Abstract
Juan E, Górska U, Kozma C, Papantonatos C, Bugnon T, Denis C, Kremen V, Worrell G, Struck AF, Bateman LM, Merricks EM, Blumenfeld H, Tononi G, Schevon C, Boly M. Brain. 20235;146(1):109-123. doi:10.1093/brain/awac291 Loss of consciousness is a hallmark of many epileptic seizures and carries risks of serious injury and sudden death. While cortical sleep-like activities accompany loss of consciousness during focal impaired awareness seizures, the mechanisms of loss of consciousness during focal to bilateral tonic-clonic seizures remain unclear. Quantifying differences in markers of cortical activation and ictal recruitment between focal impaired awareness and focal to bilateral tonic-clonic seizures may also help us to understand their different consequences for clinical outcomes and to optimize neuromodulation therapies. We quantified clinical signs of loss of consciousness and intracranial EEG activity during 129 focal impaired awareness and 50 focal to bilateral tonic-clonic from 41 patients. We characterized intracranial EEG changes both in the seizure onset zone and in areas remote from the seizure onset zone with a total of 3386 electrodes distributed across brain areas. First, we compared the dynamics of intracranial EEG sleep-like activities: slow-wave activity (1-4 Hz) and beta/delta ratio (a validated marker of cortical activation) during focal impaired awareness versus focal to bilateral tonic-clonic. Second, we quantified differences between focal to bilateral tonic-clonic and focal impaired awareness for a marker validated to detect ictal cross-frequency coupling: phase-locked high gamma (high-gamma phased-locked to low frequencies) and a marker of ictal recruitment: the epileptogenicity index. Third, we assessed changes in intracranial EEG activity preceding and accompanying behavioural generalization onset and their correlation with electromyogram channels. In addition, we analysed human cortical multi-unit activity recorded with Utah arrays during three focal to bilateral tonic-clonic seizures. Compared to focal impaired awareness, focal to bilateral tonic-clonic seizures were characterized by deeper loss of consciousness, even before generalization occurred. Unlike during focal impaired awareness, early loss of consciousness before generalization was accompanied by paradoxical decreases in slow-wave activity and by increases in high-gamma activity in parieto-occipital and temporal cortex. After generalization, when all patients displayed loss of consciousness, stronger increases in slow-wave activity were observed in parieto-occipital cortex, while more widespread increases in cortical activation (beta/delta ratio), ictal cross-frequency coupling (phase-locked high gamma) and ictal recruitment (epileptogenicity index). Behavioural generalization coincided with a whole-brain increase in high-gamma activity, which was especially synchronous in deep sources and could not be explained by EMG. Similarly, multi-unit activity analysis of focal to bilateral tonic-clonic revealed sustained increases in cortical firing rates during and after generalization onset in areas remote from the seizure onset zone. Overall, these results indicate that unlike during focal impaired awareness, the neural signatures of loss of consciousness during focal to bilateral tonic-clonic consist of paradoxical increases in cortical activation and neuronal firing found most consistently in posterior brain regions. These findings suggest differences in the mechanisms of ictal loss of consciousness between focal impaired awareness and focal to bilateral tonic-clonic and may account for the more negative prognostic consequences of focal to bilateral tonic-clonic.
Commentary
Loss of consciousness (LOC) during seizures is a devastating consequence of focal epilepsy. It leads to falls, motor vehicle collisions, problems with school or work, drownings, and likely contributes to sudden unexpected death in epilepsy. Loss of consciousness is characteristic of both focal impaired-awareness seizures (FIAS) and focal to bilateral tonic–clonic seizures (FBTCS)—two of the most disabling seizure types. However, semiology is very different in FIAS and FBTCS, so how does LOC arise in each? It may appear intuitive that LOC would occur during FBTCS, where widespread ictal involvement of bilateral brain networks is anticipated. Why does LOC occur during FIAS, where we expect seizure activity to remain focally confined? Blumenfeld first proposed the Network Inhibition Hypothesis in temporal lobe epilepsy—the most common focal epilepsy syndrome. 1 It was postulated that during FIAS, focal limbic seizure activity perturbs subcortical networks necessary for cortical activation, leading to neocortical suppression and LOC that does not involve widespread seizure propagation. This hypothesis has been supported by human intracranial EEG (iEEG) findings showing sleep-like delta activity in the frontoparietal neocortex during FIAS but not focal aware seizures, 2 and by several mechanistic animal studies from the Blumenfeld group (reviewed here 3 ). While some of these animal studies also examined the network correlates of FIAS versus FBTCS, few human iEEG studies have compared the electrographic signatures of LOC in these two seizure types. Understanding these mechanisms can lead to improved strategies to predict and potentially prevent ictal LOC.
In the highlighted article, Juan and colleagues evaluated the electrographic signatures of LOC in FIAS versus FBTCS in focal epilepsy patients undergoing iEEG with stereo-EEG (SEEG) or subdural grid electrodes. 4 In 41 patients, they examined 179 seizures (72% FIAS, 28% FBTCS) that began in the temporal lobe in most cases (85%) and in frontal (12%) or parietal-occipital (3%) cortex in others. Measures included power spectrum density across frequency bands, calculation of an epileptogenicity index to examine ictal recruitment, and evaluation of iEEG signatures of behavioral generalization in a subset of FBTCS patients where the timing of generalization was known. Seizure type was assigned by review of ictal video recordings using the methods of Englot et al, 2 or by the classification used in the source database when video was unavailable. During FIAS, the beta/delta power ratio decreased in all brain regions outside the seizure onset zone, indicating increased slow activity, whereas during FBTCS, the beta/delta power ratio decreased in most extratemporal cortical areas before generalization, but then increased sharply throughout the brain after generalization. Seizure generalization was also accompanied by increased high gamma power in temporal and parieto-occipital regions, as well as increased cross-frequency coupling in all brain areas, which was contrasted by reduced cross-frequency coupling in extratemporal cortex during FIAS. Using the epileptogenicity index, more widespread channels were recruited ictally during FBTCS than FIAS, and in a subset of patients with multiunit activity measurements, increased firing distal from the seizure onset zone was noted during FBTCS. Taken together, these findings suggest neocortical slowing and suppression during FIAS and early FBTCS, but rapid and broad spread of fast activity in FBTCS when generalization occurs, particularly in the posterior quadrant.
The iEEG study by Juan et al provides novel insight into the electrographic signatures of LOC in FIAS versus FBTCS, clearly suggesting that LOC occurs through different mechanisms in these 2 seizure types. These results are based upon well-designed analyses using a relatively large patient sample that includes data from the authors’ own center, plus additional patients from online data repositories. This work builds upon the group’s prior study comparing FIAS and FTBCS using high-density scalp EEG. 5 The data suggest that in most patients, LOC likely results from network inhibition in FIAS but network excitation from seizure spread in FBTCS. Ultimately, uncovering the electrographic signatures of LOC in focal epilepsy may lead to neuromodulation strategies aimed to both reduce seizures and prevent the downstream network effects that lead to LOC. Indeed, a small clinical trial of closed-loop thalamic stimulation for preservation of consciousness in temporal lobe epilepsy is currently underway (ClinicalTrials.gov Identifier: NCT04897776).
As the authors note, a limitation of this study is that only a small number of patients had both seizure types, so most analyses compared seizure data between 2 patient groups with little overlap. Next, analyses combined patients with varied seizure onset zones, and while most individuals suffered from temporal lobe epilepsy, some had frontal or parietal-occipital seizure onset. Prior work suggests that the mechanisms for LOC during FIAS likely differs between focal epilepsy subtypes, with LOC associated with ictal network inhibition (frontoparietal slow activity) in temporal lobe epilepsy, 2 but frontal lobe excitation from direct seizure spread (frontal low voltage fast activity) in frontal lobe epilepsy. 6 It will be worthwhile in the future to pursue separate analyses in patients with different focal epilepsy subtypes, as the network mechanisms likely differ in seizures with mesial temporal versus neocortical onset. Also, it would be interesting in forthcoming studies to compare dynamic network connectivity patterns during consciousness-impairing versus consciousness-sparing focal seizures, and determine whether ictal connectivity alterations during seizures predict long-term network disruptions on a patient level. This may lend insight into whether long-term network perturbations and their associated neurocognitive deficits develop from recurrent ictal network insults suffered during consciousness-impairing seizures, as we recently proposed in the Extended Network Inhibition Hypothesis. 7
Finally, it is interesting to speculate about the potential evolutionary contributions to ictal network inhibition phenomena observed in focal epilepsy. It is possible that ictal network suppression during FIAS, as posited in Blumenfeld’s Network Inhibition Hypothesis, evolved to prevent secondary generalization of seizures, but sometimes excitatory propagation prevails, resulting in seizure generalization. Secondary generalization increases risk of injury, and as we see in the work by Juan et al, it leads to more widespread and deleterious network effects. We also recently proposed the Interictal Suppression Hypothesis, which surmises that inward inhibitory connections from nonepileptogenic areas to the seizure onset zone during the interictal period may have evolved to prevent seizure initiation. 8 Other groups have also suggested an interictal inhibitory surround phenomenon in focal epilepsy. 9,10 So, it is possible that network inhibition—both ictally and interictally—may explain why patients with focal epilepsy are not continually having seizures, and why focal seizures do not always generalize. Mechanistic studies in both patients and animal models will be necessary to lend credence to these hypotheses. What is clear, however, is that both network excitation and network inhibition can contribute to LOC in focal epilepsy, and they represent a problem in need of advanced network-based treatments.
