Pediatric Drug-resistant Epilepsy Research Articles

P.042 Safety and efficacy of stereoelectroencephalography in pediatric epilepsy surgery

Background: There are few published reports on the safety and efficacy of stereoelectroencephalography (SEEG) in the presurgical evaluation of pediatric drug-resistant epilepsy. Our objective was to describe institutional experience with pediatric SEEG in terms of (1) insertional complications, (2) identification of the epileptogenic zone and (3) seizure outcome following SEEG-tailored resections. Methods: Retrospective review of 29 patients pediatric drug resistant epilepsy patients who underwent presurgical SEEG between 2005 – 2018. Results: 29 pediatric SEEG patients (15 male; 12.4 ± 4.6 years old) were included in this study with mean follow-up of 6.0 ± 4.1 years. SEEG-related complications occurred in 1/29 (3%)—neurogenic pulmonary edema. A total of 190 multi-contact electrodes (mean of 7.0 ± 2.5per patient) were implanted across 30 insertions which captured 437 electrographic seizures (mean 17.5 ± 27.6 per patient). The most common rationale for SEEG was normal MRI with surface EEG that failed to identify the EZ (16/29; 55%). SEEG-tailored resections were performed in 24/29 (83%). Engel I outcome was achieved following resections in 19/24 cases (79%) with 5.9 ± 4.0 years of post-operative follow-up. Conclusions: Stereoelectroencephalography in presurgical evaluation of pediatric drug-resistant epilepsy is a safe and effective way to identify the epileptogenic zone permitting SEEG-tailored resection.

Cost-effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic review of economic evaluations

BackgroundDrug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem.MethodsWe will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation.DiscussionDrug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area.Systematic review registrationPROSPERO no.: CRD42018099591.

Next-generation sequencing improves treatment efficacy and reduces hospitalization in children with drug-resistant epilepsy.

The purposes of this study were three-fold: (i) to determine the contribution of known genes to the causation of a broad-spectrum of pediatric drug-resistant epilepsy (DRE), (ii) to compare the diagnostic yield and cost among different next-generation sequencing (NGS) approaches, and especially (iii) to assess how NGS approaches can benefit patients by improving diagnosis and treatment efficiency. This study enrolled 273 pediatric DRE patients with no obvious acquired etiology. Seventy-four patients underwent whole-exome sequencing (WES), 141 patients had epilepsy-related gene panel testing, and another 58 patients had clinical WES gene panel testing. We obtained these patients' seizure and hospitalization frequency by periodic follow-up phone calls and outpatient visits. Genetic diagnosis was achieved in 86 patients (31.5%) and involved 93 likely disease-causing mutations in 33 genes. In this study, the detection rates of the epilepsy-related gene panel, the clinical WES gene panel, and WES were 32.6% (46/141), 44.8% (26/58), and 17.3% (13/74), respectively. Moreover, 34 patients accepted corrective therapy according to their mutant genes, after which 52.9% (18/34) became seizure-free and 38.2% (13/34) achieved seizure reduction. In the end, patients with either positive or negative genetic results had significantly fewer hospitalization incidents (times/half year) than before (positive genetic results group 0.58±1.14 vs 0.10±0.26; negative genetic results group 0.72±1.65 vs 0.12±0.33). These results offer further proof that NGS approaches represent powerful tools for establishing a definitive diagnosis. Moreover, this study indicated how NGS can improve treatment efficacy and reduce hospitalization in children with DRE.

S13-1. Drug-resistant epilepsy due to glial abnormality

In children, cortical resections in epilepsy surgery tend to involve multiple lobes, compared to adults, partly due to underlying pathology. We reported two types of histopathological abnormalities in glial cells in children who underwent epilepsy surgery for drug-resistant epilepsy. Oligodendroglia-like cells (OLC) can recruit multiple-lobe epileptogenic zones in pediatric drug-resistant focal epilepsy. Increased OLC presented with non-focal epileptiform discharges on scalp EEG and epileptic spasms (ES), and required multiple-lobe resections. We found increased populations of subcortical OLC in the extensive epileptogenic zone. The presence of cerebral astrocytic inclusions, called filaminopathy, recently has been described in a subset of children with early-onset drug-resistant epilepsy, with or without structural brain malformations and varying degrees of developmental delay. They often provoked cluster of ES from the beginning of seizure history. Functional hemispherectomy may be required for seizure control in a subset of children with filaminopathy.

Electrocorticographic high-gamma modulation with passive listening paradigm for pediatric extraoperative language mapping.

This prospective study compared the topography of high-gamma modulation (HGM) during a story-listening task requiring negligible patient cooperation, with the conventional electrical stimulation mapping (ESM) using a picture-naming task, for presurgical language localization in pediatric drug-resistant epilepsy. Patients undergoing extraoperative monitoring with subdural electrodes were included. Electrocorticographic signals were recorded during quiet baseline and a story-listening task. The likelihood of 70- to 150-Hz power modulation during the listening task relative to the baseline was estimated for each electrode and plotted on a cortical surface model. Sensitivity, specificity, accuracy, and diagnostic odds ratio (DOR) were estimated compared to ESM, using a meta-analytic framework. Nineteen patients (10 with left hemisphere electrodes) aged 4-19 years were analyzed. HGM during story listening was observed in bilateral posterior superior temporal, angular, supramarginal, and inferior frontal gyri, along with anatomically defined language association areas. Compared to either cognitive or both cognitive and orofacial sensorimotor interference with naming during ESM, left hemisphere HGM showed high specificity (0.82-0.84), good accuracy (0.66-0.70), and DOR of 2.23 and 3.24, respectively. HGM was a better classifier of ESM language sites in the left temporoparietal cortex compared to the frontal lobe. Incorporating visual naming with the story-listening task substantially improved the accuracy (0.80) and DOR (13.61) of HGM mapping, while the high specificity (0.85) was retained. In the right hemisphere, no ESM sites for aphasia were seen, and the results of HGM and ESM comparisons were not significant. HGM associated with story listening is a specific determinant of left hemisphere ESM language sites. It can be used for presurgical language mapping in children who cannot cooperate with conventional language tasks requiring active engagement. Incorporation of additional language tasks, if feasible, can further improve the diagnostic accuracy of language localization with HGM.

Responsive neurostimulation for treatment of pediatric drug-resistant epilepsy

Responsive neurostimulation for epilepsy involves an implanted device that delivers direct electrical brain stimulation in response to detection of incipient seizures. Responsive neurostimulation is a safe and effective treatment for adults with drug-resistant epilepsy, but although novel treatments are critically needed for younger patients, responsive neurostimulation is currently not approved for children with drug-resistant epilepsy. Here, we report a 16-year-old patient with seizures arising from eloquent cortex, who was successfully treated with responsive neurostimulation. This case highlights the potential utility of this therapy for pediatric patients and underscores the need for larger studies.

Presurgical language localization with visual naming associated ECoG high- gamma modulation in pediatric drug-resistant epilepsy.

This prospective study compared presurgical language localization with visual naming-associated high-γ modulation (HGM) and conventional electrical cortical stimulation (ECS) in children with intracranial electrodes. Patients with drug-resistant epilepsy who were undergoing intracranial monitoring were included if able to name pictures. Electrocorticography (ECoG) signals were recorded during picture naming (overt and covert) and quiet baseline. For each electrode the likelihood of high-γ (70-116Hz) power modulation during naming task relative to the baseline was estimated. Electrodes with significant HGM were plotted on a three-dimensional (3D) cortical surface model. Sensitivity, specificity, and accuracy were calculated compared to clinical ECS. Seventeen patients with mean age of 11.3years (range 4-19) were included. In patients with left hemisphere electrodes (n=10), HGM during overt naming showed high specificity (0.81, 95% confidence interval [CI] 0.78-0.85), and accuracy (0.71, 95% CI 0.66-0.75, p<0.001), but modest sensitivity (0.47) when ECS interference with naming (aphasia or paraphasic errors) and/or oral motor function was regarded as the gold standard. Similar results were reproduced by comparing covert naming-associated HGM with ECS naming sites. With right hemisphere electrodes (n=7), no ECS-naming deficits were seen without interference with oral-motor function. HGM mapping showed a high specificity (0.81, 95% CI 0.78-0.84), and accuracy (0.76, 95% CI 0.71-0.81, p=0.006), but modest sensitivity (0.44) compared to ECS interference with oral-motor function. Naming-associated ECoG HGM was consistently observed over Broca's area (left posterior inferior-frontal gyrus), bilateral oral/facial motor cortex, and sometimes over the temporal pole. This study supports the use of ECoG HGM mapping in children in whom adverse events preclude ECS, or as a screening method to prioritize electrodes for ECS testing.

The Effect of Melatonin on Pediatric Drug-Resistant Epilepsy; a Randomized Double Blind Clinical Trial

BackgroundAbout 15 to 40% of children with seizures are refractory to standard anti-epileptic drugs and for such patients, other treatments such as surgery and the ketogenic diet can reduce seizure frequency. Melatonin is a natural pineal gland hormone. The use of melatonin for controlling pediatric seizures is still controversial. This study aimed to evaluate the effect of melatonin on seizures, parent's satisfaction, sleep, and behavior in children with drug-resistant epilepsy.Materials and Methods: In a pilot crossover study, children with drug-resistant epilepsy, who referred to the epileptic clinic of Ghaem Hospital, were randomly assigned to receive treatment with melatonin or a placebo for 4 weeks followed by a one-day washout period. Then patients who started with melatonin were switched to the placebo. Melatonin was administered 30 minutes before bedtime at a dose of 10 mg /m2 in 3mg tablets.ResultsTwenty patients, of which 11 (55%) were male, were enrolled into the study. The range and mean age of patients were 2 to 13 years and 7.28 ± 3.46 years, respectively. The mean number of diurnal seizures in the study group during placebo treatment was 11.05 and during melatonin treatment was 6.25, which was statistically significant (P=0.021). However, the reduction of the mean duration of diurnal seizures in the study groups was not statistically significant (P=0.386). There was no correlation between decreasing in number or duration of seizures with melatonin plasma levels. Drowsiness was the only side effect of melatonin, which occurred in three patients. ConclusionMelatonin has probable beneficial effects on some epileptic patients with unclear mechanisms. Physicians can use it in selected epileptic children to improve seizures.

Resection of ictal high frequency oscillations is associated with favorable surgical outcome in pediatric drug resistant epilepsy secondary to tuberous sclerosis complex

Resective epilepsy surgery can improve seizures when the epileptogenic zone (EZ) is limited to a well-defined region. High frequency oscillations (HFO) have been recognized as having a high association with the seizure onset zone. Therefore, we retrospectively identified ictal HFOs and determined their relationship to specific intracranial features of cortical tubers in children with TSC who underwent resective surgery. We identified 14 patients with drug resistant epilepsy secondary to TSC who underwent subdural grid and strip implantation for presurgical evaluation and subsequent resection with adequate post-surgical follow-up. We aimed to determine the relationship between ictal HFOs, post-resection outcome and neuroimaging features in this population.The largest tuber was identified in all 14 patients (100%). Four patients (29%) had unusual tubers. HFOs were observed at ictal onset in all 14 patients. Seven of 10 patients with complete resection of HFOs were seizure free. The better seizure outcome (ILAE=1–3) was achieved with complete HFO resection regardless of the unique TSC structural features (p=0.0140).Our study demonstrates the presence of ripple and fast ripple range HFOs at ictal onset in children with TSC. Our study showed that complete HFO resection led to the better surgical outcome, independent of MR imaging findings.

Emerging surgical therapies in the treatment of pediatric epilepsy

In the approximately 1% of children affected by epilepsy, pharmacoresistance and early age of seizure onset are strongly correlated with poor cognitive outcomes, depression, anxiety, developmental delay, and impaired activities of daily living. These children often require multiple surgical procedures, including invasive diagnostic procedures with intracranial electrodes to identify the seizure-onset zone. The recent development of minimally invasive surgical techniques, including stereotactic electroencephalography (SEEG) and MRI-guided laser interstitial thermal therapy (MRgLITT), and new applications of neurostimulation, such as responsive neurostimulation (RNS), are quickly changing the landscape of the surgical management of pediatric epilepsy. In this review, the authors discuss these various technologies, their current applications, and limitations in the treatment of pediatric drug-resistant epilepsy, as well as areas for future research. The development of minimally invasive diagnostic and ablative surgical techniques together with new paradigms in neurostimulation hold vast potential to improve the efficacy and reduce the morbidity of the surgical management of children with drug-resistant epilepsy.

Clinical utility of genetic testing in pediatric drug-resistant epilepsy: A pilot study

RationaleThe utility of genetic testing in pediatric drug-resistant epilepsy (PDRE), its yield in “real life” clinical practice, and the practical implications of such testing are yet to be determined. GoalTo start to address the above gaps in our knowledge as they apply to a patient population seen in a tertiary care center. MethodsWe retrospectively reviewed our experience with the use of clinically available genetic tests in the diagnosis and management of PDRE in one clinic over one year. Genetic testing included, depending on clinical judgment, one or more of the following: karyotype, chromosomal microarray, single gene sequencing, gene sequencing panels, and/or whole exome sequencing (WES). ResultsWe were more likely to perform genetic testing in patients with developmental delay, epileptic encephalopathy, and generalized epilepsy. In our unique population, the yield of specific genetic diagnosis was relatively high: karyotype 14.3%, microarray 16.7%, targeted single gene sequencing 15.4%, gene panels 46.2%, and WES 16.7%. Overall yield of diagnosis from at least one of the above tests was 34.5%. Disease-causing mutations that were not clinically suspected based on the patients' phenotypes and representing novel phenotypes were found in 6.9% (2/29), with an additional 17.2% (5/29) demonstrating pharmacologic variants. Three patients were incidentally found to be carriers of recessive neurologic diseases (10.3%). Variants of unknown significance (VUSs) were identified in 34.5% (10/29). ConclusionsWe conclude that genetic testing had at least some utility in our patient population of PDRE, that future similar larger studies in various populations are warranted, and that clinics offering such tests must be prepared to address the complicated questions raised by the results of such testing.