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Objectives: We assessed the adherence to neuroimaging guidelines and the diagnostically relevant yield of neuroimaging in newly presenting early life epilepsy (ELE)., Methods: There were 775 children with a new diagnosis of epilepsy (<3 years old at onset) who were recruited through the ELE study at 17 US pediatric epilepsy centers (2012-2015) and managed prospectively for 1 year. The data were analyzed to assess the proportion of children who underwent neuroimaging, the type of neuroimaging, and abnormalities., Results: Of 725 children (93.5%) with neuroimaging, 714 had an MRI (87% with seizure protocols) and 11 had computed tomography or ultrasound only. Etiologically relevant abnormalities were present in 290 individuals (40%) and included: an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%). Neuroimaging was abnormal in 160 of 262 (61%) children with abnormal development at diagnosis versus 113 of 463 (24%) children with typical development. Neuroimaging abnormalities were most common in association with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%). In children without spasms or focal semiology with typical development, 29 of 185 (16%) had imaging abnormalities. Pathogenic genetic variants were identified in 53 of 121 (44%) children with abnormal neuroimaging in whom genetic testing was performed., Conclusions: Structural abnormalities occur commonly in ELE, and adherence to neuroimaging guidelines is high at US pediatric epilepsy centers. These data support the universal adoption of imaging guidelines because the yield is substantially high, even in the lowest risk group., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Wirrell has received a consulting fee from Biomarin; Dr Knupp has served as a consultant for Zogenix and has an additional grant funded by the Pediatric Epilepsy Research Foundation; Dr Sullivan has served as an expert witness in various cases that involve seizures in children in which he was not subpoenaed. Subjects who were enrolled in this study by Dr Sullivan were seen as part of routine clinical care; Dr Patel discloses consulting with Greenwich Biosciences, UCB Pharma, Supernus, and LivaNova. He has pending or active grants with the Pediatric Epilepsy Research Foundation, Upsher-Smith, Greenwich Biosciences, and LivaNova; Dr Loddenkemper discloses board membership service on the council (and as president) of the American Clinical Neurophysiology Society and the American Board of Clinical Neurophysiology. He serves as committee chair at the American Epilepsy Society (Special Interest Group and Investigator Workshop committees) and as founder and consortium principal investigator of the pediatric Status Epilepticus Research Group. He received grant support from federal epilepsy-related groups as well as from pharmaceutical companies, including research support from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Epilepsy Research Fund, the American Epilepsy Society, the Epilepsy Foundation of America, the Epilepsy Therapy Project, the Pediatric Epilepsy Research Foundation, and Citizens United for Research in Epilepsy, and he received research grants from Lundbeck, Eisai, Upsher-Smith, Mallinckrodt, Sage, and Pfizer. Dr Loddenkemper is part of pending patent applications to detect and predict seizures and to diagnose epilepsy; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Importance: More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown., Objective: To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy., Design, Setting, and Participants: The Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age., Exposures: Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure., Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations., Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60])., Conclusions and Relevance: Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

Objective: There are no evidence-based guidelines on the preferred approach to treating early-life epilepsy. We examined initial therapy selection in a contemporary US cohort of children with newly diagnosed, nonsyndromic, early-life epilepsy (onset before age three years)., Methods: Seventeen pediatric epilepsy centers participated in a prospective cohort study of children with newly diagnosed epilepsy with onset under 36 months of age. Details regarding demographics, seizure types, and initial medication selections were obtained from medical records., Results: About half of the 495 enrolled children with new-onset, nonsyndromic epilepsy were less than 12 months old at the time of diagnosis (n = 263, 53%) and about half (n = 260, 52%) had epilepsy with focal features. Of 464 who were treated with monotherapy, 95% received one of five drugs: levetiracetam (n = 291, 63%), oxcarbazepine (n = 67, 14%), phenobarbital (n = 57, 12%), topiramate (n = 16, 3.4%), and zonisamide (n = 13, 2.8%). Phenobarbital was prescribed first for 50 of 163 (31%) infants less than six months old versus seven of 300 (2.3%) of children six months or older (P < 0.0001). Although the first treatment varied across study centers (P < 0.0001), levetiracetam was the most commonly prescribed medication regardless of epilepsy presentation (focal, generalized, mixed/uncertain). Between the first and second treatment choices, 367 (74%) of children received levetiracetam within the first year after diagnosis., Conclusions: Without any specific effort, the pediatric epilepsy community has developed an unexpectedly consistent approach to initial treatment selection for early-life epilepsy. This suggests that a standard practice is emerging and could be utilized as a widely acceptable basis of comparison in future drug studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established., Objective: To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies., Design, Setting, and Participants: In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined., Exposures: Genetic diagnostic testing., Main Outcomes and Measures: Laboratory-confirmed pathogenic variant., Results: Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%])., Conclusions and Relevance: Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.

Multimodal coregistration uses multiple image datasets coregistered to an anatomical reference (i.e. MRI), allowing multiple studies to be viewed together. Commonly used in intractable epilepsy evaluation and generally accepted to improve localization of the epileptogenic zone, data showing that coregistration improves outcome is lacking. We compared seizure freedom following epilepsy surgery in paediatric patients, evaluated before and after the use of coregistration protocols at our centre, to determine whether this correlated with a change in outcome. We included paediatric epilepsy surgery patients with at least one anatomical and one functional neuroimaging study as part of their presurgical evaluation. Preoperatively designated palliative procedures and repeat surgeries were excluded. Multiple pre-, peri-, and postoperative variables were compared between groups with the primary outcome of seizure freedom. In total, 115 were included with an average age of 10.63 years (0.12-20.7). All evaluations included video-EEG (VEEG) and MRI. Seven (6%) had subtraction single-photon emission CT (SPECT), 46 (40%) had positron emission tomography (PET), and 62 (54%) had both as part of their evaluation. Sixty (52%) had extratemporal epilepsy and 25 (22%) were MRI-negative. Sixty-eight (59%) had coregistration. Coregistered patients were less likely to undergo invasive EEG monitoring (p=0.045) and were more likely to have seizure freedom at one (p=0.034) and two years (p<0.001) post-operatively. A logistic regression accounting for multiple covariates supported an association between the use of coregistration and favourable post-surgical outcome. Coregistered imaging contributes to favourable postoperative seizure reduction compared to visual analysis of individual modalities. Imaging coregistration is associated with improved outcome, independent of other variables after surgery. Coregistered imaging may reduce the need for invasive EEG monitoring, likely due to improved confidence in presurgical localization. These findings support the use of multimodal coregistered imaging as part of the presurgical assessment in patients evaluated for surgical treatment of intractable epilepsy.

Epilepsy surgery is the most effective therapeutic approach for children with drug resistant epilepsy (DRE). Recent advances in neurosurgery, such as the Laser Interstitial Thermal Therapy (LITT), improved the safety and non-invasiveness of this method. Electric and magnetic source imaging (ESI/MSI) plays critical role in the delineation of the epileptogenic focus during the presurgical evaluation of children with DRE. Yet, they are currently underutilized even in tertiary epilepsy centers. Here, we present a case of an adolescent who suffered from DRE for 16 years and underwent surgery at Cook Children's Medical Center (CCMC). The patient was previously evaluated in a level 4 epilepsy center and treated with multiple antiseizure medications for several years. Presurgical evaluation at CCMC included long-term video electroencephalography (EEG), magnetoencephalography (MEG) with simultaneous conventional EEG (19 channels) and high-density EEG (256 channels) in two consecutive sessions, MRI, and fluorodeoxyglucose - positron emission tomography (FDG-PET). Video long-term EEG captured nine focal-onset clinical seizures with a maximal evolution over the right frontal/frontal midline areas. MRI was initially interpreted as non-lesional. FDG-PET revealed a small region of hypometabolism at the anterior right superior temporal gyrus. ESI and MSI performed with dipole clustering showed a tight cluster of dipoles in the right anterior insula. The patient underwent intracranial EEG which indicated the right anterior insular as seizure onset zone. Eventually LITT rendered the patient seizure free (Engel 1; 12 months after surgery). Retrospective analysis of ESI and MSI clustered dipoles found a mean distance of dipoles from the ablated volume ranging from 10 to 25 mm. Our findings highlight the importance of recent technological advances in the presurgical evaluation and surgical treatment of children with DRE, and the underutilization of epilepsy surgery in children with DRE. [ABSTRACT FROM AUTHOR]

Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages, clinical etiologies, and associated-genes between spasms and non-spasms groups in a multicenter cohort of 509 infants (<12months) with newly-diagnosed epilepsy. Gene ontology and pathway enrichment analysis of clinical laboratory-confirmed pathogenic variant-harboring genes was performed. Pathways, functions, and cellular compartments between spasms and non-spasms groups were compared. Spasms onset age was similar in infants initially presenting with spasms (6.1 months) versus developing spasms as a later seizure type (6.9 months) but lower in the non-spasms group (4.7 months, p<0.0001). This pattern held across most etiological categories. Gestational age negatively correlated with spasms onset-age (r = -0.29, p<0.0001) but not with non-spasm seizure age. Spasms were significantly preferentially associated with broad developmental and regulatory pathways, whereas motor functions and pathways including cellular response to stimuli, cell motility and ion transport were preferentially enriched in non-spasms. Neuronal cell-body organelles preferentially associated with spasms, while, axonal, dendritic, and synaptic regions preferentially associated with other seizures. Spasms are a clinically and biologically distinct infantile seizure type. Comparative clinical-epidemiological analyses identify the middle of the first year as the time of peak expression regardless of etiology. The inverse association with gestational age suggests the preterm brain must reach a certain post-conceptional, not just chronological, neurodevelopmental stage before spasms manifest. Clear differences exist between the biological pathways leading to spasms versus other seizure types and suggest that spasms result from dysregulation of multiple developmental pathways and involve different cellular components than other seizure types. This deeper level of understanding may guide investigations into pathways most critical to target in future precision medicine efforts. [ABSTRACT FROM AUTHOR]

Objective The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia. Methods Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation. Results Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio ( OR) 2.6, 95% confidence interval ( CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment ( OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset ( OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy ( OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin ( OR 5.2 ,95% CI 2-13.7), prednisolone ( OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) . Significance First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia. [ABSTRACT FROM AUTHOR]

Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts. Children with newly diagnosed epilepsy and onset < 3 years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1 year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome. Seven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5 months (interquartile range (IQR): 4.2–16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (< 12 months). Of 680 children followed ≥ 6 months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes. Early-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles. • Early outcomes of early life epilepsy are poor. • Drug resistance develops within a year in over one-third of children. • Development is already delayed at seizure onset in over a third of children. • In children with initially no or mild delay, definite delays emerge in a quarter. • Developmental worsening is especially common in drug-resistant infantile epilepsy. [ABSTRACT FROM AUTHOR]