More Than Spikes: On the Added Value of Non-linear Intracranial EEG Analysis for Surgery Planning in Temporal Lobe Epilepsy

Epilepsy surgery can be a very effective therapy in medication refractory patients. During patient evaluation intracranial EEG is analyzed by clinical experts to identify the brain tissue generating epileptiform events. Quantitative EEG analysis increasingly complements this approach in research settings, but not yet in clinical routine. We investigate the correspondence between epileptiform events and a specific quantitative EEG marker. We analyzed 99 preictal epochs of multichannel intracranial EEG of 40 patients with mixed etiologies. Time and channel of occurrence of epileptiform events (spikes, slow waves, sharp waves, fast oscillations) were annotated by a human expert and non-linear excess interrelations were calculated as a quantitative EEG marker. We assessed whether the visually identified preictal events predicted channels that belonged to the seizure onset zone, that were later resected or that showed strong non-linear interrelations. We also investigated whether the seizure onset zone or the resection were predicted by channels with strong non-linear interrelations. In patients with temporal lobe epilepsy (32 of 40), epileptic spikes and the seizure onset zone predicted the resected brain tissue much better in patients with favorable seizure control after surgery than in unfavorable outcomes. Beyond that, our analysis did not reveal any significant associations with epileptiform EEG events. Specifically, none of the epileptiform event types did predict non-linear interrelations. In contrast, channels with strong non-linear excess EEG interrelations predicted the resected channels better in patients with temporal lobe epilepsy and favorable outcome. Also in the small number of patients with seizure onset in the frontal and parietal lobes, no association between epileptiform events and channels with strong non-linear excess EEG interrelations was detectable. In contrast to patients with temporal seizure onset, EEG channels with strong non-linear excess interrelations did neither predict the seizure onset zone nor the resection of these patients or allow separation between patients with favorable and unfavorable seizure control. Our study indicates that non-linear excess EEG interrelations are not strictly associated with epileptiform events, which are one key concept of current clinical EEG assessment. Rather, they may provide information relevant for surgery planning in temporal lobe epilepsy. Our study suggests to incorporate quantitative EEG analysis in the workup of clinical cases. We make the EEG epochs and expert annotations publicly available in anonymized form to foster similar analyses for other quantitative EEG methods.

Direct Cortical Stimulation to Probe the Ictogenicity of the Epileptogenic Nodes in Temporal Lobe Epilepsy

Accurate mapping of the seizure onset zone (SOZ) is critical to the success of epilepsy surgery outcomes. Epileptogenicity index (EI) is a statistical method that delineates hyperexcitable brain regions involved in the generation and early propagation of seizures. However, EI can overestimate the SOZ for particular electrographic seizure onset patterns. Therefore, using direct cortical stimulation (DCS) as a probing tool to identify seizure generators, we systematically evaluated the causality of the high EI nodes (>0.3) in replicating the patient's habitual seizures. Specifically, we assessed the diagnostic yield of high EI nodes, i.e., the proportion of high EI nodes that evoked habitual seizures. A retrospective single-center study that included post-stereo encephalography (SEEG) confirmed TLE patients (n = 37) that had all high EI nodes stimulated, intending to induce a seizure. We evaluated the nodal responses (true and false responder rate) to stimulation and correlated with electrographic seizure onset patterns (hypersynchronous-HYP and low amplitude fast activity patterns-LAFA) and clinically defined SOZ. The ictogenicity (i.e., the propensity to induce the patient's habitual seizure) of a high EI node was only 44.5%. The LAFA onset pattern had a significantly higher response rate to DCS (i.e., higher evoked seizures). The concordance of an evoked habitual seizure with a clinically defined SOZ with good outcomes was over 50% (p = 0.0025). These results support targeted mapping of SOZ in LAFA onset patterns by performing DCS in high EI nodes to distinguish seizure generators (true responders) from hyperexcitable nodes that may be involved in early propagation.

The Anti-Epileptic Effects of Carbenoxolone In Vitro and In Vivo

Gap junctions (GJs) are intercellular junctions that allow the direct transfer of ions and small molecules between neighboring cells, and GJs between astrocytes play an important role in the development of various pathologies of the brain, including regulation of the pathological neuronal synchronization underlying epileptic seizures. Recently, we found that a pathological change is observed in astrocytes during the ictal and interictal phases of 4-aminopyridin (4-AP)-elicited epileptic activity in vitro, which was correlated with neuronal synchronization and extracellular epileptic electrical activity. This finding raises the question: Does this signal depend on GJs between astrocytes? In this study we investigated the effect of the GJ blocker, carbenoxolone (CBX), on epileptic activity in vitro and in vivo. Based on the results obtained, we came to the conclusion that the astrocytic syncytium formed by GJ-associated astrocytes, which is responsible for the regulation of potassium, affects the formation of epileptic activity in astrocytes in vitro and epileptic seizure onset. This effect is probably an important, but not the only, mechanism by which CBX suppresses epileptic activity. It is likely that the mechanisms of selective inhibition of GJs between astrocytes will show important translational benefits in anti-epileptic therapies.

Temporal pole blurring in temporal lobe epilepsy revealed by 3D Edge-Enhancing Gradient Echo MRI

While abnormalities of the hippocampus have been well characterized in temporal lobe epilepsy, various additional temporal lobe abnormalities have also been described. One poorly understood entity, the so-called temporal pole blurring (TPB), is one of the more frequently described neocortical abnormalities in TLE and is thought to represent dysmyelination and axonal loss due to chronic electrical perturbations in early age-onset temporal lobe epilepsy. In this study, we describe the first reported cases of TPB diagnosed by a recently described MRI sequence known as 3D Edge-Enhancing Gradient Echo (3D-EDGE), which has an effective “myelin weighting” making it exquisitely sensitive to this temporal pole dysmyelination. The value of detection of TPB lies in lateralizing seizure onset, as well as predicting a lower baseline neuropsychological performance compared to temporal lobe epilepsy without TPB. Additionally, it is critical to not mistake TPB for alternative diagnoses, such as focal cortical dysplasia or neoplasm.

Ictal Blinking: Reappraisal of the Lateralization and Localization Value in Focal Seizures

Introduction. Although ictal blinking is significantly more frequent in generalized epilepsy, it has been reported as a rare but useful lateralizing sign in focal seizures when it is not associated with facial clonic twitching. This study aimed to raise awareness of eye blinking as a semiological lateralizing sign. Method. Our database over an 11-year period reviewed retrospectively to assess patients who had ictal blinking associated with focal seizures. Results. Among 632 patients, 14 (2.2%), who had 3 to 13 (7 ± 3) seizures during video-EEG monitoring, were included. Twenty-five percent of all 92 seizures displayed ictal blinking and each patient had one to five seizures with ictal blinking. Ictal blinking was unilateral in 17%, asymmetrical in 22% and symmetrical in 61%. The blinking appeared with a mean latency of 6.3 s (range 0-39) after the clinical seizure-onset, localized most often to fronto-temporal, then in frontal or occipital regions. Blinking was ipsilateral to ictal scalp EEG lateralization side in 83% (5/6) of the patients with unilateral/asymmetrical blinking. The exact lateralization and localization of ictal activity could not have been determined via EEG in most of the patients with symmetrical blinking, remarkably. Conclusions. Unilateral/asymmetrical blinking is one of the early components of the seizures and appears as a useful lateralizing sign, often associated with fronto-temporal seizure-onset. Symmetrical blinking, on the other hand, did not seem to be valuable in lateralization and localization of focal seizures. Future studies using invasive recordings and periocular electrodes are needed to evaluate the value of blinking in lateralization and localization.

Interictal SEEG resting-state connectivity localizes seizure onset zone and predicts seizure outcome

Stereotactic-electroencephalography (SEEG) is a common neurosurgical method to localize epileptogenic zone in drug resistant epilepsy patients and inform treatment recommendations. In the current clinical practice, localization of epileptogenic zone typically requires prolonged recordings to capture seizure, which may take days to weeks. Although epilepsy surgery has been proven to be effective in general, the percentage of unsatisfactory seizure outcomes is still concerning. We developed a method to identify the seizure onset zone (SOZ) and predict seizure outcome using short-time resting-state SEEG data. In a cohort of 43 drug resistant epilepsy patients, we estimated the information flow via directional connectivity and inferred the excitation-inhibition ratio from the 1/f power slope. We hypothesized that the antagonism of information flow at multiple frequencies between SOZ and non-SOZ underlying the relatively stable epilepsy resting state could be related to the disrupted excitation-inhibition balance. We found higher excitability in non-SOZ regions compared to the SOZ, with dominant information flow from non-SOZ to SOZ regions, probably reflecting inhibitory input from non-SOZ to prevent seizure initiation. Greater differences in information flow between SOZ and non-SOZ regions were associated with favorable seizure outcome. By integrating a balanced random forest model with resting-state connectivity, our method localized the SOZ with an accuracy of 85% and predicted the seizure outcome with an accuracy of 77% using clinically determined SOZ. Overall, our study suggests that brief resting-state SEEG data can significantly facilitate the identification of SOZ and may eventually predict seizure outcomes without requiring long-term ictal recordings.

The Critical Modulatory Role of Spiny Stellate Cells in Seizure Onset Based on Dynamic Analysis of a Neural Mass Model

Growing evidence suggests that excitatory neurons in the brain play a significant role in seizure generation. Nonetheless, spiny stellate cells are cortical excitatory non-pyramidal neurons in the brain, whose basic role in seizure occurrence is not well understood. In the present research, we study the critical role of spiny stellate cells or the excitatory interneurons (EI), for the first time, in epileptic seizure generation using an extended neural mass model inspired by a thalamocortical model originally introduced by another research group. Applying bifurcation analysis on this modified model, we investigated the rich dynamics corresponding to the epileptic seizure onset and transition between interictal and ictal states caused by EI connectivity to other cell types. Our results indicate that the transition between interictal and ictal states (preictal signal) corresponds to a supercritical Hopf bifurcation, and thus, the extended model suggests that before seizure onset, the amplitude and frequency of neural activities gradually increase. Moreover, we showed that (1) the altered function of GABAergic and glutamatergic receptors of EI can cause seizure, and (2) the pathway between the thalamic relay nucleus and EI facilitates the transition from interictal to ictal activity by decreasing the preictal period. Thereafter, we considered both sensory and cortical periodic inputs to study model responses to various harmonic stimulations. Bifurcation analysis of the model, in this case, suggests that the initial state of the model might be the main cause for the transition between interictal and ictal states as the stimulus frequency changes. The extended thalamocortical model shows also that the amplitude jump phenomenon and non-linear resonance behavior result from the preictal state of the modified model. These results can be considered as a step forward to a deeper understanding of the mechanisms underlying the transition from normal activities to epileptic activities.

Outcome of non-cooled asphyxiated infants with under-recognised or delayed-onset encephalopathy

ObjectiveTo describe the clinical characteristics, MRI findings and neurodevelopmental outcome of infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who were not selected for therapeutic hypothermia (TH).DesignRetrospective cohort study.Setting and patients(Near-)term infants with documented perinatal asphyxia referred to two Dutch level III neonatal units with neonatal encephalopathy (NE) and seizures <24 hours after birth not treated with TH. Infants with a diagnosis other than NE following perinatal asphyxia causing the seizures were excluded.Main outcome measuresClinical characteristics, findings on cranial MRI performed within 8 days after birth and neurodevelopmental outcome assessed using the Griffiths Mental Development Scales at 18 months or Bayley Scales of Infant and Toddler Development–Third Edition at 2 years of age.Results39 infants were included. All had abnormalities on MRI. Predominant white matter/watershed injury was the most common pattern of injury, 23 (59%). 7 (18%) infants had predominant basal ganglia/thalamus injury, 3 (8%) near total brain injury, 5 (13%) arterial ischaemic stroke, 1 (3%) an intraventricular haemorrhage. Adverse outcome was seen in 51%: 6 died, 11 developed cerebral palsy (spastic n=8, dyskinetic n=3), 2 had neurodevelopmental delay, 1 had severe hearing impairment.ConclusionsAll infants with documented perinatal asphyxia and seizure onset within 24 hours after birth who did not receive TH had abnormalities on MRI. 51% had an adverse outcome. Better methods for recognition of infants who might benefit from TH and careful neurodevelopmental follow-up are urgently needed.