Molecular landscapes of human hippocampal immature neurons across lifespan.

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents1,2 and are dysregulated in multiple human neurological disorders3-5. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate1,6-8. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.

A Novel Metric for Predicting Severity of Disease Features in Friedreich's Ataxia.

BACKGROUND: Friedreich's ataxia (FRDA), most commonly caused by a GAA triplet repeat (GAA-TR) expansion in intron 1 of the FXN gene, is characterized by deficiency of frataxin protein and clinical features such as progressive ataxia, dysarthria, impaired proprioception and vibration, abolished deep tendon reflexes, Babinski sign, and vision loss in association with non-neurological features such as skeletal anomalies, hearing loss, cardiomyopathy, and diabetes. Pathogenic GAA-TRs range in size from 60 to 1500 triplets and negatively correlate with age of onset. Clinical severity is predicted by a combination of GAA-TR length and disease duration (DD) via multivariable regressions, which cannot typically be used for the small sample sizes in most studies on this rare disease. OBJECTIVE: We aimed to develop a single metric, which we call "disease burden" (DB), that encompasses both GAA-TR length and DD for predicting disease features of FRDA in small sample sizes. METHODS: Linear regression and multivariable regression analysis was used to determine correlation coefficients between different disease features of FRDA. RESULTS: Using large datasets for validation, we found that DB predicts measures of neurological dysfunction in FRDA better than GAA-TR length or DD. Analogous results were found using small datasets. CONCLUSIONS: FRDA DB is a novel metric of disease severity that has utility in small datasets to demonstrate correlations that would not otherwise be evident with either GAA-TR or DD alone. This is important for discovering new biomarkers, as well as improving the prediction of severity of disease features in FRDA. © 2023 International Parkinson and Movement Disorder Society.

A quality improvement initiative to improve folic acid supplementation counseling for adolescent females with epilepsy.

OBJECTIVE: We designed a quality improvement (QI) project to improve rates of documented folic acid supplementation counseling for adolescent females with epilepsy, consistent with a quality measure from the American Academy of Neurology and American Epilepsy Society. Our SMART aim was to increase the percentage of visits at which folic acid counseling was addressed from our baseline rate of 23% to 50% by July 1, 2020. METHODS: This initiative was conducted in female patients ≥12 years old with epilepsy who were prescribed daily antiseizure medication and were seen by the 13 providers in our Neurology QI Program. Using provider interviews, we undertook a root cause analysis of low counseling rates and identified the following main factors: insufficient time during clinic visit to counsel, lack of provider knowledge, and forgetting to counsel. Countermeasures were designed to address these main root causes and were implemented through iterative plan-do-study-act (PDSA) cycles. Interventions included provider education and features within the electronic health record, which were introduced sequentially, culminating in the creation of a best practice advisory (BPA). We performed biweekly chart reviews of visits for applicable patients to establish baseline performance rate and track progress over time. We used a statistical process control p-chart to analyze the outcome measure of documented counseling. As a balancing measure, clinicians were surveyed using the Technology Adoption Model survey to assess acceptance of the BPA. RESULTS: From September 2019 to August 2022, the QI team improved rates of documented folic acid counseling from 23% to 73% through several PDSA cycles. This level of performance has been sustained over time. The most successful and sustainable intervention was the BPA. Provider acceptance of the BPA was overall positive. SIGNIFICANCE: We successfully used QI methodology to improve and sustain our rates of documented folic acid supplementation counseling for adolescent females with epilepsy.

Proposal for an updated seizure classification framework in clinical trials.

The International League Against Epilepsy (ILAE) seizure classification scheme has been periodically updated to improve its reliability and applicability to clinicians and researchers alike. Here, members of the Epilepsy Study Consortium propose a pragmatic seizure classification, based on the ILAE scheme, designed for use in clinical trials with a focus on outcome measures that have high reliability, broad interpretability across stakeholders, and clinical relevance in the context of the development of novel antiseizure medications. Controversies around the current ILAE classification scheme are discussed in the context of clinical trials, and pragmatic simplifications to the existing scheme are proposed, for intended use by investigators, industry sponsors, and regulatory agencies.

Stereoelectroencephalography before 2 years of age.

OBJECTIVE: Stereoelectroencephalography (SEEG) is a widely used technique for localizing seizure onset zones prior to resection. However, its use has traditionally been avoided in children under 2 years of age because of concerns regarding pin fixation in the immature skull, intraoperative and postoperative electrode bolt security, and stereotactic registration accuracy. In this retrospective study, the authors describe their experience using SEEG in patients younger than 2 years of age, with a focus on the procedure's safety, feasibility, and accuracy as well as surgical outcomes. METHODS: A retrospective review of children under 2 years of age who had undergone SEEG while at Children's Hospital of Philadelphia between November 2017 and July 2021 was performed. Data on clinical characteristics, surgical procedure, imaging results, electrode accuracy measurements, and postoperative outcomes were examined. RESULTS: Five patients younger than 2 years of age underwent SEEG during the study period (median age 20 months, range 17-23 months). The mean age at seizure onset was 9 months. Developmental delay was present in all patients, and epilepsy-associated genetic diagnoses included tuberous sclerosis (n = 1), KAT6B (n = 1), and NPRL3 (n = 1). Cortical lesions included tubers from tuberous sclerosis (n = 1), mesial temporal sclerosis (n = 1), and cortical dysplasia (n = 3). The mean number of placed electrodes was 11 (range 6-20 electrodes). Bilateral electrodes were placed in 1 patient. Seizure onset zones were identified in all cases. There were no SEEG-related complications, including skull fracture, electrode misplacement, hemorrhage, infection, cerebrospinal fluid leakage, electrode pullout, neurological deficit, or death. The mean target point error for all electrodes was 1.0 mm. All patients proceeded to resective surgery, with a mean follow-up of 21 months (range 8-53 months). All patients attained a favorable epilepsy outcome, including Engel class IA (n = 2), IC (n = 1), ID (n = 1), and IIA (n = 1). CONCLUSIONS: SEEG can be safely, accurately, and effectively utilized in children under age 2 with good postoperative outcomes using standard SEEG equipment. With minimal modification, this procedure is feasible in those with immature skulls and guides the epilepsy team's decision-making for early and optimal treatment of refractory epilepsy through effective localization of seizure onset zones.

5-Year Activity and Participation Outcomes of the First Successful Pediatric Bilateral Hand Transplantation: A Case Report.

AIMS: Describe the 5-year outcomes of the first successful pediatric bilateral hand transplantation. METHODS: The child underwent quadrimembral amputation at age two and received bilateral hand allografts at age eight. Rehabilitation included biomechanical, neurorehabilitation, and occupational approaches in acute and outpatient settings. Therapist observed outcomes, patient-reported measures, and parent-reported measures were repeated over a 5-year period. RESULTS: Observation assessments revealed functional dexterity skills and modified independence to full independence with self-care activities. The parent reported the child had moderate difficulty with upper extremity functioning 25-, 41-, and 48-months post-transplantation, and mild difficulty at 60-months; the child reported no difficulties in this domain at 41 months. Five years post-transplantation the child reported enjoying many age-appropriate activities, and high-quality peer relations were endorsed by both parent and child. CONCLUSION: The child developed hand movements for daily activities and was completing daily activities with improved efficiency. Health-related quality of life outcomes were favorable.

Periodic and rhythmic patterns in critically ill children: Incidence, interrater agreement, and seizures.

OBJECTIVES: We aimed to determine the incidence of periodic and rhythmic patterns (PRP), assess the interrater agreement between electroencephalographers scoring PRP using standardized terminology, and analyze associations between PRP and electrographic seizures (ES) in critically ill children. METHODS: This was a prospective observational study of consecutive critically ill children undergoing continuous electroencephalographic monitoring (CEEG). PRP were identified by one electroencephalographer, and then two pediatric electroencephalographers independently scored the first 1-h epoch that contained PRP using standardized terminology. We determined the incidence of PRPs, evaluated interrater agreement between electroencephalographers scoring PRP, and evaluated associations between PRP and ES. RESULTS: One thousand three hundred ninety-nine patients underwent CEEG. ES occurred in 345 (25%) subjects. PRP, ES + PRP, and ictal-interictal continuum (IIC) patterns occurred in 142 (10%), 81 (6%), and 93 (7%) subjects, respectively. The most common PRP were generalized periodic discharges (GPD; 43, 30%), lateralized periodic discharges (LPD; 34, 24%), generalized rhythmic delta activity (GRDA; 34, 24%), bilateral independent periodic discharges (BIPD; 14, 10%), and lateralized rhythmic delta activity (LRDA; 11, 8%). ES risk varied by PRP type (p < .01). ES occurrence was associated with GPD (odds ratio [OR] = 6.35, p < .01), LPD (OR = 10.45, p < .01), BIPD (OR = 6.77, p < .01), and LRDA (OR = 6.58, p < .01). Some modifying features increased the risk of ES for each of those PRP. GRDA was not significantly associated with ES (OR = 1.34, p = .44). Each of the IIC patterns was associated with ES (OR = 6.83-8.81, p < .01). ES and PRP occurred within 6 h (before or after) in 45 (56%) subjects. SIGNIFICANCE: PRP occurred in 10% of critically ill children who underwent CEEG. The most common patterns were GPD, LPD, GRDA, BIPD, and LRDA. The GPD, LPD, BIPD, LRDA, and IIC patterns were associated with ES. GRDA was not associated with ES.

Assessing seizure burden in pediatric epilepsy using an electronic medical record-based tool through a common data element approach.

OBJECTIVE: Improvement in epilepsy care requires standardized methods to assess disease severity. We report the results of implementing common data elements (CDEs) to document epilepsy history data in the electronic medical record (EMR) after 12 months of clinical use in outpatient encounters. METHODS: Data regarding seizure frequency were collected during routine clinical encounters using a CDE-based form within our EMR. We extracted CDE data from the EMR and developed measurements for seizure severity and seizure improvement scores. Seizure burden and improvement was evaluated by patient demographic and encounter variables for in-person and telemedicine encounters. RESULTS: We assessed a total of 1696 encounters in 1038 individuals with childhood epilepsies between September 6, 2019 and September 11, 2020 contributed by 32 distinct providers. Childhood absence epilepsy (n = 121), Lennox-Gastaut syndrome (n = 86), and Dravet syndrome (n = 42) were the most common epilepsy syndromes. Overall, 43% (737/1696) of individuals had at least monthly seizures, 17% (296/1696) had a least daily seizures, and 18% (311/1696) were seizure-free for >12 months. Quantification of absolute seizure burden and changes in seizure burden over time differed between epilepsy syndromes, including high and persistent seizure burden in patients with Lennox-Gastaut syndrome. Individuals seen via telemedicine or in-person encounters had comparable seizure frequencies. Individuals identifying as Hispanic/Latino, particularly from postal codes with lower median household incomes, were more likely to have ongoing seizures that worsened over time. SIGNIFICANCE: Standardized documentation of clinical data in childhood epilepsies through CDE can be implemented in routine clinical care at scale and enables assessment of disease burden, including characterization of seizure burden over time. Our data provide insights into heterogeneous patterns of seizure control in common pediatric epilepsy syndromes and will inform future initiatives focusing on patient-centered outcomes in childhood epilepsies, including the impact of telemedicine and health care disparities.

Differential antiseizure medication sensitivity of the Affective Reactivity Index: A randomized controlled trial in new-onset pediatric focal epilepsy.

BACKGROUND: Irritability is a adverse effect of many antiseizure medications (ASMs), but there are no validated measures currently available to characterize this behavioral risk. We examined both child and parent/guardian versions of the Affective Reactivity Index (ARI), a validated measure developed for application in adolescent psychiatry, to determine its sensitivity to ASM-related irritability. We hypothesized irritability increases associated with levetiracetam (LEV) but not lamotrigine (LTG) or oxcarbazepine (OXC). METHOD: The ARI was administered to 71 child and parent/guardian pairs randomized to one of three common ASMs (LEV, LTG, OXC) used to treat new-onset focal (localization-related) epilepsy. Subjects were recruited as part of a prospective multicenter, randomized, open-label, parallel group design. The ARI was administered at baseline prior to treatment initiation and again at 3 months after ASM initiation. RESULTS: There was a significant increase in ARI ratings for both child and parent/guardian ratings for LEV but not LTG or OXC when assessed 3 months after treatment initiation. When examined on the individual subject level using a criterion of at least a 3-point ARI increase, there was an increase associated with LEV for child ratings but not parent/guardian scores. CONCLUSION: Both child and parent/guardian versions of the ARI appear sensitive to medication-induced irritability associated with LEV on both the group and individual levels. The findings extend the applicability of ARI from characterizing the presence of clinical irritability as a psychiatric diagnostic feature to a more modifiable aspect of behavior change related to medication management and support its use in clinical trial applications.

Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy.

OBJECTIVE: Autosomal-recessive mutations in TBCK cause intellectual disability of variable severity. Although the physiological function of TBCK remains unclear, loss-of-function mutations are associated with inhibition of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Given that mTORC1 signaling is known to regulate autophagy, we hypothesized that TBCK-encephalopathy patients with a neurodegenerative course have defects in autophagic-lysosomal dysfunction. METHODS: Children (n = 8) of Puerto Rican (Boricua) descent affected with homozygous TBCK p.R126X mutations underwent extensive neurological phenotyping and neurophysiological studies. We quantified autophagosome content in TBCK-/- patient-derived fibroblasts by immunostaining and assayed autophagic markers by western assay. Free sialylated oligosaccharide profiles were assayed in patient's urine and fibroblasts. RESULTS: The neurological phenotype of children with TBCK p.R126X mutations, which we call TBCK-encephaloneuronopathy (TBCKE), include congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy, and epilepsy. Systemic features include coarse facies, dyslipidemia, and osteoporosis. TBCK-/- fibroblasts in vitro exhibit increased numbers of LC3+ autophagosomes and increased autophagic flux by immunoblots. Free oligosaccharide profiles in fibroblasts and urine of TBCKE patients differ from control fibroblasts and are ameliorated by treatment with the mTORC1 activator leucine. INTERPRETATION: TBCKE is a clinically distinguishable syndrome with progressive central and peripheral nervous system dysfunction, consistently observed in patients with the p.R126X mutation. We provide evidence that inappropriate autophagy in the absence of cellular stressors may play a role in this disorder, and that mTORC1 activation may ameliorate the autophagic-lysosomal system dysfunction. Free oligosaccharide profiles could serve as a novel biomarker for this disorder as well as a tool to evaluate potential therapeutic interventions. Ann Neurol 2018;83:153-165.

Magnifying the View of the Hand Changes Its Cortical Representation. A Transcranial Magnetic Stimulation Study.

Changes in the perceived size of a body part using magnifying lenses influence tactile perception and pain. We investigated whether the visual magnification of one's hand also influences the motor system, as indexed by transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs). In Experiment 1, MEPs were measured while participants gazed at their hand with and without magnification of the hand. MEPs were significantly larger when participants gazed at a magnified image of their hand. In Experiment 2, we demonstrated that this effect is specific to the hand that is visually magnified. TMS of the left motor cortex did not induce an increase of MEPs when participants looked at their magnified left hand. Experiment 3 was performed to determine if magnification altered the topography of the cortical representation of the hand. To that end, a 3 × 5 grid centered on the cortical hot spot (cortical location at which a motor threshold is obtained with the lowest level of stimulation) was overlaid on the participant's MRI image, and all 15 sites in the grid were stimulated with and without magnification of the hand. We confirmed the increase in the MEPs at the hot spot with magnification and demonstrated that MEPs significantly increased with magnification at sites up to 16.5 mm from the cortical hot spot. In Experiment 4, we used paired-pulse TMS to measure short-interval intracortical inhibition and intracortical facilitation. Magnification was associated with an increase in short-interval intracortical inhibition. These experiments demonstrate that the visual magnification of one's hand induces changes in motor cortex excitability and generates a rapid remapping of the cortical representation of the hand that may, at least in part, be mediated by changes in short-interval intracortical inhibition.

Early discontinuation of antiseizure medications in neonates with hypoxic-ischemic encephalopathy.

OBJECTIVE: Neonates with hypoxic-ischemic encephalopathy (HIE) managed with therapeutic hypothermia (TH) often experience acute symptomatic seizures, prompting treatment with antiseizure medications (ASMs). Because the risk of seizure occurrence after hospital discharge is unknown, the optimal ASM treatment duration is unclear. We aimed to determine the risk of seizure occurrence after hospital discharge and the impact of ASM treatment duration on this outcome. METHODS: We performed a single-center, retrospective study of consecutive neonates with HIE managed with TH who received ASMs for acute symptomatic seizures from June 2010 through December 2014. Neonates were monitored with continuous electroencephalography (EEG) during TH. RESULTS: Follow-up data were available for 59 (82%) of 72 neonates who survived to discharge, with a median follow-up period of 19 months (interquartile range [IQR] 11-25). Acute symptomatic seizures occurred in 35 neonates (59%), including electrographic seizures in 21 neonates (36%). ASMs were continued upon discharge in 17 (49%) of 35 neonates. Seizures occurred in follow-up in four neonates (11%). No patient for whom ASMs were discontinued prior to discharge experienced seizures during the follow-up period. SIGNIFICANCE: Among neonates with HIE, seizures after hospital discharge were rare in those with acute symptomatic seizures and did not occur in neonates without acute symptomatic seizures. ASM discontinuation prior to discharge did not increase the risk of seizures during the follow-up period, suggesting that ASMs may be discontinued in many neonates prior to discharge.

16p11.2 deletion and duplication: Characterizing neurologic phenotypes in a large clinically ascertained cohort.

Chromosome 16p11.2 deletions and duplications are among the most frequent genetic etiologies of autism spectrum disorder (ASD) and other neurodevelopmental disorders, but detailed descriptions of their neurologic phenotypes have not yet been completed. We utilized standardized examination and history methods to characterize a neurologic phenotype in 136 carriers of 16p11.2 deletion and 110 carriers of 16p11.2 duplication-the largest cohort to date of uniformly and comprehensively characterized individuals with the same 16p copy number variants (CNVs). The 16p11.2 deletion neurologic phenotype is characterized by highly prevalent speech articulation abnormalities, limb and trunk hypotonia with hyporeflexia, abnormalities of agility, sacral dimples, seizures/epilepsy, large head size/macrocephaly, and Chiari I/cerebellar tonsillar ectopia. Speech articulation abnormalities, hypotonia, abnormal agility, sacral dimples, and seizures/epilepsy are also seen in duplication carriers, along with more prominent hyperreflexia; less, though still prevalent, hyporeflexia; highly prevalent action tremor; small head size/microcephaly; and cerebral white matter/corpus callosum abnormalities and ventricular enlargement. The neurologic phenotypes of these reciprocal 16p11.2 CNVs include both shared and distinct features. Reciprocal phenotypic characteristics of predominant hypo- versus hyperreflexia and macro- versus microcephaly may reflect opposite neurobiological abnormalities with converging effects causing the functional impairments shared between 16p11.2 deletion and duplication carriers (i.e., abnormal motor agility and articulation). While the phenotypes exhibit overlap with other genetically-caused neurodevelopmental disorders, clinicians should be aware of the more striking features-such as the speech and motor impairments, growth abnormalities, tremor, and sacral dimples-when evaluating individuals with developmental delay, intellectual disability, ASD, and/or language disorders. © 2016 Wiley Periodicals, Inc.

Lacosamide use in children with epilepsy: Retention rate and effect of concomitant sodium channel blockers in a large cohort.

OBJECTIVES: To evaluate the effectiveness of lacosamide (LCM) in pediatric patients, using time to treatment failure as the outcome measure, and to assess the impact of concomitant sodium channel blocker (SCB) use on LCM retention. METHODS: This is a retrospective cohort study of patients <21 years old receiving LCM from 2010 to 2015. Kaplan-Meier survival curves were generated for time to LCM failure, defined as discontinuation of LCM or addition of another antiepileptic therapy. The impact of concomitant use of traditional SCB agents (phenytoin, carbamazepine, oxcarbazepine, and/or lamotrigine) and other factors including age, seizure types, fast drug titration, and prior antiepileptic drug history were evaluated using Cox regression. RESULTS: The analysis cohort included 223 patients, of whom 116 were taking one or more SCBs, with median follow-up of 7.4 months (1-53 months). For all patients, the probability of remaining on LCM without addition of another therapy was 44.7% at 12 months and 25.6% at 24 months. Concomitant SCB use was an independent predictor of time to LCM failure (hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.38-2.65, p < 0.001).Although treatment emergent adverse effects were reported more often in patients taking SCB (65% vs. 39%, p < 0.001), intolerability was rarely the sole reason cited for LCM discontinuation, and SCB use was strongly associated with LCM failure, even when controlling for presence of treatment emergent adverse effects (adjusted HR 1.99, 95% CI 1.36-2.90, p < 0.001). SIGNIFICANCE: This study provides observational evidence for treatment persistence of LCM in children, in a large cohort with long-term follow-up, using time to treatment failure as the outcome measure. Concomitant SCB use was a key factor increasing risk of LCM failure, but not due to treatment-emergent adverse effects alone.

Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.

OBJECTIVES: We aimed to determine whether implementation of a structured multidisciplinary electroencephalography (EEG) monitoring pathway improved the timeliness of administration of antiseizure medication in response to electrographic seizures in encephalopathic critically ill children. METHODS: A multidisciplinary team developed a pathway to standardize EEG monitoring and seizure management in encephalopathic critically ill children, aiming to decrease the time from electrographic seizure onset to antiseizure medication administration. Data were collected to inform the team of improvement opportunities, which were then provided by an institutional pathway, staff education, and streamlined communication. Measurements were obtained before and after pathway implementation to assess for improvement. RESULTS: We collected data on 41 patients before and 21 after pathway implementation. There were no differences between the baseline and pathway groups in demographic characteristics, acute encephalopathy etiologies, or antiseizure medications utilized. The median duration [interquartile range, IQR] from seizure onset to antiseizure medication administration was shorter for patients treated with the pathway (64 min [50, 101]) compared to patients treated prior to pathway implementation (139 min [71, 189]; p = 0.0006). The median [IQR] interval from seizure onset to antiseizure medication order was shorter for the pathway group (31 min [20, 49]) than the baseline group (71 min [33, 131]; p = 0.003). The median [IQR] interval from antiseizure medication order to administration was shorter for the pathway group (30 min [19, 40]) than the baseline group (40 min [17, 68]) (p = 0.047). Seizure termination was more likely to occur following initial antiseizure medication administration in the pathway than baseline group (67% vs. 27%, p = 0.002). SIGNIFICANCE: Implementation of the pathway resulted in a significant reduction in the duration between electrographic seizure onset and antiseizure medication administration, and a significant increase in the rate of electrographic seizure termination following an initial antiseizure medication. Further study is needed to determine whether these changes are associated with improved outcomes.

Risk of seizure recurrence after achieving initial seizure freedom on the ketogenic diet.

OBJECTIVE: Few studies have examined the long-term sustainability of complete seizure freedom on the ketogenic diet (KD). The purpose of this study was to describe the risk of seizure recurrence in children who achieved at least 1 month of seizure freedom on the KD, and to assess clinical features associated with sustained seizure freedom. METHODS: Records of patients initiated on the KD at The Children's Hospital of Philadelphia (CHOP) from 1991 to 2009 were reviewed. Subjects who attained seizure freedom for at least 1 month within 2 years were included in the study. Seizure frequency was recorded based on caregiver-reported seizure diaries as unchanged, improved, or worse compared to baseline. Those patients with seizure freedom ≥1 year were compared to those with seizure freedom <1 year in terms of demographics, age of seizure onset, number of antiepileptic drugs (AEDs) prior to KD, and epilepsy classification. RESULTS: Of 276 patients initiated on the KD, 65 patients (24%) attained seizure freedom for a minimum of 1 month. The majority of these patients had daily seizures. The median time to seizure freedom after KD initiation was 1.5 months. Seizures recurred in 53 patients (82%), with a median time to seizure recurrence of 3 months. However, seizure frequency after initial recurrence remained far less than baseline. No clinical features were identified as risk factors for seizure recurrence. SIGNIFICANCE: Seizure recurrence on the KD after 1 month of seizure freedom most often occurred as occasional breakthrough seizures and not a return to baseline seizure frequency. This study provides evidence to support the continued use of the KD in patients with initial seizure freedom even after breakthrough seizures. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Diagnostic Yield of CSF Testing in Infants for Disorders of Biogenic Amine Neurotransmitter Metabolism.

BACKGROUND AND OBJECTIVES: Biochemical testing of CSF for neurotransmitter metabolites and their cofactors is often used in the diagnostic evaluation of infants with neurologic disorders but requires an invasive, labor-intensive procedure with many potential sources of error. Our aim was to determine the diagnostic yield of CSF testing for biogenic amines (serotonin, norepinephrine, epinephrine, and dopamine) and their cofactors in identifying inborn errors of neurotransmitter metabolism among infants. METHODS: We evaluated all infants aged 1 year or younger who underwent CSF biogenic amine neurotransmitter (CSFNT) testing at Children's Hospital of Philadelphia (CHOP) and Boston Children's Hospital (BCH) between 2008 and 2017 in this cross-sectional study. The primary outcome was the proportion of individuals who received a diagnostic result from CSFNT testing. Secondary assessments included the proportion of infants who obtained a diagnostic result from other types of diagnostic testing. RESULTS: The cohort included 323 individuals (191 from CHOP and 232 from BCH). The median age at presentation was 110 days (range 36-193). The most common presenting features were seizures (71%), hypotonia (47%), and developmental delay (43%). The diagnostic yield of CSFNT testing was zero. When CSF pyridoxal-5-phosphate level was assayed with CSFNT testing, 1 patient had a diagnostic result. An etiologic diagnosis was identified in 163 patients (50%) of the cohort, with genetic testing having the highest yield (120 individuals, 37%). DISCUSSION: Our findings support the case for deimplementation of CSFNT testing as a standard diagnostic test of etiology in infants aged 1 year or younger presenting with neurologic disorders.

Surgical Treatments for Epilepsies in Children Aged 1-36 Months: A Systematic Review.

BACKGROUND AND OBJECTIVES: Early life epilepsies (epilepsies in children 1-36 months old) are common and may be refractory to antiseizure medications. We summarize findings of a systematic review commissioned by the American Epilepsy Society to assess evidence and identify evidence gaps for surgical treatments for epilepsy in children aged 1-36 months without infantile spasms. METHODS: EMBASE, MEDLINE, PubMed, and the Cochrane Library were searched for studies published from 1/1/1999 to 8/19/21. We included studies reporting data on children aged 1 month to ≤36 months undergoing surgical interventions or neurostimulation for epilepsy and enrolling ≥10 patients per procedure. We excluded studies of infants with infantile spasms or status epilepticus. For effectiveness outcomes (seizure freedom, seizure frequency), studies were required to report follow-up at ≥ 12 weeks. For harm outcomes, no minimum follow-up was required. Outcomes for all epilepsy types, regardless of etiology, were reported together. RESULTS: Eighteen studies (in 19 articles) met the inclusion criteria. Sixteen prestudies/poststudies reported on efficacy, and 12 studies addressed harms. Surgeries were performed from 1979 to 2020. Seizure freedom for infants undergoing hemispherectomy/hemispherotomy ranged from 7% to 76% at 1 year after surgery. For nonhemispheric surgeries, seizure freedom ranged from 40% to 70%. For efficacy, we concluded low strength of evidence (SOE) suggests some infants achieve seizure freedom after epilepsy surgery. Over half of infants undergoing hemispherectomy/hemispherotomy achieved a favorable outcome (Engel I or II, International League Against Epilepsy I to IV, or >50% seizure reduction) at follow-up of >1 year, although studies had key limitations. Surgical mortality was rare for functional hemispherectomy/hemispherotomy and nonhemispheric resections. Low SOE suggests postoperative hydrocephalus is uncommon for infants undergoing nonhemispheric procedures for epilepsy. DISCUSSION: Although existing evidence remains sparse and low quality, some infants achieve seizure freedom after surgery and ≥50% achieve favorable outcomes. Future prospective studies in this age group are needed. In addition to seizure outcomes, studies should evaluate other important outcomes (developmental outcomes, quality of life [QOL], sleep, functional performance, and caregiver QOL). TRIAL REGISTRATION INFORMATION: This systematic review was registered in PROSPERO (CRD42021220352) on March 5, 2021.

Pharmacologic and Dietary Treatments for Epilepsies in Children Aged 1-36 Months: A Systematic Review.

BACKGROUND AND OBJECTIVES: Early life epilepsies are common and often debilitating, but no evidence-based management guidelines exist outside of those for infantile spasms. We conducted a systematic review of the effectiveness and harms of pharmacologic and dietary treatments for epilepsy in children aged 1-36 months without infantile spasms. METHODS: We searched EMBASE, MEDLINE, PubMed, and the Cochrane Library for studies published from January 1, 1999, to August 19, 2021. Using prespecified criteria, we identified studies reporting data on children aged 1-36 months receiving pharmacologic or dietary treatments for epilepsy. We did not require that studies report etiology-specific data. We excluded studies of neonates, infantile spasms, and status epilepticus. We included studies administering 1 of 29 pharmacologic treatments and/or 1 of 5 dietary treatments reporting effectiveness outcomes at ≥ 12 weeks. We reviewed the full text to find any subgroup analyses of children aged 1-36 months. RESULTS: Twenty-three studies met inclusion criteria (6 randomized studies, 2 nonrandomized comparative studies, and 15 prestudies/poststudies). All conclusions were rated low strength of evidence. Levetiracetam leads to seizure freedom in some infants (32% and 66% in studies reporting seizure freedom), but data on 6 other medications were insufficient to permit conclusions about effectiveness (topiramate, lamotrigine, phenytoin, vigabatrin, rufinamide, and stiripentol). Three medications (levetiracetam, topiramate, and lamotrigine) were rarely discontinued because of adverse effects, and severe events were rare. For diets, the ketogenic diet leads to seizure freedom in some infants (rates 12%-37%), and both the ketogenic diet and modified Atkins diet reduce average seizure frequency, but reductions are greater with the ketogenic diet (1 RCT reported a 71% frequency reduction at 6 months for ketogenic diet vs only a 28% reduction for the modified Atkins diet). Dietary harms were not well-reported. DISCUSSION: Little high-quality evidence exists on pharmacologic and dietary treatments for early life epilepsies. Future research should isolate how treatments contribute to outcomes, conduct etiology-specific analyses, and report patient-centered outcomes such as hospitalization, neurodevelopment, functional performance, sleep quality, and patient and caregiver quality of life. TRIAL REGISTRATION INFORMATION: This systematic review was registered in PROSPERO (CRD42021220352) on March 5, 2021.

Leveraging electronic medical record-embedded standardised electroencephalogram reporting to develop neonatal seizure prediction models: a retrospective cohort study.

BACKGROUND: Accurate prediction of seizures can help to direct resource-intense continuous electroencephalogram (CEEG) monitoring to neonates at high risk of seizures. We aimed to use data from standardised EEG reports to generate seizure prediction models for vulnerable neonates. METHODS: In this retrospective cohort study, we included neonates who underwent CEEG during the first 30 days of life at the Children's Hospital of Philadelphia (Philadelphia, PA, USA). The hypoxic ischaemic encephalopathy subgroup included only patients with CEEG data during the first 5 days of life, International Classification of Diseases, revision 10, codes for hypoxic ischaemic encephalopathy, and documented therapeutic hypothermia. In January, 2018, we implemented a novel CEEG reporting system within the electronic medical record (EMR) using common data elements that incorporated standardised terminology. All neonatal CEEG data from Jan 10, 2018, to Feb 15, 2022, were extracted from the EMR using age at the time of CEEG. We developed logistic regression, decision tree, and random forest models of neonatal seizure prediction using EEG features on day 1 to predict seizures on future days. FINDINGS: We evaluated 1117 neonates, including 150 neonates with hypoxic ischaemic encephalopathy, with CEEG data reported using standardised templates between Jan 10, 2018, and Feb 15, 2022. Implementation of a consistent EEG reporting system that documents discrete and standardised EEG variables resulted in more than 95% reporting of key EEG features. Several EEG features were highly correlated, and patients could be clustered on the basis of specific features. However, no simple combination of features adequately predicted seizure risk. We therefore applied computational models to complement clinical identification of neonates at high risk of seizures. Random forest models incorporating background features performed with classification accuracies of up to 90% (95% CI 83-94) for all neonates and 97% (88-99) for neonates with hypoxic ischaemic encephalopathy; recall (sensitivity) of up to 97% (91-100) for all neonates and 100% (100-100) for neonates with hypoxic ischaemic encephalopathy; and precision (positive predictive value) of up to 92% (84-96) in the overall cohort and 97% (80-99) in neonates with hypoxic ischaemic encephalopathy. INTERPRETATION: Using data extracted from the standardised EEG report on the first day of CEEG, we predict the presence or absence of neonatal seizures on subsequent days with classification performances of more than 90%. This information, incorporated into routine care, could guide decisions about the necessity of continuing EEG monitoring beyond the first day, thereby improving the allocation of limited CEEG resources. Additionally, this analysis shows the benefits of standardised clinical data collection, which can drive learning health system approaches to personalised CEEG use. FUNDING: Children's Hospital of Philadelphia, the Hartwell Foundation, the National Institute of Neurological Disorders and Stroke, and the Wolfson Foundation.