Absence of an MRI lesion not only discourages consideration of a patient for surgical candidacy, but is also associated with poor surgical outcome. In our study, the overall seizure-free outcome was 50% when all 3 noninvasive modalities were used. This seizure-free outcome compares well with other published series of nonlesional epilepsy.6,11,17,–21
Although seizure-free outcome in these challenging patients is still lower than in the lesional focal epilepsy group, high seizure burdens and frequently associated cognitive dysfunction should be weighed in favor of surgical consideration.
There are several noninvasive localization tests available to help detect epileptogenic foci in nonlesional epilepsy. Most recently, SISCOM, MEG, and FDG-PET have become more widely available. However, most epilepsy centers may not have access to all of these modalities, therefore, there are few studies directly comparing all 3 tests with iEEG and surgical outcome in the same patients. The current study shows that both SISCOM and MEG have better lobar concordance with iEEG than SPM-PET. This is consistent with recent studies showing that SISCOM and MSI had a high predictive value for localizing seizures with iEEG.22,23
Although FDG-PET has been shown to be useful in temporal lobe epilepsy,24
its diagnostic value in nonlesional neocortical epilepsy is less clear.25,26
We used SPM analysis in an attempt to eliminate some of the subjectivity required with visual analysis and to control for differences in expertise and experience between readers.27
Using SPM analysis of FDG-PET, the lobar concordance rate with iEEG was lower for FDG-PET than the other modalities. The extent of hypometabolism on FDG-PET is often larger than the true epileptogenic zone, and often extends beyond one lobe into an adjacent lobe. In addition, the epileptogenic zone is often observed in the periphery of hypometabolism rather than in the center.28
As a result, FDG-PET may be more often lateralizing than localizing to a single lobe. In fact, FDG-PET successfully lateralized seizure onset zone in 71% (10/14) of our patients. PET and iEEG lateralization disagreed in 4 patients; 3 had a Class III or IV outcome. Therefore, discordant FDG-PET with other noninvasive tests may be associated with poor surgical outcome in nonlesional epilepsy. Similar findings have been reported in adult temporal lobe epilepsy.29
Our data support the role of multimodal approach in presurgical evaluation of nonlesional epilepsy. First, multimodality imaging allowed us to extend the surgical treatment to patients who could not be considered good candidates without the tests. Based on ictal scalp EEG and clinical semiology, we were able to localize the possible epileptogenic zone in only 1 out of 14 patients (7%, 1/14) and to lateralize the epileptogenic hemisphere in an additional 8 patients (57%, 8/14). Without multimodality approach, 36% of patients (5/14) with poor lateralization may have been discouraged from epilepsy surgery. Second, we were able to refine the hypothesis on the possible epileptogenic zone and therefore to reduce the size of craniotomy and number of subdural electrodes. In our series, 57% of patients with lateralizing but nonlocalizing seizure onset may have required diffuse hemispheric iEEG coverage without the multimodal tests. Third, high concordance score across these tests tended to be associated with favorable surgical outcome even though it did not reach statistical significance, probably due to small sample size. This agrees with a previous study demonstrating that positivity of all tests including MSI, FDG-PET, and ictal SPECT predicts increased odds for seizure-free outcome after surgery.22
Histologic examination revealed that all 11 patients with available pathology had focal cortical dysplasia. FCD type I was noted in 91% (10/11) of patients in this study. In previous reports, type I FCD was often associated with negative MRI and poor surgical outcome while type II FCD was associated with more visible MRI findings and better outcome.30
Higher incidence of FCD in our series than previous series of nonlesional epilepsy17
and the presence of disagreement between the initial and second reviewer (18%, 2/11) suggest that there exists some variability of diagnostic threshold for FCD.
We recognize that there are limitations to this study. First, this is a single-center retrospective review, which is subject to selection bias given specific referral patterns. It is possible that more difficult cases of nonlesional epilepsy may have been discouraged from surgical consideration by the patients' primary neurologists. Second, our study did not analyze the cost-benefit aspect of this multimodality approach. With surging health care costs, many epilepsy centers may not offer all available noninvasive tests. However, considering the long-term financial burden of caring for intractable epilepsy patients, this multimodality approach may be justified. Long-term follow-up of this patient population may provide further answers. Third, we applied SPM analysis of FDG-PET using a normal adult template. Even though SPM-PET has been reported to be useful in evaluating children over 6 years,31
small differences in the pattern of glucose metabolism may occur especially during late childhood and adolescence. Development of a normal pediatric template needs to be undertaken to apply SPM analysis more widely in the pediatric group, especially in children less than 6 years of age. Finally, we compared individual presurgical tests with iEEG to evaluate their diagnostic accuracy. Even though iEEG is considered the gold standard to map the ictal onset zone, sampling error is still possible, especially in nonlesional cases. Therefore, we tried to differentiate between the primary ictal onset zone vs the secondary spread zone based on iEEG pattern. Another shortcoming of using iEEG as the gold standard is that the placement of iEEG is to some degree influenced by the presurgical tests and thus the iEEG findings are not completely independent from the 3 presurgical tests.
Although combined multimodality imaging approach could enhance our ability to localize the epileptogenic zone in nonlesional focal epilepsy, extraoperative iEEG cannot be completely avoided presently. Aside from the exact localization of the epileptogenic zone, the extent of curative resection may not be accurately determined without proper iEEG monitoring and cortical stimulation mapping. A larger prospective study may be necessary to elucidate the role of multimodality imaging in this selected group of patients.