Interictal EEG source connectivity to localize the epileptogenic zone in patients with drug-resistant epilepsy: A machine learning approach.

OBJECTIVE: To deconstruct the epileptogenic networks of patients with drug-resistant epilepsy (DRE) using source functional connectivity (FC) analysis; unveil the FC biomarkers of the epileptogenic zone (EZ); and develop machine learning (ML) models to estimate the EZ using brief interictal electroencephalography (EEG) data. METHODS: We analyzed scalp EEG from 50 patients with DRE who had surgery. We reconstructed the activity (electrical source imaging [ESI]) of virtual sensors (VSs) across the whole cortex and computed FC separately for epileptiform and non-epileptiform EEG epochs (with or without spikes). In patients with good outcome (Engel 1a), four cortical regions were defined: EZ (resection) and three non-epileptogenic zones (NEZs) in the same and opposite hemispheres. Region-specific FC features in six frequency bands and three spatial ranges (long, short, inner) were compared between regions (Wilcoxon sign-rank). We developed ML classifiers to identify the VSs in the EZ using VS-specific FC features. Cross-validation was performed using good outcome data. Performance was compared with poor outcomes and interictal spike localization. RESULTS: FC differed between EZ and NEZs (p < .05) during non-epileptiform and epileptiform epochs, showing higher FC in the EZ than its homotopic contralateral NEZ. During epileptiform epochs, the NEZ in the epileptogenic hemisphere showed higher FC than its contralateral NEZ. In good outcome patients, the ML classifiers reached 75% accuracy to the resection (91% sensitivity; 74% specificity; distance from EZ: 38 mm) using epileptiform epochs (gamma and beta frequency bands) and 62% accuracy using broadband non-epileptiform epochs, both outperforming spike localization (accuracy = 47%; p < .05; distance from EZ: 57 mm). Lower performance was seen in poor outcomes. SIGNIFICANCE: We present an FC approach to extract EZ biomarkers from brief EEG data. Increased FC in various frequencies characterized the EZ during epileptiform and non-epileptiform epochs. FC-based ML models identified the resection better in good than poor outcome patients, demonstrating their potential for presurgical use in pediatric DRE.

Non-invasive mapping of epileptogenic networks predicts surgical outcome.

Epilepsy is increasingly considered a disorder of brain networks. Studying these networks with functional connectivity can help identify hubs that facilitate the spread of epileptiform activity. Surgical resection of these hubs may lead patients who suffer from drug-resistant epilepsy to seizure freedom. Here, we aim to map non-invasively epileptogenic networks, through the virtual implantation of sensors estimated with electric and magnetic source imaging, in patients with drug-resistant epilepsy. We hypothesize that highly connected hubs identified non-invasively with source imaging can predict the epileptogenic zone and the surgical outcome better than spikes localized with conventional source localization methods (dipoles). We retrospectively analysed simultaneous high-density electroencephalography (EEG) and magnetoencephalography data recorded from 37 children and young adults with drug-resistant epilepsy who underwent neurosurgery. Using source imaging, we estimated virtual sensors at locations where intracranial EEG contacts were placed. On data with and without spikes, we computed undirected functional connectivity between sensors/contacts using amplitude envelope correlation and phase locking value for physiologically relevant frequency bands. From each functional connectivity matrix, we generated an undirected network containing the strongest connections within sensors/contacts using the minimum spanning tree. For each sensor/contact, we computed graph centrality measures. We compared functional connectivity and their derived graph centrality of sensors/contacts inside resection for good (n = 22, ILAE I) and poor (n = 15, ILAE II-VI) outcome patients, tested their ability to predict the epileptogenic zone in good-outcome patients, examined the association between highly connected hubs removal and surgical outcome and performed leave-one-out cross-validation to support their prognostic value. We also compared the predictive values of functional connectivity with those of dipoles. Finally, we tested the reliability of virtual sensor measures via Spearman's correlation with intracranial EEG at population- and patient-level. We observed higher functional connectivity inside than outside resection (P < 0.05, Wilcoxon signed-rank test) for good-outcome patients, on data with and without spikes across different bands for intracranial EEG and electric/magnetic source imaging and few differences for poor-outcome patients. These functional connectivity measures were predictive of both the epileptogenic zone and outcome (positive and negative predictive values ≥55%, validated using leave-one-out cross-validation) outperforming dipoles on spikes. Significant correlations were found between source imaging and intracranial EEG measures (0.4 ≤ rho ≤ 0.9, P < 0.05). Our findings suggest that virtual implantation of sensors through source imaging can non-invasively identify highly connected hubs in patients with drug-resistant epilepsy, even in the absence of frank epileptiform activity. Surgical resection of these hubs predicts outcome better than dipoles.

Spike propagation mapping reveals effective connectivity and predicts surgical outcome in epilepsy.

Neurosurgical intervention is the best available treatment for selected patients with drug resistant epilepsy. For these patients, surgical planning requires biomarkers that delineate the epileptogenic zone, the brain area that is indispensable for the generation of seizures. Interictal spikes recorded with electrophysiological techniques are considered key biomarkers of epilepsy. Yet, they lack specificity, mostly because they propagate across brain areas forming networks. Understanding the relationship between interictal spike propagation and functional connections among the involved brain areas may help develop novel biomarkers that can delineate the epileptogenic zone with high precision. Here, we reveal the relationship between spike propagation and effective connectivity among onset and areas of spread and assess the prognostic value of resecting these areas. We analysed intracranial EEG data from 43 children with drug resistant epilepsy who underwent invasive monitoring for neurosurgical planning. Using electric source imaging, we mapped spike propagation in the source domain and identified three zones: onset, early-spread and late-spread. For each zone, we calculated the overlap and distance from surgical resection. We then estimated a virtual sensor for each zone and the direction of information flow among them via Granger causality. Finally, we compared the prognostic value of resecting these zones, the clinically-defined seizure onset zone and the spike onset on intracranial EEG channels by estimating their overlap with resection. We observed a spike propagation in source space for 37 patients with a median duration of 95 ms (interquartile range: 34-206), a spatial displacement of 14 cm (7.5-22 cm) and a velocity of 0.5 m/s (0.3-0.8 m/s). In patients with good surgical outcome (25 patients, Engel I), the onset had higher overlap with resection [96% (40-100%)] than early-spread [86% (34-100%), P = 0.01] and late-spread [59% (12-100%), P = 0.002], and it was also closer to resection than late-spread [5 mm versus 9 mm, P = 0.007]. We found an information flow from onset to early-spread in 66% of patients with good outcomes, and from early-spread to onset in 50% of patients with poor outcome. Finally, resection of spike onset, but not area of spike spread or the seizure onset zone, predicted outcome with positive predictive value of 79% and negative predictive value of 56% (P = 0.04). Spatiotemporal mapping of spike propagation reveals information flow from onset to areas of spread in epilepsy brain. Surgical resection of the spike onset disrupts the epileptogenic network and may render patients with drug resistant epilepsy seizure-free without having to wait for a seizure to occur during intracranial monitoring.

Sleep Spindle Generation Before and After Epilepsy Surgery: A Source Imaging Study in Children with Drug-Resistant Epilepsy.

INTRODUCTION: Literature lacks studies investigating the cortical generation of sleep spindles in drug-resistant epilepsy (DRE) and how they evolve after resection of the epileptogenic zone (EZ). Here, we examined sleep EEGs of children with focal DRE who became seizure-free after focal epilepsy surgery, and aimed to investigate the changes in the spindle generation before and after the surgery using low-density scalp EEG and electrical source imaging (ESI). METHODS: We analyzed N2-sleep EEGs from 19 children with DRE before and after surgery. We identified slow (8-12 Hz) and fast spindles (13-16 Hz), computed their spectral features and cortical generators through ESI and computed their distance from the EZ and irritative zone (IZ). We performed two-way ANOVA testing the effect of spindle type (slow vs. fast) and surgical phase (pre-surgery vs. post-surgery) on each feature. RESULTS: Power, frequency and cortical activation of slow spindles increased after surgery (p < 0.005), while this was not seen for fast spindles. Before surgery, the cortical generators of slow spindles were closer to the EZ (57.3 vs. 66.2 mm, p = 0.007) and IZ (41.3 vs. 55.5 mm, p = 0.02) than fast spindle generators. CONCLUSIONS: Our data indicate alterations in the EEG slow spindles after resective epilepsy surgery. Fast spindle generation on the contrary did not change after surgery. Although the study is limited by its retrospective nature, lack of healthy controls, and reduced cortical spatial sampling, our findings suggest a spatial relationship between the slow spindles and the epileptogenic generators.

Spinal catheter revision in pediatric intrathecal baclofen pumps: risk factors and postoperative outcomes.

OBJECTIVE: Intrathecal baclofen (ITB) pumps are commonly used in pediatric patients with cerebral palsy (CP) and medically refractory spasticity. However, catheter malfunction and associated risk factors are not well understood. The aim of this study was to examine potential risk factors for spinal catheter malfunction and characterize postoperative follow-up to understand the clinical consequences. METHODS: Patients who received ITB pump replacement or revision at Boston Children's Hospital between 2010 and 2023 were retrospectively reviewed. The spinal catheter revision cohort (SCRC) included patients whose spinal catheter was occluded requiring lumbar catheter revision. The second cohort included abdominal pump replacements only (APRC). Between-group comparisons and multivariable regression identified factors associated with catheter revision and postoperative outcomes. RESULTS: Forty-one (33.6%) patients underwent spinal catheter revision and were compared with 81 patients (66.4%) who underwent abdominal pump replacement only. Younger age at surgery and an elevated preoperative lower-extremity modified Ashworth scale grade were associated with spinal catheter revision (p < 0.05). Catheter model type, tip location, and history of spinal fusion were not associated with obstruction. Postoperatively, SCRC patients experienced a higher rate of infection (17.1%) relative to APRC patients (0%) within 30 days from their ITB pump replacement procedure (p < 0.05) and greater likelihood of subsequent ITB system removal compared with the APRC (24.4% vs 7.4%, p < 0.05). Although not differing preoperatively, SCRC patients had lower postoperative ITB doses when compared with the APRC group (median dose 143 vs 350 µg/day, p < 0.05) at hospital discharge and remained statistically different at the 6-month and 1-year follow-ups (p < 0.05). There were no postoperative differences in baclofen overdose, withdrawal, or median number of hospital readmissions within 30 days. Overall, 31.7% of spinal catheter revisions were unanticipated by the clinical team at time of surgery. CONCLUSIONS: Younger age at surgery and increased preoperative lower-extremity tone may be risk factors for catheter obstruction, resulting in a higher rate of postoperative infection and subsequent ITB pump removal compared with pump replacement alone. Spinal catheter occlusion can complicate revision or replacement procedures, especially when unanticipated. Routine clinical assessment may be inadequate for diagnosing insidious catheter malfunction. Catheter occlusion deserves further study, and routine assessment of catheter patency may be warranted to prevent suboptimal tone therapy.

Epidural Analgesia Versus Lumbar Plexus Blockade After Hip Reconstruction Surgery in Children With Cerebral Palsy and Intrathecal Baclofen Pumps: A Comparison of Safety and Efficacy.

BACKGROUND: Epidural analgesia is commonly used for pain control after reconstructive hip surgery, but its use is controversial in the presence of an intrathecal baclofen pump (ITB). The purpose of this retrospective study was to investigate the rate of serious anesthetic and postoperative complications as well as the efficacy of epidural analgesia compared with lumbar plexus blocks (LPBs) for pain management after neuromuscular hip reconstruction in children with cerebral palsy (CP) and ITB. METHODS: Pediatric patients with CP and ITB undergoing hip reconstructive surgery from 2010 to 2019 were retrospectively identified. Patients receiving epidural analgesia were compared with those receiving LPB. Morphine milligram equivalents per kilogram were used as a surrogate measure for pain-related outcomes, as pain scores were reported with wide ranges (eg, 0 to 5/10), making it unfeasible to compare them across the cohort. Postoperative complications were graded using the modified Clavien-Dindo classification. RESULTS: Forty-four patients (26/44, 59% male) underwent surgery at an average age of 10.3 years (SD=3.4 y, range: 4 to 17 y). The majority utilized LPB (28/44, 64%) while the remaining utilized epidural (16/44, 36%). There were no differences in rates of serious complications, including no cases of ITB malfunction, damage, or infection. During the immediate postoperative course, patients who received LPB had higher morphine milligram equivalents per kilogram requirements than patients who received epidural analgesia. CONCLUSIONS: In patients with CP undergoing hip reconstruction surgery with an ITB in situ, epidural anesthesia was associated with improved analgesia compared with LPB analgesia, with a similar risk for adverse outcomes. Epidural catheters placed using image-guided insertion techniques can avoid damage to the ITB catheter while providing effective postoperative pain control without increasing rates of complications in this complex patient population. LEVEL OF EVIDENCE: Level III.

Drug-Responsive Inhomogeneous Cortical Modulation by Direct Current Stimulation.

OBJECTIVE: Cathodal direct current stimulation (cDCS) induces long-term depression (LTD)-like reduction of cortical excitability (DCS-LTD), which has been tested in the treatment of epilepsy with modest effects. In part, this may be due to variable cortical neuron orientation relative to the electric field. We tested, in vivo and in vitro, whether DCS-LTD occurs throughout the cortical thickness, and if not, then whether drug-DCS pairing can enhance the uniformity of the cortical response and the cDCS antiepileptic effect. METHODS: cDCS-mediated changes in cortical excitability were measured in vitro in mouse motor cortex (M1) and in human postoperative neocortex, in vivo in mouse somatosensory cortex (S1), and in a mouse kainic acid (KA)-seizure model. Contributions of N-methyl-D-aspartate-type glutamate receptors (NMDARs) to cDCS-mediated plasticity were tested with application of NMDAR blockers (memantine/D-AP5). RESULTS: cDCS reliably induced DCS-LTD in superficial cortical layers, and a long-term potentiation (LTP)-like enhancement (DCS-LTP) was recorded in deep cortical layers. Immunostaining confirmed layer-specific increase of phospho-S6 ribosomal protein in mouse M1. Similar nonuniform cDCS aftereffects on cortical excitability were also found in human neocortex in vitro and in S1 of alert mice in vivo. Application of memantine/D-AP5 either produced a more uniform DCS-LTD throughout the cortical thickness or at least abolished DCS-LTP. Moreover, a combination of memantine and cDCS suppressed KA-induced seizures. INTERPRETATION: cDCS aftereffects are not uniform throughout cortical layers, which may explain the incomplete cDCS clinical efficacy. NMDAR antagonists may augment cDCS efficacy in epilepsy and other disorders where regional depression of cortical excitability is desirable. ANN NEUROL 2020;88:489-502.

Intrathecal catheter and port placement for nusinersen infusion in children with spinal muscular atrophy and spinal fusion.

BACKGROUND: Spinal administration of medications is challenging in patients with complete posterior spinal fusion. We describe percutaneous image-guided intrathecal port placement for administration of the antisense oligonucleotide nusinersen for children and young adults with spinal muscular atrophy. OBJECTIVE: To describe and present our initial experience with a new technique for administering nusinersen in patients with spinal muscular atrophy and posterior spinal fusion. MATERIALS AND METHODS: We reviewed medical records of 13 patients who received intrathecal ports using DynaCT, biplane fluoroscopy and iGuide from April 2018 through June 2019, and we describe the clinical course over 1 year. RESULTS: Image-guided catheter and port implantation was successful in all cases. Two ports were subsequently removed, one for persistent cerebrospinal fluid leak and one for superficial infection. The other 11 have functioned successfully for a minimum of 23 months. CONCLUSION: We report our experience with image-guided intrathecal port placement in children with complete posterior spine fusion. The implanted port permits dosing in an outpatient setting and avoids the need for multiple future radiologic procedures, and it reduces discomfort, procedural costs and potential risks and sequelae of multiple anesthetics and radiation exposures. Further studies are needed to define the relative risks and benefits of intrathecal ports compared to other approaches such as repeated transforaminal lumbar punctures.

Recurrent abdominal dislodgement of intrathecal pump and utility of infraclavicular site for patients with elevated body mass index: illustrative case.

BACKGROUND: Intrathecal baclofen, delivered via implanted pump, has been used to manage spasticity for approximately 40 years. The device is typically subcutaneously or subfascially implanted in the abdominal wall. There are very few cases reported of the pump being implanted in other locations. OBSERVATIONS: This case describes the complicated course of a patient presenting with multiple episodes of catheter malfunction related to pump flipping in the abdominal pocket. The patient was successfully treated with repositioning of the pump into the infraclavicular fossa. LESSONS: Infraclavicular placement of the implanted pump allowed for a more secure pocket base for this patient and less strain applied to the pump, minimizing the risk of disruption of pump positioning and interruption of drug delivery.

Functional connectivity discriminates epileptogenic states and predicts surgical outcome in children with drug resistant epilepsy.

Normal brain functioning emerges from a complex interplay among regions forming networks. In epilepsy, these networks are disrupted causing seizures. Highly connected nodes in these networks are epilepsy surgery targets. Here, we assess whether functional connectivity (FC) using intracranial electroencephalography can quantify brain regions epileptogenicity and predict surgical outcome in children with drug resistant epilepsy (DRE). We computed FC between electrodes on different states (i.e. interictal without spikes, interictal with spikes, pre-ictal, ictal, and post-ictal) and frequency bands. We then estimated the electrodes' nodal strength. We compared nodal strength between states, inside and outside resection for good- (n = 22, Engel I) and poor-outcome (n = 9, Engel II-IV) patients, respectively, and tested their utility to predict the epileptogenic zone and outcome. We observed a hierarchical epileptogenic organization among states for nodal strength: lower FC during interictal and pre-ictal states followed by higher FC during ictal and post-ictal states (p < 0.05). We further observed higher FC inside resection (p < 0.05) for good-outcome patients on different states and bands, and no differences for poor-outcome patients. Resection of nodes with high FC was predictive of outcome (positive and negative predictive values: 47-100%). Our findings suggest that FC can discriminate epileptogenic states and predict outcome in patients with DRE.

Influence of extent and age at corpus callosotomy on seizure outcomes. A single center experience.

Corpus callosotomy (CC) is a palliative treatment for drop seizures in patients with drug-resistant nonlocalizable epilepsy. We compared drop seizure outcomes between patients undergoing anterior CC versus complete CC and examined factors impacting outcomes for drop seizures including age at CC and duration of epilepsy. A retrospective review of patients who underwent CC between 2003 and 2022 with a minimum of 6 months postsurgical follow-up was included. Outcome measure for drop seizures included seizure reduction ≥50% from baseline as well as elimination of drop seizures. Thirty-eight patients were included. Overall, ≥50% reduction in drop seizures occurred in nearly 70% (23 out of 33) patients with complete elimination in 58% (19 out of 33). Compared with anterior CC (n = 13), patients undergoing complete CC (n = 25) had increased likelihood of ≥50% reduction (p = 0.006) or elimination (p = 0.024) of drop seizures. Regression analysis showed that complete CC was the primary predictor for improved drop seizure outcomes (elimination, p = 0.014 or ≥50% reduction, p = 0.006), while age at CC and duration of epilepsy did not impact the outcomes. Compared to anterior CC, complete CC was significantly more likely to lead to improvement/freedom from drop seizures. Age at CC or duration of epilepsy did not influence drop seizure outcomes.

Endoscopic third ventriculostomy with choroid plexus cauterization: predictors of long-term success and comparison with shunt placement for primary treatment of infant hydrocephalus.

OBJECTIVE: Endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) can avoid ventriculoperitoneal shunt (VPS) dependence in very young hydrocephalic children, although long-term success as a primary treatment in North America has not been previously reported. Moreover, optimal age at surgery, impact of preoperative ventriculomegaly, and relationship to prior cerebrospinal fluid (CSF) diversion remain poorly defined. The authors compared ETV/CPC and VPS placement for averting reoperation, and they evaluated preoperative predictors for reoperation and shunt placement after ETV/CPC. METHODS: All patients under 12 months of age who underwent initial hydrocephalus treatment via ETV/CPC or VPS placement at Boston Children's Hospital between December 2008 and August 2021 were reviewed. Analyses included Cox regression for independent outcome predictors, and both Kaplan-Meier and log-rank rank tests for time-to-event outcomes. Cutoff values for age and preoperative frontal and occipital horn ratio (FOHR) were determined with receiver operating characteristic curve analysis and Youden's J index. RESULTS: In total, 348 children (150 females) were included with principal etiologies of posthemorrhagic hydrocephalus (26.7%), myelomeningocele (20.1%), and aqueduct stenosis (17.0%). Of these, 266 (76.4%) underwent ETV/CPC and 82 (23.6%) underwent VPS placement. Treatment choice largely reflected surgeon preferences before practice shifted toward endoscopy, with endoscopy not considered for > 70% of initial VPS cases. ETV/CPC patients trended toward fewer reoperations, and Kaplan-Meier analysis estimated that 59% of patients would achieve long-term shunt freedom through 11 years (median 42 months of actual follow-up). Among all patients, corrected age < 2.5 months (p < 0.001), prior temporizing CSF diversion (p = 0.003), and excess intraoperative bleeding (p < 0.001) independently predicted reoperation. Among ETV/CPC patients, corrected age < 2.5 months (p = 0.031), prior CSF diversion (p = 0.001), preoperative FOHR > 0.613 (p = 0.011), and excessive intraoperative bleeding (p = 0.001) independently predicted ultimate conversion to VPS. The actual VPS insertion rates remained low in patients who were ≥ 2.5 months old at ETV/CPC either with prior CSF diversion (2/10 [20.0%]) or without prior CSF diversion (24/123 [19.5%]); however, the actual VPS insertion rates increased in patients who were < 2.5 months old at ETV/CPC with prior CSF diversion (19/26 [73.1%]) or without prior CSF diversion (44/107 [41.1%]). CONCLUSIONS: ETV/CPC successfully treated hydrocephalus in most patients younger than 1 year irrespective of etiology, averting observed shunt dependence in 80% of patients ≥ 2.5 months of age regardless of prior CSF diversion and in 59% of those < 2.5 months of age without prior CSF diversion. For infants aged < 2.5 months with prior CSF diversion, particularly those with severe ventriculomegaly, ETV/CPC was unlikely to succeed unless safely delayed.

Stereoelectroencephalography followed by combined electrode removal and MRI-guided laser interstitial thermal therapy or open resection: a single-center series in pediatric patients with medically refractory epilepsy.

OBJECTIVE: Stereoelectroencephalography (SEEG) and MRI-guided laser interstitial thermal therapy (MRgLITT) have emerged as safe, effective, and less invasive alternatives to subdural grid placement and open resection, respectively, for the localization and treatment of medically refractory epilepsy (MRE) in children. Reported pediatric experience combining these complementary techniques is limited, with traditional workflows separating electrode removal and ablation/resection. The authors describe the largest reported series of pediatric epilepsy patients who underwent MRgLITT following SEEG contrasted with a cohort that underwent craniotomy following SEEG, combining ablation/resection with electrode explantation as standard practice. METHODS: The medical records of all patients with MRE who had undergone SEEG followed by MRgLITT or open resection/disconnection at Boston Children's Hospital between November 2015 and December 2020 were retrospectively reviewed. Primary outcome variables included surgical complication rates, length of hospital stay following treatment, and Engel classification at the last follow-up. RESULTS: Of 74 SEEG patients, 27 (median age 12.1 years, 63% female) underwent MRgLITT and 47 (median age 12.1 years, 49% female) underwent craniotomy. Seventy patients (95%) underwent SEEG followed by combined electrode removal and treatment. Eight MRgLITT cases (30%) and no open cases targeted the insula (p < 0.001). Complication rates did not differ, although trends toward more subdural/epidural hematomas, infarcts, and permanent unanticipated neurological deficits were evident following craniotomy, whereas a trend toward more temporary unanticipated neurological deficits was seen following MRgLITT. The median duration of hospitalization after treatment was 3 and 5 days for MRgLITT and open cases, respectively (p = 0.078). Seizure outcomes were similar between the cohorts, with 74% of MRgLITT and craniotomy patients attaining Engel class I or II outcomes (p = 0.386) at the last follow-up (median 1.1 and 1.9 years, respectively). CONCLUSIONS: MRgLITT and open resection following SEEG can both effectively treat MRE in pediatric patients and generally can be performed in a two-surgery workflow during a single hospitalization. In appropriately selected patients, MRgLITT tended to be associated with shorter hospitalizations and fewer complications following treatment and may be best suited for focal deep-seated targets associated with relatively challenging open surgical approaches.

Machine learning models for predicting seizure outcome after MR-guided laser interstitial thermal therapy in children.

OBJECTIVE: MR-guided laser interstitial thermal therapy (MRgLITT) is associated with lower seizure-free outcome but better safety profile compared to open surgery. However, the predictors of seizure freedom following MRgLITT remain uncertain. This study aimed to use machine learning to predict seizure-free outcome following MRgLITT and to identify important predictors of seizure freedom in children with drug-resistant epilepsy. METHODS: This multicenter study included children treated with MRgLITT for drug-resistant epilepsy at 13 epilepsy centers. The authors used clinical data, diagnostic investigations, and ablation features to predict seizure-free outcome at 1 year post-MRgLITT. Patients from 12 centers formed the training cohort, and patients in the remaining center formed the testing cohort. Five machine learning algorithms were developed on the training data by using 10-fold cross-validation, and model performance was measured on the testing cohort. The models were developed and tested on the complete feature set. Subsequently, 3 feature selection methods were used to identify important predictors. The authors then assessed performance of the parsimonious models based on these important variables. RESULTS: This study included 268 patients who underwent MRgLITT, of whom 44.4% had achieved seizure freedom at 1 year post-MRgLITT. A gradient-boosting machine algorithm using the complete feature set yielded the highest area under the curve (AUC) on the testing set (AUC 0.67 [95% CI 0.50-0.82], sensitivity 0.71 [95% CI 0.47-0.88], and specificity 0.66 [95% CI 0.50-0.81]). Logistic regression, random forest, support vector machine, and neural network yielded lower AUCs (0.58-0.63) compared to the gradient-boosting machine but the findings were not statistically significant (all p > 0.05). The 3 feature selection methods identified video-EEG concordance, lesion size, preoperative seizure frequency, and number of antiseizure medications as good prognostic features for predicting seizure freedom. The parsimonious models based on important features identified by univariate feature selection slightly improved model performance compared to the complete feature set. CONCLUSIONS: Understanding the predictors of seizure freedom after MRgLITT will assist with prognostication.

Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory.

Deep brain stimulation (DBS) is an established therapeutic modality for the treatment of movement disorders and an emerging therapeutic approach for the treatment of disorders of mood and thought. For example, recently we have shown that DBS of the fornix may ameliorate cognitive decline associated with dementia. However, like other applications of DBS, the mechanisms mediating these clinical effects are unknown. As DBS modulates neurophysiological activity in targeted brain regions, DBS might influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters analogous to clinical high-frequency DBS, here we addressed this question in mice. We found that acute stimulation of the entorhinal cortex (EC) transiently promoted proliferation in the dentate gyrus (DG). Cells generated as a consequence of stimulation differentiated into neurons, survived for at least several weeks, and acquired normal dentate granule cell (DGC) morphology. Importantly, stimulation-induced promotion of neurogenesis was limited to the DG and not associated with changes in apoptotic cell death. Using immunohistochemical approaches, we found that, once sufficiently mature, these stimulation-induced neurons integrated into hippocampal circuits supporting water-maze memory. Finally, formation of water-maze memory was facilitated 6 weeks (but not 1 week) after bilateral stimulation of the EC. The delay-dependent nature of these effects matches the maturation-dependent integration of adult-generated DGCs into dentate circuits supporting water-maze memory. Furthermore, because the beneficial effects of EC stimulation were prevented by blocking neurogenesis, this suggests a causal relationship between stimulation-induced promotion of adult neurogenesis and enhanced spatial memory.

Interictal Connectivity Revealed by Granger Analysis of Stereoelectroencephalography: Association With Ictal Onset Zone, Resection, and Outcome.

BACKGROUND: Stereoelectroencephalography (sEEG) facilitates electrical sampling and evaluation of complex deep-seated, dispersed, and multifocal locations. Granger causality (GC), previously used to study seizure networks using interictal data from subdural grids, may help identify the seizure-onset zone from interictal sEEG recordings. OBJECTIVE: To examine whether statistical analysis of interictal sEEG helps identify surgical target sites and whether surgical resection of highly ranked nodes correspond to favorable outcomes. METHODS: Ten minutes of extraoperative recordings from sequential patients who underwent sEEG evaluation were analyzed (n = 20). GC maps were compared with clinically defined surgical targets using rank order statistics. Outcomes of patients with focal resection/ablation with median follow-up of 3.6 years were classified as favorable (Engel 1, 2) or poor (Engel 3, 4) to assess their relationship with the removal of highly ranked nodes using the Wilcoxon rank-sum test. RESULTS: In 12 of 20 cases, the rankings of contacts (based on the sum of outward connection weights) mapped to the seizure-onset zone showed higher causal node connectivity than predicted by chance ( P ≤ .02). A very low aggregate probability ( P < 10 -18 , n = 20) suggests that causal node connectivity predicts seizure networks. In 8 of 16 with outcome data, causal connectivity in the resection was significantly greater than in the remaining contacts ( P ≤ .05). We found a significant association between favorable outcome and the presence of highly ranked nodes in the resection ( P < .05). CONCLUSION: Granger analysis can identify seizure foci from interictal sEEG and correlates highly ranked nodes with favorable outcome, potentially informing surgical decision-making without reliance on ictal recordings.

Discrepant expressive language lateralization in children and adolescents with epilepsy.

Neuronavigated transcranial magnetic stimulation (nTMS) has emerged as a presurgical language mapping tool distinct from the widely used functional magnetic resonance imaging (fMRI). We report fMRI and nTMS language-mapping results in 19 pediatric-epilepsy patients and compare those to definitive testing by electrical cortical stimulation, Wada test, and/or neuropsychological testing. Most discordant results occurred when fMRI found right-hemispheric language. In those cases, when nTMS showed left-hemispheric or bilateral language representation, left-hemispheric language was confirmed by definitive testing. Therefore, we propose nTMS should be considered for pediatric presurgical language-mapping when fMRI shows right-hemispheric language, with nTMS results superseding fMRI results in those scenarios.

The low utility of routine cranial imaging after pediatric shunt revision.

OBJECTIVE: Postoperative routine imaging is common after pediatric ventricular shunt revision, but the benefit of scanning in the absence of symptoms is questionable. In this study, the authors aimed to assess how often routine scanning results in a change in clinical management after shunt revision. METHODS: The records of a large, tertiary pediatric hospital were retrospectively reviewed for all consecutive cases of pediatric shunt revision between July 2013 and July 2018. Postoperative imaging was classified as routine (i.e., in the absence of symptoms, complications, or other direct indications) or nonroutine. Reinterventions within 30 days were assessed in these groups. RESULTS: Of 387 included shunt revisions performed in 232 patients, postoperative imaging was performed in 297 (77%), which was routine in 244 (63%) and nonroutine in 53 (14%). Ninety revisions (23%) underwent any shunt-related procedure after postoperative imaging, including shunt reprogramming (n = 35, 9%), shunt tap (n = 10, 3%), and a return to the operating room (OR; n = 58, 15%). Of the 244 cases receiving routine imaging, 241 did not undergo a change in clinical management solely based on routine imaging findings. The remaining 3 cases returned to the OR, accounting for 0.8% (95% CI 0.0%-1.7%) of all cases or 1.2% (95% CI 0.0%-2.6%) of cases that received routine imaging. Furthermore, 27 of 244 patients in this group returned to the OR for other reasons, namely complications (n = 12) or recurrent symptoms (n = 15); all arose after initial routine imaging. CONCLUSIONS: The authors found a low yield to routine imaging after pediatric shunt revision, with only 0.8% of cases undergoing a change in management based on routine imaging findings without corresponding clinical findings. Moreover, routine imaging without abnormal findings was no guarantee of an uneventful postoperative course. Clinical monitoring can be considered as an alternative in asymptomatic, uncomplicated patients.

Limited utility of structural MRI to identify the epileptogenic zone in young children with tuberous sclerosis.

BACKGROUND AND PURPOSE: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC. METHODS: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up. Two neuroradiologists, blinded to surgical outcome data, reviewed 10 candidate lesions on preoperative MRI for characteristics of the tuber (large affected area, calcification, cyst-like properties) and of focal cortical dysplasia (FCD) features (cortical malformation, gray-white matter junction blurring, transmantle sign). They selected lesions suspect for the EZ based on structural MRI, and reselected after unblinding to seizure onset location on electroencephalography (EEG). RESULTS: None of the tuber characteristics and FCD features were distinctive for the EZ, indicated by resected lesions in seizure-free children. With structural MRI alone, the EZ was identified out of 10 lesions in 31%, and with addition of EEG data, this increased to 48%. However, rates of identification of resected lesions in non-seizure-free children were similar. Across 251 lesions, interrater agreement was moderate for large size (κ = .60), and fair (κ = .24) for all other features. CONCLUSIONS: In young children with TSC, the utility of structural MRI features is limited in the identification of the epileptogenic tuber, but improves when combined with EEG data.