Radiotherapy and Localization of Seizures Cited as Promising Therapies for Epilepsy

Neurology Today
18 December 2008; Volume 8(24); pp 12,14

MACREADY, NORRA

Novel ways of delivering radiotherapy and a promising approach to localizing seizures characterize the studies chosen for Neurology Today as noteworthy epilepsy research by two prominent experts in the field.

The radiotherapy studies address one of the biggest current issues in neurology: how to keep therapeutic interventions noninvasive, said Joseph I. Sirven, MD, associate professor of neurology at the Mayo Clinic College of Medicine in Scottsdale, AZ.

Figure. DR. JOSEPH I. SIRVEN: Radiation therapy delivered via gamma knife or interstitially is a noninvasive theoretical alternative to resective epilepsy surgery… neither approach is anywhere near the point of replacing resective epilepsy surgery.

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Figure. TYPICAL MRI CHANGES AFTER GAMMA KNIFE RADIOSURGERY FOR MTLE: Prominent changes are seen at 17 months: inside the target volume is a heterogeneous T1 signal hypointensity and a contrast enhancement ring corresponding to the periphery of the target region. A gradual disappearance of signs over time was observed. Last MRI shows a residual necrotic cavity in the target volume.

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Figure. TIME COURSE OF TRANSIENT EDEMA after radiosurgery seed implantation as shown by MRI: (A) Contrast-enhanced T1-weighted image shows rim of enhancement within the hamartoma 1 month after seed implantation. (B-D) FLAIR images show prominent perifocal edema extending into adjacent brain regions three months after implantation (B), with successive dissolution after six (C) and 12 (D) months.

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Radiation therapy delivered via gamma knife or interstitially is a noninvasive theoretical alternative to resective epilepsy surgery. However, while they are promising, neither approach is anywhere near the point of replacing resective epilepsy surgery, he told Neurology Today. What makes them important is that they are another step in the evolution of epilepsy therapy. Time and further research will show if they become meaningful alternatives. Gamma knife radiosurgery was as effective as classic microsurgery, with similar long-term results, in a study of patients with mesial temporal lobe epilepsy (MTLE). This form of epilepsy is common, and surgery often is indicated because MTLE frequently is drug-resistant, wrote lead author Fabrice Bartolomei, MD, PhD, of the University of Marseiile in France, and colleagues in the May 6 Neurology.

However, the long-term results following surgery have been disappointing, with a mean success rate of 70 percent at one year, and deteriorating rates after that. They noted that in recent European studies, the gamma knife has had good effects on seizure control and quality of life among people with MTLE, with an as-yet unconfirmed suggestion of similar benefits on memory. However, little evidence exists regarding the long-term persistence of these improvements.

The investigators reported on 15 patients with unilateral mesial temporal lobe seizures who had undergone gamma knife surgery and were followed for a mean of eight years. At the last follow-up, conducted six months prior to data analysis for each patient, nine patients (60 percent) were considered seizure-free; 66 percent of them had recurrences of auras or complex partial seizures as they were weaned off their antiseizure medication, but those symptoms ceased when the medication was restored. The most common side effect was transient mild headache requiring treatment with corticosteroids.

Other investigators, led by Andreas Schulze-Bonhage, MD, of the University Hospital Freiburg in Germany, studied the effect of interstitial radiosurgery through the implantation of radioactive seeds in 24 consecutive patients with drug-resistant gelastic epilepsy, a rare but severe form of the disease characterized by seizures preceded by brief periods of inappropriate laughter. In all cases, the seizures were caused by hypothalamic hamartomas, the investigators reported in the July 22 Neurology.

The patients ranged in age from 3 to 46 years. At a mean follow-up of 24 months, 11 (46 percent) of the patients were seizure-free or had at least a 90 percent reduction in seizures, but some of those patients required repeated treatment. Patients in whom epilepsy duration was shortest had the best chances of treatment success. Four patients gained at least 11 pounds (5 kg). Headache, fatigue, and lethargy were other side effects, but they were transient.

Cognitive function improved in some patients, but two patients experienced a persistent deterioration of episodic memory. Side effects associated with microsurgical hamartoma removal did not occur. The authors concluded that about half of the patients in this trial benefited from interstitial radiosurgery, and recommended treating as early as possible for the best chances of seizure control and to minimize the risk of cognitive effects.

Whatever the choice of treatment, it is made more challenging by the fact that in many cases, doctors cannot identify the source of the seizures, or seizure onset zone (SOZ).

Using macroelectrodes, lead author Julia Jacobs, MD, and colleagues at the Montreal Neurological Institute and Hospital, studied interictal high-frequency oscillations (HFOs) of 80 to 500 Hz in 10 patients in an effort to locate the SOZs. The patients, who had intractable focal epilepsy with the SOZs previously identified, ranged in age from 24 to 54 years. They all had HFOs, with more recorded from mesial temporal than neocortical structures. The HFOs appeared to be largely independent of interictal discharges, or spikes, and were significantly higher in rate and duration inside rather than outside the SOZ.

It was possible to establish a rate of HFOs to identify the SOZ with better sensitivity and specificity than with the rate of spikes, the authors wrote in the November Epilepsia. They were able to identify the SOZ after studying only 10 minutes of HFO activity.

Until now, researchers have mostly used microwires to record HFOs, said Jacqueline A. French, MD, professor of neurology at New York University (NYU) and director of the Clinical Trials Consortium at the NYU Comprehensive Epilepsy Center.

Macroelectrodes have a surface contact area approximately 700 times greater, so they can gather information from a larger portion of the brain, she explained. Microwires are still considered investigational, so they are not used clinically and are not available at all centers. Moreover, there may be a small amount of brain injury that might occur with insertion of microwires. Thus, it would be much more practical if macroelectrodes could be used, rather than microwires, Dr. French said.

Currently, clinicians use spikes to help locate the SOZ, but those zones often have a broad area, and interictal spikes are not always specific for them, Dr. French added. High frequency oscillations offer a new path to seizure localization, but the requirement for microwires made recording of these phenomena very complex.

Figure. DR. JACQUELINE A. FRENCH: High frequency oscillations offer a new path to seizure localization, but the requirement for microwires made recording of these phenomena very complex.

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Macroelectrodes make the recording process easier, but we still have a ways to go to determine the exact place of this technique in the presurgical evaluation, she warned. Also, this technique would not assist in determining the area where intracranial electrodes should be placed. It only may make these electrodes more sensitive and specific for locating the seizure focus.

• Bartolomei F, Hayashi M, Reégis J, et al. Long-term efficacy of gamma knife radiosurgery in mesial temporal lobe epilepsy.

• Schulze-Bonhage A, Trippel M, Osterta C, et al. Outcome and predictors of interstitial radiosurgery in the treatment of gelastic epilepsy.

• Jacobs J, LeVan P, Gotman J, et al. Interictal high-frequency oscillations (80-500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain.