Continuous Seizure Emergency Evoked in Mice with Pharmacological, Electrographic, and Pathological Features Distinct from Status Epilepticus

Objectives. Benzodiazepines are the standard of care for the management of sustained seizure emergencies, including status epilepticus (SE) and seizure clusters. Seizure clusters are a variably defined seizure emergency wherein a patient has multiple seizures above a baseline rate, with intervening periods of recovery, distinguishing clusters from SE. While phenotypically distinct, the precise pathophysiological and mechanistic differences between SE and seizure clusters are under studied. Preclinical interrogation is needed to help uncover the behavioral, physiological, and pathological mechanisms associated with seizure emergencies in order to better manage these events in the susceptible individual. Methods. Herein, we characterize a novel model of sustained seizure emergency induced in CF-1 mice through the combined administration of high-dose phenytoin (PHT; 50 mg/kg, i.p.) and pentylenetetrazol (PTZ; 100 mg/kg, s.c.). Results. In the present manuscript we describe a mouse model of sustained seizure emergency that is physiologically, pharmacologically, and histologically distinct from SE. Acute administration of PHT 1 hour prior to s.c.PTZ led to significantly more mice with continuous seizure activity (CSA; 73.4%) versus vehicle-pretreated mice (13.8%; p<0.0001). CSA was sensitive to lorazepam and valproic acid when administered at seizure onset, as well as 30-minutes post-seizure onset. Carbamazepine worsened seizure control and post-CSA survival. Mice in CSA exhibited EEG patterns distinct from kainic acid-induced SE and s.c.PTZ alone, clearly differentiating CSA from SE and s.c.PTZ-induced myoclonic seizures. Neuropathological assessment by FluoroJade-C staining of brains collected 24-hours later revealed no neurodegeneration in any mice with CSA, whereas there was widespread neuronal death in brains from KA-SE mice. Significance. This study defines a novel mouse model on which to elucidate the mechanistic differences between sustained seizure emergencies (i.e. SE and seizure clusters) to improve discovery of effective clinical interventions and define mechanisms of seizure termination.

Quantification of seizure termination patterns reveals limited pathways to seizure end

Seizures result from a variety of pathologies and exhibit great diversity in their dynamics. Although many studies have examined the dynamics of seizure initiation, few have investigated the mechanisms leading to seizure termination. We examined intracranial recordings from patients with intractable focal epilepsy to differentiate seizure termination patterns and investigate whether these termination patterns are indicative of different underlying mechanisms. Seizures (n=710) were recorded intracranially from 104 patients and visually classified as focal or secondarily generalized. Only two patterns emerged from this analysis: (a) those that end simultaneously across the brain (synchronous termination), and (b) those whose ictal activity terminates in some regions but continues in others (asynchronous termination). Finally, seizures ended with either an intermittent bursting pattern (burst suppression pattern), or continuous activity (continuous bursting). These findings allowed for a classification and quantification of the burst suppression ratio, absolute energy and network connectivity of all seizures and comparison across different seizure termination patterns. We found that different termination patterns can manifest within a single patient, even in seizures originating from the same onset locations. Most seizures terminate with patterns of burst suppression regardless of generalization but that seizure that secondarily generalize show burst suppression patterns in 90% of cases, while only 60% of focal seizures exhibit burst suppression. Interestingly, we found similar absolute energy and burst suppression ratios in seizures with synchronous and asynchronous termination, while seizures with continuous bursting were found to be different from seizures with burst suppression, showing lower energy during seizure and lower burst suppression ratio at the start and end of seizure. Finally, network density was observed to increase with seizure progression, with significantly lower densities in seizures with continuous bursting compared to seizures with burst suppression. Our study demonstrates that there are a limited number of seizure termination patterns, suggesting that, unlike seizure initiation, the number of mechanisms underlying seizure termination is constrained. The study of termination patterns may provide useful clues about how these seizures may be managed, which in turn may lead to more targeted modes of therapy for seizure control.

Prolonged postictal hemianopsia after a focal extraoccipital onset seizure

We report a case of a prolonged postictal hemianopsia occurring after a focal extraoccipital seizure. A 55-year-old man with a history of neurosyphilis, treated with penicillin, presented to our epilepsy monitoring unit (EMU) for diagnostic evaluation of his spells occurring for 2 years. The spell semiology was stereotypical, described as oral and manual automatisms, speech difficulty and unresponsiveness. During the EMU stay, after his typical seizure was recorded, he experienced right hemianopsia lasting for 2 hours. Electrographically, the ictal pattern was prominent over the left temporal derivation and propagated to the left occipital derivation as the seizure progressed. Interictal epileptiform activity was over the left temporal derivations. We support the view that postictal phenomenon may represent merely a seizure termination zone and not be necessarily localising to the seizure onset zone. Furthermore, prolonged isolated postictal symptom of hemianopsia could also be noted in rare situations.

Anterior Nucleus of Thalamus Gates Progression of Mesial Temporal Seizures by Modulating Thalamocortical Synchrony

The anterior nucleus of the thalamus (ANT) mediates cortical-subcortical interactions between the limbic system and is hypothesized to facilitate the early organization of temporal lobe seizures. We set out to investigate the dynamic changes in synchronization parameters between the seizure onset zone (SOZ) and ANT during seizure stages (pre-onset to post-termination) in seven patients (n=26 seizures) with drug-resistant nonlesional temporal lobe epilepsy. Using local field potentials recorded directly from the limbic system and the ANT during stereoelectroencephalography, we confirm that the onset of mesial temporal lobe seizure is associated with increased thalamocortical network excitability and phase-amplitude coupling. The increase in thalamocortical phase synchronization preceded seizure onset, thereby suggesting that the early organization of temporal lobe seizures involves the integration of the ANT within the epileptic network. Towards seizure termination, there is a significant decrease in thalamic excitability, thalamocortical synchronization, and decoupling, thereby suggesting a breakdown in thalamocortical connectivity. A higher disease burden is significantly correlated with increased synchronization between the ANT and epileptic networks. Collectively, the results elucidate mechanistic insights and provide the temporal architecture of thalamocortical interactions that can be targeted in the rational designing of closed-loop seizure abortive interventions.HighlightsAnterior nucleus of thalamus is coactivated at the onset of temporal lobe seizuresIncrease thalamocortical synchronization and excitability is observed at seizure onsetSeizure termination is characterized by a breakdown in thalamocortical connectivityIncreased seizure burden affects thalamocortical synchronization

Tracking multi-site seizure propagation using ictal high frequency activity

Objective: Characterization of progressive multi-site seizure recruitment using high frequency oscillations. Methods: Ictal and interictal high frequency oscillations were identified in a series of 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Channels with ictal high frequency oscillations were assigned to distinct spatial clusters, and seizure hubs were identified by stereotypically recruited non-overlapping clusters. Clusters were correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap of ictal and interictal high frequency oscillations were compared. Results: Ictal high frequency oscillations were detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (Odds Ratio=10, 95% CI 2.9-41, p<0.001). Interictal high frequency oscillations demonstrated greater spatial overlap with ictal high frequency oscillations in cases with single seizure hubs than in those with multiple hubs (100% vs 66% per patient, p=0.03). Significance: Analysis of ictal high frequency oscillations can serve as a useful adjunctive technique to distinguish contiguous seizure spread from propagation to remote seizure sites. This study demonstrated that multiple seizure hubs were commonly identified by spatial clustering of ictal high frequency oscillations, including in cases that were considered unifocal. The distinction between initially activated and delayed seizure hubs was not evident based on interictal high frequency analysis, but may provide important prognostic information.

Noise-Assisted MEMD-Based Phase-Connectivity Analysis to Personalize Closed-Loop DBS Therapy in Epilepsy Patients

Deep brain stimulation (DBS) is a treatment that has been explored for controlling seizures in patients with intractable epilepsy. Many clinical and pre-clinical studies using DBS therapy determine stimulation parameters through trial and error. The same stimulation parameters are often applied to the whole cohort, which consequently produces mixed results of responders and non-responders. In this paper, an adaptive non-linear analytical methodology is proposed to extract stimulation frequency and location(s) from endogenous brain dynamics of epilepsy patients, using phase-synchrony and phase-connectivity analysis, as seizures evolve. The proposed analytical method was applied to seizures recorded using depth electrodes implanted in hippocampus and amygdala in three patients. A reduction in phase-synchrony was observed in all patients around seizure onset. However, phase-synchrony started to gradually increase from mid-ictal and achieved its maximum level at seizure termination. This result suggests that hyper-synchronization of the epileptic network may be a crucial mechanism by which the brain naturally terminates seizure. Stimulation frequency and locations that matched the network phase-synchrony at seizure termination were extracted using phase-connectivity analysis. One patient with temporal lobe epilepsy (TLE) had a stimulation frequency ∼15 Hz with the stimulation locations confined to the hippocampus. The other two patients with extra-temporal lobe epilepsy (ETE) had stimulation frequency ∼90 Hz with at least one stimulation location outside of hippocampus. These results suggest that DBS parameters should vary based on the patient’s underlying pathology. The proposed methodology provides an algorithm for tuning DBS parameters for individual patients in an effort to increase the clinical efficacy of the therapy.