Abstract
Epilepsy Surgery of Focal Cortical Dysplasia–Associated Tumors
Cossu M, Fuschillo D, Bramerio M, Galli C, Gozzo F, Pelliccia V, Casaceli G, Tassi L, Lo Russo G. Epilepsia 2013;54(Suppl 9):115–122
The goal of the present study was to evaluate the clinical characteristics and postoperative seizure outcome of epileptogenic tumors associated with focal cortical dysplasias (FCDs) compared to both solitary FCD type I and solitary tumors. Particular attention is given to FCD type IIIb (tumors associated with FCD type I), which have been recently classified as a separate entity. We retrospectively reviewed the clinical charts of 1,109 patients who were operated on for drug-resistant focal epilepsy, including 492 patients with a histologic diagnosis of solitary FCD I and II (83 and 157 cases, respectively), solitary tumors (179 cases), and FCD-associated tumors (73 cases, 58 of which met the criteria of FCD IIIb of the new International League Against Epilepsy [ILAE] classification). The different subgroups were evaluated for clinical characteristics and postoperative surgical outcome. Clinical variables and postoperative seizure outcome of patients with coexisting tumor and FCDs (FCD IIIb and tumor associated FCD II) were similar to those of patients with a solitary tumor and differed significantly from patients with solitary FCDs. Nevertheless, tumors associated with FCDs are characterized by a striking male predominance and a higher seizure frequency as compared to solitary tumors. Patients with drug-resistant focal epilepsy secondary to a solitary tumor or with a tumor-associated FCD have similar basic clinical presentation and postoperative seizure outcome. Nevertheless, the epileptogenic contribution of the associated FCDs can be crucial, and it needs to be adequately assessed. The impact of FCD on tumor-related epilepsy deserves future research in order to optimize the surgical strategies aimed at seizure relief.
Commentary
Low-grade supratentorial tumors constitute 10 to 40% of the pathological diagnoses in patients following resective surgery for refractory focal-onset epilepsy (1, 2). The most common tumor subtypes in this group include inherently indolent and intrinsically epileptogenic gangliogliomas (GG) (3) and dysembryoplastic neuroepithelial tumors (DNT). Temporal lobe tumors in this group exhibit certain distinct features. About 90% of such tumors were found within or adjacent to the gray–white junction or hippocampal formation with frequent involvement of associated mesial temporal structures (4, 5). Several studies have identified young age, male predominance, long history of refractory epilepsy, healthy neurological examination, an indolent biological nature with long-term survival, and favorable surgical outcome as common characteristics in this group (6, 4, 5).
Supratentorial GG and DNT tumors demonstrate a strong association with focal cortical dysplasias (FCD). It is notable that FCD are a common cause of intractable epilepsy in both children and adults. It is well-known that FCD are associated with epileptogenic brain tissue, although surgical resection achieves seizure control to a variable extent (7, 8). The optimal surgical strategy for these patients continues to be debated. Some centers typically recommend, when possible, isolated tumor resection while others include resection of surrounding epileptogenic structures guided by electrocorticography (ECoG). Such ECoG studies have challenged the idea that epilepsy in a subgroup of FCD is associated with a solitary epileptogenic lesion. That is, epileptogenic areas remote from the primary dysplastic lesion are often associated with less favorable clinical outcomes.
All forms of FCD lead to disorganization of the normal structure of the cerebral cortex. Characteristic findings include often subtle aberrant radial or tangential lamination of the neocortex (FCD Type I) and/or cytological abnormalities (FCD Type II). FCD in combination with GG and DNT tumors appear to occur isolated in temporal and/or extratemporal regions. In particular, FCD Type I is associated with subtle neuroimaging, histopathology, and less favorable post resective seizure outcomes. The indolent progression and associated epileptogenicity of glioneural tumors have raised the hypothesis of a developmental rather than neoplastic origin of these lesions (9).
A recent International League Against Epilepsy (ILAE) task force has re-evaluated available data and proposed a neuropathological classification system of FCD (10). The major modification to the previous classification includes the introduction of FCD Type III, which occurs always in combination with mesial temporal sclerosis (FCD Type IIIA), or with epilepsy-associated tumors (FCD Type IIIB). FCD Type IIIC is found adjacent to gliosis and vascular malformations, and FCD Type IIID is associated with all other lesions, such as encephalitis, in an epileptic brain. In contrast, FCD Type I refers to isolated lesions, which present either as radial (FCD Type IA) or tangential (FCD Type IB) cortical dyslamination, microscopically identified in one or multiple lobes. This three-tiered classification system can facilitate exploring clinico-electrocerebral features with associated epileptogenicity, neuroimaging relationships, and underlying molecular pathological mechanisms of FCD (7).
Cossu et al. published a single center retrospective study in which an extensive chart review was performed for 1109 patients who had a temporal or extratemporal resection for medically refractory epilepsy. The authors evaluated the clinical characteristics and postoperative seizure outcomes of patients following resection of epileptogenic glioneural tumors associated with FCD compared with both solitary FCD Type I and solitary tumors. The authors found that FCD IIIb significantly differed from solitary FCDs Type I in age at seizure onset, seizure frequency, presence of MRI findings, necessity for stereo-en-cephalography (SEEG) evaluation, site of surgery (temporal vs. extratemporal regions), and seizure outcome. FCD IIIb differed from solitary tumors in terms of gender, seizure frequency, and site of surgery (temporal vs. extratemporal regions).
The key finding of this study is that FCD IIIb demonstrates characteristics more similar to solitary tumors than to FCD I, including less challenging resection and improved seizure outcome. The authors also report a slightly higher seizure frequency refractory to medication management detected in FCD IIIb patients. These findings may be due to a presence of cortical disorganization representing enhanced excitability within the epileptogenic zone. Usage of ECoG has challenged the idea that epilepsy in FCD is associated with a solitary epileptogenic lesion. ECoG data have demonstrated both epileptogenic discrete dysplastic foci and remote, structurally normal-appearing epileptogenic cortex (11, 12). The authors emphasize that solitary FCD Type I likely represents a more widespread structural abnormality compared with dysplastic FCD IIIb that share characteristics similar to discrete solitary tumors. The authors reported MRI-negative studies in 30% of their series. It is likely that FCD Type I contributes to extensive epileptogenic networks that include pathways connecting deep modulatory territories, such as thalamus and distant pathological neocortex. The FCD Type I associated ‘epileptic focus’ becomes a misnomer when such epileptic circuits are discussed. This hypothesis fuels the debate at two levels. First, does resective surgery provide favorable outcomes in patients with significant neuroimaging-positive FCD lesions? An important complementary discussion surrounds the localization methodology for GG and DNT tumors in the presence of FCD Type I. Specifically, it remains controversial whether ECoG provides useful information for potentially extending the resection beyond the boundaries of the tumor.
The authors emphasize that FCD Type IIIb appears to be correlated with the tumor rather than the FCD. The authors also set forth a statement that their analyses make the ILAE classification of FCD IIIb using strict histopathological criteria less relevant. Regardless of the study limitations that include a relatively small sample size, lack of a multicenter design, and retrospective approach, this study serves as an important platform on which to design and implement a larger collaborative effort attempting to understand the impact of FCD on tumor-related refractory epilepsy. In addition, the study provides an impetus for developing better detection methods and clarity of the contribution of these distributed epileptogenic foci potentially impacting surgical efficacy in patients with GG and DNT tumors.