Using design thinking to strengthen the community pharmacist's role in epilepsy care.

OBJECTIVE: To use design thinking to develop a community pharmacist-led intervention for people living with epilepsy (PWE) with desirable, feasible, and viable features. METHODS: This study used design thinking. Three patient personas were created based on previous research: a newly diagnosed PWE, a well-controlled PWE, and a complex PWE with uncontrolled seizures. An intervention prototype was developed for each of the three personas. Structured interviews were conducted with pharmacists, pharmacy students, patients with diagnosed epilepsy, and caregivers to elicit feedback on which features of each intervention prototype were desirable, feasible, and viable. Interviews were analyzed using rapid content analysis. A multidisciplinary advisory group and the research team prioritized features of the prototypes to include in the final intervention. RESULTS: The following four features were identified as desirable, feasible, and viable for a pharmacist-led intervention for PWE: (1) pharmacist-patient consultations, (2) care plan development, (3) regular check-ins, and (4) care coordination with other health care providers. SIGNIFICANCE: This study identified evidence-based features for a community pharmacist intervention to support epilepsy care using design thinking. A pilot study to evaluate this intervention on the quality of life (QoL), health outcomes and satisfaction of PWE can inform the implementation and feasibility of such patient services.

Community Pharmacist-Centered training program improves confidence in delivering epilepsy care.

RATIONALE: Incorporating pharmacists into interdisciplinary healthcare teams can improve patient outcomes across disease states; however, there is little evidence describing pharmacists' contributions to epilepsy care. Previous research from our group revealed that community pharmacists are well positioned to serve as patient advocates, monitor medications, and provide education for people living with epilepsy. However, pharmacists would like to receive additional training in epilepsy management. Advanced training in neurology is not a practical approach for community pharmacists who engage daily with patients having a variety of conditions and medications. OBJECTIVE: To develop and evaluate a flexible, community pharmacist-centered training program to improve both confidence and competence in delivering epilepsy care. METHODS: The training program consisted of five 1-hour, self-paced online modules and two 90-minute synchronous virtual sessions. Topics included the classification of the epilepsies, comorbid conditions, antiseizure medicine (ASM) therapy, special populations (pregnancy, people of childbearing potential, older adults), seizure emergencies, and sudden unexpected death in epilepsy (SUDEP), as well as social determinants of health. The training program was delivered over 6 weeks to pharmacists located at two community pharmacies in Washington State. Learning was assessed using a pre- and post-training questionnaire containing questions that evaluated knowledge and confidence in the training material. RESULTS: The training program did not significantly change pharmacists' mastery of the material. However, the pharmacists' confidence in delivering the material significantly improved in 14 of the 16 areas that were evaluated. Pharmacists' mastery and confidence were strongest in areas around ASM management, SUDEP and seizure emergencies, people of child-bearing potential and older adults with epilepsy, and comorbidities, whereas social health disparities in epilepsy care remained an area that required further training. CONCLUSION: Our findings support the idea that community pharmacists are well positioned with the knowledge to play an important role in epilepsy care. However, dedicated training tailored to community pharmacists' needs may improve their confidence in providing such care.

A clinically applicable functional MRI memory paradigm for use with pediatric patients.

OBJECTIVE: Clinically employable functional MRI (fMRI) memory paradigms are not yet established for pediatric patient epilepsy surgery workups. Seeking to establish such a paradigm, we evaluated the effectiveness of memory fMRI tasks we developed by quantifying individual activation in a clinical pediatric setting, analyzing patterns of activation relative to the side of temporal lobe (TL) pathology, and comparing fMRI and Wada test results. METHODS: We retrospectively identified 72 patients aged 6.7-20.9 years with pathology (seizure focus and/or tumor) limited to the TL who had attempted memory and language fMRI tasks over a 9-year period as part of presurgical workups. Memory fMRI tasks required visualization of autobiographical memories in a block design alternating with covert counting. Language fMRI protocols involved verb and sentence generation. Scans were both qualitatively interpreted and quantitatively assessed for blood oxygenation level dependent (BOLD) signal change using region of interest (ROI) masks. We calculated the percentage of successfully scanned individual cases, compared 2 memory task activation masks in cases with left versus right TL pathology, and compared fMRI with Wada tests when available. Patients who had viable fMRI and Wada tests had generally concordant results. RESULTS: Of the 72 cases, 60 (83%), aged 7.6-20.9 years, successfully performed the memory fMRI tasks and 12 (17%) failed. Eleven of 12 unsuccessful scans were due to motion and/or inability to perform the tasks, and the success of a twelfth was indeterminate due to orthodontic metal artifact. Seven of the successful 60 cases had distorted anatomy that precluded employing predetermined masks for quantitative analysis. Successful fMRI memory studies showed bilateral mesial temporal activation and quantitatively demonstrated: (1) left activation (L-ACT) less than right activation (R-ACT) in cases with left temporal lobe (L-TL) pathology, (2) nonsignificant R-ACT less than L-ACT in cases with right temporal lobe (R-TL) pathology, and (3) lower L-ACT plus R-ACT activation for cases with L-TL versus R-TL pathology. Patients who had viable fMRI and Wada tests had generally concordant results. SIGNIFICANCE: This study demonstrates evidence of an fMRI memory task paradigm that elicits reliable activation at the individual level and can generally be accomplished in clinically involved pediatric patients. This autobiographical memory paradigm showed activation in mesial TL structures, and cases with left compared to right TL pathology showed differences in activation consistent with extant literature in TL epilepsy. Further studies will be required to assess outcome prediction.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

OBJECTIVE: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). METHODS: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM. RESULTS: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. SIGNIFICANCE: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.

Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study.

OBJECTIVES: To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients. DESIGN: Retrospective cohort study with prospectively collected data between June 2011 and January 2019. SETTING: Seventeen academic hospitals in the United States. PATIENTS: We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments. CONCLUSIONS: Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus.

Structural MRI and tract-based spatial statistical analysis of diffusion tensor imaging in children with hemimegalencephaly.

PURPOSE: To investigate the gross white matter abnormalities in the structural brain MR imaging as well as white matter microstructural alterations using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in both affected and contralateral cerebral hemispheres of children with hemimegalencephaly (HMEG). METHODS: From 2003 to 2019, we retrospectively reviewed brain MR images in 20 children (11 boys, 2 days-16.5 years) with HMEG, focusing on gross white matter abnormalities. DTI was evaluated in 12 patients (8 boys, 3 months-16.5 years) with HMEG and 12 age-, sex-, and magnetic field strength-matched control subjects. TBSS analysis was performed to analyze main white matter tracts. Regions of significant differences in fractional anisotropy (FA) were determined between HMEG and control subjects and between affected and contralateral hemispheres of HMEG. RESULTS: Gross white matter abnormalities were noted in both affected (n = 20, 100%) and contralateral hemisphere (n = 4, 20%) of HMEG. FA values were significantly decreased in both hemispheres of HMEG, compared with control subjects (P < 0.05). Contralateral hemispheres of HMEG showed regions with significantly decreased FA values compared with affected hemispheres (P < 0.05). CONCLUSIONS: In addition to gross white matter abnormalities particularly evident in affected hemispheres, DTI analysis detected widespread microstructural alterations in both affected and contralateral hemispheres in HMEG suggesting HMEG may involve broader abnormalities in neuronal networks.

Awake Mapping of the Auditory Cortex during Tumor Resection in an Aspiring Musical Performer: A Case Report.

INTRODUCTION: Preoperative functional MRI (fMRI) and intraoperative awake cortical mapping are established strategies to identify and preserve critical language structures during neurosurgery. There is growing appreciation for the need to similarly identify and preserve eloquent tissue critical for music production. CASE REPORT: A 19-year-old female musician, with a 3- to 4-year history of events concerning for musicogenic seizures, was found to have a right posterior temporal tumor, concerning for a low-grade glial neoplasm. Preoperative fMRI assessing passive and active musical tasks localized areas of activation directly adjacent to the tumor margin. Cortical stimulation during various musical tasks did not identify eloquent tissue near the surgical site. A gross total tumor resection was achieved without disruption of singing ability. At 9-month follow-up, the patient continued to have preserved musical ability with full resolution of seizures and without evidence of residual lesion or recurrence. CONCLUSION: A novel strategy for performing an awake craniotomy, incorporating preoperative fMRI data for music processing with intraoperative cortical stimulation, interpreted with the assistance of a musician expert and facilitated gross total resection of the patient's tumor without comprising her musical abilities.

Stereotactic laser ablation for hypothalamic and deep intraventricular lesions.

OBJECTIVE Laser ablation is a novel, minimally invasive procedure that utilizes MRI-guided thermal energy to treat epileptogenic and other brain lesions. In addition to treatment of mesial temporal lobe epilepsy, laser ablation is increasingly being used to target deep or inoperable lesions, including hypothalamic hamartoma (HH), subependymal giant cell astrocytoma (SEGA), and exophytic intrinsic hypothalamic/third ventricular tumors. The authors reviewed their early institutional experience with these patients to characterize clinical outcomes in patients undergoing this procedure. METHODS A retrospective cohort (n = 12) of patients undergoing laser ablation at a single institution was identified, and clinical and radiographic records were reviewed. RESULTS Laser ablation was successfully performed in all patients. No permanent neurological or endocrine complications occurred; 2 (17%) patients developed acute obstructive hydrocephalus or shunt malfunction following treatment. Laser ablation of HH resulted in seizure freedom (Engel Class I) in 67%, with the remaining patients having a clinically significant reduction in seizure frequency of greater than 90% compared with preoperative baseline (Engel Class IIB). Treatment of SEGAs resulted in durable clinical and radiographic tumor control in 2 of 3 cases, with one patient receiving adjuvant everolimus and the other receiving no additional therapy. Palliative ablation of hypothalamic/third ventricular tumors resulted in partial tumor control in 1 of 3 patients. CONCLUSIONS Early experience suggests that laser ablation is a generally safe, durable, and effective treatment for patients harboring HHs. It also appears effective for local control of SEGAs, especially in combination therapy with everolimus. Its use as a palliative treatment for intrinsic hypothalamic/deep intraventricular tumors was less successful and associated with a higher risk of serious complications. Additional experience and long-term follow-up will be beneficial in further characterizing the effectiveness and risk profile of laser ablation in treating these lesions in comparison with conventional resective surgery or stereotactic radiosurgery.

Reducing Time to Electroencephalography in Pediatric Convulsive Status Epilepticus: A Quality Improvement Initiative.

BACKGROUND: Pediatric convulsive status epilepticus (CSE) is a neurological emergency utilizing electroencephalography (EEG) to guide therapeutic interventions. Guidelines recommend EEG initiation within one hour of seizure onset, but logistic and structural barriers often lead to significant delays. We aimed to reduce the time to EEG in pediatric CSE. METHODS: From 2017 to 2022, we implemented process improvements, including EEG order sets with priority-based timing guidance, technologist workflow changes, a satisfaction survey, and feedback from key stakeholder groups, over five plan-do-study-act (PDSA) cycles. Seizure start time, time of EEG order, and time to EEG initiation were extracted. Time to interpretable EEG was determined from manual review of the EEG tracing. RESULTS: Time from EEG order to interpretable EEG decreased by nearly 50%, from a median of 90 minutes to 48 minutes. There were clinically and statistically significant improvements in time from EEG order to EEG initiation, time from EEG order to interpretable EEG, and EEG start to interpretable EEG. Ongoing provider education and guidance enabled improvements, whereas a new electronic health care record negatively impacted electronic ordering. EEG technologists reported that they understood the importance of emergent EEG for clinical care and did not find that the new workflow caused excessive disruption. CONCLUSIONS: Timely access to EEG for pediatric patients with CSE can be improved through clinical processes that use existing devices and that maintain the benefits of full-montage EEG recordings. Similar process improvement efforts may be generalizable to other institutions to increase adherence to guidelines and provide improved care.

Tissue localization during resective epilepsy surgery.

OBJECT: Imaging-guided surgery (IGS) systems are widely used in neurosurgical practice. During epilepsy surgery, the authors routinely use IGS landmarks to localize intracranial electrodes and/or specific brain regions. The authors have developed a technique to coregister these landmarks with pre- and postoperative scans and the Montreal Neurological Institute (MNI) standard space brain MRI to allow 1) localization and identification of tissue anatomy; and 2) identification of Brodmann areas (BAs) of the tissue resected during epilepsy surgery. Tracking tissue in this fashion allows for better correlation of patient outcome to clinical factors, functional neuroimaging findings, and pathological characteristics and molecular studies of resected tissue. METHODS: Tissue samples were collected in 21 patients. Coordinates from intraoperative tissue localization were downloaded from the IGS system and transformed into patient space, as defined by preoperative high-resolution T1-weighted MRI volume. Tissue landmarks in patient space were then transformed into MNI standard space for identification of the BAs of the tissue samples. RESULTS: Anatomical locations of resected tissue were identified from the intraoperative resection landmarks. The BAs were identified for 17 of the 21 patients. The remaining patients had abnormal brain anatomy that could not be meaningfully coregistered with the MNI standard brain without causing extensive distortion. CONCLUSIONS: This coregistration and landmark tracking technique allows localization of tissue that is resected from patients with epilepsy and identification of the BAs for each resected region. The ability to perform tissue localization allows investigators to relate preoperative, intraoperative, and postoperative functional and anatomical brain imaging to better understand patient outcomes, improve patient safety, and aid in research.

Clinical outcomes of pediatric hemispherectomy following unsuccessful subhemispheric resection for refractory epilepsy: a case review study.

OBJECTIVE: Epilepsy surgery remains one of the most underutilized procedures in epilepsy despite its proven superiority to other available therapies. This underutilization is greater in patients in whom initial surgery fails. This case series examined the clinical characteristics, reasons for initial surgery failure, and outcomes in a cohort of patients who underwent hemispherectomy following unsuccessful smaller resections for intractable epilepsy (subhemispheric group [SHG]) and compared them to those of a cohort of patients who underwent hemispherectomy as the first surgery (hemispheric group [HG]). The objective of this paper was to determine the clinical characteristics of patients in whom a small, subhemispheric resection failed, who went on to become seizure free after undergoing a hemispherectomy. METHODS: Patients who underwent hemispherectomy at Seattle Children's Hospital between 1996 and 2020 were identified. Inclusion criteria for SHG were as follows: 1) patients ≤ 18 years of age at the time of hemispheric surgery; 2) initial subhemispheric epilepsy surgery that did not produce seizure freedom; 3) hemispherectomy or hemispherotomy after the subhemispheric surgery; and 4) follow-up for at least 12 months after hemispheric surgery. Data collected included the following: patient demographics; seizure etiology; comorbidities; prior neurosurgeries; neurophysiological studies; imaging studies; and surgical details-plus surgical, seizure, and functional outcomes. Seizure etiology was classified as follows: 1) developmental, 2) acquired, or 3) progressive. The authors compared SHG to HG in terms of demographics, seizure etiology, and seizure and neuropsychological outcomes. RESULTS: There were 14 patients in the SHG and 51 patients in the HG. All patients in the SHG had Engel class IV scores after their initial resective surgery. Overall, 86% (n = 12) of the patients in the SHG had good posthemispherectomy seizure outcomes (Engel class I or II). All patients in the SHG who had progressive etiology (n = 3) had favorable seizure outcomes, with eventual hemispherectomy (1 each with Engel classes I, II, and III). Engel classifications posthemispherectomy between the groups were similar. There were no statistical differences in postsurgical Vineland Adaptive Behavior Scales Adaptive Behavior Composite scores or postsurgical full-scale IQ scores between groups when accounting for presurgical scores. CONCLUSIONS: Hemispherectomy as a repeat surgery after unsuccessful subhemispheric epilepsy surgery has a favorable seizure outcome, with stable or improved intelligence and adaptive functioning. Findings in these patients are similar to those in patients who had hemispherectomy as their first surgery. This can be explained by the relatively small number of patients in the SHG and the higher likelihood of hemispheric surgeries to resect or disconnect the entire epileptogenic lesion compared to smaller resections.

Pediatric status epilepticus management by Emergency Medical Services (the pSERG cohort).

PURPOSE: Delayed treatment in status epilepticus (SE) is independently associated with increased treatment resistance, morbidity, and mortality. We describe the prehospital management pathway and Emergency Medical Services (EMS) timeliness in children who developed refractory convulsive status epilepticus (RCSE). METHODS: Retrospective multicenter study in the United States using prospectively collected observational data from June 2011 to March 2020. We selected pediatric patients (one month-21 years) with RCSE initiated outside the hospital and transported to the hospital by EMS. RESULTS: We included 91 patients with a median (percentile25-percentile75) age of 3.0 (1.5-7.3) years. The median time from seizure onset to hospital arrival was 45 (30-67) minutes, with a median time cared for by EMS of 24 (15-36) minutes. Considering treatment by caregivers and EMS before hospital arrival, 20 (22%) patients did not receive any anti-seizure medications (ASM) and 71 (78%) received one to five doses of benzodiazepines (BZD), without non-BZD ASM. We provided the prehospital treatment flow path of these patients through caregivers and EMS including relevant time points. Patients with a history of SE were more likely to receive the first BZD in the prehospital setting compared to patients without a history of SE (adjusted HR 3.25, 95% CI 1.72-6.12, p<0.001). CONCLUSION: In this multicenter study of pediatric RCSE, prehospital treatment may be streamlined further. Patients with a history of SE were more likely to receive prehospital rescue medication.

Electrocorticography to Investigate Age-Related Brain Lateralization on Pediatric Motor Inhibition.

Response inhibition refers to the ability to suppress inappropriate actions that interfere with goal-driven behavior. The inferior frontal gyrus (IFG) is known to be associated with inhibition of a motor response by assuming executive control over motor cortex outputs. This study aimed to evaluate the pediatric development of response inhibition through subdural electrocorticography (ECoG) recording. Subdural ECoG recorded neural activities simultaneously during a Go/No-Go task, which was optimized for children. Different frequency power [theta: 4-8 Hz; beta: 12-40 Hz; high-gamma (HG): 70-200 Hz] was estimated within the IFG and motor cortex. Age-related analysis was computed by each bandpass power ratio between Go and No-Go conditions, and phase-amplitude coupling (PAC) over IFG by using the modulating index metric in two conditions. For all the eight pediatric patients, HG power was more activated in No-Go trials than in Go trials, in either right- or left-side IFG when available. In the IFG region, the power over theta and HG in No-Go conditions was higher than those in Go conditions, with significance over the right side (p < 0.05). The age-related lateralization from both sides to the right side was observed from the ratio of HG power and PAC value between the No-Go and Go trials. In the pediatric population, the role of motor inhibition was observed in both IFG, with age-related lateralization to the right side, which was proved in the previous functional magnetic resonance imaging studies. In this study, the evidence correlation of age and response inhibition was observed directly by the evidence of cortical recordings.

Precision medicine in pediatric temporal epilepsy surgery: optimization of outcomes through functional MRI memory tasks and tailored surgeries.

OBJECTIVE: The goal of epilepsy surgery is both seizure cessation and maximal preservation of function. In temporal lobe (TL) cases, the lack of functional MRI (fMRI) tasks that effectively activate mesial temporal structures hampers preoperative memory risk assessment, especially in children. This study evaluated pediatric TL surgery outcome optimization associated with tailored resection informed by an fMRI memory task. METHODS: The authors identified focal onset TL epilepsy patients with 1) TL resections; 2) viable fMRI memory scans; and 3) pre- and postoperative neuropsychological (NP) evaluations. They retrospectively evaluated preoperative fMRI memory scans, available Wada tests, pre- and postoperative NP scores, postoperative MRI scans, and postoperative Engel class outcomes. To assess fMRI memory task outcome prediction, the authors 1) overlaid preoperative fMRI activation onto postoperative structural images; 2) classified patients as having "overlap" or "no overlap" of activation and resection cavities; and 3) compared these findings with memory improvement, stability, or decline, based on Reliable Change Index calculations. RESULTS: Twenty patients met the inclusion criteria. At a median of 2.1 postoperative years, 16 patients had Engel class IA outcomes and 1 each had Engel class IB, ID, IIA, and IID outcomes. Functional MRI activation was linked to NP memory outcome in 19 of 20 cases (95%). Otherwise, heterogeneity characterized the cohort. CONCLUSIONS: Functional MRI memory task activation effectively predicted individual NP outcomes in the context of tailored TL resections. Patients had excellent seizure and overall good NP outcomes. This small study adds to extant literature indicating that pediatric TL epilepsy does not represent a single clinical syndrome. Findings support individualized surgical intervention using fMRI memory activation to help guide this precision medicine approach.

Concordance of functional MRI memory task and resting-state functional MRI connectivity used in surgical planning for pediatric temporal lobe epilepsy.

OBJECTIVE: Assessing memory is often critical in surgical evaluation, although difficult to assess in young children and in patients with variable task abilities. While obtaining interpretable data from task-based functional MRI (fMRI) measures is common in compliant and awake patients, it is not known whether functional connectivity MRI (fcMRI) data show equivalent results. If this were the case, it would have substantial clinical and research generalizability. To evaluate this possibility, the authors evaluated the concordance between fMRI and fcMRI data collected in a presurgical epilepsy cohort. METHODS: Task-based fMRI data for autobiographical memory tasks and resting-state fcMRI data were collected in patients with epilepsy evaluated at Seattle Children's Hospital between 2010 and 2017. To assess memory-related activation and laterality, signal change in task-based measures was computed as a percentage of the average blood oxygen level-dependent signal over the defined regions of interest. An fcMRI data analysis was performed using 1000 Functional Connectomes Project scripts based on Analysis of Functional NeuroImages and FSL (Functional Magnetic Resonance Imaging of the Brain Software Library) software packages. Lateralization indices (LIs) were estimated for activation and connectivity measures. The concordance between these two measures was evaluated using correlation and regression analysis. RESULTS: In this epilepsy cohort studied, the authors observed concordance between fMRI activation and fcMRI connectivity, with an LI regression coefficient of 0.470 (R2 = 0.221, p = 0.00076). CONCLUSIONS: Previously published studies have demonstrated fMRI and fcMRI overlap between measures of vision, attention, and language. In the authors' clinical sample, task-based measures of memory and analogous resting-state mapping were similarly linked in pattern and strength. These results support the use of fcMRI methods as a proxy for task-based memory performance in presurgical patients, perhaps including those who are more limited in their behavioral compliance. Future investigations to extend these results will be helpful to explore how the magnitudes of effect are associated with neuropsychological performance and postsurgical behavioral changes.

Dynamic time course of typical childhood absence seizures: EEG, behavior, and functional magnetic resonance imaging.

Absence seizures are 5-10 s episodes of impaired consciousness accompanied by 3-4 Hz generalized spike-and-wave discharge on electroencephalography (EEG). The time course of functional magnetic resonance imaging (fMRI) changes in absence seizures in relation to EEG and behavior is not known. We acquired simultaneous EEG-fMRI in 88 typical childhood absence seizures from nine pediatric patients. We investigated behavior concurrently using a continuous performance task or simpler repetitive tapping task. EEG time-frequency analysis revealed abrupt onset and end of 3-4 Hz spike-wave discharges with a mean duration of 6.6 s. Behavioral analysis also showed rapid onset and end of deficits associated with electrographic seizure start and end. In contrast, we observed small early fMRI increases in the orbital/medial frontal and medial/lateral parietal cortex >5 s before seizure onset, followed by profound fMRI decreases continuing >20 s after seizure end. This time course differed markedly from the hemodynamic response function (HRF) model used in conventional fMRI analysis, consisting of large increases beginning after electrical event onset, followed by small fMRI decreases. Other regions, such as the lateral frontal cortex, showed more balanced fMRI increases followed by approximately equal decreases. The thalamus showed delayed increases after seizure onset followed by small decreases, most closely resembling the HRF model. These findings reveal a complex and long-lasting sequence of fMRI changes in absence seizures, which are not detectable by conventional HRF modeling in many regions. These results may be important mechanistically for seizure initiation and termination and may also contribute to changes in EEG and behavior.

Impaired attention and network connectivity in childhood absence epilepsy.

Patients with childhood absence epilepsy (CAE) often demonstrate impaired interictal attention, even with control of their seizures. No previous study has investigated the brain networks involved in this impairment. We used the continuous performance task (CPT) of attentional vigilance and the repetitive tapping task (RTT), a control motor task, to examine interictal attention in 26 children with CAE and 22 matched healthy controls. Each subject underwent simultaneous 3T functional magnetic resonance imaging-electroencephalography (fMRI-EEG) and CPT/RTT testing. Areas of activation on fMRI during the CPT task were correlated with behavioral performance and used as seed regions for resting functional connectivity analysis. All behavioral measures reflecting inattention were significantly higher in patients. Correlation analysis revealed that impairment on all measures of inattention on the CPT task was associated with decreased medial frontal cortex (MFC) activation during CPT. In addition, analysis of resting functional connectivity revealed an overall decrease within an 'attention network' in patients relative to controls. Patients demonstrated significantly impaired connectivity between the right anterior insula/frontal operculum (In/FO) and MFC relative to controls. Our results suggest that there is impaired function in an attention network comprising anterior In/FO and MFC in patients with CAE. These findings provide an anatomical and functional basis for impaired interictal attention in CAE, which may allow the development of improved treatments targeted at these networks.

Functional MRI connectivity as a predictor of the surgical outcome of epilepsy.

PURPOSE: In planning epilepsy surgery, it is important to be able to assess the likelihood of success of surgery for each patient so that the possible risk and benefit can be properly considered. In this study, functional connectivity was investigated as a means for predicting surgical outcome from the preoperative functional magnetic resonance imaging (fMRI) of epilepsy patients. METHODS: Resting-state simultaneous electroencephalography (EEG)-fMRI data were collected from 18 patients with intractable epilepsy before surgery and from 14 healthy subjects. For each patient, EEG-spike correlated fMRI analysis was performed and an activation cluster that overlapped the most with the planned resection area for each patient was chosen as the seed for the functional connectivity analysis. After the functional connectivity maps were computed, laterality indices of functional connectivity were contrasted between patients who had seizures after surgeries (seizure-recurrence group) and those who did not have them for at least a year (seizure-free group). KEY FINDINGS: Patients in the seizure-recurrence group had less-lateralized functional connectivity than patients in the seizure-free group (t(16) = 2.3, after control subtracted and Fisher transformed, p < 0.05, two-tailed). SIGNIFICANCE: This study suggests the potential for using preoperative fMRI connectivity analysis as a predictive outcome measure. If confirmed by further research, a high laterality will be an important addition to the other predictors of better surgical outcome such as febrile seizures, mesial temporal sclerosis, tumors, abnormal MRI, and EEG/MRI concordance.

Time to Treatment in Pediatric Convulsive Refractory Status Epilepticus: The Weekend Effect.

BACKGROUND: Time to treatment in pediatric refractory status epilepticus is delayed. We aimed to evaluate the influence of weekends and holidays on time to treatment of this pediatric emergency. METHODS: We performed a retrospective analysis of prospectively collected observational data of pediatric patients with refractory status epilepticus. RESULTS: We included 329 patients (56% males) with a median (p25 to p75) age of 3.8 (1.3 to 9) years. The median (p25 to p75) time to first BZD on weekdays and weekends/holidays was 20 (6.8 to 48.3) minutes versus 11 (5 to 35) minutes, P = 0.01; adjusted hazard ratio (HR) = 1.20 (95% confidence interval [CI]: 0.95 to 1.55), P = 0.12. The time to first non-BZD ASM was longer on weekdays than on weekends/holidays (68 [42.8 to 153.5] minutes versus 59 [27 to 120] minutes, P = 0.006; adjusted HR = 1.38 [95% CI: 1.08 to 1.76], P = 0.009). However, this difference was mainly driven by status epilepticus with in-hospital onset: among 108 patients, the time to first non-BZD ASM was longer during weekdays than during weekends/holidays (55.5 [28.8 to 103.5] minutes versus 28 [15.8 to 66.3] minutes, P = 0.003; adjusted HR = 1.65 [95% CI: 1.08 to 2.51], P = 0.01). CONCLUSIONS: The time to first non-BZD ASM in pediatric refractory status epilepticus is shorter on weekends/holidays than on weekdays, mainly driven by in-hospital onset status epilepticus. Data on what might be causing this difference may help tailor policies to improve medication application timing.

Simultaneous EEG, fMRI, and behavior in typical childhood absence seizures.

PURPOSE: Absence seizures cause transient impairment of consciousness. Typical absence seizures occur in children, and are accompanied by 3-4-Hz spike-wave discharges (SWDs) on electroencephalography (EEG). Prior EEG-functional magnetic resonance imaging (fMRI) studies of SWDs have shown a network of cortical and subcortical changes during these electrical events. However, fMRI during typical childhood absence seizures with confirmed impaired consciousness has not been previously investigated. METHODS: We performed EEG-fMRI with simultaneous behavioral testing in 37 children with typical childhood absence epilepsy (CAE). Attentional vigilance was evaluated by a continuous performance task (CPT), and simpler motor performance was evaluated by a repetitive tapping task (RTT). RESULTS: SWD episodes were obtained during fMRI scanning from 9 patients among the 37 studied. fMRI signal increases during SWDs were observed in the thalamus, frontal cortex, primary visual, auditory, somatosensory, and motor cortex, and fMRI decreases were seen in the lateral and medial parietal cortex, cingulate gyrus, and basal ganglia. Omission error rate (missed targets) with SWDs during fMRI was 81% on CPT and 39% on RTT. For those seizure epochs during which CPT performance was impaired, fMRI changes were seen in cortical and subcortical structures typically involved in SWDs, whereas minimal changes were observed for the few epochs during which performance was spared. DISCUSSION: These findings suggest that typical absence seizures involve a network of cortical-subcortical areas necessary for normal attention and primary information processing. Identification of this network may improve understanding of cognitive impairments in CAE, and may help guide development of new therapies for this disorder.