1211(90)90009-k. [DOI] [PubMed] [Google Scholar]
53. Shim KW, Chang JH, Park YG, Kim HD, Choi JU, Kim DS. Treatment modality for intractable epilepsy in hypothalamic hamartomatous lesions. Neurosurgery. 2008;62:847–856. doi: 10.1227/01.neu.0000318170.82719.7c. discussion 856. [DOI] [PubMed] [Google Scholar]
54. Srikijvilaikul T, Najm I, Foldvary-Schaefer N, Lineweaver T, Suh JH, Bingaman WE. Failure of gamma knife radiosurgery for mesial temporal lobe epilepsy: report of five cases. Neurosurgery. 2004;54:1395–1402. doi: 10.1227/01.neu.0000124604.29767.eb. discussion 1402–1394. [DOI] [PubMed] [Google Scholar]
55. Steiner L, Karlsson B, Yen CP, Torner JC, Lindquist C, Schlesinger D. Radiosurgery in cavernous malformations: anatomy of a controversy. J Neurosurg. 2010;113:16–21. doi: 10.3171/2009.11.JNS091733. discussion 21–12. [DOI] [PubMed] [Google Scholar]
56. Steiner L, Lindquist C, Adler JR, Torner JC, Alves W, Steiner M. Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg. 1992;77:1–8. doi: 10.3171/jns.1992.77.1.0001. [DOI] [PubMed] [Google Scholar]
57. Stroup E, Langfitt J, Berg M, McDermott M, Pilcher W, Como P. Predicting verbal memory decline following anterior temporal lobectomy (ATL) Neurology. 2003;60:1266–1273. doi: 10.1212/01.wnl.0000058765.33878.0d. [DOI] [PubMed] [Google Scholar]
58. Talairach J, Bancaud J, Szikla G. Approche nouvelle de la neurochirurgie de l’epilepsie. Méthodologie stéréotaxique et résultats thérapeutiques. Neurochirurgie: Congrés Annuel de la Société de Langue Française; Masson, Marseille. 1974. pp. 205–213. [PubMed] [Google Scholar]
59. Tan YF, Rosenzweig S, Jaffray D, Wojtowicz JM. Depletion of new neurons by image guided irradiation. Front Neurosci. 2011;5:59. doi: 10.3389/fnins.2011.00059. [DOI] [PMC free article] [PubMed] [Google Scholar]
60. Tsuchitani S, Drummond J, Kamiryo T, Anzivino MJ, Chen ZF, Steiner L, Lee KS. Selective vulnerability of interneurons to low dosage radiosurgery. Society for Neuroscience Annual Meeting [abstract]; New Orleans. 2003. [Google Scholar]
61. Vignal JP, Maillard L, McGonigal A, Chauvel P. The dreamy state: hallucinations of autobiographic memory evoked by temporal lobe stimulations and seizures. Brain. 2007;130:88–99. doi: 10.1093/brain/awl329. [DOI] [PubMed] [Google Scholar]
62. Vojtěch Z, Vladyka V, Kalina M, Nespor E, Seltenreichova K, Semnicka J, Liscak R. The use of radiosurgery for the treatment of mesial temporal lobe epilepsy and long-term results. Epilepsia. 2009;50:2061–71. doi: 10.1111/j.1528-1167.2009.02071.x. [DOI] [PubMed] [Google Scholar]
63. Wyler A, Hermann B, Somes G. Extent of medial temporal resection on outcome from anterior temporal lobectomy: a randomized prospective study. Neurosurgery. 1995;37:982–990. doi: 10.1227/00006123-199511000-00019. [DOI] [PubMed] [Google Scholar]