Determinants of successful ictal SPECT injection in phase 1 epilepsy presurgical evaluation: Findings from the pediatric epilepsy research consortium surgery database project.

OBJECTIVES: The main goal of presurgical evaluation in drug-resistant focal epilepsy is to identify a seizure onset zone (SOZ). Of the noninvasive, yet resource-intensive tests available, ictal single-photon emission computed tomography (SPECT) aids SOZ localization by measuring focal increases in blood flow within the SOZ via intravenous peri-ictal radionuclide administration. Recent studies indicate that geographic and center-specific factors impact utilization of these diagnostic procedures. Our study analyzed successful ictal SPECT acquisition (defined as peri-ictal injection during inpatient admission) using surgery-related data from the Pediatric Epilepsy Research Consortium (PERC) surgery database. We hypothesized that a high seizure burden, longer duration of video EEG monitoring (VEEG), and more center-specific hours of SPECT availability would increase the likelihood of successful ictal SPECT. METHODS: We identified study participants (≤18 years of age) who underwent SPECT as part of their phase 1 VEEG from January 2018 to June 2022. We assessed association between ictal SPECT outcomes (success vs. failure) and variables including patient demographics, epilepsy history, and center-specific SPECT practices. RESULTS: Phase 1 VEEG monitoring with ictal SPECT injection was planned in 297 participants and successful in 255 participants (85.86%). On multivariable analysis, the likelihood of a successful SPECT injection was higher in patients of non-Hispanic ethnicity (p = 0.040), shorter duration VEEG (p = 0.004), and higher hours of available SPECT services (p < 0.001). Higher seizure frequency (p = 0.033) was significant only in bivariate analysis. Patients treated at centers with more operational hours were more likely to experience pre-admission protocols prior to VEEG (p = 0.002). SIGNIFICANCE: There is inter-center variability in protocols and SPECT acquisition capabilities. Shorter duration of EEG monitoring, non-Hispanic ethnicity (when on private insurance), extended operational hours of nuclear medicine as noted on multivariate analysis and higher seizure frequency in bivariate analysis are strongly associated with successful ictal SPECT injection. PLAIN LANGUAGE SUMMARY: In pediatric patients with drug-resistant epilepsy, single-photon emission computed tomography (SPECT) scans can be helpful in localizing seizure onset zone. However, due to many logistical challenges described below, which include not only the half-life of the technetium isotope used to inject intravenously during a seizure (called the ictal SPECT scan) but also available nuclear scanner time in addition to the unpredictability of seizures, obtaining an ictal SPECT during a planned elective inpatient hospital stay is not guaranteed. Thus, as healthcare costs increase, planning a prolonged hospital stay during which an ictal SPECT scan is not feasible is not optimal. We leveraged our prospective surgery database to look at center-specific factors and patient-specific factors associated with an ictal SPECT injection in the first, pediatric-focussed, large-scale, multicenter, prospective, SPECT feasibility study. We found that longer availability of the scanner is the most important center-specific factor in assuring ictal SPECT injection. Although seizure frequency is an important patient-specific factor on bivariate analysis, this factor lost statistical significance when other factors like patient insurance status and video EEG duration were also considered in our multivariable logistical model.

Pediatric neuromodulation for drug-resistant epilepsy: Survey of current practices, techniques, and outcomes across US epilepsy centers.

Neuromodulation via Responsive Neurostimulation (RNS) or Deep Brain Stimulation (DBS) is an emerging treatment strategy for pediatric drug-resistant epilepsy (DRE). Knowledge gaps exist in patient selection, surgical technique, and perioperative care. Here, we use an expert survey to clarify practices. Thirty-two members of the Pediatric Epilepsy Research Consortium were surveyed using REDCap. Respondents were from 17 pediatric epilepsy centers (missing data in one): Four centers implant RNS only while 13 implant both RNS and DBS. Thirteen RNS programs commenced in or before 2020, and 10 of 12 DBS programs began thereafter. The busiest six centers implant 6-10 new RNS devices per year; all DBS programs implant <5 annually. The youngest RNS patient was 3 years old. Most centers (11/12) utilize MP2RAGE and/or FGATIR sequences for planning. Centromedian thalamic nuclei were the unanimous target for Lennox-Gastaut syndrome. Surgeon exposure to neuromodulation occurred mostly in clinical practice (14/17). Clinically significant hemorrhage (n = 2) or infection (n = 3) were rare. Meaningful seizure reduction (>50%) was reported by 81% (13/16) of centers. RNS and DBS are rapidly evolving treatment modalities for safe and effective treatment of pediatric DRE. There is increasing interest in multicenter collaboration to gain knowledge and facilitate dialogue. PLAIN LANGUAGE SUMMARY: We surveyed 32 pediatric epilepsy centers in USA to highlight current practices of intracranial neuromodulation. Of the 17 that replied, we found that most centers are implanting thalamic targets in pediatric drug-resistant epilepsy using the RNS device. DBS device is starting to be used in pediatric epilepsy, especially after 2020. Different strategies for target identification are enumerated. This study serves as a starting point for future collaborative research.

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

BACKGROUND: Epilepsy 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. METHODS: The 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. RESULTS: Six 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. CONCLUSIONS: Patients 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.

Expansion of the neurodevelopmental phenotype of individuals with EEF1A2 variants and genotype-phenotype study.

Translation elongation factor eEF1A2 constitutes the alpha subunit of the elongation factor-1 complex, responsible for the enzymatic binding of aminoacyl-tRNA to the ribosome. Since 2012, 21 pathogenic missense variants affecting EEF1A2 have been described in 42 individuals with a severe neurodevelopmental phenotype including epileptic encephalopathy and moderate to profound intellectual disability (ID), with neurological regression in some patients. Through international collaborative call, we collected 26 patients with EEF1A2 variants and compared them to the literature. Our cohort shows a significantly milder phenotype. 83% of the patients are walking (vs. 29% in the literature), and 84% of the patients have language skills (vs. 15%). Three of our patients do not have ID. Epilepsy is present in 63% (vs. 93%). Neurological examination shows a less severe phenotype with significantly less hypotonia (58% vs. 96%), and pyramidal signs (24% vs. 68%). Cognitive regression was noted in 4% (vs. 56% in the literature). Among individuals over 10 years, 56% disclosed neurocognitive regression, with a mean age of onset at 2 years. We describe 8 novel missense variants of EEF1A2. Modeling of the different amino-acid sites shows that the variants associated with a severe phenotype, and the majority of those associated with a moderate phenotype, cluster within the switch II region of the protein and thus may affect GTP exchange. In contrast, variants associated with milder phenotypes may impact secondary functions such as actin binding. We report the largest cohort of individuals with EEF1A2 variants thus far, allowing us to expand the phenotype spectrum and reveal genotype-phenotype correlations.

Epilepsy surgery in children with genetic etiologies: A prospective evaluation of current practices and outcomes.

OBJECTIVE: This study assesses current practices and outcomes of epilepsy surgery in children with a genetic etiology. It explores the pre-surgical workup, types of surgeries, and post-surgical outcomes in a broad array of disorders. METHODS: Patients ≤18 years who completed epilepsy surgery and had a known genetic etiology prior to surgical intervention were extrapolated from the Pediatric Epilepsy Research Consortium (PERC) surgery database, across 18 US centers. Data were assessed univariably by neuroimaging and EEG results, genetic group (structural gene, other gene, chromosomal), and curative intent. Outcomes were based on a modified International League Against Epilepsy (ILAE) outcome score. RESULTS: Of 81 children with genetic epilepsy, 72 % had daily seizures when referred for surgery evaluation, which occurred a median of 2.2 years (IQR 0.3, 5.2) after developing drug resistance. Following surgery, 68 % of subjects had >50 % seizure reduction, with 33 % achieving seizure freedom [median follow-up 11 months (IQR 6, 17). Seizure freedom was most common in the monogenic structural group, but significant palliation was present across all groups. Presence of a single EEG focus was associated with a greater likelihood of seizure freedom (p=0.02). SIGNIFICANCE: There are meaningful seizure reductions following epilepsy surgery in the majority of children with a genetic etiology, even in the absence of a single structural lesion and across a broad spectrum of genetic causes. These findings highlight the need for expedited referral for epilepsy surgery and support of a broadened view of which children may benefit from epilepsy surgery, even when the intent is palliative.