Trajectories of parent well-being in children with drug-resistant epilepsy.

OBJECTIVE: This longitudinal cohort study aimed to identify trajectories of parent well-being over the first 2 years after their child's evaluation for candidacy for epilepsy surgery, and to identify the baseline clinical and demographic characteristics associated with these trajectories. Parent well-being was based on parent depressive and anxiety symptoms and family resources (i.e., family mastery and social support). METHODS: Parents of 259 children with drug-resistant epilepsy (105 of whom eventually had surgery) were recruited from eight epilepsy centers across Canada at the time of their evaluation for epilepsy surgery candidacy. Participants were assessed at baseline and 6-month, 1-year, and 2-year follow-up. The trajectories of parents' depressive symptoms, anxiety symptoms, and family resources were jointly estimated using multigroup latent class growth models. RESULTS: The analyses identified three trajectories: an optimal-stable group with no/minimal depressive or anxiety symptoms, and high family resources that remained stable over time; a mild-decreasing-plateau group with mild depressive and anxiety symptoms that decreased over time then plateaued, and intermediate family resources that remained stable; and a moderate-decreasing group with moderate depressive and anxiety symptoms that decreased slightly, and low family resources that remained stable over time. Parents of children with higher health-related quality of life, fathers, and parents who had higher household income were more likely to have better trajectories of well-being. Treatment type was not associated with the trajectory groups, but parents whose children were seizure-free at the time of the last follow-up were more likely to have better trajectories (optimal-stable or mild-decreasing-plateau trajectories). SIGNIFICANCE: This study documented distinct trajectories of parent well-being, from the time of the child's evaluation for epilepsy surgery. Parents who present with anxiety and depressive symptoms and low family resources do not do well over time. They should be identified and offered supportive services early in their child's epilepsy treatment history.

Pre-Operative Predictors of Health-Related Quality of Life Two Years After Pediatric Epilepsy Surgery: A Prospective Cohort Study.

PURPOSE: Seizure freedom is an important predictor of health-related quality of life (HRQOL) after pediatric epilepsy surgery. This study aimed to identify the pre-operative predictors of HRQOL 2 years after epilepsy surgery in children with drug-resistant epilepsy. METHODS: This multicenter prospective cohort study assessed pre-operative predictors including child (demographics and clinical variables), caregiver (including caregiver depressive and anxiety symptoms) and family characteristics. HRQOL was assessed using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE)-55 pre-operatively and 2-years after surgery. Univariable linear regression analyses were done to identify significant preoperative predictors of HRQOL 2-years after surgery, followed by multivariable regression. RESULTS: Ninety-five children underwent surgery, mean age was 11.4 (SD=4.2) years, and 59 (62%) were male. Mean QOLCE scores were 57.4 (95%CI: 53.8, 61.0) pre-operatively and 65.6 (95%CI: 62.0, 69.1) after surgery. Univariable regression showed fewer anti-seizure medications (ß=-6.1 [95%CI: -11.2, -1.0], p = 0.019), older age at seizure onset (ß=1.6 [95%CI: 0.8, 2.4], p<0.001), higher pre-operative HRQOL (ß=0.7 [95%CI: 0.5, 0.8], p<0.001), higher family resources (ß=0.6 [95%CI: 0.3, 0.9], p<0.001), better family relationships (ß=1.7 [95%CI: 0.3, 3.1], p = 0.017) and lower family demands (ß=-0.9 [95%CI: -1.5, -0.4], p<0.001) were associated with higher HRQOL after surgery. Caregiver characteristics did not predict HRQOL after surgery (p>0.05). Multivariable regression showed older age at seizure onset (ß=4.6 [95%CI: 1.6, 7.6], p = 0.003) and higher pre-operative HRQOL (ß=10.2 [95%CI: 6.8, 13.6], p<0.001) were associated with higher HRQOL after surgery. CONCLUSION: This study underscores the importance of optimizing pre-operative HRQOL to maximize HRQOL outcome after pediatric epilepsy surgery.

A longitudinal cohort study of mediators of health-related quality of life after pediatric epilepsy surgery or medical treatment.

OBJECTIVES: The purpose of this longitudinal cohort study was to examine the variables that influence health-related quality of life (HRQOL) after epilepsy surgery in children. We examined whether treatment type (surgical vs medical therapy) and seizure control are related to other variables that have been shown to influence HRQOL, namely depressive symptoms in children with epilepsy or their parents, and the availability of family resources. METHODS: In total, 265 children with drug-resistant epilepsy were recruited from eight epilepsy centers across Canada at the time of their evaluation for candidacy for epilepsy surgery and were assessed at baseline, 6-month, 1-year, and 2-year follow-up. Parents completed the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-55) and measures of family resources and depression; children completed depression inventories. Causal mediation analyses using natural effect models were used to evaluate the extent to which the relationship between treatment and HRQOL was explained by seizure control, child and parent depressive symptoms, and family resources. RESULTS: Overall, 111 children underwent surgery and 154 were treated with medical therapy only. The HRQOL scores of surgical patients were 3.4 points higher (95% confidence interval [CI]: -0.2, 7.0) relative to medical patients at the 2-year follow-up after adjusting for baseline covariates, with 66% of the effect of surgery attributed to seizure control. Child or parent depressive symptoms and family resources had negligible mediation effects between treatment and HRQOL. The effect of seizure control on HRQOL was not mediated by child or parent depressive symptoms, or by family resources. SIGNIFICANCE: The findings demonstrate that seizure control is on the causal pathway between epilepsy surgery and improved HRQOL in children with drug-resistant epilepsy. However, child and parent depressive symptoms and family resources were not significant mediators. The results highlight the importance of achieving seizure control to improve HRQOL.

Trajectory of Health-Related Quality of Life After Pediatric Epilepsy Surgery.

Importance: Health-related quality of life (HRQOL) is regarded as a key outcome for evaluating treatment efficacy. However, it is uncertain how HRQOL evolves after epilepsy surgery compared with medical therapy, such as whether it continues to improve over time, improves and then remains stable, or deteriorates after a period of time. Objective: To assess trajectory of HRQOL over 2 years in children with drug-resistant epilepsy (DRE) treated with surgery compared with medical therapy. Design, Setting, and Participants: Prospective cohort study assessing HRQOL longitudinally over 2 years. Participants were children recruited from 8 epilepsy centers in Canada from 2014 to 2019 with suspected DRE aged 4 to 18 years who were evaluated for surgery. Data were analyzed from May 2014 to December 2021. Exposures: Epilepsy surgery or medical therapy. Main Outcomes and Measures: HRQOL was measured using the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE)-55. HRQOL and seizure frequency were assessed at baseline, 6-month, 1-year, and 2-year follow-ups. Clinical, parent, and family characteristics were assessed at baseline. A linear mixed model was used to evaluate HRQOL over time, adjusting for baseline clinical, parent, and family characteristics. Results: There were 111 surgical and 154 medical patients (mean [SD] age at baseline was 11.0 [4.1] years; 118 [45%] were female). At baseline, HRQOL was similar among surgical and medical patients. HRQOL of surgical patients was 3.0 (95% CI, -0.7 to 6.8) points higher at 6-month, 4.9 (95% CI, 0.7 to 9.1) points higher at 1-year, and 5.1 (95% CI, 0.7 to 9.5) points higher at 2-year follow-ups compared with medical patients. Surgical patients experienced greater improvements in social functioning relative to medical patients, but not for cognitive, emotional, and physical functioning. At 2-year follow-up, 72% of surgical patients were seizure-free, compared with 33% of medical patients. Seizure-free patients reported higher HRQOL than those who were not. Conclusions and Relevance: This study provided evidence on the association between epilepsy surgery and children's HRQOL, with improvement in HRQOL occurring within the first year and remaining stable 2 years after surgery. By demonstrating that surgery improved seizure freedom and HRQOL, which has downstream effects such as better educational attainment, reduced health care resource utilization, and health care cost, these findings suggest that the high costs of surgery are justified, and that improved access to epilepsy surgery is necessary.

The Epilepsy Surgery Experience in Children With Infantile Epileptic Spasms Syndrome at a Tertiary Care Center in Canada.

Background: Infantile epileptic spasms syndrome is an epileptic encephalopathy, characterized by spasms, hypsarrhythmia, and developmental regression. Appropriately selected patients with infantile epileptic spasms syndrome may be candidates for epilepsy surgery. Methods: This is a single-center retrospective case series of children 0-18 years with a current or previous diagnosis of infantile epileptic spasms syndrome with a lesion on magnetic resonance imaging (MRI) and/or positron emission tomography scan who underwent epilepsy surgery at The Hospital for Sick Children (HSC) in Toronto, Canada. The records of 223 patients seen in the infantile epileptic spasms syndrome clinic were reviewed. Results: Nineteen patients met inclusion criteria. The etiology of infantile epileptic spasms syndrome was encephalomalacia in 6 patients (32%), malformations of cortical development in 12 patients (63%), and atypical hypoglycemic injury in 1 patient (5%). Nine patients (47%) underwent hemispherectomy, and 10 patients (53%) underwent lobectomy/lesionectomy. Three patients (16%) underwent a second epilepsy surgery. Fifteen patients (79%) were considered ILAE seizure outcome class 1 (completely seizure free; no auras) at their most recent follow-up visit. The percentage of patients who were ILAE class 1 at most recent follow-up decreased with increasing duration of epilepsy prior to surgery. Developmental outcome after surgery was improved in 14 of 19 (74%) and stable in 5 of 19 (26%) patients. Conclusions: Our study found excellent seizure freedom rates and improved developmental outcomes following epilepsy surgery in patients with a history of infantile epileptic spasms syndrome with a structural lesion detected on MRI brain. Patients who undergo surgery earlier have improved seizure freedom rates and improved developmental outcomes.

Connectomic Profiles and Cognitive Trajectories After Epilepsy Surgery in Children.

BACKGROUND AND OBJECTIVES: Neurocognitive outcomes after surgery for temporal lobe epilepsy in childhood are variable. Postoperative changes are not directly predicted by seizure freedom, and associations between epilepsy, neuropsychological function, and developing neural networks are poorly understood. Here, we leveraged whole-brain connectomic profiling in magnetoencephalography (MEG) to retrospectively study associations between brain connectivity and neuropsychological function in children with temporal lobe epilepsy undergoing resective surgery. METHODS: Clinical and MEG data were retrospectively analyzed for children who underwent temporal lobe epilepsy surgery at the Hospital for Sick Children from 2000 to 2021. Resting-state connectomes were constructed from neuromagnetic oscillations via the weighted-phase lag index. Using a partial least-squares (PLS) approach, we assessed multidimensional associations between patient connectomes, neuropsychological scores, and clinical covariates. Bootstrap resampling statistics were performed to assess statistical significance. RESULTS: A total of 133 medical records were reviewed, and 5 PLS analyses were performed. Each PLS analysis probed a particular neuropsychological domain and the associations between its baseline and postoperative scores and the connectomic data. In each PLS analysis, a significant latent variable was identified, representing a specific percentage of the variance in the data and relating neural networks to clinical covariates, which included changes in rote verbal memory (n = 41, p = 0.01, σ2 = 0.38), narrative/verbal memory (n = 57, p = 0.00, σ2 = 0.52), visual memory (n = 51, p = 0.00, σ2 = 0.43), working memory (n = 44, p = 0.00, σ2 = 0.52), and overall intellectual function (n = 59, p = 0.00, σ2 = 0.55). Children with more diffuse, bilateral intrinsic connectivity across several frequency bands showed lower scores on all neuropsychological assessments but demonstrated a greater propensity for gains after resective surgery. DISCUSSION: Here, we report that connectomes characterized by diffuse connectivity, reminiscent of developmentally immature networks, are associated with lower preoperative cognition and postoperative cognitive improvement. These findings provide a potential means to understand neurocognitive function in children with temporal lobe epilepsy and expected changes postoperatively.

Health Care System Costs Associated With Surgery and Medical Therapy for Children With Drug-Resistant Epilepsy in Ontario.

BACKGROUND AND OBJECTIVES: Improvement in seizure control after epilepsy surgery could lead to lower health care resource use and costs, but it is uncertain whether this could offset the high costs related to surgery. This study aimed to evaluate phase-specific and cumulative long-term health care costs of surgery compared to medical therapy in children with drug-resistant epilepsy from the health care payer perspective. METHODS: Children who were evaluated for epilepsy surgery and treated with surgery or medical therapy from 2003 to 2018 at the Hospital for Sick Children in Toronto were identified from chart review and linked to their health administrative databases in Ontario, Canada. Inverse probability of treatment weighting with stabilized weights was used to balance the baseline covariates between the 2 groups. Patients were assigned to presurgery, surgery, short-term (first 2 years), intermediate-term (2-5 years), and long-term (>5 years) postsurgery care phases on the basis of treatment trajectory. Phase-specific and cumulative long-term health care costs were evaluated. Costs were converted from Canadian to US dollars year 2018 value. RESULTS: There were 372 surgical and 258 medical patients. Costs were higher in surgical than medical patients for presurgery (3 and 39 weeks), surgery, and short-term care phase, and the attributable costs of surgery per 7 patient-days were $1,602 (95% CI $1,438-$1,785), $172 (95% CI $147-$185), $19,819 (95% CI $18,822-$20,932), and $28 (95% CI $22-$32), respectively. Costs were lower in surgical patients for intermediate- and long-term care phase, and the attributable costs were -$72 (95% CI -$124 to -$35) and -$94 (95% CI -$129 to -$63), respectively. In surgical patients, costs were highest for surgery followed by presurgery care phase, with hospitalizations accounting for the highest cost component. In medical patients, costs increased gradually from presurgery to long-term care phase. Cumulative costs were higher for surgical than medical patients in the first 7 years after surgery, but from 8 years on, costs were lower for surgical patients. DISCUSSION: This study demonstrated the long-term economic benefits of epilepsy surgery compared to medical therapy for the health care system with the use of real-world data, which would justify the high costs of surgery. The results will support future economic evaluation comparing minimally invasive treatment such as laser therapy to surgery.

Surgical outcomes in children with bottom-of-sulcus dysplasia and drug-resistant epilepsy: a retrospective cohort study.

OBJECTIVE: Bottom-of-sulcus dysplasia (BOSD) is challenging to identify radiologically. The aim of this study was to explore seizure outcomes after resective surgery or MR-guided laser interstitial thermal therapy (MRgLITT) in children with BOSD. METHODS: Children with radiologically defined BOSD who underwent resective surgery or MRgLITT, with at least 1 year of follow-up were included. Clinical, radiological, neurophysiological, and histological data were extracted from medical records. Invasive video EEG (IVEEG) was used to evaluate the ictal onset zone or motor/language mapping, wherever appropriate. Histology of MRI-visible BOSD, including the overlying and adjacent cortex, was also evaluated. RESULTS: Forty-one children with BOSD underwent surgical treatment. The lesion was initially overlooked on MRI in 20 patients (48.8%). Of 34 patients who underwent IVEEG and who had available ictal data, the ictal onset zone extended beyond the MRI-visible BOSD in 23 patients (67.6%). Surgical treatment included lesionectomy (24 patients), extended lesionectomy (12 patients), lobectomy (1 patient), and ablation of BOSD (4 patients). The pathology in 37 patients who underwent resection showed focal cortical dysplasia type IIB and type IIA in 21 (53.8%) and 16 patients (41%), respectively. Seizure freedom was achieved in 32 patients (78.1%) after a mean follow-up of 4.3 years. CONCLUSIONS: Seizure outcomes after resective surgery or MRgLITT in children with BOSD were generally favorable. The authors found that the neurophysiological abnormality and pathology often extended beyond the MRI-visible BOSD.

Supplementing Extraoperative Electrocorticography With Real-Time Intraoperative Recordings Using the Same Chronically Implanted Electrodes.

BACKGROUND: The practice of intraoperative electrocorticography (iECoG) to guide resective epilepsy surgery is variable. Limitations of iECoG include variability in recordings from previously unsampled cortex, increased operative time and cost, and a lack of clear benefit to surgical decision-making. OBJECTIVE: To describe a simple technique to supplement extraoperative intracranial recordings with real-time iECoG using the same chronically implanted electrodes that overcome some of these limitations. METHODS: We describe the technical procedure, intraoperative findings, and outcomes of 7 consecutive children undergoing 2-stage resective epilepsy surgery with invasive subdural grid monitoring between January 2017 and December 2019. All children underwent placement of subdural grids, strips, and depth electrodes. Planned neocortical resection was based on extraoperative mapping of ictal and interictal recordings. During resection in the second stage, the same electrodes were used to perform real-time iECoG. RESULTS: Real-time iECoG using this technique leads to modification of resection for 2 of the 7 children. The first was extended due to an electroencephalographic seizure from a distant electrode not part of the original resection plan. The second was restricted due to attenuation of epileptiform activity following a partial resection, thereby limiting the extent of a Rolandic resection. No infections or other adverse events were encountered. CONCLUSION: We report a simple technique to leverage chronically implanted electrodes for real-time iECoG during 2-stage resective surgery. This technique presents fewer limitations than traditional approaches and may alter intraoperative decision-making.

Brainstem Associated Somatosensory Evoked Potentials and Response to Vagus Nerve Stimulation: An Investigation of the Vagus Afferent Network.

Despite decades of clinical usage, selection of patients with drug resistant epilepsy who are most likely to benefit from vagus nerve stimulation (VNS) remains a challenge. The mechanism of action of VNS is dependent upon afferent brainstem circuitry, which comprises a critical component of the Vagus Afferent Network (VagAN). To evaluate the association between brainstem afferent circuitry and seizure response, we retrospectively collected intraoperative data from sub-cortical recordings of somatosensory evoked potentials (SSEP) in 7 children with focal drug resistant epilepsy who had failed epilepsy surgery and subsequently underwent VNS. Using multivariate linear regression, we demonstrate a robust negative association between SSEP amplitude (p < 0.01), and seizure reduction. There was no association between SSEP latency and seizure outcomes. Our findings provide novel insights into the mechanism of VNS and inform our understanding of the importance of brainstem afferent circuitry within the VagAN for seizure responsiveness following VNS.

Longitudinal changes in emotional functioning following pediatric resective epilepsy surgery: 2-Year follow-up.

OBJECTIVE: To examine longitudinal changes and predictors of depression and anxiety 2 years following resective epilepsy surgery, compared to no surgery, in children with drug-resistant epilepsy (DRE). METHOD: This multicenter cohort study involved 128 children and adolescents with DRE (48 surgical, 80 nonsurgical; 8-18 years) who completed self-report measures of depression and anxiety at baseline and follow-up (6-month, 1-year, 2-year). Child demographic (age, sex, IQ) and seizure (age at onset, duration, frequency, site and side) variables were collected. RESULTS: Linear mixed-effects models controlling for age at enrolment found a time by treatment by seizure outcome interaction for depression. A negative linear trend across time (reduction in symptoms) was found for surgical patients, irrespective of seizure outcome. In contrast, the linear trend differed depending on seizure outcome in nonsurgical patients; a negative trend was found for those with continued seizures, whereas a positive trend (increase in symptoms) was found for those who achieved seizure freedom. Only a main effect of time was found for anxiety indicating a reduction in symptoms across patient groups. Multivariate regressions failed to find baseline predictors of depression or anxiety at 2-year follow-up in surgical patients. Older age, not baseline anxiety or depression, predicted greater symptoms of anxiety and depression at 2-year follow-up in nonsurgical patients. CONCLUSION: Children with DRE reported improvement in anxiety and depression, irrespective of whether they achieve seizure control, across the 2 years following surgery. In contrast, children with DRE who did not undergo surgery, but achieved seizure freedom, reported worsening of depressive symptoms, which may indicate difficulty adjusting to life without seizures and highlight the potential need for ongoing medical and psychosocial follow-up and support.

Temporal-plus epilepsy in children: A connectomic analysis in magnetoencephalography.

OBJECTIVE: Seizure recurrence following surgery for temporal lobe (TL) epilepsy may be related to extratemporal epileptogenic foci, so-called temporal-plus (TL+) epilepsy. Here, we sought to leverage whole brain connectomic profiling in magnetoencephalography (MEG) to identify neural networks indicative of TL+ epilepsy in children. METHODS: Clinical and MEG data were analyzed for 121 children with TL and TL+ epilepsy spanning 20 years at the Hospital for Sick Children. Resting-state connectomes were derived using the weighted phase lag index from neuromagnetic oscillations. Multidimensional associations between patient connectomes, TL versus TL+ epilepsy, seizure freedom, and clinical covariates were performed using a partial least squares (PLS) analysis. Bootstrap resampling statistics were performed to assess statistical significance. RESULTS: A single significant latent variable representing 66% of the variance in the data was identified with significant contributions from extent of epilepsy (TL vs TL+), duration of illness, and underlying etiology. This component was associated with significant bitemporal and frontotemporal connectivity in the theta, alpha, and beta bands. By extracting a brain score, representative of the observed connectivity profile, patients with TL epilepsy were dissociated from those with TL+, independent of their postoperative seizure outcome. SIGNIFICANCE: By analyzing 121 connectomes derived from MEG data using a PLS approach, we find that connectomic profiling could dissociate TL from TL+ epilepsy. These findings may inform patient selection for resective procedures and guide decisions surrounding invasive monitoring.

Misleading Focal Clinical, Neurophysiologic, and Imaging Features in 2 Children With Generalized Epilepsy Who Underwent Invasive Electroencephalographic (EEG) Monitoring.

Children and adults with genetic generalized epilepsy may have focal clinical seizure symptoms as well as electroencephalographic (EEG) findings. This may pose a diagnostic challenge to clinicians, especially when concomitant focal neuroimaging findings exist and the epilepsy is medically refractory. We sought to highlight the challenges that clinicians may face through the description of 2 children with suspected genetic generalized epilepsy who had both focal seizure symptoms and EEG/neuroimaging findings and underwent invasive EEG monitoring. Ultimately, invasive monitoring failed to demonstrate a focal origin for the seizures in both cases, and instead confirmed the presence of genetic generalized epilepsy. We demonstrate that ≥3-Hz generalized monomorphic spike and waves are less likely to represent secondary bilateral synchrony, that focal neuroimaging findings may not always be causal and that repeated hyperventilation is an essential activation procedure for genetic generalized epilepsy.

Utility of depth electrode placement in the neurosurgical management of bottom-of-sulcus lesions: technical note.

OBJECTIVE: Small lesions at the depth of the sulcus, such as with bottom-of-sulcus focal cortical dysplasia, are not visible from the surface of the brain and can therefore be technically challenging to resect. In this technical note, the authors describe their method of using depth electrodes as landmarks for the subsequent resection of these exacting lesions. METHODS: A retrospective review was performed on pediatric patients who had undergone invasive electroencephalography with depth electrodes that were subsequently used as guides for resection in the period between July 2015 and June 2017. RESULTS: Ten patients (3-15 years old) met the criteria for this study. At the same time as invasive subdural grid and/or strip insertion, between 2 and 4 depth electrodes were placed using a hand-held frameless neuronavigation technique. Of the total 28 depth electrodes inserted, all were found within the targeted locations on postoperative imaging. There was 1 patient in whom an asymptomatic subarachnoid hemorrhage was demonstrated on postprocedural imaging. Depth electrodes aided in target identification in all 10 cases. CONCLUSIONS: Depth electrodes placed at the time of invasive intracranial electrode implantation can be used to help localize, target, and resect primary zones of epileptogenesis caused by bottom-of-sulcus lesions.

Thalamocortical dysrhythmia in intraoperative recordings of focal epilepsy.

Resonant interactions between the thalamus and cortex subserve a critical role for maintenance of consciousness as well as cognitive functions. In states of abnormal thalamic inhibition, thalamocortical dysrhythmia (TCD) has been described. The characteristics of TCD include a slowing of resting oscillations, ectopic high-frequency activity, and increased cross-frequency coupling. Here, we demonstrate the presence of TCD in four patients who underwent resective epilepsy surgery with chronically implanted electrodes under anesthesia, continuously recording activity from brain regions at the periphery of the epileptogenic zone before and after resection. Following resection, we report an acceleration of the large-scale network resting frequency coincident with decreases in cross-frequency phase-amplitude coupling. Interregional functional connectivity in the surrounding cortex was also increased following resection of the epileptogenic focus. These findings provide evidence for the presence of TCD in focal epilepsy and highlight the importance of reciprocal thalamocortical oscillatory interactions in defining novel biomarkers for resective surgeries. NEW & NOTEWORTHY Thalamocortical dysrhythmia (TCD) occurs in the context of thalamic dysfacilitation and is characterized by slowing of resting oscillations, ectopic high-frequency activity, and cross-frequency coupling. We provide evidence for TCD in focal epilepsy by studying electrophysiological changes occurring at the periphery of the resection margin. We report acceleration of resting activity coincident with decreased cross-frequency coupling and increased functional connectivity. The study of TCD in epilepsy has implications as a biomarker and therapeutic target.

A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

INTRODUCTION: Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 - a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life. METHODS: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives. RESULTS: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%. CONCLUSIONS: TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

Intra-operative cortical motor mapping using subdural grid electrodes in children undergoing epilepsy surgery evaluation and comparison with the conventional extra-operative motor mapping.

OBJECTIVES: The objective of this study was to review our experience with intra-operative "train of five" stimulation using subdural grid for motor mapping in children undergoing epilepsy surgery evaluation. METHODS: Twenty consecutive children below 18-years of age with drug-refractory epilepsy who underwent invasive-EEG monitoring using subdural-grid placement and intra-operative motor mapping using direct cortical stimulation by sub-dural grid electrodes (IODCS-SDG) at our institution between January-2016 and June-2017 were reviewed. Stimulation was delivered through the subdural-grid electrodes using a train-of-five pulses and muscle responses were recorded by motor-evoked-potentials (MEPs). Intra-operative direct cortical stimulation delivered through a ball-tipped probe (IODCS-probe) and extra-operative motor-mapping (EODCS-SDG) were also performed. RESULTS: IODCS-SDG was completed in 20 patients and subsequent EODCS-SDG was done in 17/20 patients. MEP responses were more commonly obtained in the deltoid (19/20), extensor-digitorum-communis (20/20) and first-dorsal-interosseus (19/20). The median thresholds varied between 40 V and 60 V for the six muscle groups. The respective IODCS-probe thresholds tended to be similar. No stimulation-provoked seizures or anaesthesia-related complications were noted during IODCS-SDG. EODCS-SDG could not be completed in 4/17 children and mapping data obtained was frequently inadequate. Nine patients demonstrated 100% concordance between IODCS-SDG and EODCS-SDG for the common mapped body regions. Stimulation-provoked seizures during EODCS-SDG were seen in 6/17 (35.3%) and after-discharges in 7/17 (41.2%) children. CONCLUSIONS: IODCS-SDG could be performed safely in children with drug refractory epilepsy undergoing invasive EEG monitoring. SIGNIFICANCE: IODCS-SDG may be a useful adjunct to EODCS-SDG in motor mapping for children.

Strong coupling between slow oscillations and wide fast ripples in children with epileptic spasms: Investigation of modulation index and occurrence rate.

OBJECTIVE: Epileptic spasms (ES) often become drug-resistant. To reveal the electrophysiological difference between children with ES (ES+) and without ES (ES-), we compared the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI) of coupling between slow and fast oscillations. In ES+, we hypothesized that (1) pathological HFOs are more widely distributed and (2) slow oscillations show stronger coupling with pathological HFOs than in ES-. METHODS: We retrospectively reviewed 24 children with drug-resistant multilobar onset epilepsy, who underwent intracranial video electroencephalography prior to multilobar resections. We measured the OR of HFOs and determined the electrodes with a high rate of HFOs by cluster analysis. We calculated MI, which reflects the degree of coupling between HFO (ripple/fast ripple [FR]) amplitude and 5 different frequency bands of delta and theta activities (0.5-1 Hz, 1-2 Hz, 2-3 Hz, 3-4 Hz, 4-8 Hz). RESULTS: In ES+ (n = 10), the OR(FRs) , the number of electrodes with high-rate FRs, and the MI(FRs & 3-4 Hz) in all electrodes were significantly higher than in ES- (n = 14). In both the ES+ and ES- groups, MI(ripples/FRs & 3-4 Hz) was the highest among the 5 frequency bands. Within the good seizure outcome group, the OR(FRs) and the MI(FRs & 3-4 Hz) in the resected area in ES+ were significantly higher than in ES- (OR[FRs] , P = .04; MI[FRs & 3-4 Hz] , P = .04). SIGNIFICANCE: In ES+, the larger number of high-rate FR electrodes indicates more widespread epileptogenicity than in ES-. High values of OR(FRs) and MI(FRs & 3-4 Hz) in ES+ compared to ES- are a signature of the severity of epileptogenicity. We proved that ES+ children who achieved seizure freedom following multilobar resections exhibited strong coupling between slow oscillations and FRs.

Reoperation after failed resective epilepsy surgery in children.

OBJECTIVE Although epilepsy surgery is an effective treatment option, at least 20%-40% of patients can continue to experience uncontrolled seizures resulting from incomplete resection of the lesion, epileptogenic zone, or secondary epileptogenesis. Reoperation could eliminate or improve seizures. Authors of this study evaluated outcomes following reoperation in a pediatric population. METHODS A retrospective single-center analysis of all patients who had undergone resective epilepsy surgery in the period from 2001 to 2013 was performed. After excluding children who had repeat hemispherotomy, there were 24 children who had undergone a second surgery and 2 children who had undergone a third surgery. All patients underwent MRI and video electroencephalography (VEEG) and 21 underwent magnetoencephalography (MEG) prior to reoperation. RESULTS The mean age at the first and second surgery was 7.66 (SD 4.11) and 10.67 (SD 4.02) years, respectively. The time between operations ranged from 0.03 to 9 years. At reoperation, 8 patients underwent extended cortical resection; 8, lobectomy; 5, lesionectomy; and 3, functional hemispherotomy. One year after reoperation, 58% of the children were completely seizure free (International League Against Epilepsy [ILAE] Class 1) and 75% had a reduction in seizures (ILAE Classes 1-4). Patients with MEG clustered dipoles were more likely to be seizure free than to have persistent seizures (71% vs 40%, p = 0.08). CONCLUSIONS Reoperation in children with recurrent seizures after the first epilepsy surgery could result in favorable seizure outcomes. Those with residual lesion after the first surgery should undergo complete resection of the lesion to improve seizure outcome. In addition to MRI and VEEG, MEG should be considered as part of the reevaluation prior to reoperation.

Epileptogenic high-frequency oscillations skip the motor area in children with multilobar drug-resistant epilepsy.

OBJECTIVE: Subtotal hemispherectomy involves the resection of multiple lobes in children with drug-resistant epilepsy, skipping the motor area (MA). We determined epileptogenicity using the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI), demonstrating strength of coupling between HFO and slow wave. We hypothesized that epileptogenicity increased over the multiple lobes but skipped the MA. METHODS: We analyzed 23 children (14 subtotal hemispherectomy; 9 multilobar resections). Scalp video-EEG and magnetoencephalography were performed before surgery. We analyzed the OR(HFO) and MI(5 phases=0.5-8 Hz) on electrodes of total area, resection areas, and MA. We compared the data between good [International League Against Epilepsy (ILAE) class I-II] and poor (III-VI) seizure outcome groups. RESULTS: ILAE class Ia outcome was achieved in 18 children. Among the MI(5 phases) in the resection areas, MI(3-4 Hz) was the highest. The OR(HFO) and MI(3-4 Hz) in both total area and resection areas were significantly higher in the good seizure outcome group than in the poor outcome group. The OR(HFO) and MI(3-4 Hz) in resection areas were significantly higher than in the MA. CONCLUSIONS: Our patients with multilobar drug-resistant epilepsy showed evidence of multifocal epileptogenicity that specifically skipped the MA. SIGNIFICANCE: This is the first study demonstrating that the electrophysiological phenotype of multifocal epilepsy specifically skips the MA using OR(HFO) and MI(3-4 Hz).