Citations

Abstract The epileptic network hypothesis and epileptogenic zone hypothesis are two theories of ictogenesis. The network hypothesis posits that coordinated activity among interconnected nodes produces seizures. The epileptogenic zone hypothesis posits that distinct regions are necessary and sufficient for seizure generation. High-frequency oscillations, and particularly fast ripples, are thought to be biomarkers of the epileptogenic zone. We sought to test these theories by comparing high-frequency oscillation rates and networks in surgical responders and non-responders, with no appreciable change in seizure frequency or severity, within a retrospective cohort of 48 patients implanted with stereo-EEG electrodes. We recorded inter-ictal activity during non-rapid eye movement sleep and semi-automatically detected and quantified high-frequency oscillations. Each electrode contact was localized in normalized coordinates. We found that the accuracy of seizure onset zone electrode contact classification using high-frequency oscillation rates was not significantly different in surgical responders and non-responders, suggesting that in non-responders the epileptogenic zone partially encompassed the seizure onset zone(s) (P > 0.05). We also found that in the responders, fast ripple on oscillations exhibited a higher spectral content in the seizure onset zone compared with the non-seizure onset zone (P < 1 × 10−5). By contrast, in the non-responders, fast ripple had a lower spectral content in the seizure onset zone (P < 1 × 10−5). We constructed two different networks of fast ripple with a spectral content >350 Hz. The first was a rate–distance network that multiplied the Euclidian distance between fast ripple-generating contacts by the average rate of fast ripple in the two contacts. The radius of the rate–distance network, which excluded seizure onset zone nodes, discriminated non-responders, including patients not offered resection or responsive neurostimulation due to diffuse multifocal onsets, with an accuracy of 0.77 [95% confidence interval (CI) 0.56–0.98]. The second fast ripple network was constructed using the mutual information between the timing of the events to measure functional connectivity. For most non-responders, this network had a longer characteristic path length, lower mean local efficiency in the non-seizure onset zone, and a higher nodal strength among non-seizure onset zone nodes relative to seizure onset zone nodes. The graphical theoretical measures from the rate–distance and mutual information networks of 22 non- responsive neurostimulation treated patients was used to train a support vector machine, which when tested on 13 distinct patients classified non-responders with an accuracy of 0.92 (95% CI 0.75–1). These results indicate patients who do not respond to surgery or those not selected for resection or responsive neurostimulation can be explained by the epileptic network hypothesis that is a decentralized network consisting of widely distributed, hyperexcitable fast ripple-generating nodes.

Abstract Objective Anterior temporal lobectomy (ATL) is a widely performed and successful intervention for drug‐resistant temporal lobe epilepsy (TLE). However, up to one third of patients experience seizure recurrence within 1 year after ATL. Despite the extensive literature on presurgical electroencephalography (EEG) and magnetic resonance imaging (MRI) abnormalities to prognosticate seizure freedom following ATL, the value of quantitative analysis of visually reviewed normal interictal EEG in such prognostication remains unclear. In this retrospective multicenter study, we investigate whether machine learning analysis of normal interictal scalp EEG studies can inform the prediction of postoperative seizure freedom outcomes in patients who have undergone ATL. Methods We analyzed normal presurgical scalp EEG recordings from 41 Mayo Clinic (MC) and 23 Cleveland Clinic (CC) patients. We used an unbiased automated algorithm to extract eyes closed awake epochs from scalp EEG studies that were free of any epileptiform activity and then extracted spectral EEG features representing (a) spectral power and (b) interhemispheric spectral coherence in frequencies between 1 and 25 Hz across several brain regions. We analyzed the differences between the seizure‐free and non–seizure‐free patients and employed a Naïve Bayes classifier using multiple spectral features to predict surgery outcomes. We trained the classifier using a leave‐one‐patient‐out cross‐validation scheme within the MC data set and then tested using the out‐of‐sample CC data set. Finally, we compared the predictive performance of normal scalp EEG‐derived features against MRI abnormalities. Results We found that several spectral power and coherence features showed significant differences correlated with surgical outcomes and that they were most pronounced in the 10–25 Hz range. The Naïve Bayes classification based on those features predicted 1‐year seizure freedom following ATL with area under the curve (AUC) values of 0.78 and 0.76 for the MC and CC data sets, respectively. Subsequent analyses revealed that (a) interhemispheric spectral coherence features in the 10–25 Hz range provided better predictability than other combinations and (b) normal scalp EEG‐derived features provided superior and potentially distinct predictive value when compared with MRI abnormalities (>10% higher F1 score). Significance These results support that quantitative analysis of even a normal presurgical scalp EEG may help prognosticate seizure freedom following ATL in patients with drug‐resistant TLE. Although the mechanism for this result is not known, the scalp EEG spectral and coherence properties predicting seizure freedom may represent activity arising from the neocortex or the networks responsible for temporal lobe seizure generation within vs outside the margins of an ATL.

The objective of this study was to characterize network-level changes in nonfluent/agrammatic Primary Progressive Aphasia (agPPA) and Primary Progressive Apraxia of Speech (PPAOS) with graph theory (GT) measures derived from scalp electroencephalography (EEG) recordings. EEGs of 15 agPPA and 7 PPAOS patients were collected during relaxed wakefulness with eyes closed (21 electrodes, 10–20 positions, 256 Hz sampling rate, 1–200 Hz bandpass filter). Eight artifact-free, non-overlapping 1024-point epochs were selected. Via Brainwave software, GT weighted connectivity and minimum spanning tree (MST) measures were calculated for theta and upper and lower alpha frequency bands. Differences in GT and MST measures between agPPA and PPAOS were assessed with Wilcoxon rank-sum tests. Of greatest interest, Spearman correlations were computed between behavioral and network measures in all frequency bands across all patients. There were no statistically significant differences in GT or MST measures between agPPA and PPAOS. There were significant correlations between several network and behavioral variables. The correlations demonstrate a relationship between reduced global efficiency and clinical symptom severity (e.g., parkinsonism, AOS). This preliminary, exploratory study demonstrates potential for EEG GT measures to quantify network changes associated with degenerative speech–language disorders.

OBJECTIVE Epilepsy originating from the central lobule (i.e., the primary sensorimotor cortex) is a challenging entity to treat given its involvement of eloquent cortex. The objective of this study was to review available evidence on treatment options for central lobule epilepsy. METHODS A comprehensive literature search (PubMed/Medline, EMBASE, and Scopus) was conducted for studies (1990 to date) investigating postoperative outcomes for central lobule epilepsy. The primary and secondary endpoints were seizure freedom at last follow-up and postoperative neurological deficit, respectively. The following procedures were included: open resection, multiple subpial transections (MSTs), laser and radiofrequency ablation, deep brain stimulation (DBS), responsive neurostimulation (RNS), and continuous subthreshold cortical stimulation (CSCS). RESULTS A total of 52 studies and 504 patients were analyzed. Most evidence was based on open resection, yielding a total of 400 patients (24 studies), of whom 62% achieved seizure freedom at a mean follow-up of 48 months. A new or worsened motor deficit occurred in 44% (permanent in 19%). Forty-six patients underwent MSTs, of whom 16% achieved seizure freedom and 30% had a neurological deficit (permanent in 12%). There were 6 laser ablation cases (cavernomas in 50%) with seizure freedom in 4 patients and 1 patient with temporary motor deficit. There were 5 radiofrequency ablation cases, with 1 patient achieving seizure freedom, 2 patients each with Engel class III and IV outcomes, and 2 patients with motor deficit. The mean seizure frequency reduction at the last follow-up was 79% for RNS (28 patients), 90% for CSCS (15 patients), and 73% for DBS (4 patients). There were no cases of temporary or permanent neurological deficit in the CSCS or DBS group. CONCLUSIONS This review highlights the safety and efficacy profile of resection, ablation, and stimulation for refractory central lobe epilepsy. Resection of localized regions of epilepsy onset zones results in good rates of seizure freedom (62%); however, nearly 20% of patients had permanent motor deficits. The authors hope that this review will be useful to providers and patients when tailoring decision-making for this intricate pathology.

AbstractBackgroundProgressive dysexecutive syndrome (dAD) is an atypical presentation of early onset Alzheimer’s disease (AD) with increased frontal and parietal region hypometabolism on FDG‐PET imaging compared to classic amnestic AD. We compared electroencephalogram (EEG) and FDG‐PET in dAD patients to determine if there was a correlation between EEG spectral activity and standard uptake value ratios (SUVR) in those regions.MethodFDG‐PET and resting state scalp EEG were obtained on AD‐biomarker confirmed, behavioral neurologist diagnosed cases of dAD (n = 11). We isolated awake‐eyes‐closed segments (mean duration: 113s, median:118s, range: 58‐138s) of each EEG and calculated the relative power of delta, theta, alpha, beta, and gamma bands within a wideband of 0.5‐40 Hz. In bilateral frontal and parietal regions, we averaged select channels across 6 to 14 10‐second windows per subject (fig.1). We evaluated the correlation between relative band powers and SUVRs of the regions by linear regression analysis.ResultThere is a strong negative correlation (R2 = 0.54, p < 0.01) between alpha band relative power and SUVR in bilateral frontal regions (fig 2). Delta band relative power showed a strong positive correlation (R2 = 0.54, p < 0.05) with SUVR in the left frontal region. A positive trend was noted in the delta band in the right frontal region but did not reach statistical significance. Beta band relative power was negatively correlated with frontal region SUVR bilaterally, but only the left side reached statistical significance. These findings remained significant after multiple comparisons correction. No statistically significant correlations were noted in the parietal regions. Exploratory analysis revealed negative correlations between alpha bands and temporal region SUVRs bilaterally.ConclusionIn this small sample of selected individuals with dysexecutive AD, we report a strong correlation between EEG relative spectral power and PET regional SUVR in multiple EEG frequency bands and brain regions. In the bilateral frontal regions, slower delta frequencies and faster alpha and beta frequencies were associated with lower FDG‐PET signal. Future studies are needed to determine if this spectral power pattern and other EEG properties of dAD differ from other clinical dementia phenotypes and its clinical significance.

OBJECTIVE Due to their deep and medial location, range of seizure semiologies, and poor localization on ictal electroencephalography (EEG), cingulate gyrus seizures can be difficult to diagnose and treat. The aim of this study was to review the available evidence on postoperative outcomes after cingulate epilepsy surgery. METHODS A comprehensive literature search of the PubMed/MEDLINE, Ovid Embase, Ovid Scopus, and Cochrane Library databases was conducted to identify studies that investigated postoperative outcomes of patients with cingulate epilepsy. Seizure freedom at the last follow-up (at least 12 months) was the primary endpoint. The literature search was supplemented by the authors’ institutional series (4 patients). RESULTS Twenty-one studies were identified, yielding a total of 105 patients (68 with lesional epilepsy [65%]). Median age at surgery was 23 years, and 56% of patients were male. Median epilepsy duration was 7.5 years. Invasive EEG recording was performed on 69% of patients (53% of patients with lesional epilepsy and 97% of those with nonlesional epilepsy, p < 0.001). The most commonly resected region was the anterior cingulate (55%), followed by the posterior (17%) and middle (14%) cingulate. Lesionectomy alone was performed in 9% of patients. Additional extracingulate treatment was performed in 54% of patients (53% of patients with lesional epilepsy vs 57% of those with nonlesional epilepsy, p = 0.87). The most common pathology was cortical dysplasia (54%), followed by low-grade neoplasm (29%) and gliosis (8%). Seizure freedom was noted in 72% of patients (median follow-up 24 months). A neurological deficit was noted in 27% of patients (24% had temporary deficit), with the most common deficit being motor weakness (13%) followed by supplementary motor area syndrome (9.5%). Univariate survival analysis revealed significantly greater probability of seizure freedom in patients with lesional epilepsy (p = 0.015, log-rank test). CONCLUSIONS Surgical treatment of drug-resistant focal epilepsy originating from the cingulate gyrus is safe, leads to low rates of permanent adverse effects, and leads to high rates of long-term seizure freedom in carefully selected patients. These data may serve as a benchmark for surgical counseling of patients with cingulate epilepsy.

OBJECTIVE The prevalence of epilepsy in the older adult population is increasing. While surgical intervention in younger patients is supported by level I evidence, the safety and efficacy of epilepsy surgery in older individuals is less well established. The aim of this study was to evaluate seizure freedom rates and surgical outcomes in older epilepsy patients. METHODS The authors’ institutional electronic database was queried for patients older than 50 who had undergone epilepsy surgery during 2002–2018. Cases were grouped into 50–59, 60–69, and 70+ years old. Seizure freedom at the last follow-up constituted the primary outcome of interest. The institutional analysis was supplemented by a literature review and meta-analysis (random effects model) of all published studies on this topic as well as by an analysis of complication rates, mortality rates, and cost data from a nationwide administrative database (Vizient Inc., years 2016–2019). RESULTS A total of 73 patients (n = 16 for 50–59 years, n = 47 for 60–69, and n = 10 for 70+) were treated at the authors’ institution. The median age was 63 years, and 66% of the patients were female. At a median follow-up of 24 months, seizure freedom was 73% for the overall cohort, 63% for the 50–59 group, 77% for the 60–69 group, and 70% for the 70+ group. The literature search identified 15 additional retrospective studies (474 cases). Temporal lobectomy was the most commonly performed procedure (73%), and mesial temporal sclerosis was the most common pathology (52%), followed by nonspecific gliosis (19%). The pooled mean follow-up was 39 months (range 6–114.8 months) with a pooled seizure freedom rate of 65% (95% CI 59%–72%). On multivariable meta-regression analysis, an older mean age at surgery (coefficient [coeff] 2.1, 95% CI 1.1–3.1, p < 0.001) and the presence of mesial temporal sclerosis (coeff 0.3, 95% CI 0.1–0.6, p = 0.015) were the most important predictors of seizure freedom. Finally, analysis of the Vizient database revealed mortality rates of 0.5%, 1.1%, and 9.6%; complication rates of 7.1%, 10.1%, and 17.3%; and mean hospital costs of $31,977, $34,586, and $40,153 for patients aged 50–59, 60–69, and 70+ years, respectively. CONCLUSIONS While seizure-free outcomes of epilepsy surgery are excellent, there is an expected increase in morbidity and mortality with increasing age. Findings in this study on the safety and efficacy of epilepsy surgery in the older population may serve as a useful guide during preoperative decision-making and patient counseling.

OBJECTIVE Insular lobe epilepsy is a challenging condition to diagnose and treat. Due to anatomical intricacy and proximity to eloquent brain regions, resection of epileptic foci in that region can be associated with significant postoperative morbidity. The aim of this study was to review available evidence on postoperative outcomes following insular epilepsy surgery. METHODS A comprehensive literature search (PubMed/MEDLINE, Scopus, Cochrane) was conducted for studies investigating the postoperative outcomes for seizures originating in the insula. Seizure freedom at last follow-up (at least 12 months) comprised the primary endpoint. The authors also present their institutional experience with 8 patients (4 pediatric, 4 adult). RESULTS A total of 19 studies with 204 cases (90 pediatric, 114 adult) were identified. The median age at surgery was 23 years, and 48% were males. The median epilepsy duration was 8 years, and 17% of patients had undergone prior epilepsy surgery. Epilepsy was lesional in 67%. The most common approach was transsylvian (60%). The most commonly resected area was the anterior insular region (n = 42, 21%), whereas radical insulectomy was performed in 13% of cases (n = 27). The most common pathology was cortical dysplasia (n = 68, 51%), followed by low-grade neoplasm (n = 16, 12%). In the literature, seizure freedom was noted in 60% of pediatric and 69% of adult patients at a median follow-up of 29 months (75% and 50%, respectively, in the current series). A neurological deficit occurred in 43% of cases (10% permanent), with extremity paresis comprising the most common deficit (n = 35, 21%), followed by facial paresis (n = 32, 19%). Language deficits were more common in left-sided approaches (24% vs 2%, p < 0.001). Univariate analysis for seizure freedom revealed a significantly higher proportion of patients with lesional epilepsy among those with at least 12 months of follow-up (77% vs 59%, p = 0.032). CONCLUSIONS These findings may serve as a benchmark when tailoring decision-making for insular epilepsy, and may assist surgeons in their preoperative discussions with patients. Although seizure freedom rates are quite high with insular epilepsy treatment, the associated morbidity needs to be weighed against the potential for seizure freedom.

Abstract Localizing hyperexcitable brain tissue to treat focal seizures remains challenging. We want to identify the seizure onset zone from interictal EEG biomarkers. We hypothesize that a combination of interictal EEG biomarkers, including a novel low frequency marker, can predict mesial temporal involvement and can assist in prognosis related to surgical resections. Interictal direct current wide bandwidth invasive EEG recordings from 83 patients implanted with 5111 electrodes were retrospectively studied. Logistic regression was used to classify electrodes and patient outcomes. A feed-forward neural network was implemented to understand putative mechanisms. Interictal infraslow frequency EEG activity was decreased for seizure onset zone electrodes while faster frequencies such as delta (2–4 Hz) and beta-gamma (20–50 Hz) activity were increased. These spectral changes comprised a novel interictal EEG biomarker that was significantly increased for mesial temporal seizure onset zone electrodes compared to non-seizure onset zone electrodes. Interictal EEG biomarkers correctly classified mesial temporal seizure onset zone electrodes with a specificity of 87% and positive predictive value of 80%. These interictal EEG biomarkers also correctly classified patient outcomes after surgical resection with a specificity of 91% and positive predictive value of 87%. Interictal infraslow EEG activity is decreased near the seizure onset zone while higher frequency power is increased, which may suggest distinct underlying physiologic mechanisms. Narrowband interictal EEG power bands provide information about the seizure onset zone and can help predict mesial temporal involvement in seizure onset. Narrowband interictal EEG power bands may be less useful for predictions related to non-mesial temporal electrodes. Together with interictal epileptiform discharges and high-frequency oscillations, these interictal biomarkers may provide prognostic information prior to surgical resection. Computational modelling suggests changes in neural adaptation may be related to the observed low frequency power changes.

Abstract Objective Verbal memory dysfunction is common in focal, drug‐resistant epilepsy (DRE). Unfortunately, surgical removal of seizure‐generating brain tissue can be associated with further memory decline. Therefore, localization of both the circuits generating seizures and those underlying cognitive functions is critical in presurgical evaluations for patients who may be candidates for resective surgery. We used intracranial electroencephalographic (iEEG) recordings during a verbal memory task to investigate word encoding in focal epilepsy. We hypothesized that engagement in a memory task would exaggerate local iEEG feature differences between the seizure onset zone (SOZ) and neighboring tissue as compared to wakeful rest (“nontask”). Methods Ten participants undergoing presurgical iEEG evaluation for DRE performed a free recall verbal memory task. We evaluated three iEEG features in SOZ and non‐SOZ electrodes during successful word encoding and compared them with nontask recordings: interictal epileptiform spike (IES) rates, power in band (PIB), and relative entropy (REN; a functional connectivity measure). Results We found a complex pattern of PIB and REN changes in SOZ and non‐SOZ electrodes during successful word encoding compared to nontask. Successful word encoding was associated with a reduction in local electrographic functional connectivity (increased REN), which was most exaggerated in temporal lobe SOZ. The IES rates were reduced during task, but only in the non‐SOZ electrodes. Compared with nontask, REN features during task yielded marginal improvements in SOZ classification. Significance Previous studies have supported REN as a biomarker for epileptic brain. We show that REN differences between SOZ and non‐SOZ are enhanced during a verbal memory task. We also show that IESs are reduced during task in non‐SOZ, but not in SOZ. These findings support the hypothesis that SOZ and non‐SOZ respond differently to task and warrant further exploration into the use of cognitive tasks to identify functioning memory circuits and localize SOZ.