Cortical and subcortical contributions to absence seizure onset examined with EEG/fMRI

Abstract

In patients with idiopathic generalized epilepsies (IGEs), bursts of generalized spike and wave discharges (GSWDs) lasting ≥ 2 seconds are considered absence seizures. The location of the absence seizures generators in IGEs is thought to involve interplay between various components of thalamocortical circuits; we have recently postulated that medication resistance may, in part, be related to the location of the GSWD generators [Szaflarski JP, Lindsell CJ, Zakaria T, Banks C, Privitera MD. Epilepsy Behav. 2010;17:525–30]. In the present study we hypothesized that patients with medication-refractory IGE (R-IGE) and continued absence seizures may have GSWD generators in locations other than the thalamus, as typically seen in patients with IGE. Hence, the objective of this study was to determine the location of the GSWD generators in patients with R-IGE using EEG/fMRI. Eighty-three patients with IGE received concurrent EEG/fMRI at 4 T. Nine of them (aged 15–55) experienced absence seizures during EEG/fMRI and were included; all were diagnosed with R-IGE. Subjects participated in up to three 20-minute EEG/fMRI sessions (400 volumes, TR = 3 seconds) performed at 4 T. After removal of fMRI and ballistocardiographic artifacts, 36 absence seizures were identified. Statistical parametric maps were generated for each of these sessions correlating seizures to BOLD response. Timing differences between brain regions were tested using statistical parametric maps generated by modeling seizures with onset times shifted relative to the GSWD onsets. Although thalamic BOLD responses peaked approximately 6 seconds after the onset of absence seizures, other areas including the prefrontal and dorsolateral cortices showed brief and nonsustained peaks occurring ∼ 2 seconds prior to the maximum of the thalamic peak. Temporal lobe peaks occurred at the same time as the thalamic peak, with a cerebellar peak occurring ∼ 1 second later. Confirmatory analysis averaging cross-correlation between cortical and thalamic regions of interest across seizures corroborated these findings. Finally, Granger causality analysis showed effective connectivity directed from frontal lobe to thalamus, supporting the notion of earlier frontal than thalamic involvement. The results of this study support our original hypothesis and indicate that in the patients with R-IGE studied, absence seizures may be initiated by widespread cortical (frontal and parietal) areas and sustained in subcortical (thalamic) regions, suggesting that the examined patients have cortical onset epilepsy with propagation to thalamus.

Introduction

Epilepsy is one of the most common neurological illnesses, with 6.4–35.8% of patients carrying the diagnosis of idiopathic generalized epilepsy (IGE) [1], [2], [3]. Overall, IGEs are clinically and genetically heterogeneous. Because of their presumed genetic etiologies and generalized seizure onset, IGEs are not amenable to surgical management and antiepileptic drugs (AEDs) are thought to be the only remedy for these patients. In up to 30% of patients with IGEs, polypharmacy with multiple AEDs and/or vagus nerve stimulator (VNS) does not control seizures [4], [5]. These patients with so-called atypical or medication-refractory IGEs (R-IGEs) often face lifelong medication-resistant seizures and associated complications including low self-esteem, emotional and mood problems, and poor quality of life [6], [7], [8]. Despite the fact that resistance to AEDs in patients with IGEs is common, relatively little is known about the sources of the generalized spike-and-wave discharges (GSWDs) in these patients. If available, such information could provide clues regarding the potential reasons for medication resistance.

The typical EEG pattern in patients with IGEs consists of abrupt-onset 2- to 5-Hz GSWDs, frequently with bifrontal and paracentral predominance, superimposed on a normal alpha background. By definition (“generalized”), GSWDs should be present in all brain areas and should be associated with the typical IGE seizure patterns: absences, myoclonic jerks, or generalized tonic–clonic seizures [9], [10]. The fact that GSWDs are symmetric suggests deep brain structures (e.g., thalamus) as their source. But the results of studies of EEG patterns in patients with IGEs are divergent and suggest the possibility of either cortical or deep brain sources of GSWDs. In one study, asymmetry of the epileptiform discharges on scalp EEG pointed toward potentially different seizure onset as the etiology of AED resistance in patients with juvenile myoclonic epilepsy (JME), an idiopathic generalized epilepsy syndrome [11]; patients with asymmetric GSWDs are much more likely to have R-IGE [9], [11]. Studies using dipole modeling showed widespread cortical (predominantly frontal) GSWD onset in patients with IGEs (medication response not provided) [12], [13] and corroborated the evidence from morphometric studies suggestive of frontal cortical anatomical abnormalities in patients with IGEs [14], [15]. Similarly, recent magnetoencephalographic (MEG) source analysis in patients with predominantly R-IGEs showed localization of the GSWD generators mainly in the central and premotor regions of the frontal lobes [16]. In contrast to those studies, a recent EEG/fMRI study of patients with IGEs showed increases in BOLD signal responses in the thalami and decreases in the frontal and parietal cortical structures suggestive of the presence of GSWD generators in the deep brain structures [17], whereas another EEG/fMRI study of AED-naïve patients with absence seizures showed clear thalamic BOLD signal increases with only negative BOLD signal correlates to GSWDs in other brain regions [18]. Therefore, the origins of GSWDs in patients with IGEs remain unclear and contributions from both deep brain and cortical structures are suspected. Some of the differences seen in the studies performed thus far may be related to patient selection, with studies usually including mixed groups of AED-responsive and AED-resistant patients. Further, technical difficulties with localization of sources deep within the brain using scalp EEG arrays or magnetoencephalography and algorithms for localization that rely on assumptions about the discrete, dipole character of the sources may also lead to ambiguous localization of thalamic sources. On the basis of the aforementioned evidence from studies in patients with typical IGEs and R-IGEs, we hypothesized that in patients with R-IGEs, GSWD generators are located in frontal/cortical areas and that thalami either contribute to the generation of the GSWDs or support their propagation.