High frequency oscillations in intracranial EEGs mark epileptogenicity rather than lesion type

Abstract

High frequency oscillations (HFOs) called ripples (80-250 Hz) and fast ripples (FR, 250-500 Hz) can be recorded from intracerebral EEG macroelectrodes in patients with intractable epilepsy. HFOs occur predominantly in the seizure onset zone (SOZ) but their relationship to the underlying pathology is unknown. It was the aim of this study to investigate whether HFOs are specific to the SOZ or result from pathologically changed tissue, whether or not it is epileptogenic. Patients with different lesion types, namely mesial temporal atrophy (MTA), focal cortical dysplasia (FCD) and nodular heterotopias (NH) were investigated. Intracranial EEG was recorded from depth macroelectrodes with a sampling rate of 2000 Hz. Ripples (80-250 Hz) and Fast Ripples (250-500 Hz) were visually marked in 12 patients: five with MTA, four with FCD and three with NH. Rates of events were statistically compared in channels in four areas: lesional SOZ, non-lesional SOZ, lesional non-SOZ and non-lesional non-SOZ. HFO rates were clearly more linked to the SOZ than to the lesion. They were highest in areas in which lesion and SOZ overlap, but in patients with a SOZ outside the lesion, such as in NHs, HFO rates were clearly higher in the non-lesional SOZ than in the inactive lesions. No specific HFO pattern could be identified for the different lesion types. The findings suggest that HFOs represent a marker for SOZ areas independent of the underlying pathology and that pathologic tissue changes alone do not lead to high rates of HFOs.

Figures

Figure 1

This figure demonstrates the different relationships between SOZ and lesional areas in the different lesion types. In all patients contacts outside of lesion and SOZ were most frequent (non-Lesional/non-SOZ). (A and B) In MTA SOZ and lesional areas were most overlapping on the side of the lesional mesial temporal structure (lesional/SOZ) and some of the lesional areas did not show seizure onset (lesional/non-SOZ) (Part A). Contra-laterally to the lesion a second SOZ was seen in some patients (non-lesional/SOZ, Part B). (C and D) In Nodular Heterotopia most of the SOZ areas were not located in the lesion (nodule) but in non-lesional mesial temporal structures (non-lesional-SOZ) (Part C). Some SOZ areas were located within the nodule (lesional/SOZ) and many nodules did not show any seizure activity (lesional/non-SOZ) (Part D). (F) In patients with FCD the seizure onset mostly overlapped with parts of the lesion (lesional/SOZ) and in one patient extended outside the borders of the lesion on MRI (non-lesional/SOZ). Parts of the lesion could be inactive (lesional/non-SOZ).

Figure 2

Rates per minute for the different events and the different regions as analysed, including all lesion types. Significant differences were found for the comparison SOZ versus non-SOZ but not for the comparison lesional versus non-lesional. In the ANOVA the rates of all event types were significantly higher in the lesional SOZ areas than in all areas outside the SOZ (*P<0.001). The same was observed for all rates of non-lesional SOZ areas compared with areas outside the SOZ (*P<0.001).

Figure 3

Rates of the different events in the different regions for the three lesion types separately and statistical results of the post hoc test after ANOVA comparing the four different regions (lesional SOZ, non-lesional SOZ, lesional non-SOZ and non-lesional non-SOZ). In MTA all rates of the different events were significantly higher in the lesional and non-lesional SOZ areas compared with areas outside the SOZ (*P<0.001). The rate of fast ripples was significantly higher in lesional than in non-lesional SOZ areas (&P<0.001). The rate of spikes showed the same pattern but with less significance ($P = 0.04). In FCD rates of fast ripples in the lesional SOZ and rates of spikes in the non-lesional SOZ were significantly higher than in all areas of the SOZ (*P<0.001). Rates of ripples in the lesional SOZ and rates of ripples and fast ripples in the lesional and non-lesional SOZ were higher than in non-lesional areas outside the SOZ (^P<0.001), but not towards lesional areas outside the SOZ. Only fast ripple rates were higher in lesional SOZ areas than in lesional non-SOZ areas (%P = 0.04). In NH all rates of the different events were significantly higher in the lesional and non-lesional SOZ areas compared with areas outside the SOZ (*P<0.001). The rates of ripples and fast ripples were significantly higher in the non-lesional SOZ than in lesional SOZ areas (ripples &P<0.001; fast ripples #P<0.001).

Figure 4

Overview of the significant results in the post hoc analysis of all lesion together (A–C), and separately for MTA (D–F), FCD (G–I) and NH (J–K) patients. Arrows are given for all significant results (P<0.05), vertical arrows presenting the SOZ versus non-SOZ comparison and horizontal arrows the lesional versus non-lesional comparison. Diagonal arrows are shown with interrupted lines as their meaning can only be interpreted in combination with other arrows. The predominance of downward pointing vertical arrows underlines the conclusion of our results, that HFOs are predominant in SOZ areas and this statement is supported by the diagonal arrows.

Figure 5

Patient with right mesial temporal atrophy and bilateral SOZ areas (Patient #2). (A) implantation sites in relation to the lesional and SOZ contacts on the right side, showing the implantation of the mesial temporal structures as used in most patients. This patient had additionally the same implantation on the left side. (B) anatomical images (FLAIR and IRFSE) of the patient’s hippocampal atrophy, confirmed by volumetric measures. (C) intracranial EEG. The left panel shows the unfiltered EEG with a normal time scale; the middle shows the grey section from the left panel in extended time scale and high gain, and with a high pass filter of 80 Hz; and the right the same section with a filter of 250 Hz. A ripple in R-HC1 and 2 and a fast ripple in R-HC1 in the lesional/SOZ area are demonstrated. The left mesial temporal structures showed HFOs as well; this region was part of a SOZ and not of the lesional area. L = left; R = right; HC = Hippocampus; PHC = Parahippocampus; A = Amygdala.

Figure 6

Patient with a focal cortical dysplasia in the left fronto-orbital region (Patient 9). The SOZ is limited to the lesion. (A) EEG displayed as in Fig. 5 showing highpass-filtered data extended time scale in the middle (80 Hz) and on the right (250 Hz). A ripple oscillation in the lesional/SOZ area LOF1-3 without a co-occuring fast ripple can be seen. No HFOs are observed over both hippocampal contacts during that time and rates were generally low in this patient, who did not show any seizures deriving from the mesial temporal structures. (B) implantation site of the electrode L-OF aiming at the lesion and SOZ. The patient had additional electrodes, not shown here, including bitemporal electrodes implanted as shown in Fig. 5. (C) FCD shown within the red frame on the axial T2 and the coronal T1 image. The T1 image also shows the electrode tract after explantation. L = left; R = right; OF = orbito-frontal.

Figure 7

This patient (#6) had two nodular heterotopias close to the ventricles. His seizures all derived from the mesial temporal structures without involvement of the nodules. (A) implantation of the contacts RAN (anterior portion of the nodule) and RPN (posterior portion of the nodule). Additionally the patient had electrodes placed in the right mesial temporal structures similarly to those shown in Fig. 4. (B) EEG illustrated as in Fig. 5, showing a ripple oscillations as well as a co-occurring fast ripple oscillation in R-HC1. No HFOs were observed within the nodules. L = left, R = right, HC = hippocampus, AN = anterior nodule, PN = posterior nodule.