Advances in Epilepsy Surgery and Radiosurgery (Acta Neurochirurgica Supplement)

Acta Neurochirurgica Supplement interested in the latest developments in the field of epilepsy surgery and radiosurgery, both at basic and clinical levels.
Table of contents

Stereotactic radiosurgery, well established in the noninvasive treatment of focal lesions that are otherwise difficult to access through open surgery, is an emerging technology in the treatment of focal epileptic lesions. Recent studies suggest that seizures from hypothalamic hamartomas and mesial temporal lobe epilepsy remit at clinically significant rates with radiosurgery, but large variations among different studies have raised questions about appropriate treatment protocols and mechanisms.

Proposed anticonvulsant mechanisms include neuromodulatory effects or ischemic necrosis of epileptic tissue. An ongoing trial that directly compares efficacy, morbidities, and cost of radiosurgery versus open surgery for mesial temporal lobe epilepsy is underway. The devices available for stereotactic radiosurgery RS share the common feature of focusing ionizing radiation to small targets deep within brain tissue, sparing damage to surrounding tissue. This ability has been used to treat difficult-to-access lesions such as deep tumors and arteriovenous malformations.

In fact, the efficacy of RS in treating epilepsy associated with these lesions was the main factor leading to its use in recent trials of mesial temporal lobe epilepsy MTLE. That RS is an outpatient procedure that does not require general anesthesia or postoperative intensive care is additionally attractive. We review the devices of RS, discuss briefly the antiepileptic effects in treatment of epileptogenic mass lesions, and update its status in treatment of MTLE. Because the results in MTLE vary considerably, we also discuss available animal model and clinical data to investigate anticonvulsant mechanisms of the radiosurgical lesion.

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. Despite these advantages, the limited availability of proton beam accelerators, their high costs Mehta , and relative difficulties in constructing complexly shaped targets limit widespread use.

The other carriers of ionizing radiation, photons, are easier to generate. 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 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. In these cases, however, successful treatment of seizures is difficult to distinguish from successful treatment of the underlying lesions. Although the usefulness of RS in treatment of cavernous malformation is controversial mainly from high rates of hemorrhage in some series Steiner, et al.

RS has been used to treat epileptogenic hypothalamic hamartomas HH given difficulties with access in open surgery. Although no studies exist for HH surgery that are randomized by treatment method, retrospective case series suggest that other surgical methods besides RS may have better outcomes in terms of seizure remission. Transventricular endoscopic resection also has similar rates of success Ng and Rekate , Shim, et al.

These invasive techniques, however, may not be able to be used depending on the characteristics and location of the HH. A variety of single-center case reports and case series followed Cmelak, et al. With one exception Hoggard, et al. None of the 14 patients were seizure free after 39 months. 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. Measurements of cognitive function at 12 postoperatively again corresponding to the period of maximum radiosurgical edema Chang, et al.

At 24 months postoperatively when edema resolves in most patients, leaving atrophic residual tissue Chang, et al. These proportions compare favorably against findings after open anterior temporal lobectomy Stroup, et al. 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. Since RS is a surgical technique, some side effects of RS are similar to those of standard surgery. Formal comparison is pending a randomized study see below. Some side effects, especially during development of the radiosurgical lesion, are unique to RS.

Barbaro et al Barbaro, et al. 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.

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At 24 months, the mass effects resolve to mild atrophy of the mesial temporal lobe. Additional mortality was reported by Srikijvilaikul et al. 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.

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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. These side effects have, as of yet, not been observed in RS. Trials of RS for MTLE show a wide variation of clinical efficacies; therefore, differences in protocols and potential mechanisms require examination. All studies of MTLE cited above, despite minor variations in description, target essentially the same anatomy: On this basis, Barbaro et al specified treatment volumes limited to 5. Responses are reported in an edema-severity scale Hayashi, et al.

A relatively narrow window of efficacy and toxicity appears between 5. 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.

As Figure 2 suggests, 20Gy appears to serve as a threshold at or over which seizure remission occurs. Each point designates the total number of patients in each trial paired with a letter designating first author of each report. Studies with more than one dose are shown divided among doses.

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  7. 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 , Khan Susceptibility to ionizing radiation is proportional to DNA synthesis.

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    Differentiated neurons are relatively radio-resistant; actively proliferating tissue, like vasculature, is radiosensitive. 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. Cognitive functions were spared; for example, water maze performance was unimpaired after treatment Maesawa, et al. Tsuchitani et al Tsuchitani, et al. 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. 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. Whereas lower doses allow a compensatory proliferation of neuronal precursors during recovery, higher doses completely block compensatory proliferation Tan, et al. Neuromodulatory effects, however, may not be entirely beneficial, as demonstrated by proconvulsant effects outlined in above animal experiments Jenrow, et al.

    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.

    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. 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.

    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. These findings may help triage patients for subsequent standard open surgery if noninvasive RS is insufficient Chang, et al.

    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. 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. Electron microscopy demonstrates thickening of the vascular basement membrane. These vascular changes precede development of necrosis within the radiosurgical target.

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    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. 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. Surgery was performed 15 months after radiosurgery with 24Gy because of persisting headaches and visual changes. The radiation dose is usually measured in grays one gray Gy is the absorption of one joule of energy per kilogram of mass.

    A unit that attempts to take into account both the different organs that are irradiated and the type of radiation is the sievert , a unit that describes both the amount of energy deposited and the biological effectiveness. The New York Times reported in December that radiation overdoses had occurred with the linear accelerator method of radiosurgery, due in large part to inadequate safeguards in equipment retrofitted for stereotactic radiosurgery. The NYT article focused on Varian equipment and associated software, but the problem is likely not to be limited to that manufacturer.

    This is evidence that immunotherapy may be useful for treatment of radiation necrosis following stereotactic radiotherapy. The selection of the proper kind of radiation and device depends on many factors including lesion type, size, and location in relation to critical structures. Data suggest that similar clinical outcomes are possible with all of the various techniques. More important than the device used are issues regarding indications for treatment, total dose delivered, fractionation schedule and conformity of the treatment plan.

    The Gamma Knife also known as the Leksell Gamma Knife , a creation of Elekta AB , a Swedish public company, is used to treat brain tumors by administering high-intensity gamma radiation therapy in a manner that concentrates the radiation over a small volume. The device aims gamma radiation through a target point in the patient's brain.

    The patient wears a specialized helmet that is surgically fixed to the skull, so that the brain tumor remains stationary at the target point of the gamma rays. An ablative dose of radiation is thereby sent through the tumor in one treatment session, while surrounding brain tissues are relatively spared. Gamma Knife therapy, like all radiosurgery, uses doses of radiation to kill cancer cells and shrink tumors, delivered precisely to avoid damaging healthy brain tissue.

    Gamma Knife radiosurgery is able to accurately focus many beams of gamma radiation on one or more tumors. Each individual beam is of relatively low intensity, so the radiation has little effect on intervening brain tissue and is concentrated only at the tumor itself. Acute complications following Gamma Knife radiosurgery are rare, [27] and complications are related to the condition being treated. A linear accelerator linac produces x-rays from the impact of accelerated electrons striking a high z target usually tungsten.

    With a Linac the gantry moves in space to change the delivery angle. Linear accelerator equipment can also move the patient lying on the treatment couch to change the delivery point. These treatments involve using a stereotactic frame to restrict the patient's movement. The Novalis Shaped Beam Radiosurgery system and Tx Radiosurgery platform, from Brainlab, implement a frameless, non-invasive technique with X-ray imaging that has proven to be both comfortable for the patient and accurate.

    The Trilogy from Varian, or CyberKnife from Accuray, can also be used with non-invasive immobilization devices coupled with real-time imaging to detect any patient motion during a treatment. Linear accelerators emit high energy X-rays; the process is usually referred to as "X-ray therapy" or "photon therapy. Such radiation is not substantially different from that emitted by high voltage accelerators. In linear accelerator therapy, the emission head called " gantry " is mechanically rotated around the patient, in a full or partial circle. The table where the patient is lying, the "couch", can also be moved in small linear or angular steps.

    The combination of the movements of the gantry and of the couch makes possible the computerized planning of the volume of tissue that is going to be irradiated. The diameter of the energy beam leaving the emission head can be adjusted to the size of the lesion by means of collimators. As of [update] Linacs are capable of achieving extremely narrow beam geometries, such as 0. Therefore, they can be used for several kinds of surgeries which hitherto had been carried out by open or endoscopic surgery, such as for trigeminal neuralgia, etc.

    The exact mechanism of its effectiveness for trigeminal neuralgia is not known; however, its use for this purpose has become very common. Long-term follow-up data has shown it to be as effective as radiofrequency ablation, but inferior to surgery in preventing the recurrence of pain.

    A type of linear accelerator therapy which uses a small accelerator mounted on a moving arm to deliver X-rays to a very small area which can be seen on fluoroscopy, is called Cyberknife therapy. Several generations of the frameless robotic Cyberknife system have been developed since its initial inception in It was invented by John R. Many such CyberKnife systems are available worldwide. Cyberknife may be compared to Gamma Knife therapy see above , but it does not use gamma rays emitted by radioisotopes.

    It also does not use a frame to hold the patient, as a computer monitors the patient's position during treatment, using fluoroscopy. The robotic concept of Cyberknife radiosurgery allows the tumor to be tracked, rather than fixing the patient with a stereotaxic frame. Since no frame is needed, some of the radiosurgical concepts can be extended to treat extracranial tumors.

    In this case, the Cyberknife robotic arm tracks the tumor motion i. They are then released toward the region to be treated in the patient's body, the irradiation target. In some machines, which deliver protons of only a specific energy, a custom mask made of plastic is interposed between the beam source and the patient to adjust the beam energy to provide the appropriate degree of penetration. The phenomenon of the Bragg peak of ejected protons gives proton therapy advantages over other forms of radiation, since most of the proton's energy is deposited within a limited distance, so tissue beyond this range and to some extent also tissue inside this range is spared from the effects of radiation.

    This property of protons, which has been called the " depth charge effect" by analogy to the explosive weapons used in anti-submarine warfare, allows for conformal dose distributions to be created around even very irregularly shaped targets, and for higher doses to targets surrounded or backstopped by radiation-sensitive structures such as the optic chiasm or brainstem. The development of "intensity modulated" techniques allowed similar conformities to be attained using linear accelerator radiosurgery.

    As of [update] there was no evidence that proton therapy is better than any other types of treatment in most cases, except for a "handful of rare pediatric cancers". Critics, responding to the increasing number of very expensive PBT installations, spoke of a "medical arms race " and "crazy medicine and unsustainable public policy". From Wikipedia, the free encyclopedia. This article is about the medical procedure.


    For the album by Kayo Dot, see Gamma Knife album. Journal of Clinical Oncology. International journal of radiation oncology, biology, physics.