Frequent Interictal Epileptiform Discharges Research Articles

Acute effects of spaced cathodal transcranial direct current stimulation in drug resistant focal epilepsies

ObjectiveTo evaluate the safety and temporal dynamic of the antiepileptic effect of spaced transcranial direct current stimulation (tDCS) in different focal epilepsies. MethodsCathodal tDCS with individual electrode placement was performed in 15 adults with drug resistant focal epilepsy. An amplitude of 2 mA was applied twice for 9 minutes, with an interstimulation interval of 20 minutes. Tolerability was assessed via the Comfort Rating Questionnaire and the frequency of interictal epileptiform discharges (IEDs) was sequentially compared between the 24 hours before and after tDCS. ResultsTDCS led to a significant reduction in the total number of IEDs/24 h by up to 68% (mean ± SD: −30.4 ± 21.1%, p = 0.001) as well as in seizure frequency (p = 0.041). The maximum IED reduction was observed between the 3rd and 21st hour after stimulation. Favorable clinical response was associated with structural etiology and clearly circumscribed epileptogenic foci but did not differ between frontal and temporal epilepsies. Overall, the tDCS treatment was well tolerated and did not lead to severe adverse events. ConclusionsThe spaced stimulation approach proved to be safe and well-tolerated in patients with drug-resistant unifocal epilepsies, leading to sustained IED and seizure frequency reduction. SignificanceSpaced tDCS induces mediate antiepileptic effects with promising therapeutic potential.

Rapidly spreading seizures arise from large-scale functional brain networks in focal epilepsy

It remains unclear whether epileptogenic networks in focal epilepsy develop on physiological networks. This work aimed to explore the association between the rapid spread of ictal fast activity (IFA), a proposed biomarker for epileptogenic networks, and the functional connectivity or networks of healthy subjects. We reviewed 45 patients with focal epilepsy who underwent electrocorticographic (ECoG) recordings to identify the patients showing the rapid spread of IFA. IFA power was quantified as normalized beta-gamma band power. Using published resting-state functional magnetic resonance imaging databases, we estimated resting-state functional connectivity of healthy subjects (RSFC-HS) and resting-state networks of healthy subjects (RSNs-HS) at the locations corresponding to the patients' electrodes. We predicted the IFA power of each electrode based on RSFC-HS between electrode locations (RSFC-HS-based prediction) using a recently developed method, termed activity flow mapping. RSNs-HS were identified using seed-based and atlas-based methods. We compared IFA power with RSFC-HS-based prediction or RSNs-HS using non-parametric correlation coefficients. RSFC and seed-based RSNs of each patient (RSFC-PT and seed-based RSNs-PT) were also estimated using interictal ECoG data and compared with IFA power in the same way as RSFC-HS and seed-based RSNs-HS. Spatial autocorrelation-preserving randomization tests were performed for significance testing. Nine patients met the inclusion criteria. None of the patients had reflex seizures. Six patients showed pathological evidence of a structural etiology. In total, we analyzed 49 seizures (2–13 seizures per patient). We observed significant correlations between IFA power and RSFC-HS-based prediction, seed-based RSNs-HS, or atlas-based RSNs-HS in 28 (57.1%), 21 (42.9%), and 28 (57.1%) seizures, respectively. Thirty-two (65.3%) seizures showed a significant correlation with either seed-based or atlas-based RSNs-HS, but this ratio varied across patients: 27 (93.1%) of 29 seizures in six patients correlated with either of them. Among atlas-based RSNs-HS, correlated RSNs-HS with IFA power included the default mode, control, dorsal attention, somatomotor, and temporal-parietal networks. We could not obtain RSFC-PT and RSNs-PT in one patient due to frequent interictal epileptiform discharges. In the remaining eight patients, most of the seizures showed significant correlations between IFA power and RSFC-PT-based prediction or seed-based RSNs-PT. Our study provides evidence that the rapid spread of IFA in focal epilepsy can arise from physiological RSNs. This finding suggests an overlap between epileptogenic and functional networks, which may explain why functional networks in patients with focal epilepsy frequently disrupt.

Magnetic resonance-guided laser interstitial thermal therapy: Correlations with seizure outcome.

This study was undertaken to identify clinical factors associated with seizure freedom after magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) in temporal lobe epilepsy patients with unilateral mesial temporal sclerosis (MTS). We identified 56 patients with magnetic resonance imaging-defined MTS who underwent MRgLiTT with at least 1year of follow-up. Primary outcome was seizure freedom at 1 year. We examined the association of seizure freedom and the following clinical factors: age at surgery, gender, history of febrile seizures, history of focal to bilateral tonic-clonic seizures, duration of epilepsy at the time of surgery, frequency of interictal epileptiform discharges (IEDs), seizure frequency, and presence of bilateral IEDs. Thirty-five (62.5%) patients were seizure-free at 1year. The presence of bilateral IEDs and age at surgery were associated with 1-year seizure freedom after MRgLiTT. The presence of bilateral IEDS was associated with lower odds of seizure freedom (odds ratio [OR] = .05, 95% confidence interval [CI] = .01-.46, p=.008), whereas increasing age at surgery was associated with increased odds of seizure freedom (OR = 1.10, 95% CI = 1.03-1.19, p=.009). This study demonstrates associations between presence of bilateral IEDs and age at surgery and seizure freedom at 1year after MRgLiTT.

Sonographic hypoechogenicity of brainstem raphe nucleus is correlated with electroencephalographic spike frequency in patients with epilepsy

BackgroundBrainstem raphe nucleus (BRN) hypoechogenicity in transcranial sonography (TCS) has been demonstrated in patients with major depression, possibly representing a sonographic manifestation of serotonergic dysfunction in depression. Most patients with epilepsy with comorbid depression exhibit hypoechogenic BRN in TCS. However, the role of BRN in the pathogenesis of epilepsy is unclear. This study aimed to evaluate the correlation of BRN echogenicity with epilepsy itself, and the echogenicity of other midbrain structures and the size of lateral ventricle (LV) will also be evaluated in patients with epilepsy. MethodsThirty-six patients with epilepsy without depression and 37 healthy controls were recruited. Sonographic echogenicity of BRN, caudate nucleus (CN), lentiform nucleus (LN), substantia nigra (SN), and the width of frontal horns of the lateral ventricles (LV) and the third ventricle (TV) were evaluated with TCS. The frequency of interictal epileptiform discharges (IEDs) was assessed with ambulatory electroencephalogram (AEEG). ResultsHypoechogenicity of BRN was depicted in 36.1% of patients with epilepsy and 18.9% of controls, showing no significant difference. Patients with epilepsy with BRN hypoechogenicity had higher epileptic discharge index (EDI) than those with normal BRN echogenecity. Especially, higher EDI in patients with BRN hypoechogenicity was observed during the sleep period but not during awake period. The width of TV was significantly larger in patients with epilepsy than that in controls. We did not find any difference between patients with epilepsy and controls in the echogenicity of CN, LN, and SN, as well as in the width of frontal horn of LV. ConclusionsHypoechogenic BRN is correlated with a high frequency of epileptic discharges in electroencephalogram (EEG), especially during sleep period but not during awake period, indicating that BRN alterations may play a potential role in the pathogenesis of epilepsy in association with sleep cycle.

Amygdala Low-Frequency Stimulation Reduces Pathological Phase-Amplitude Coupling in the Pilocarpine Model of Epilepsy.

Temporal-lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy and warrants the development of new therapies, such as deep-brain stimulation (DBS). DBS was applied to different brain regions for patients with epilepsy; however, the mechanisms of action are not fully understood. Therefore, we tried to characterize the effect of amygdala DBS on hippocampal electrical activity in the lithium-pilocarpine model in male Wistar rats. After status epilepticus (SE) induction, seizure patterns were determined based on continuous video recordings. Recording electrodes were inserted in the left and right hippocampus and a stimulating electrode in the left basolateral amygdala of both Pilo and age-matched control rats 10 weeks after SE. Daily stimulation protocol consisted of 4 × 50 s stimulation trains (4-Hz, regular interpulse interval) for 10 days. The hippocampal electroencephalogram was analyzed offline: interictal epileptiform discharge (IED) frequency, spectral analysis, and phase-amplitude coupling (PAC) between delta band and higher frequencies were measured. We found that the seizure rate and duration decreased (by 23% and 26.5%) and the decrease in seizure rate correlated negatively with the IED frequency. PAC was elevated in epileptic animals and DBS reduced the pathologically increased PAC and increased the average theta power (25.9% ± 1.1 vs. 30.3% ± 1.1; p < 0.01). Increasing theta power and reducing the PAC could be two possible mechanisms by which DBS may exhibit its antiepileptic effect in TLE; moreover, they could be used to monitor effectiveness of stimulation.

The clinical significance of small sharp spikes: A retrospective study of 909 patients in epilepsy monitoring unit

ObjectivesTo determine the incidence and clinical significance of small sharp spikes (SSS) in the patient population of the adult Epilepsy Monitoring Unit (EMU). MethodsThis is a retrospective study of EEG data and medical records from consecutive patients who underwent video-EEG recording in the adult EMU from March 2013 to February 2019. SSS, interictal epileptiform discharges (IEDs), and ictal patterns were identified. ResultsOf the 909 patients reviewed, SSS were observed in110 (12.1 %) patients. Epilepsy was present in 101 of the 110 (91.8 %) patients with SSS and in 441 of the 799 (55.2 %) patients without SSS. The incidence of epilepsy was significantly higher in patients with SSS than in those without SSS (OR = 9.1, 95 % CI: 4.5–18.3, P < 0.01). The sensitivity of SSS for epilepsy was 18.6 % and the specificity was 97.5 %. The incidence of SSS was strongly correlated with the frequency of IEDs (OR 1.89; 95 %CI: 1.60–2.24, P < 0.01). When both present, SSS and IEDs were co-lateralized in the same hemisphere. ConclusionsThere is a statistically significant association between SSS and focal epilepsy. SSS have similar clinical implications to IEDs in the lateralization and localization of temporal lobe seizures. SSS can be an epileptiform EEG pattern for temporal lobe epilepsy.

Effect of priming low-frequency magnetic fields on zero-Mg2+ -induced epileptiform discharges in rat hippocampal slices

During the process of seizures, the addition of low-frequency magnetic fields has been proved to be an effective method to suppress epileptic discharges. However, whether adding magnetic fields before the appearance of epileptic discharges can produce this inhibition has not been studied. In the present study, we first constructed epilepsy models on brain slices by perfusing them with Mg2+-free artificial cerebrospinal fluid (aCSF). The events of seizures evolved from inter-ictal epileptiform discharges (IIDs) to inter-epileptiform discharges (IDs). Combined with the multi-electrode array platform, we designed a flexible moving coil to generate a 0.5 Hz magnetic field on the brain slices. Using this method, we added the magnetic fields to brain slices for 30 min before epileptiform discharges were induced. The experimental results demonstrated that although the priming magnetic fields could not completely inhibit epileptiform discharges, they can significantly reduce the frequency of IDs and increase the frequency of IIDs in the CA3 region of the hippocampal slices. In the control group, the rates of IDs and IIDs were 0.0024 ± 0.0006 Hz and 0.0138 ± 0.0043 Hz, respectively, while in the magnetic stimulation group, the rates were 0.0012 ± 0.0004 Hz and 0.0251 ± 0.0067 Hz. Moreover, the results indicated that changing the frequency of interictal discharges did not affect ictogenesis. The results demonstrated that the priming magnetic fields had a certain weakening effect on the frequency of IDs, which was achieved by reducing the signal propagation speed and increasing the excitability threshold of hippocampal neurons.

Safe and sound: Meta-analyzing the Mozart effect on epilepsy

ObjectiveThe use of music-based neuro-stimulation for treating seizures and interictal epileptiform discharges (IED) (the so-called “Mozart effect”) remains a controversial issue. We have conducted an updated meta-analysis in order to systematically review literature evidence and provide further insights about the role of the Mozart effect in epilepsy. MethodsFollowing the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines, we searched three bibliographic databases from their date of inception to January 2020. Nine meta-analyses were performed according to both music stimulation protocols and outcome measures. We applied the Cochrane Q-test and the I2-index for heterogeneity evaluation, and either fixed-effect or random-effect models to compute mean differences and pool data. ResultsOf 147 abstracts, 12 studies were included and grouped according to stimulation protocols and outcome measures. The nine meta-analyses showed significant reductions in seizures and IED frequencies after long-term music treatment, and in IED frequency during and after a single music stimulus. ConclusionsMusic-based neurostimulation may improve the clinical outcome of individuals with epilepsy, by reducing the frequency of seizures and IED. Further and stronger evidence will allow defining its potential in the different forms of epilepsy, and the most effective stimulation protocols. SignificanceMusic therapy should be considered as a complementary, non-invasive approach for treating epilepsy and epileptiform discharges.

The Significance of Interictal Spike Frequency in Temporal Lobe Epilepsy.

Purpose. In this study, the frequency of interictal epileptiform discharges (IEDs) in patients with drug-resistant temporal lobe epilepsy (TLE) was measured to determine its correlation with epilepsy duration, seizure frequency, brain magnetic resonance imaging (MRI) findings, and recent occurrence of focal to bilateral tonic clonic seizures (FBTCS). Methods. Our study was performed on TLE patients, who admitted to epilepsy monitoring unit of Loghman-Hakim hospital, Tehran, from 2016 to 2018. The patients' IEDs frequency were measured from their scalp EEG recording during no-rapid eye movement (NREM) sleep. The IEDs frequency was classified into 3 groups of rare, occasional, and frequent. Results. A total of 142 patients, with the mean age of 33.95 ± 12.73 years, were included in the study. The patients' mean epilepsy duration was 17.27 ± 12.19 years and the mean seizure frequency was 10.56 ± 12.95 attacks per month. The mean IEDs frequency was 123.48 ± 513.01 per hour. Thirty-five (24.6%) patients had history of FBTCS in the past year. Our findings revealed no significant association between IEDs frequency with epilepsy duration (P = .22), the recent occurrence of FBTCS (P = .42), and the type of MRI abnormalities (P = .66). There was only a weak positive correlation between seizure frequency and interictal spike density (r = 0.2, P = .007). Conclusions. In patients with TLE, standard EEG recording may not be a reliable method to predict the probability of occurring future seizures.

Value of transcranial direct current polarisation in people with focal drug resistant epilepsy

Drug resistant epilepsy (DRE) accounts for about one third of people with epilepsy (PWE), even after introduction of more than twenty antiepileptic drugs. Accordingly, Cathodal transcranial direct current stimulation (Cathodal tDCS) considered as a neuromodulation protocol which is emerging to reduce cortical excitability and consider as potential antiepileptic therapy. To investigate whether Cathodal tDCS can modify seizure frequency in People with drug resistant focal epilepsy, assessed by clinical evaluation, seizure diary and electroencephalography (EEG). A randomized, double blind, placebo controlled clinical trial on 20 PWE diagnosed with focal DRE were enrolled in our study. The patients were randomized into 2 groups. First Group received real 5-day sessions of cathodal tDCS over the area of most frequent interictal epileptiform discharges (ED) or the area of suspected ictal onset. The second group received sham sessions. Outcome indicators were baseline and post sessions (4 weeks) seizure diary and ED which were counted per hour. Patients subgroups were matched as regard the baseline characteristics. The percentage reduction of ED was greater for real stimulation versus the placebo group (p = 0.0124). also, the percentagereduction of seizure frequency was greater for real stimulation group versus the placebo group (p = 0.0308). Our study shows that cathodal tDCS is a promising therapeutic tool for short term seizure reduction in chronic drug resistant focal epilepsy patients.

Transcranial direct current stimulation (tDCS) modify the interictal epileptiform activity in deep cerebral structures observed on SEEG (stereoelectroencephalographie)

Background: tDCS is a widely investigated noninvasive neuromodulation technic in neurological and psychiatric disorders. Some studies demonstrate the effect of tDCS on interictal epileptiform discharges (IED) (Fregni et al., 2006). Objectives: The objective of our study was to investigate the tDCS effect on IED (frequency of occurrence and amplitudes) in intracerebral structures thanks to SEEG investigation. Methods: Two patients with focal drug-resistant epilepsy were included: one medial and one lateral temporal lobe epilepsy. In average, they were implanted with 15 SEEG electrodes. Thanks to the SEEG recordings (5 days), epileptologists localized the irritative zone. The experiment was divided in 3 sessions: 20 min sham, then 20 min tDCS (−1 mA) and finaly 20 min sham. The amplitudes and the number of occurrences were analyzed. The results were compared between the sessions. Results: For the medial temporal lobe study, 64 and 33 IED were detected respectively before and after tDCS. The averaged amplitudes in the hippocampus were respectively 742 ± 422 μV and 152 ± 43 μV correspond to a 20% decrease (P < 0.001; Mann–Whitney U test). For the lateral temporal lobe study, we detected respectively 192 and 165 discharges. The averaged amplitudes in the superior temporal gyrus were respectively 136 ± 55 μV and 117 ± 36 μV correspond to a 14% decrease (P < 0.001; Mann–Whitney U test). Conclusion: In this study, we demonstrated that the cathodal tDCS can reduce the number and the amplitude of epileptic discharges in intracerebral structures. The strength of this study is related to the simultaneous SEEG recordings with non-invasive tDCS and the in-vivo human brain investigation (deep and superficial).

Association Between Magnetoencephalographic Interictal Epileptiform Discharge and Cognitive Function in Young Children With Typical Development and With Autism Spectrum Disorders.

Electroencephalograms of individuals with autism spectrum disorders (ASD) show higher rates of interictal epileptiform discharges (IEDs), which are known to have an inverse association with cognitive function in typically developed (TD) children. Nevertheless, that phenomenon has not been investigated adequately in children with ASD. From university and affiliated hospitals, 163 TD children (84 male, 79 female, aged 32–89 months) and 107 children (85 male, 22 female, aged 36–98 months) with ASD without clinical seizure were recruited. We assessed their cognitive function using the Kaufman Assessment Battery for Children (K-ABC) and recorded 10 min of MEG. Original waveforms were visually inspected. Then a linear regression model was applied to evaluate the association between the IED frequency and level of their cognitive function. Significantly higher rates of IEDs were found in the ASD group than in the TD group. In the TD group, we found significant negative correlation between mental processing scale scores (MPS) and the IED frequency. However, for the ASD group, we found significant positive correlation between MPS scores and the IED frequency. In terms of the achievement scale, correlation was not significant in either group. Although we found a correlative rather than a causal effect, typically developed children with higher IED frequency might better be followed up carefully. Furthermore, for children with ASD without clinical seizure, clinicians might consider IEDs as less harmful than those observed in TD children.

Significance of FDG-PET Hypermetabolism in Children with Intractable Focal Epilepsy

Background: Interictal ¹⁸F-fluorodeoxyglucose-positron emission topography (FDG-PET) hypometabolism is routinely used in the presurgical workup of children with medically intractable epilepsy (MIE). FDG-PET hypermetabolism, however, is rarely seen, and the significance of this finding in the epilepsy workup is not well established. Methods: We performed a retrospective study of patients who underwent FDG-PET during the presurgical workup of MIE over a 4-year period, between 1 January 2010 and 31 December 2013, at the Children’s Hospital Colorado, CO, USA. Results: Focal FDG-PET hypermetabolism was identified in 7 (2.2%) of 317 patients. The median age was 124 months, all cases with catastrophic epilepsy. Surface electroencephalography (EEG) performed concomitantly with FDG injections revealed ictal EEG discharges in 2 patients, frequent interictal epileptiform discharges (IEDs) in 3, occasional IEDs in 1, and no IEDs in 1. All 7 patients underwent functional hemispherectomies. Histopathology revealed type 1 focal cortical dysplasia in all patients. Six (86%) were completely seizure-free (Engel class I) and 1 had extremely infrequent seizures (Engel class II) (mean follow-up, 47.4 months). Conclusion: While a rare finding, interictal PET hypermetabolism does occur, may help identify epileptogenic zones, and assessment to reveal it should be made by concomitant use of surface EEG during PET scans.

Circadian rhythm of interictal epileptiform discharges and changes of spindles in patients with temporal lobe epilepsy

Background: This study aims to explore the circadian rhythm of interictal epileptiform discharges (IEDs) and changes of spindles in patients with temporal lobe epilepsy (TLE). Methods: Subjects were divided into two groups: research group (patients diagnosed with TLE, n=50) and control group (n=30). The whole-night natural sleep of all subjects was monitored, analysis and statistics were performed on IED, and the number, amplitude and the average duration of spindles were compared between these two groups. Results: (1) In TLE patients, the number of IED was larger in non-rapid eye movement (NREM) stages 1+2 and NREM stages 3+4 than in the waking stage and rapid eye movement (REM) stage, and the differences were statistically significant (P<0.05). (2) TLE patients had bilateral asymmetric sleep spindles, and their amplitude was lower in the affected side than in the unaffected side. Furthermore, the number, amplitude and mean duration of sleep spindles in the affected side in NREM stage 2 was significantly reduced compared with that in the control group (P<0.05). Conclusions: (1) TLE patients have the highest frequency of IED in slow wave sleep, followed by NREM stages 1+2, waking and REM stages. Slow wave sleep easily induces IED. (2) The number, amplitude and mean duration of sleep spindles in the affected side in NREM stage 2 were significantly reduced, compared with that in the control group. This suggests that changes in spindles have a lateralization value.

Differential patterns of dynamic functional connectivity variability of striato-cortical circuitry in children with benign epilepsy with centrotemporal spikes.

Benign epilepsy with centrotemporal spikes (BECTS) is characterized by abnormal (static) functional interactions among cortical and subcortical regions, regardless of the active or chronic epileptic state. However, human brain connectivity is dynamic and associated with ongoing rhythmic activity. The dynamic functional connectivity (dFC) of the distinct striato-cortical circuitry associated with or without interictal epileptiform discharges (IEDs) are poorly understood in BECTS. Herein, we captured the pattern of dFC using sliding window correlation of putamen subregions in the BECTS (without IEDs, n = 23; with IEDs, n = 20) and sex- and age-matched healthy controls (HCs, n = 28) during rest. Furthermore, we quantified dFC variability using their standard deviation. Compared with HCs and patients without IEDs, patients with IEDs exhibited excessive variability in the dorsal striatal-sensorimotor circuitry related to typical seizure semiology. By contrast, excessive stability (decreased dFC variability) was found in the ventral striatal-cognitive circuitry (p < .05, GRF corrected). In addition, correlation analysis revealed that the excessive variability in the dorsal striatal-sensorimotor circuitry was related to highly frequent IEDs (p < .05, uncorrected). Our finding of excessive variability in the dorsal striatal-sensorimotor circuitry could be an indication of increased sensitivity to regional fluctuations in the epileptogenic zone, while excessive stability in the ventral striatal-cognitive circuitry could represent compensatory mechanisms that prevent or postpone cognitive impairments in BECTS. Overall, the differentiated dynamics of the striato-cortical circuitry extend our understanding of interactions among epileptic activity, striato-cortical functional architecture, and neurocognitive processes in BECTS.

Immature Status Epilepticus: In Vitro Models Reveal Differences in Cholinergic Control and HFO Properties of Adult CA3 Interictal Discharges in Temporal vs Septal Hippocampus

We have earlier demonstrated that a Status Epilepticus (SE) during CNS development has long-lasting effects on cholinergic neurotransmission, detectable in vitro and in vivo. In this work, we aimed to localize changes in temporal (T) vs septal (S) hippocampus and to correlate adult CA3 interictal epileptiform discharge (IED) frequency changes to those of Ripples (R) and Fast Ripples (FR) of the High-Frequency Oscillations (HFOs). Spontaneous IEDs were induced by bathing slices in Mg2+-free ACSF or in 4-Aminopyridine (4-AP, 50 µM) and data were analyzed separately for each model. IED frequencies were similar in same origin normal (N) slices across models, but differed in SE slices, being lower in Mg2+-free ACSF than in 4-AP, suggesting a post-SE long-term increase in a K+ conductance. Rs and FRs detected within IEDs had generally higher power in 4-AP than in Mg2+-free ACSF; FR/R ratio was the highest in T-SE slices in 4-AP and similar in all other slice groups. Carbachol or eserine increased IED rates universally, but had region- and conditioning-specific effects on HFOs, suggesting that IED frequency and HFOs represent possibly independent indices of excitability. The muscarinic antagonist atropine depressed IED rates with increasing effectiveness in S slices post-SE in both models. In conclusion, the long-term effects of an immature SE are region-specific within the hippocampus, affect differently synchronizing components like the IED frequency and HFOs and may shape neurotransmitter effects (ACh) on neuronal networks, thus affecting seizure threshold and information processing, especially in behavioral conditions of rising extracellular ACh levels.

The relation between cortisol and functional connectivity in people with and without stress-sensitive epilepsy.

The most common reported seizure-precipitant is stress. We recently showed a biologic basis for stress sensitivity of seizures: cortisol levels in people with stress-sensitive epilepsy correlated with focal interictal epileptiform discharges (IEDs) on electroencephalography (EEG). Here we aimed to determine whether the effect of cortisol on the epileptic brain is global or focal, and whether cortisol affects all brains or just those of stress-sensitive people. Because epilepsy is associated with changes in functional brain connectivity, we studied the relationship between cortisol and changes in global and focal (node-centered) functional connectivity measures for individuals with stress-sensitive and non-stress-sensitive epilepsy. Seventeen people with epilepsy underwent long-term (>24h) EEG recording. During the first 5h after waking, saliva was collected every 15min for cortisol measurements. Theta-band functional connectivity was assessed for every 15min of the recording. We calculated the average phase-lag index (PLI) between all channels as a measure of global functional connectivity. We used network Strength, the averaged PLI per channel, as focal functional connectivity measure. We correlated cortisol, global, and focal functional connectivity (Strength) with IED frequency using linear mixed models. Analyses were split for people with and without stress-sensitivity of seizures. Cortisol was negatively correlated with global functional connectivity in people with stress-sensitive seizures (estimate -0.0020; P<.01), whereas not in those without stress-sensitivity (estimate -0.0003; P=.46). This relationship occurred irrespective of the presence of IEDs on a channel (channels without IEDs and stress-sensitivity: estimate -0.0019; P<.01, non-stress-sensitive -0.0003; P=.41). Global and focal functional connectivity were negatively correlated with IED frequency, irrespective of stress sensitivity of seizures or channel type. People with stress-sensitive epilepsy have a whole-brain neuronal response to cortisol that is different from that of people with non-stress-sensitive epilepsy. This offers a basis for understanding seizure genesis in stress-sensitive epilepsy, which might require a different treatment approach.

Cognitive Outcome After Epilepsy Surgery in Children

Cognitive dysfunction in children with epilepsy is primarily contributed by etiology, seizures, frequency of interictal epileptiform discharges, and adverse effects of antiepileptic drugs. The direct effect of epilepsy surgery on cognitive outcome depends on two key factors: the function that is present in the epileptogenic zone to be removed, and the dysfunction outside the epileptogenic zone caused by epilepsy. Studies on cognitive outcome in children after various types of epilepsy surgery estimate "no significant change" in about 70% of children, improvement in cognition in 10%-15%, and decline in 10%-15%. In young children with epileptic encephalopathy, the reversible dysfunction outside the epileptogenic zone is larger and hence carry better chances of improved outcome after successful surgery. If the epileptogenic zone harbors significant cognitive function (memory, language, or other function), then a decline in function may occur with its resection. Understanding the pathophysiological basis for the cognitive changes after epilepsy surgery assists in counseling patients and families before surgery.

Two-Dimensional Temporal Clustering Analysis for Patients with Epilepsy: Detecting Epilepsy-Related Information in EEG-fMRI Concordant, Discordant and Spike-Less Patients.

EEG acquired simultaneously with fMRI (EEG-fMRI) is a multimodal method that has shown promise in mapping the seizure onset zone in patients with focal epilepsy. However, there are many instances when this method is unsuccessful or not applicable, and other data driven fMRI methods may be utilized. One such method is the two-dimensional temporal clustering analysis (2dTCA). In this study we compared the classic EEG-fMRI and 2dTCA performance in mapping regions related to the seizure onset region in 18 focal epilepsy patients (12 presenting interictal epileptiform discharges (IEDs), during EEG-fMRI acquisition) with Engel I or II surgical outcome. Activation maps of both 2dTCA timing outputs (positive and negative histograms) and EEG detected IEDs were computed and compared to the region of epilepsy surgical resection. Patients were evaluated in three categories based on frequency of EEG detected spiking during the MRI. EEG-fMRI maps were concordant to the epilepsy region in 5/12 subjects, four with frequent IEDs on EEG. The 2dTCA was successful in mapping 13/18 patients including 3/6 with no IEDs detected (10/12 with IEDs detected). The epilepsy-related activities were successfully mapped by both methods in only 4/12 patients. This work suggests that the epilepsy-related information detected by each method may be different: while EEG-fMRI is more accurate in patients with high rather than lower numbers of EEG detected IEDs; 2dTCA can be useful in evaluating patients even when no concurrent EEG spikes are detected or EEG-fMRI is not effective. Therefore, our results support that 2dTCA might be an alternative for mapping epilepsy-related BOLD activity in negative EEG-fMRI (6/7 patients) and spike-less patients.

Preventing cognitive impairment in children with epilepsy

Cognitive impairments are common in children with epilepsy. They may already be present before the onset of epilepsy or occur - and even progress - during its course. Many variables contribute to cognitive dysfunction. Those that can be targeted to prevent (further) cognitive impairment will be highlighted in this review. Ideally, but not yet realistically, epileptogenesis is prevented to avert seizures and cognitive impairments in high-risk patients. New and targeted treatments of progressive epileptogenic disorders and precision medicine approaches in genetic epilepsies are increasingly applied. Cognitive outcome benefits from early diagnosis and treatment of epileptic encephalopathy. Ongoing seizures may cause permanent and progressive changes in brain structure and connectivity, suggesting that early seizure control optimizes eventual cognitive functioning. Frequent interictal epileptiform discharges justify treatment in children with cognitive impairments that are otherwise unexplained. Cognitive adverse effects of antiepileptic drugs should be closely monitored and balanced against potential benefits. Finally, early surgical treatment in selected candidates will improve their cognitive outcome. Although important determinants of intellectual functioning - including the child's genetic and environmental background and the epileptogenic pathology - may not be modifiable, several variables that contribute to cognitive impairment can be targeted to improve outcome. Early etiological diagnosis, personalized therapies, presurgical evaluation, and strict control of seizures - or in some patients interictal discharges - can prevent (further) cognitive impairments.