Ictal Direct Current Shifts Preceded Much Earlier Than High Frequency Oscillations After Status: Is It the Effect of Status or Antiseizure Medication?

PURPOSE: While spikes and sharp waves are considered as markers of epilepsy in conventional electroencephalography, ictal direct current (DC) shifts and high-frequency oscillations (HFOs) appear to be useful biomarkers for epileptogenicity. We analyzed how ictal DC shifts and HFOs were affected by focal status epilepticus and antiseizure medications (ASMs). METHODS: A 20-year-old female patient who underwent long-term intracranial electrode implantation for epilepsy surgery presented with 72 habitual seizures and a focal status epilepticus episode lasting for 4 h. Ten, 3, and 10 consecutive habitual seizures were analyzed before the status, after the status, and after ASM (valproate) loading, respectively. RESULTS: Before and immediately after the status, ictal DC shifts remained the same in terms of the amplitude, duration, and slope of DC shifts. High-frequency oscillations also remained the same in terms of the duration, frequency, and power except for the power of the lower frequency band. After ASM loading, the duration, amplitude, and slope of the ictal DC shift were significantly attenuated. The duration, frequency, and power of the HFOs were significantly attenuated. Furthermore, the interval between the DC onset and HFO onset was significantly longer and the interval between the HFO onset and ictal DC shift peak was significantly shorter. CONCLUSIONS: The attenuation of ictal DC shifts and HFOs after ASM loading implies that astrocyte and neuronal activity may be both attenuated by ASMs. This finding may help with our understanding of the pathophysiology of epilepsy and can aid with the discovery of new approaches for epilepsy management.

Ictal direct current shifts contribute to defining the core ictal focus in epilepsy surgery.

Identifying the minimal and optimal epileptogenic area to resect and cure is the goal of epilepsy surgery. To achieve this, EEG analysis is recognized as the most direct way to detect epileptogenic lesions from spatiotemporal perspectives. Although ictal direct-current shifts (below 1 Hz) and ictal high-frequency oscillations (above 80 Hz) have received increasing attention as good indicators that can add more specific information to the conventionally defined seizure-onset zone, large cohort studies on postoperative outcomes are still lacking. This work aimed to clarify whether this additional information, particularly ictal direct-current shifts which is assumed to reflect extracellular potassium concentration, really improve postoperative outcomes. To assess the usefulness in epilepsy surgery, we collected unique EEG data sets recorded with a longer time constant of 10 s using an alternate current amplifier. Sixty-one patients (15 with mesial temporal lobe epilepsy and 46 with neocortical epilepsy) who had undergone invasive presurgical evaluation for medically refractory seizures at five institutes in Japan were retrospectively enrolled in this study. Among intracranially implanted electrodes, the two core electrodes of both ictal direct-current shifts and ictal high-frequency oscillations were independently identified by board-certified clinicians based on unified methods. The occurrence patterns, such as their onset time, duration, and amplitude (power) were evaluated to extract the features of both ictal direct-current shifts and ictal high-frequency oscillations. Additionally, we examined whether the resection ratio of the core electrodes of ictal direct-current shifts and ictal high-frequency oscillations independently correlated with favourable outcomes. A total of 53 patients with 327 seizures were analyzed for wide-band EEG analysis, and 49 patients were analyzed for outcome analysis. Ictal direct-current shifts were detected in the seizure-onset zone more frequently than ictal high-frequency oscillations among both patients (92% versus 71%) and seizures (86% versus 62%). Additionally, ictal direct-current shifts significantly preceded ictal high-frequency oscillations in patients exhibiting both biomarkers, and ictal direct-current shifts occurred more frequently in neocortical epilepsy patients than in mesial temporal lobe epilepsy patients. Finally, although a low corresponding rate was observed for ictal direct-current shifts and ictal high-frequency oscillations (39%) at the electrode level, complete resection of the core area of ictal direct-current shifts significantly correlated with favourable outcomes, similar to ictal high-frequency oscillation outcomes. Our results provide a proof of concept that the independent significance of ictal direct-current shifts from ictal high-frequency oscillations should be considered as reliable biomarkers to achieve favourable outcomes in epilepsy surgery. Moreover, the different distribution of the core areas of ictal direct-current shifts and ictal high-frequency oscillations may provide new insights into the underlying mechanisms of epilepsy, in which not only neurons but also glial cells may be actively involved via extracellular potassium levels.

Corrigendum: A Long Time Constant May Endorse Sharp Waves and Spikes Over Sharp Transients in Scalp Electroencephalography: A Comparison of After-Slow Among Different Time Constants Concordant With High-Frequency Activity Analysis.

[This corrects the article DOI: 10.3389/fnhum.2021.748893.].

Two types of clinical ictal direct current shifts in invasive EEG of intractable focal epilepsy identified by waveform cluster analysis.

OBJECTIVE: To determine clinically ictal direct current (DC) shifts that can be identified by a time constant (TC) of 2 s and to delineate different types of DC shifts by different attenuation patterns between TC of 10 s and 2 s. METHODS: Twenty-one patients who underwent subdural electrode implantation for epilepsy surgery were investigated. For habitual seizures, we compared (1) the peak amplitude and (2) peak latency of the earliest ictal DC shifts between TC of 10 s and 2 s. Cluster and logistic regression analyses were performed based on the attenuation rate of amplitude and peak latency with TC 10 s. RESULTS: Ictal DC shifts in 120 seizures were analyzed; 89.1% of which were appropriately depicted even by a TC of 2 s. Cluster and logistic regression analyses revealed two types of ictal DC shift. Namely, a rapid development pattern was defined as the ictal DC shifts with a shorter peak latency and they also showed smaller attenuation rate of amplitude (73/120 seizures). Slow development pattern was defined as the ictal DC shifts with crosscurrent of a rapid development pattern, i.e., a longer peak latency and larger attenuation rate of amplitude (47/120 seizures). Focal cortical dysplasia (FCD) 1A tended to show a rapid development pattern (22/29 seizures) and FCD2A tended to show a slow development pattern (13 /18 seizures), indicating there might be some correlations between two types of ictal DC shift and certain pathologies. CONCLUSIONS: Ictal DC shifts, especially rapid development pattern, can be recorded and identified by the AC amplifiers of TC of 2 s which is widely used in many institutes compared to that of TC of 10 s. Two types of ictal DC shifts were identified with possibility of corresponding pathology. SIGNIFICANCE: Ictal DC shifts can be distinguished by their attenuation patterns.

A Long Time Constant May Endorse Sharp Waves and Spikes Over Sharp Transients in Scalp Electroencephalography: A Comparison of After-Slow Among Different Time Constants Concordant With High-Frequency Activity Analysis.

Objective: To clarify whether long time constant (TC) is useful for detecting the after-slow activity of epileptiform discharges (EDs): sharp waves and spikes and for differentiating EDs from sharp transients (Sts). Methods: We employed 68 after-slow activities preceded by 32 EDs (26 sharp waves and six spikes) and 36 Sts from 52 patients with partial and generalized epilepsy (22 men, 30 women; mean age 39.08 ± 13.13 years) defined by visual inspection. High-frequency activity (HFA) associated with the apical component of EDs and Sts was also investigated to endorse two groups. After separating nine Sts that were labeled by visual inspection but did not fulfill the amplitude criteria for after-slow of Sts, 59 activities (32 EDs and 27 Sts) were analyzed about the total area of after-slow under three TCs (long: 2 s; conventional: 0.3 s; and short: 0.1 s). Results: Compared to Sts, HFA was found significantly more with the apical component of EDs (p < 0.05). The total area of after-slow in all 32 EDs under TC 2 s was significantly larger than those under TC 0.3 s and 0.1 s (p < 0.001). Conversely, no significant differences were observed in the same parameter of 27 Sts among the three different TCs. Regarding separated nine Sts, the total area of after-slow showed a similar tendency to that of 27 Sts under three different TCs. Significance: These results suggest that long TC could be useful for selectively endorsing after-slow of EDs and differentiating EDs from Sts. These findings are concordant with the results of the HFA analysis. Visual inspection is also equally good as the total area of after-slow analysis.

Individual localization value of resting-state fMRI in epilepsy presurgical evaluation: A combined study with stereo-EEG.

OBJECTIVE: To examine the individual-patient-level localization value of resting-state functional MRI (rsfMRI) metrics for the seizure onset zone (SOZ) defined by stereo-electroencephalography (SEEG) in patients with medically intractable focal epilepsies. METHODS: We retrospectively included 19 patients who underwent SEEG implantation for epilepsy presurgical evaluation. Voxel-wise whole-brain analysis was performed on 3.0 T rsfMRI to generate clusters for amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo) and degree centrality (DC), which were co-registered with the SEEG-defined SOZ to evaluate their spatial overlap. Subgroup and correlation analyses were conducted for various clinical characteristics. RESULTS: ALFF demonstrated concordant clusters with SEEG-defined SOZ in 73.7% of patients, with 93.3% sensitivity and 77.8% PPV. The concordance rate showed no significant difference when subgrouped by lesional/non-lesional MRI, SOZ location, interictal epileptiform discharges on scalp EEG, pathology or seizure outcomes. No significant correlation was seen between ALFF concordance rate and epilepsy duration, seizure-onset age, seizure frequency or number of antiseizure medications. ReHo and DC did not achieve favorable concordance results (10.5% and 15.8%, respectively). All concordant clusters showed regional activation, representing increased neural activities. CONCLUSION: ALFF had high concordance rate with SEEG-defined SOZ at individual-patient level. SIGNIFICANCE: ALFF activation on rsfMRI can add localizing information for the noninvasive presurgical workup of intractable focal epilepsies.

Interictal Slow and High-Frequency Oscillations: Is it an Epileptic Slow or Red Slow?

PURPOSE: We reported the presence of interictal slow and high-frequency oscillations (HFOs) (IIS + HFO) and its temporal change so as to elucidate its clinical usefulness as a surrogate marker of epileptogenic zone in a patient with intractable focal epilepsy. METHODS: We focused on one of the core electrodes of epileptogenicity, and investigated IIS + HFO in the pre- and post-segment of 30 minutes to all the 6 seizures. We adopted interictal slow in duration of 0.33 to 10 seconds, amplitude ≥50 µV and co-occurring with HFOs, and then divided into 5 groups depending on the amplitude of slow wave. RESULTS: Before and after all the 6 seizures, the number of IIS + HFO was 2,890 at one electrode in the core epileptogenic zone. The number of IIS + HFO significantly decreased for 30 minutes after seizures. Furthermore, the number of IIS + HFO with the amplitude of 200 to 399 µV significantly decreased after seizures. CONCLUSIONS: IIS + HFO with the amplitude of 200 to 399 µV was influenced by and decreased after seizures. It may reflect the core part of epileptogenic area as similarly as ictal direct current shifts and ictal HFOs do. IIS + HFO could be called as the term "red slow," which may be useful to delineate at least a part of the epileptogenic zone.