Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

BACKGROUND: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. RESULTS: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. CONCLUSION: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.

Is Resting State Functional MRI Effective Connectivity in Movement Disorders Helpful? A Focused Review Across Lifespan and Disease.

In the evolving modern era of neuromodulation for movement disorders in adults and children, much progress has been made recently characterizing the human motor network (MN) with potentially important treatment implications. Herein is a focused review of relevant resting state fMRI functional and effective connectivity of the human motor network across the lifespan in health and disease. The goal is to examine how the transition from functional connectivity to dynamic effective connectivity may be especially informative of network-targeted movement disorder therapies, with hopeful implications for children.

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

OBJECTIVE: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). METHODS: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever. RESULTS: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. SIGNIFICANCE: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

Efficacy and tolerability of a whey-based, medium-chain triglyceride-enhanced ketogenic formula in children with refractory epilepsy: A retrospective study.

PURPOSE: Ketogenic metabolic therapy (KMT) has demonstrated effectiveness in seizure reduction. However, patient compliance and adverse effects limit its use. Ready-to-feed (RTF) ketogenic formulas improve compliance and include components that mitigate adverse effects. This study is the first to evaluate the efficacy and tolerability of an RTF, whey-based, medium-chain triglyceride-enhanced (WBME) ketogenic formula. METHODS: Retrospective data from patients who received KMT between January 1, 2015, and February 28, 2018, were analyzed. Patients who received ≥75% of their total calories from the WBME formula and who were monitored for 3 months were included. Outcome measures were gastrointestinal issues, acidosis, serum blood glucose and beta-hydroxybutyrate levels, unintentional weight changes, diet response (≥50% reduction in seizures), seizure freedom, and change in formula or discontinuation of therapy. Patients with incomplete outcome data or who received <75% of total calories from the formula were excluded. RESULTS: Twenty-six patients (13 males; mean [SD] age, 6.1 [5.8] years) met the inclusion criteria. Thirteen patients were established patients who received a standard ketogenic formula before changing to the WBME formula; 13 were patients new to KMT whose therapy was initiated using the WBME formula. This formula was well tolerated; no patient in either group discontinued therapy or required a change in formula. The combined diet response rate (95% CI) for established and new patients was 96% (80-100%). Seizure-freedom (95% CI) for both groups at 3 months posttreatment was 20% (7-41%). The most prevalent adverse effect was constipation (69% [95% CI, 48-86%]). CONCLUSION: The WBME ketogenic formula appears to be effective and well tolerated by pediatric patients with refractory epilepsy.

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.

Multicenter Research Data of Epilepsy Management in Patients With Sturge-Weber Syndrome.

BACKGROUND: Epilepsy in typical Sturge-Weber syndrome (SWS) is common, and many questions remain regarding the treatment outcomes. We analyzed a large multicenter database with focus on neurological drug treatment in different demographic and SWS characteristic groups. METHODS: A total of 268 patients with brain involvement and a history of seizures were selected from a research data registry generated from a multicenter cross-sectional questionnaire. We examined associations between medication use and binary variables such as sex, ethnicity, and brain, skin, and eye involvement laterality. We analyzed group differences in mean number of antiseizure medications and age at diagnosis, enrollment, and seizure onset and examined differences in median SWS neurological scores in groups of interest. RESULTS: The most frequently used medications were levetiracetam (48.1%), low-dose aspirin (44.8%), oxcarbazepine (39.9%), and phenobarbital (14.9%). Lamotrigine was more frequently used in adults than in children (P = 0.001). History of neurosurgery was associated with no current antiseizure medication use (P = 0.001), whereas bilateral brain involvement and family history of seizures were associated with using a higher number of antiseizure medications (P = 0.002, P = 0.027, respectively). Subjects with bilateral brain involvement and early seizure onset were associated with using a higher number of antiseizure medications (P = 0.002) and phenobarbital use (0.003). CONCLUSIONS: Levetiracetam, low-dose aspirin, and oxcarbazepine were the most frequently used medications. More severely affected patients were frequently on a greater number of antiseizure medications. Surgery for epilepsy was associated with the ability to discontinue antiseizure medication. Longitudinal studies are needed to further investigate medication use in patients with SWS.

Epileptic Spasms in a Large Hypothalamic Hamartoma Cohort.

INTRODUCTION: Hypothalamic hamartoma is rarely associated with epileptic spasms. We describe epileptic spasms in a large cohort of hypothalamic hamartoma patients. METHODS: We performed a retrospective chart review between March 2011 and March 2020 to identify patients with hypothalamic hamartoma and epilepsy. RESULTS: We identified 114 patients with hypothalamic hamartoma and epilepsy, only 3 male patients (2.6%) also had epileptic spasms. The epileptic spasms developed between 6 and 18 months of age. Epileptic spasms resolved with oral prednisolone in 1 and with vigabatrin in the second patient. The third patient continued epileptic spasms despite multiple antiepileptic drugs and partial resection of hypothalamic hamartoma. All 3 patients underwent laser-ablation of hypothalamic hamartoma at the age of 14, 29, and 63 months. The seizure burden decreased by 100%, 84%, and 93% at follow-up (3-47 months). CONCLUSIONS: Epileptic spasms are rare in hypothalamic hamartoma patients and early laser-ablation could potentially treat epileptic spasms and all other seizure types associated with hypothalamic hamartoma.

Resting-state functional MRI connectivity impact on epilepsy surgery plan and surgical candidacy: prospective clinical work.

OBJECTIVE: The authors' goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning. METHODS: Fifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre- and post-rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar's test. RESULTS: Resting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted. CONCLUSIONS: This study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing.

Network-targeted approach and postoperative resting-state functional magnetic resonance imaging are associated with seizure outcome.

OBJECTIVE: Postoperative resting-state functional magnetic resonance imaging (MRI) in children with intractable epilepsy has not been quantified in relation to seizure outcome. Therefore, its value as a biomarker for epileptogenic pathology is not well understood. METHODS: In a sample of children with intractable epilepsy who underwent prospective resting-state seizure onset zone (SOZ)-targeted epilepsy surgery, postoperative resting-state functional MRI (rs-fMRI) was performed 6 to 12 months later. Graded normalization of the postoperative resting-state SOZ was compared to seizure outcomes, patient, surgery, and anatomical MRI characteristics. RESULTS: A total of 64 cases were evaluated. Network-targeted surgery, followed by postoperative rs-fMRI normalization was significantly (p < 0.001) correlated with seizure reduction, with a Spearman rank correlation coefficient of 0.83. Of 39 cases with postoperative rs-fMRI SOZ normalization, 38 (97%) became completely seizure free. In contrast, of the 25 cases without complete rs-fMRI SOZ normalization, only 3 (5%) became seizure free. The accuracy of rs-fMRI as a biomarker predicting seizure freedom is 94%, with 96% sensitivity and 93% specificity. INTERPRETATION: Among seizure localization techniques in pediatric epilepsy, network-targeted surgery, followed by postoperative rs-fMRI normalization, has high correlation with seizure freedom. This study shows that rs-fMRI SOZ can be used as a biomarker of the epileptogenic zone, and postoperative rs-fMRI normalization is a biomarker for SOZ quiescence. ANN NEUROL 2019;86:344-356.

Temporal encephalocele: a novel indication for magnetic resonance-guided laser interstitial thermal therapy for medically intractable epilepsy.

Temporal encephalocele (TE) is a rare but surgically treatable/curable cause of temporal lobe epilepsy (TLE). The surgical intervention varies from local disconnection to extensive anterior temporal lobectomy and amygdalohippocampectomy (ATL/AH). Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has evolved as a minimally invasive alternative for intractable epilepsy with good results, however, application of MRgLITT for intractable pediatric epilepsy secondary to TE has not been reported. We present a detailed technical report and clinical experience of MRgLITT in two adolescent children with medically intractable TLE secondary to TE. Pre-surgical evaluation revealed anterior inferior TE with concordant clinico-electrophysiological data. Both the patients underwent MRgLITT after review with the institutional multidisciplinary epilepsy team and discussion with the patient and the family. Both the patients were discharged on post-operative day one and have been seizure-free since the procedure at the last follow-up visit at 18 months and 6 months, respectively. The present series demonstrates first-ever clinical and technical experience of MRgLITT for TE with intractable pediatric epilepsy. The excellent post-operative seizure outcome and favorable postoperative course support MRgLITT as the first line of surgical intervention for TE with intractable TLE and broadens the application of MRgLITT.

Electroencephalographic Reporting for Refractory Status Epilepticus.

PURPOSE: We aimed to determine whether clinical EEG reports obtained from children in the intensive care unit with refractory status epilepticus could provide data for comparative effectiveness research studies. METHODS: We conducted a retrospective descriptive study to assess the documentation of key variables within clinical continuous EEG monitoring reports based on the American Clinical Neurophysiology Society's standardized EEG terminology for children with refractory status epilepticus from 10 academic centers. Two pediatric electroencephalographers reviewed the EEG reports. We compared reports generated using free text or templates. RESULTS: We reviewed 191 EEG reports. Agreement between the electroencephalographers regarding whether a variable was described in the report ranged from fair to very good. The presence of electrographic seizures (ES) was documented in 46% (87/191) of reports, and these reports documented the time of first ES in 64% (56/87), ES duration in 72% (63/85), and ES frequency in 68% (59/87). Reactivity was documented in 16% (31/191) of reports, and it was more often documented in template than in free-text reports (40% vs. 14%, P = 0.006). Other variables were not differentially reported in template versus free-text reports. CONCLUSIONS: Many key EEG features are not documented consistently in clinical continuous EEG monitoring reports, including ES characteristics and reactivity assessment. Standardization may be needed for clinical EEG reports to provide informative data for large multicenter observational studies.

Physical and Family History Variables Associated With Neurological and Cognitive Development in Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber syndrome (SWS) is caused by a somatic mutation in GNAQ leading to capillary venous malformations in the brain presenting with various neurological, ophthalmic, and cognitive symptoms of variable severity. This clinical variability makes accurate prognosis difficult. We hypothesized that the greater extent of physical factors (extent of skin, eye, and brain involvement), presence of possible genetic factors (gender and family history), and age of seizure onset may be associated with greater symptom severity and need for surgery in patients with SWS. METHODS: The questionnaire was collected from 277 participants (age: two months to 66 years) with SWS brain involvement at seven US sites. RESULTS: Bilateral brain involvement was associated with both learning disorder and intellectual disability, whereas port-wine birthmark extent was associated with epilepsy and an increased likelihood of glaucoma surgery. Subjects with family history of vascular birthmarks were also more likely to report symptomatic strokes, and family history of seizures was associated with earlier seizure onset. Learning disorder, intellectual disability, strokelike episodes, symptomatic stroke, hemiparesis, visual field deficit, and brain surgery were all significantly associated with earlier onset of seizures. CONCLUSION: The extent of brain and skin involvement in SWS, as well as the age of seizure onset, affect prognosis. Other genetic factors, particularly variants involved in vascular development and epilepsy, may also contribute to neurological prognosis, and further study is needed.

Language lateralization with resting-state and task-based functional MRI in pediatric epilepsy.

In Brief: The study compared two types of functional MRI (fMRI) to see which side of the brain is most responsible for language: traditional task-based fMRI, which requires a high level of patient interaction, and resting-state fMRI, which is typically performed with the patient under light sedation and has no interaction requirement. The authors found that the test correlation was 93%, indicating resting state fMRI has potential to locate language in those unable to participate in task-based fMRI.

Subcentimeter epilepsy surgery targets by resting state functional magnetic resonance imaging can improve outcomes in hypothalamic hamartoma.

OBJECTIVE: The purpose of this study is to investigate the outcomes of epilepsy surgery targeting the subcentimeter-sized resting state functional magnetic resonance imaging (rs-fMRI) epileptogenic onset zone (EZ) in hypothalamic hamartoma (HH). METHODS: Fifty-one children with HH-related intractable epilepsy received anatomical MRI-guided stereotactic laser ablation (SLA) procedures. Fifteen of these children were control subjects (CS) not guided by rs-fMRI. Thirty-six had been preoperatively guided by rs-fMRI (RS) to determine EZs, which were subsequently targeted by SLA. The primary outcome measure for the study was a predetermined goal of 30% reduction in seizure frequency and improvement in class I Engel outcomes 1 year postoperatively. Quantitative and qualitative volumetric analyses of total HH and ablated tissue were also assessed. RESULTS: In the RS group, the EZ target within the HH was ablated with high accuracy (>87.5% of target ablated in 83% of subjects). There was no difference between the groups in percentage of ablated hamartoma volume (P = 0.137). Overall seizure reduction was higher in the rs-fMRI group: 85% RS versus 49% CS (P = 0.0006, adjusted). The Engel Epilepsy Surgery Outcome Scale demonstrated significant differences in those with freedom from disabling seizures (class I), 92% RS versus 47% CS, a 45% improvement (P = 0.001). Compared to prior studies, there was improvement in class I outcomes (92% vs 76%-81%). No postoperative morbidity or mortality occurred. SIGNIFICANCE: For the first time, surgical SLA targeting of subcentimeter-sized EZs, located by rs-fMRI, guided surgery for intractable epilepsy. Our outcomes demonstrated the highest seizure freedom rate without surgical complications and are a significant improvement over prior reports. The approach improved freedom from seizures by 45% compared to conventional ablation, regardless of hamartoma size or anatomical classification. This technique showed the same or reduced morbidity (0%) compared to recent non-rs-fMRI-guided SLA studies with as high as 20% permanent significant morbidity.

Efficacy and safety of ketogenic diet for treatment of pediatric convulsive refractory status epilepticus.

PURPOSE: To describe the efficacy and safety of ketogenic diet (KD) for convulsive refractory status epilepticus (RSE). METHODS: RSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ≥2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20 mg/dl (1.9 mmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7 days of starting KD, defined as absence of seizures and ≥50% suppression below 10 µV on longitudinal bipolar montage (suppression-burst ratio ≥50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded. RESULTS: Fourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13 days (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2 days (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7 days of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline. CONCLUSIONS: This series suggests efficacy and safety of KD for treatment of pediatric RSE.

MR-guided laser ablation for the treatment of hypothalamic hamartomas.

Hypothalamic hamartoma is an archetypal example of subcortical epilepsy that can be associated with intractable gelastic epilepsy, secondary epilepsy, and epileptic encephalopathy. The history of its surgical treatment is fraught with mislocalization of the seizure focus, modest efficacy and a high complication rate. Many minimally invasive techniques have been described to mitigate this high complication profile of which MR-guided laser ablation is one. The technology combines instant effect of thermal coagulation with stereotactic precision and guidance with real time MR thermography. This article presents a series of 71 hypothalamic hamartoma patients operated with laser ablation. Ninety-three percent (93%) were free of gelastic seizures at one year with 23% of the patients requiring more than one ablation. One patient experienced a significant memory deficit and one patient experienced worsening diabetes insipidus. Stereotactic laser ablation appears to be a safe and effective surgical option in the treatment of hypothalamic hamartoma.

Connectivity changes after laser ablation: Resting-state fMRI.

Resting-state functional magnetic resonance imaging (rsfMRI) is emerging as a useful tool in the multimodal assessment of patients with epilepsy. In pediatric patients who cannot perform task-based fMRI, rsfMRI may present an adjunct and alternative. Although changes in brain activation during task-based fMRI have been described after surgery for epilepsy, there is limited data on the role of postoperative rsfMRI. In this short review, we discuss the role of postoperative rsfMRI after laser ablation of seizure foci. By establishing standardized anesthesia protocols and imaging parameters, we have been able to perform serial rsfMRI at postoperative follow-up. The development of in-house software that can merge rsfMRI images to surgical navigation systems has allowed us to enhance the clinical applications of this technique. Resting-state fMRI after laser ablation has the potential to identify changes in connectivity, localize new seizure foci, and guide antiepileptic therapy. In our experience, rsfMRI complements conventional MR imaging and task-based fMRI for the evaluation of patients with seizure recurrence after laser ablation, and represents a potential noninvasive biomarker for functional connectivity.

Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients.

OBJECTIVES: Patients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations. METHODS: A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. RESULTS: Fourteen patients met inclusion criteria. The fos-PHT neonatal (20.1 vs 11.3 mg/kg/day, p = 0.044), PB composite (33.9 vs 21.6 mg/kg/day, p = 0.012), and PB neonatal (40.3 vs 20 mg/kg/day, p = 0.04) had larger 24-hour cumulative doses compared with non-ECMO patients. Lower serum concentrations were observed in the PB composite ECMO group (19.1 vs 35.4 mg/L, p < 0.001) and the PB neonatal ECMO group (20.5 vs 27.8 mg/L, p = 0.01) compared with non-ECMO patients. CONCLUSION: Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

Correlating Resting-State Functional Magnetic Resonance Imaging Connectivity by Independent Component Analysis-Based Epileptogenic Zones with Intracranial Electroencephalogram Localized Seizure Onset Zones and Surgical Outcomes in Prospective Pediatric Intractable Epilepsy Study.

The purpose of this study was to prospectively investigate the agreement between the epileptogenic zone(s) (EZ) localization by resting-state functional magnetic resonance imaging (rs-fMRI) and the seizure onset zone(s) (SOZ) identified by intracranial electroencephalogram (ic-EEG) using novel differentiating and ranking criteria of rs-fMRI abnormal independent components (ICs) in a large consecutive heterogeneous pediatric intractable epilepsy population without an a priori alternate modality informing EZ localization or prior declaration of total SOZ number. The EZ determination criteria were developed by using independent component analysis (ICA) on rs-fMRI in an initial cohort of 350 pediatric patients evaluated for epilepsy surgery over a 3-year period. Subsequently, these rs-fMRI EZ criteria were applied prospectively to an evaluation cohort of 40 patients who underwent ic-EEG for SOZ identification. Thirty-seven of these patients had surgical resection/disconnection of the area believed to be the primary source of seizures. One-year seizure frequency rate was collected postoperatively. Among the total 40 patients evaluated, agreement between rs-fMRI EZ and ic-EEG SOZ was 90% (36/40; 95% confidence interval [CI], 0.76-0.97). Of the 37 patients who had surgical destruction of the area believed to be the primary source of seizures, 27 (73%) rs-fMRI EZ could be classified as true positives, 7 (18%) false positives, and 2 (5%) false negatives. Sensitivity of rs-fMRI EZ was 93% (95% CI 78-98%) with a positive predictive value of 79% (95% CI, 63-89%). In those with cryptogenic localization-related epilepsy, agreement between rs-fMRI EZ and ic-EEG SOZ was 89% (8/9; 95% CI, 0.52-99), with no statistically significant difference between the agreement in the cryptogenic and symptomatic localization-related epilepsy subgroups. Two children with negative ic-EEG had removal of the rs-fMRI EZ and were seizure free 1 year postoperatively. Of the 33 patients where at least 1 rs-fMRI EZ agreed with the ic-EEG SOZ, 24% had at least 1 additional rs-fMRI EZ outside the resection area. Of these patients with un-resected rs-fMRI EZ, 75% continued to have seizures 1 year later. Conversely, among 75% of patients in whom rs-fMRI agreed with ic-EEG SOZ and had no anatomically separate rs-fMRI EZ, only 24% continued to have seizures 1 year later. This relationship between extraneous rs-fMRI EZ and seizure outcome was statistically significant (p = 0.01). rs-fMRI EZ surgical destruction showed significant association with postoperative seizure outcome. The pediatric population with intractable epilepsy studied prospectively provides evidence for use of resting-state ICA ranking criteria, to identify rs-fMRI EZ, as developed by the lead author (V.L.B.). This is a high yield test in this population, because no seizure nor particular interictal epilepiform activity needs to occur during the study. Thus, rs-fMRI EZ detected by this technique are potentially informative for epilepsy surgery evaluation and planning in this population. Independent of other brain function testing modalities, such as simultaneous EEG-fMRI or electrical source imaging, contextual ranking of abnormal ICs of rs-fMRI localized EZs correlated with the gold standard of SOZ localization, ic-EEG, across the broad range of pediatric epilepsy surgery candidates, including those with cryptogenic epilepsy.