Patients Undergoing Epilepsy Surgery Research Articles

Hippocampal activations obtained during language fMRI tasks: A complementary tool for predicting postoperative memory prognosis

In medial temporal lobe epilepsy (MTLE), the benefits of surgery must be balanced against the risk of post-operative memory decline. Prediction of postoperative outcomes based on functional magnetic resonance imaging (fMRI) tasks is increasingly common but remains uncertain. The aim of this retrospective study was to determine whether hippocampal activations elicited by fMRI language tasks could enhance or refine memory fMRI in MTLE patients candidates to surgery. Forty-six patients were included: 30 right and 16 left MTLE, mostly with hippocampal sclerosis. Preoperative assessment included neuropsychological tests and fMRI with language (syntactic verbal fluency) and memory tasks (encoding, delayed, and immediate recognition of images of objects). Thirty patients underwent surgery and had neuropsychological evaluations one year after surgery. Worsening was defined as a degradation of more than 10 % in postoperative forgetting scores compared to preoperative scores in verbal, non-verbal and global memory. Memory fMRI had the best sensitivity with hippocampal activations obtained in 95 % of patients, versus 65 % with language fMRI. Considering the patients who elicited an hippocampal activation, language fMRI led to 80 %, 65 % and 85 % of correct predictions for respectively global, verbal and non verbal memory (versus 71 %, 64 % and 68 % with memory fMRI). Memory and language fMRI predictions outperformed those made by neuropsychological tests. In summary, language fMRI was less sensitive than memory fMRI to elicit hippocampal activations but when it did, the proportion of correct memory predictions was better. Moreover, it proved to be an independent predictive factor regardless of the side of the epileptic focus. Given the ease of setting up a language task in fMRI, we recommend the systematic combination of memory and language tasks to predict the post-operative memory outcome of MTLE patients undergoing epilepsy surgery.

Electrocorticographic Patterns in Frontal Epilepsy and Long-Term Outcomes [RETRACTED

The prognostic significance of tailored resection guided with intraoperative electrocorticography (iECoG) in frontal lobe epilepsy surgery has not been fully elucidated. To analyze influence of preresection and postresection iECoG patterns on long-term seizure control of adults with frontal lobe epilepsy undergoing epilepsy surgery. We retrospectively analyzed 27 patients undergoing epilepsy surgery from two centers with preresection and postresection iECoG and reported clinical variables, preresection and postresection iECoG patterns, and outcome using the Engel Outcome Scale. Descriptive statistics, Kaplan-Meier, the logistic regression model, and analysis of variance tests were used. Fifteen males (55.6%), a mean and mode follow-up after surgery of 43 (range 2-117) and 19 months, respectively. At 6 months, seizure frequency outcome according to Engel Scale was I 74.1% (20/27), II 7.4% (2/27), III 3.7% (1/27), and IV 14.8% (4/27). We found that 51.9% (14/27) and 40.8% (11/27) of patients without residual epileptiform discharges in postresective iECoG become seizure-free at 6 and 12 months of follow-up, respectively, compared with other postresective iECoG patterns. Disregarding the presence of lack of residual epileptiform discharges (interictal epileptiform discharges) after resection, Engel I outcome was seen between 74.1% and 63% at 6- and 12-month postresection follow-up, suggesting the outcome might be in relation with other factors.

Pediatric Palliative Epilepsy Surgery: A Report From the Pediatric Epilepsy Research Consortium (PERC) Surgery Database

BackgroundEpilepsy surgery is an underutilized resource for children with drug-resistant epilepsy. Palliative and definitive surgical options can reduce seizure burden and improve quality of life. Palliative epilepsy surgery is often seen as a “last resort” compared to definitive surgical options. We compare patient characteristics between palliative and definitive epilepsy surgical patients and present palliative surgical outcomes from the Pediatric Epilepsy Research Consortium surgical database. MethodsThe Pediatric Epilepsy Research Consortium Epilepsy Surgery database is a prospective registry of patients aged 0-18 years undergoing evaluation for epilepsy surgery at 20 pediatric epilepsy centers. We included all children with completed surgical therapy characterized as definitive or palliative. Demographics, epilepsy type, age of onset, age at referral, etiology of epilepsy, treatment history, time-to-referral/evaluation, number of failed anti-seizure medications (ASMs), imaging results, type of surgery, and postoperative outcome were acquired. ResultsSix hundred forty patients undergoing epilepsy surgery were identified. Patients undergoing palliative procedures were younger at seizure onset (median: 2.1 vs 4 years, P= 0.0008), failed more ASM trials before referral for presurgical evaluation (P=<0.0001), and had longer duration of epilepsy before referral for surgery (P=<0.0001). During presurgical evaluation, patients undergoing palliative surgery had shorter median duration of video-EEG data collected (P=0.007) but number of cases where ictal data were acquired was similar between groups. The most commonly performed palliative procedure was corpus callosotmy (31%), followed by lobectomy (21%) and neuromodulation (82% responsive neurostimulation vs 18% deep brain stimulation). Palliative patients were further categorized into traditionally palliative procedures vs traditionally definitive procedures. The majority of palliative patients had 50% reduction or better in seizure burden. Seizure free outcomes were significantly higher among those with traditional definitive surgeries, 41% (95% confidence interval: 26% to 57%) compared with traditional palliative surgeries and 9% (95% confidence interval: 2% to 17%). Rate of seizure freedom was 46% at 24 months or greater of follow-up in the traditional definitive group. ConclusionsPatients receiving palliative epilepsy surgery trialed more ASMs, were referred later after becoming drug resistant, and had longer gaps between drug resistance and epilepsy surgery compared with patients undergoing definitive epilepsy surgery. The extent of surgical evaluation is impacted if surgery is thought to be palliative. A majority of palliative surgery patients achieved >50% seizure reduction at follow-up, both in groups that received traditionally palliative and traditionally definitive surgical procedures. Palliative surgical patients can achieve greater seizure control and should be referred to an epilepsy surgery center promptly after failing two appropriate anti-seizure medications.

Clinical Correlation of Altered Molecular Signatures in Epileptic Human Hippocampus and Amygdala

Widespread alterations in the expression of various genes could contribute to the pathogenesis of epilepsy. The expression levels of various genes, including major inhibitory and excitatory receptors, ion channels, cell type-specific markers, and excitatory amino acid transporters, were assessed and compared between the human epileptic hippocampus and amygdala, and findings from autopsy controls. Moreover, the potential correlation between molecular alterations in epileptic brain tissues and the clinical characteristics of patients undergoing epilepsy surgery was evaluated. Our findings revealed significant and complex changes in the expression of several key regulatory genes in both the hippocampus and amygdala of patients with intractable epilepsy. The expression changes in various genes differed considerably between the epileptic hippocampus and amygdala. Different correlation patterns were observed between changes in gene expression and clinical characteristics, depending on whether the patients were considered as a whole or were subdivided. Altered molecular signatures in different groups of epileptic patients, defined within a given category, could be viewed as diagnostic biomarkers. Distinct patterns of molecular changes that distinguish these groups from each other appear to be associated with epilepsy-specific functional consequences.

Emergence Patterns from General Anesthesia after Epilepsy Surgery: An Observational Pilot Study.

Objective Emergence from anesthesia starts from the limbic structures and then spreads outwards to brainstem, reticular activating systems, and then to the cortex. Epilepsy surgery often involves resection of limbic structures and hence may disrupt the pattern of emergence. The aim of this study was to explore the pattern of emergence from anesthesia following epilepsy surgery and to determine associated variables affecting the emergence pattern. Setting and Design Tertiary care center, prospective observational study. Materials and Methods We conducted a prospective observation pilot study on adult patients undergoing anterior temporal lobectomy and amygdalohippocampectomy for epilepsy. Anesthesia management was standardized in all patients, and they were allowed to wake up with "no touch" technique. Primary outcome of the study was the pattern of emergence (normal emergence, agitated emergence, or slow emergence) from anesthesia. Secondary outcomes were to explore the differences in preoperative neuropsychological profile and limbic structure volumes between the different patterns of emergence. Quantitative variables were analyzed using Student's t -test. Qualitative variables were analyzed using chi-square test. Results Twenty-nine patients completed the study: 9 patients (31%) had agitated emergence, and 20 patients had normal emergence. Among the agitated emergence, 2 patients had Riker scale of 7 indicating violent emergence. Patient demographics, anesthetic used, neuropsychological profile, and limbic structure volumes were similar between normal emergence and agitated emergence groups. However, two patients who had severe agitation (Riker scale of 7) had the lowest intelligence quotient. Conclusion Our pilot study showed that emergence agitation is not uncommon in patients undergoing epilepsy surgery. However, due to smaller sample size, the role of preoperative neuropsychologic profile and hippocampal volumes in predicting the pattern of emergence is inconclusive.

18F]FDG PET metabolic patterns in mesial temporal lobe epilepsy with different pathological types.

To investigate [18F]FDG PET patterns of mesial temporal lobe epilepsy (MTLE) patients with distinct pathologic types and provide possible guidance for predicting long-term prognoses of patients undergoing epilepsy surgery. This was a retrospective review of MTLE patients who underwent anterior temporal lobectomy between 2016 and 2021. Patients were classified as having chronic inflammation and gliosis (gliosis, n = 44), hippocampal sclerosis (HS, n = 43), or focal cortical dysplasia plus HS (FCD-HS, n = 13) based on the postoperative pathological diagnosis. Metabolic patterns and the severity of metabolic abnormalities were investigated among MTLE patients and healthy controls (HCs). The standardized uptake value (SUV), SUV ratio (SUVr), and asymmetry index (AI) of regions of interest were applied to evaluate the severity of metabolic abnormalities. Imaging processing was performed with statistical parametric mapping (SPM12). With a mean follow-up of 2.8years, the seizure freedom (Engel class IA) rates of gliosis, HS, and FCD-HS were 54.55%, 62.79%, and 69.23%, respectively. The patients in the gliosis group presented a metabolic pattern with a larger involvement of extratemporal areas, including the ipsilateral insula. SUV, SUVr, and AI in ROIs were decreased for patients in all three MTLE groups compared with those of HCs, but the differences among all three MTLE groups were not significant. MTLE patients with isolated gliosis had the worst prognosis and hypometabolism in the insula, but the degree of metabolic decrease did not differ from the other two groups. Hypometabolic regions should be prioritized for [18F]FDG PET presurgical evaluation rather than [18F]FDG uptake values. This study proposes guidance for optimizing the operation scheme in patients with refractory MTLE and emphasizes the potential of molecular neuroimaging with PET using selected tracers to predict the postsurgical histology of patients with refractory MTLE epilepsy. • MTLE patients with gliosis had poor surgical outcomes and showed a distinct pattern of decreased metabolism in the ipsilateral insula. • In the preoperative assessment of MTLE, it is recommended to prioritize the evaluation of glucose hypometabolism areas over [18F]FDG uptake values. • The degree of glucose hypometabolism in the epileptogenic focus was not associated with the surgical outcomes of MTLE.

Seizure features and outcomes in 50 children with GATOR1 variants: A retrospective study, more favorable for epilepsy surgery.

To summarize the clinical features of epilepsy related to DEPDC5, NPRL2, and NPRL3 genes encoding the GATOR1 complex in children, and to evaluate the factors affecting the prognosis of these epilepsies. In this retrospective study, we reviewed the clinical and genetic characteristics of children with epilepsy related to GATOR1 variants who were admitted to the Peking University First Hospital between January 2016 and December 2021. Potential prognostic factors were assessed by comparing children with and without ongoing seizures. Fifty probands, including 31 boys and 19 girls were recruited. The median age at onset of epilepsy was 4 months, and 64% of patients had early-onset epilepsy (≤1 year). The most frequent epileptic seizure type was focal seizure (86%). Among the 50 patients, only 6 were with de novo variants. According to the novel classification framework for GATOR1 variants, 36 patients were with pathogenic variants and 14 with likely pathogenic variants. DEPDC5 variants were found in 37 patients, NPRL3 in 9, and NPRL2 in 4. The phenotype was similar among the probands, with variants in DEPDC5, NRPL2, or NPRL3 respectively. 76% (38/50) epilepsy related to GATOR1 complex gene variants were neuroimaging positive, including Brain MRI positive in 31 patients, and MRI combined FDG-PET positive in the other 7 patients. Twenty-seven patients underwent epilepsy surgery. In total, after initial anti-seizure medications alone, 92% (46/50) patients were drug-resistant epilepsies, only 8% (4/50) of the probands became seizure-free but seizure-free (≥6m) occurred in 92.6% (25/27) of patients with drug-resistant epilepsy after epilepsy surgery at the last follow-up. Patients undergoing epilepsy surgery had better epilepsy prognosis. Epilepsy related to GATOR1 complex gene variant had high possibility to be drug-resistant epilepsy and to have positive neuroimaging finding. Epilepsy surgery is the only favorable factor for better seizure prognosis in this kind epilepsy.

Baseline frailty status, not advanced patient age, predicts epilepsy surgery outcomes: An analysis of 696 patients from the NSQIP database

ObjectivePreoperative risk stratification of patients undergoing epilepsy surgery remains challenging. Recently, the efforts to look beyond age alone as an outcomes predictor has resulted in the development of measures of physiological reserve, or ‘frailty indices.’ The most frequently cited index in neurosurgery is the 11-item or 5-item modified frailty index (mFI11 or mFI-5). The present study aimed to use a large national registry to evaluate the effect of frailty (as measured by mFI-5 versus age on postoperative outcomes of patients undergoing epilepsy surgery. MethodsThe National Surgical Quality Improvement Program (NSQIP) database, overseen by the American College of Surgeons (ACS), was used to extract data for patients undergoing epilepsy surgery from 2015 to 2019. Univariate and multivariate analyses for age and mFI-5 were performed for the following 30-day outcomes of extended length of hospital stay (eLOS) and non-home discharge (NHD). The effect sizes were summarized by odds ratio and associated 95 % confidence intervals. Receiver operating characteristic (ROC) curve analysis, including area under the curve (AUC), was used to quantify the discrimination. ResultsUnivariate and multivariate analyses demonstrated that frailty statuses from mFI-5, not age, were significantly predictive of eLOS and NHD. On ROC curve analysis, mFI-5 was a stronger predictor of eLOS (C = 0.59, 95 % CI 0.54–0.64, p < 0.001) and NHD (C = 0.69, 95 % CI 0.64–0.76, p < 0.001) than age (C = 0.53, 95 % CI 0.48–0.58, p = 0.21 and C = 0.53, 95 % CI 0.46–0.59, p = 0.44, respectively). ConclusionFrailty, not age, is an independent risk factor for poor postoperative outcomes, particularly eLOS and NHD, in patients undergoing epilepsy surgery. Usage of mFI-5 for preoperative risk stratification of epilepsy surgery patients can help in prognostication.

Clinical factors associated with late seizure remission after failed epilepsy surgery

BackgroundSome patients who initially fail epilepsy surgery later become seizure-free, but it is not clear how the clinical characteristics of the patients or post-operative modifications of anti-seizure medication (ASM) regimens contribute to late seizure remission. MethodsWe performed a retrospective chart review of patients undergoing epilepsy surgery at the University of Washington Regional Epilepsy Center between 2007 and 2017, including patients receiving neocortical resection, temporal lobectomy, and hippocampal laser interstitial therapy (LITT) ablation. We assessed seizure freedom, ASM changes, seizure frequency at the first and last follow-up, and type of lesion. Two-tailed Fisher’s exact test and Mann-Whitney U test were used for statistical analyses. ResultsTwo hundred and fifteen patients undergoing epilepsy surgery between 2007 and 2017 had both first and last follow-ups. Ninety-eight (46%) were not seizure-free at the first follow-up (mean 1.1 years post-operative). By the last follow-up (mean 4.7 years post-operative), 20% of those not initially seizure-free had become so. Those who were seizure-free at the last visit had lower median seizures per month in the first post-operative year (0.21 versus 0.95 per month in those not seizure-free, p < 0.001). There was also a significantly higher proportion of patients with cavernomas who were seizure-free at the last visit (25% vs. 1% of those not seizure-free at the last visit; p = 0.001), but no other differences in clinical characteristics. Of the 98 patients who had seizures at the first follow-up, 63% underwent post-operative modification of their ASM regimens. The rate of late seizure freedom was similar for patients with or without ASM changes: 21% were seizure-free at the last visit with ASM changes and 19% without ASM changes. There were no significant differences in which ASMs were changed between those who became seizure-free and those who did not, but patients who were subjected to further medical management were less likely to have had mesial temporal sclerosis (MTS) than those who were not. A number of patients not initially seizure-free who underwent ASM changes achieved seizure freedom as long as 10 years post-surgery. ConclusionA substantial proportion of patients who initially fail epilepsy surgery will have late seizure remission. Those with cavernous hemangiomas were more likely to achieve late remission from seizures as were those with lower rates of seizures in the first year after surgery. The chances of achieving remission were similar in those with or without modification of their ASM regimens, but those with pre-operative MTS were more likely to achieve late seizure freedom without medication changes. At the individual level, patients may still achieve seizure freedom with ASM changes as long as ten years after the initial surgery.

Health care resource utilization and costs before and after epilepsy surgery

ObjectiveTo describe the demographics of epilepsy surgery utilization and its impact on health care resource use. MethodsRetrospective descriptive study using the MarketScan commercial claims database. We studied children and adults who underwent epilepsy surgery in the USA in the period 2006-2019. Our main outcome was health care resource utilization. ResultsAmong the 87,368 patients with refractory epilepsy, 2,011 (2.3%) patients underwent resective epilepsy surgery, 188 (0.2%) patients underwent partial or total hemispherectomy, and 183 (0.2%) patients underwent corpus callosotomy. The proportion of patients undergoing epilepsy surgery has barely increased in the period 2006 to 2019. The year of resective epilepsy surgery was associated with high healthcare costs per person-year [median (p25-p75): $140,322 ($88,749-$225,862)], but healthcare costs per person-year substantially decreased in the 5 years after compared to the 5 years before the year of resective epilepsy surgery [$7,691 ($2,738-$22,092) versus $18,750 ($7,361-$47,082), p-value < 0.0001]. This result held in all resective epilepsy surgery subgroups: children, adults, temporal, extratemporal, subdural EEG monitoring, stereoEEG monitoring, and no intracranial monitoring. Similarly, the year of hemispherectomy was associated with high healthcare costs per person-year [$260,983 ($154,791-$453,986)], but healthcare costs per person-year substantially decreased in the 5 years after compared to the 5 years before the year of hemispherectomy [$26,834 ($12,842-$52,627) versus $54,596 ($19,547-$136,412), p-value < 0.0001]. In contrast, the year of corpus callosotomy was associated with high healthcare costs per person-year [$162,399 ($108,150-$253,156)], but healthcare costs per person-year did not substantially decrease in the 5 years after than in the 5 years before the year of corpus callosotomy [$25,464 ($10,764-$69,338) versus $36,221 ($12,841-$85,747), p-value = 0.2142]. ConclusionIn privately insured patients in the USA, resective epilepsy surgery and hemispherectomy substantially decrease healthcare utilization in subsequent years. Epilepsy surgery may help contain costs in the field of epilepsy.

Outcome following surgery for insulo-opercular epilepsies.

The purpose of this study was to evaluate the clinical outcome in patients with medically refractory epilepsy who had undergone resective or ablative surgery for suspected insulo-opercular epileptogenic foci. The prospectively maintained database of patients undergoing epilepsy surgery was reviewed, and all patients who underwent insulo-opercular surgery for medically refractory epilepsy with a minimum of 12 months of postoperative follow-up were identified, excluding those who had insulo-opercular resection in combination with temporal lobectomy. The presurgical electroclinicoradiological data, stereo-EEG (SEEG) findings, resection/ablation patterns, surgical pathology, postoperative seizure outcome, and neurological complications were analyzed. Of 407 patients undergoing epilepsy surgery in a 5-year period at the Amrita Advanced Centre for Epilepsy, 24 patients (5.9%) who underwent exclusive insulo-opercular interventions were included in the study. Eleven (46%) underwent surgery on the right side, 12 (50%) on the left side, and the operation was bilateral in 1 (4%). The mean age at surgery was 24.5 ± 12.75 years. Onset of seizures occurred on average at 10.6 ± 9.7 years of life. Characteristic auras were identified in 66% and predominant seizure type was hypermotor (15.4%), automotor (15.4%), hypomotor (11.5%), or a mixed pattern. Seventy-five percent of the seizures recorded on scalp video-EEG occurred during sleep. The 3T MRI results were normal in 12 patients (50%). Direct single-stage surgery was undertaken in 5 patients, and SEEG followed by intervention in 19. Eighteen patients (75%) underwent exclusive resective surgery, 4 (16.7%) underwent exclusive volumetric radiofrequency ablation, and 2 (8.3%) underwent staged radiofrequency ablation and resective surgery. Immediate postoperative neurological deficits occurred in 10/24 (42%), which persisted beyond 12 postoperative months in 3 (12.5%). With a mean follow-up of 25.9 ± 14.6 months, 18 patients (75%) had Engel class I outcome, 3 (12.5%) had Engel class II, and 3 (12.5%) had Engel class III or IV. There was no statistically significant difference in outcomes between MRI-positive versus MRI-negative cases. Surgery for medically refractory epilepsy in insulo-opercular foci is less common and remains a challenge to epilepsy surgery centers. Localization is aided significantly by a careful study of auras and semiology followed by EEG and imaging. The requirement for SEEG is generally high. Satisfactory rates of seizure freedom were achievable independent of the MRI lesional/nonlesional status. Morbidity is higher for insulo-opercular epilepsy surgery compared to other focal epilepsies; hence, the practice and development of minimally invasive strategies for this subgroup of patients undergoing epilepsy surgery is perhaps most important.

Clinical significance of ictal magnetoencephalography in patients undergoing epilepsy surgery

ObjectiveThe significance of ictal magnetoencephalography (MEG) is not well appreciated. We evaluated the relationships between ictal MEG, MRI, intracranial electroencephalography (ICEEG), surgery and postoperative seizure outcome. MethodsA total of 45 patients (46 cases) with ictal MEG who underwent epilepsy surgery was included. We examined the localization of each modality, surgical resection area and seizure freedom after surgery. ResultsTwenty-one (45.7%) out of 46 cases were seizure-free at more than 6 months follow-up. Median duration of postoperative follow-up was 16.5 months. The patients in whom ictal, interictal single equivalent current dipole (SECD) and MRI lesion localization were completely included in the resection had a higher chance of being seizure-free significantly (p < 0.05). Concordance between ictal and interictal SECD localizations was significantly associated with seizure-freedom. Concordance between MRI lesion and ictal SECD, concordance between ictal ICEEG and ictal and interictal SECD, as well as concordance between ictal ICEEG and MRI lesion were significantly associated with seizure freedom. ConclusionsIctal MEG can contribute useful information for delineating the resection area in epilepsy surgery. SignificanceResection should include ictal, interictal SECDs and MRI lesion localization, when feasible. Concordant ictal and interictal SECDs on MEG can be a favorable predictor of seizure freedom.

Brain-Computer Interface: Applications to Speech Decoding and Synthesis to Augment Communication

Damage or degeneration of motor pathways necessary for speech and other movements, as in brainstem strokes or amyotrophic lateral sclerosis (ALS), can interfere with efficient communication without affecting brain structures responsible for language or cognition. In the worst-case scenario, this can result in the locked in syndrome (LIS), a condition in which individuals cannot initiate communication and can only express themselves by answering yes/no questions with eye blinks or other rudimentary movements. Existing augmentative and alternative communication (AAC) devices that rely on eye tracking can improve the quality of life for people with this condition, but brain-computer interfaces (BCIs) are also increasingly being investigated as AAC devices, particularly when eye tracking is too slow or unreliable. Moreover, with recent and ongoing advances in machine learning and neural recording technologies, BCIs may offer the only means to go beyond cursor control and text generation on a computer, to allow real-time synthesis of speech, which would arguably offer the most efficient and expressive channel for communication. The potential for BCI speech synthesis has only recently been realized because of seminal studies of the neuroanatomical and neurophysiological underpinnings of speech production using intracranial electrocorticographic (ECoG) recordings in patients undergoing epilepsy surgery. These studies have shown that cortical areas responsible for vocalization and articulation are distributed over a large area of ventral sensorimotor cortex, and that it is possible to decode speech and reconstruct its acoustics from ECoG if these areas are recorded with sufficiently dense and comprehensive electrode arrays. In this article, we review these advances, including the latest neural decoding strategies that range from deep learning models to the direct concatenation of speech units. We also discuss state-of-the-art vocoders that are integral in constructing natural-sounding audio waveforms for speech BCIs. Finally, this review outlines some of the challenges ahead in directly synthesizing speech for patients with LIS.

BIOM-19. DECIPHERING THE METHYLATION SIGNATURE OF CIRCULATING EXTRACELLULAR VESICLE DNA FOR CNS TUMOR CLASSIFICATION

Abstract Genome-wide methylation profiling has recently been developed into a tool that allows subtype tumor classification in central nervous system (CNS) tumors. We previously showed that extracellular vesicle (EV) DNA faithfully reflects the tumor methylation class, including information on the IDH mutation and MGMT promoter methylation status. Furthermore we showed that circulating plasma EVs are elevated in CNS tumor patients in comparison to non-tumor donors (HD) controls with tumor related protein profiles. We now investigated, whether the methylation signatures of circulating DNA (both EV and cfNDA) can be used in liquid biopsy approaches for CNS tumor detection and classification. We isolated DNA from circulating EVs (n=27), cfDNA (n=27) and tumor tissue DNA (n=90) of patients with glioblastoma (GBM), meningioma (MGN) and cerebral metastases (CM). Patients undergoing epilepsy surgery as well as aneurysm clipping were used as non-tumor controls (HD, n= 7). EVs were classified by nanoparticle analysis, immunoblotting, imaging flow cytometry and electron microscopy. Isolated EV-DNA comprised many sorts of molecular weight (up tp &amp;gt;10Kb) in comparison to cfDNA (130-140bp). Healthy donors and tumor patients showed not differences in their DNA size profiles. We performed genome-wide methylation profiling by 850k Illumina EPIC arrays for all DNA analytes and tumor entities. Linear models and empirical Bayes methods identified significant differentially methylated CpGs (GBM vs. HD, MGN, vs HD, CM vs. HD), that revealed tumor specific signatures to detect and discriminate different CNS tumor entities. Visualization of differentially methylated CPGs by dimension reduction (PCA, t-SNE, Umap) verified tumor specific clusters. cfDNA and EV-DNA exhibited distinctive individual CpG profiles. Our study shows that the methylation signature of circulating EV DNA and cfDNA can be used to separate healthy individuals from tumor patients and could potentially complement standard-of-care imaging to improve tumor detection, classification and surveillance.

Automated ictal EEG source imaging: A retrospective, blinded clinical validation study

ObjectiveEEG source imaging (ESI) is a validated tool in the multimodal workup of patients with drug resistant focal epilepsy. However, it requires special expertise and it is underutilized. To circumvent this, automated analysis pipelines have been developed and validated for the interictal discharges. In this study, we present the clinical validation of an automated ESI for ictal EEG signals. MethodsWe have developed an automated analysis pipeline of ictal EEG activity, based on spectral analysis in source space, using an individual head model of six tissues. The analysis was done blinded to all other data. As reference standard, we used the concordance with the resected area and one-year postoperative outcome. ResultsWe analyzed 50 consecutive patients undergoing epilepsy surgery (34 temporal and 16 extra-temporal). Thirty patients (60%) became seizure-free. The accuracy of the automated ESI was 74% (95% confidence interval: 59.66–85.37%). ConclusionsAutomated ictal ESI has a high accuracy for localizing the seizure onset zone. SignificanceAutomating the ESI of the ictal EEG signals will facilitate implementation of this tool in the presurgical evaluation.

Validation of automatic MRI hippocampal subfield segmentation by histopathological evaluation in patients with temporal lobe epilepsy

ObjectiveThe present study validates the results of automated hippocampal subfield segmentation with histopathology in epilepsy patients undergoing epilepsy surgery. MethodsWe performed an automated hippocampal subfield segmentation on presurgical three-dimensional, T1-weighted magnetization Prepared Rapid Acquisition of Gradient Echoes Magnetic Resonance Imaging (MRI) data of 25 patients with unilateral mesial temporal lobe epilepsy due to hippocampal sclerosis (HS), using Freesurfer Version 6.0. The resulting volumes of cornu ammonis (CA) subfields CA1, CA2/3, CA4 and the dentate gyrus (DG) were compared to the histopathological cell count. ResultsWe found a significant correlation between histopathology in subregion CA2 and automated segmentation of subregion CA1 (p = 0.0062), CA2/3 (p = 0.004), CA4 (p = 0.0062) and the DG (p = 0.0054), between histopathology in CA3 and automated segmentation of CA1 (p = 0.0132), CA2/3 (p = 0.0004), CA4 (p = 0.0032) and the DG (p = 0.0037), as well as between histopathology in the DG and automated segmentation of CA1 (p = 0.0115), CA2/3 (p < 0.0001), CA4 (p < 0.0001) and the DG (p = 0.0001). The histopathological finding of HS type 1 could correctly be classified in all cases on MRI. SignificanceThe present study shows significant correlations between histopathological evaluation and results of the automated segmentation of the hippocampus, thereby validating the automated segmentation method. As the differential involvement of different hippocampal subfields may be associated with clinical parameters and the outcome after epilepsy surgery, the automated segmentation is also promising for prognostic purposes.

The role of preoperative diffusion tensor imaging in predicting and improving functional outcome in pediatric patients undergoing epilepsy surgery: a systematic review.

Objective:Diffusion tensor imaging (DTI) is a useful neuroimaging technique for surgical planning in adult patients. However, no systematic review has been conducted to determine its utility for pre-operative analysis and planning of Pediatric Epilepsy surgery. We sought to determine the benefit of pre-operative DTI in predicting and improving neurological functional outcome after epilepsy surgery in children with intractable epilepsy.Methods:A systematic review of articles in English using PubMed, EMBASE and Scopus databases, from inception to January 10, 2020 was conducted. All studies that used DTI as either predictor or direct influencer of functional neurological outcome (motor, sensory, language and/or visual) in pediatric epilepsy surgical candidates were included. Data extraction was performed by two blinded reviewers. Risk of bias of each study was determined using the QUADAS 2 Scoring System.Results:13 studies were included (6 case reports/series, 5 retrospective cohorts, and 2 prospective cohorts) with a total of 229 patients. Seven studies reported motor outcome; three reported motor outcome prediction with a sensitivity and specificity ranging from 80 to 85.7 and 69.6 to 100%, respectively; four studies reported visual outcome. In general, the use of DTI was associated with a high degree of favorable neurological outcomes after epilepsy surgery.Conclusion:Multiple studies show that DTI helps to create a tailored plan that results in improved functional outcome. However, more studies are required in order to fully assess its utility in pediatric patients. This is a desirable field of study because DTI offers a non-invasive technique more suitable for children.Advances in knowledge:This systematic review analyses, exclusively, studies of pediatric patients with drug-resistant epilepsy and provides an update of the evidence regarding the role of DTI, as part of the pre-operative armamentarium, in improving post-surgical neurological sequels and its potential for outcome prediction.

Gene expression analysis in epileptic hippocampi reveals a promoter haplotype conferring reduced aldehyde dehydrogenase 5a1 expression and responsiveness.

Increasing evidence indicates the pathogenetic relevance of regulatory genomic motifs for variability in the manifestation of brain disorders. In this context, cis-regulatory effects of single nucleotide polymorphisms (SNPs) on gene expression can contribute to changing transcript levels of excitability-relevant molecules and episodic seizure manifestation in epilepsy. Biopsy specimens of patients undergoing epilepsy surgery for seizure relief provide unique insights into the impact of promoter SNPs on corresponding mRNA expression. Here, we have scrutinized whether two linked regulatory SNPs (rs2744575; 4779C>G and rs4646830; 4854C>G) located in the aldehyde dehydrogenase 5a1 (succinic semialdehyde dehydrogenase; ALDH5A1) gene promoter are associated with expression of corresponding mRNAs in epileptic hippocampi (n=43). The minor ALDH5A1-GG haplotype associates with significantly lower ALDH5A1 transcript abundance. Complementary in vitro analyses in neural cell cultures confirm this difference and further reveal a significantly constricted range for the minor ALDH5A1 haplotype of promoter activity regulation through the key epileptogenesis transcription factor Egr1 (early growth response 1). The present data suggest systematic analyses in human hippocampal tissue as a useful approach to unravel the impact of epilepsy candidate SNPs on associated gene expression. Aberrant ALDH5A1 promoter regulation in functional terms can contribute to impaired γ-aminobutyric acid homeostasis and thereby network excitability and seizure propensity.

The clinical utility of intraoperative electrocorticography in pediatric epilepsy surgical strategy and planning.

In this study, the authors aimed to determine 1) whether the use of intraoperative electrocorticography (ECoG) affects outcomes and complication rates of children undergoing resective epilepsy surgery; 2) which patient- and epilepsy-related variables might influence ECoG-based surgical strategy; and 3) what the predictors of epilepsy surgery outcomes are. Over a period of 12 years, data were collected on pediatric patients who underwent tailored brain resections in the Motol Epilepsy Center. In patients in whom an abnormal ECoG pattern (e.g., spiking, suppression burst, or recruiting rhythm) was not observed beyond presurgically planned resection margins, the authors did not modify the surgical plan (group A). In those with significant abnormal ECoG findings beyond resection margins, the authors either did (group B) or did not (group C) modify the surgical plan, depending on the proximity of the eloquent cortex or potential extent of resection. Using Fisher's exact test and the chi-square test, the 3 groups were compared in relation to epilepsy surgery outcomes and complication rate. Next, multivariate models were constructed to identify variables associated with each of the groups and with epilepsy surgery outcomes. Patients in group C achieved significantly lower rates of seizure freedom compared to groups A (OR 30.3, p < 0.001) and B (OR 35.2, p < 0.001); groups A and B did not significantly differ (p = 0.78). Patients in whom the surgical plan was modified suffered from more frequent complications (B vs A+C, OR 3.8, p = 0.01), but these were mostly minor (duration < 3 months; B vs A+C, p = 0.008). In all cases, tissue samples from extended resections were positive for the presence of the original pathology. Patients with intended modification of the surgical plan (groups B+C) suffered more often from daily seizures, had a higher age at first seizure, had intellectual disability, and were regarded as MR-negative (p < 0.001). Unfavorable surgical outcome (Engel class II-IV) was associated with focal cortical dysplasia, incomplete resection based on MRI and/or ECoG findings, negative MRI finding, and inability to modify the surgical plan when indicated. Intraoperative ECoG serves as a reliable tool to guide resection and may inform the prognosis for seizure freedom in pediatric patients undergoing epilepsy surgery. ECoG-based modification of the surgical plan is associated with a higher rate of minor complications. Children in whom ECoG-based modification of the surgical plan is indicated but not feasible achieve significantly worse surgical outcomes.

A European questionnaire survey on epilepsy monitoring units' current practice for postoperative psychogenic nonepileptic seizures' detection

BackgroundIn cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures' outcome and the clinical management.We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES. MethodsWe developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project. ResultsTwenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 ( ± 19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 ± 7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project. ConclusionPostoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES.