Physiological Ripples Associated With Sleep Spindles Can Be Identified in Patients With Refractory Epilepsy Beyond Mesio-Temporal Structures

Abstract

Introduction: High frequency oscillations (HFO) are promising biomarkers of epileptic tissue. While group analysis suggested a correlation between surgical removal of HFO generating tissue and seizure free outcome, HFO could not predict seizure outcome on an individual patient level. One possible explanation is the lack of differentiation between physiological and epileptic HFO. In the mesio-temporal lobe, a proportion of physiological ripples can be identified by their association with scalp sleep spindles. Spike associated ripples in contrast can be considered epileptic. This study investigated whether categorizing ripples by the co-occurrence with sleep spindles or spikes improves outcome prediction after surgery. Additionally, it aimed to investigate whether spindle-ripple association is limited to the mesio-temporal lobe structures or visible across the whole brain. Methods: We retrospectively analyzed EEG of 31 patients with chronic intracranial EEG. Sleep spindles in scalp EEG and ripples and epileptic spikes in iEEG were automatically detected. Three ripple subtypes were obtained: SpindleR, Non-SpindleR, and SpikeR. Rate ratios between removed and non-removed brain areas were calculated. We compared the distinct ripple subtypes and their rates in different brain regions, inside and outside seizure onset areas and between patients with good and poor seizure outcome. Results: SpindleR were found across all brain regions. SpikeR had significantly higher rates in the SOZ than in Non-SOZ channels. A significant positive correlation between removal of ripple-events and good outcome was found for the mixed ripple group (r_s = 0.43, p = 0.017) and for ripples not associated with spindles (r_s=0.40, p = 0.044). Also, a significantly high proportion of spikes associated with ripples were removed in seizure free patients (p = 0.036). Discussion: SpindleR are found in mesio-temporal and neocortical structures, indicating that ripple-spindle-coupling might have functional importance beyond mesio-temporal structures. Overall, the proportion of SpindleR was low and separating spindle and spike associated ripples did not improve outcome prediction in our patient group. SpindleR analysis therefore can be a tool to identify physiological events but needs to be used in combination with other methods to have clinical relevance.

Keywords: epileptic spikes; high frequency oscillations; post-surgical outcome; refractory epilepsy; ripples; sleep spindles.

Figure 1

Schematic illustration of thalamic sleep-spindles and hippocampal ripples nesting in the depolarizing up-states of neocortical slow oscillations.

Figure 2

It summarizes the methodological approach of this study. We used scalp and intracranial EEG (DE, depth electrodes) of the video-EEG-monitoring of patients with refractory epilepsy. The raw EEG data was then visually examined to exclude channels in white matter or with too many artefacts. Afterwards, sleep spindles were automatically detected in frontal/parietal scalp EEG contacts; ripples and spikes were automatically detected in intracranial EEG. Rate ratios (mirroring the extent of removal of HFO generating tissue) were calculated for All Ripples, ripples outside spindles (Non-SpindleR) and Spike-Ripples. All included patients received surgery and a 1 year-follow-up. We hypothesized, that the removal of brain tissue generating ripples outside spindles would lead to a good postsurgical outcome after 12 months, whereas the remaining of respective tissue would lead to a bad postsurgical outcome.

Figure 3

Distribution of Spindle-Ripple (SpindleR) and Spike-Ripple (SpikeR) in different brain areas. SpindleR and SpikeR were more frequent in mesio-temporal structures than in neocortical structures. Mesio-temporal lobe: A, amygdala; HC, hippocampus; PHC, parahippocampal; Neocortex: TNC, temporal neocortex; F, frontal neocortex; P, parietal neocortex; O, occipital neocortex.

Figure 4

Percentage distribution of the three different ripple subtypes in mesio-temporal and neocortical channels. The amount of SpikeR was higher in mesio-temporal structures compared to the amount of SpindleR, whereas the amount of SpikeR and SpindleR was more alike in the neocortex. Mesio-temporal lobe: A, amygdala; HC, hippocampus; PHC, parahippocampal; Neocortex: TNC, temporal neocortex; F, frontal neocortex; P, parietal neocortex; O, occipital neocortex.

Figure 5

Rates of four different ripple subtypes in mesio-temporal and neocortical channels. Mesio-temporal (MTL) channels showed significantly higher rates of all four ripple subtypes than neocortical (NC) channels. The share of likely pathological ripples [Spike-ripple (SpikeR) and ripples outside spindles (Non-SpindleR)] was significantly higher in the mesio-temporal contacts. SpindleR, Spindle-Ripples.

Figure 6

Rates of different ripple subtypes in SOZ and Non-SOZ channels. All Ripple subtype rates were significantly higher in SOZ (=seizure onset zone) channels than in Non-SOZ channels. (SpindleR, Spindle-ripples; SpikeR, spike-ripples; Non-SpindleR, ripples outside spindles).

Figure 7

SOZ channel ratio in good vs. bad post-surgical outcome. Patients with the majority of SOZ-channels successfully removed showed a significantly better outcome in comparison to patients with SOZ-channels still in place after resection. Significant difference to the correspondent boxplot (same colour).

Figure 8

Rate ratios of three ripple subgroups with good vs. bad outcome. The ratio of removed Spike-Ripples were significantly higher in patients with a good (Engel I) compared to patients with a bad postsurgical outcome (Engel II-IV). No significant differences in ratios for Ripples outside spindles and All Ripples between both patient groups were seen. Significant difference to the correspondent boxplot (same colour).

Figure 9

High-rate (HR) ratios of four ripple subgroups with good vs. bad outcome. Significant difference to the correspondent boxplot (same colour).