Clinical Experience With Lacosamide as an Adjunct Treatment for Neonatal Seizures: A Retrospective Single-Center Study.

BACKGROUND: Lacosamide (LCM) is a third-generation antiseizure medication (ASM) currently approved for the treatment of focal seizures in children aged greater than one month. There are limited data on its efficacy in the neonatal age group. We describe our experience with LCM as an adjunct ASM for the treatment of neonatal seizures. METHODS: A retrospective chart review over a five-year period (2018 to 2022) was conducted at Le Bonheur Children's Hospital to identify neonates with electroencephalography (EEG)-proven seizures who were treated with LCM. Data were collected on electroclinical seizure characteristics, underlying etiology, ASMs, treatment response, and any adverse effects. RESULTS: A total of 15 neonates with EEG-confirmed seizures who were treated with LCM were included. Ten neonates achieved seizure cessation after LCM was added to their ASM regimen consisting of phenobarbital, levetiracetam, or both. No new treatment-related adverse effects were noted. CONCLUSIONS: LCM is effective as an adjunct treatment for neonatal seizures. Randomized controlled studies are needed to establish its effectiveness and adequate dosing regimen in this population.

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.

Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy.

Importance: Genomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling. Objective: To delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy. Design, Setting, and Participants: This cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy. Exome sequencing was performed for 522 patients and available biological parents, and sequencing data were analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs). Variant pathogenicity was assessed, patients were provided with their diagnostic results, and clinical utility was evaluated. Patients were enrolled from August 2018 to October 2021, and data were analyzed through December 2022. Exposures: Phenotypic features associated with diagnostic genetic results. Main Outcomes and Measures: Main outcomes included diagnostic yield and clinical utility. Diagnostic findings included variants curated as pathogenic, likely pathogenic (PLP), or diagnostic variants of uncertain significance (VUS) with clinical features consistent with the involved gene's associated phenotype. The proportion of the cohort with diagnostic findings, the genes involved, and their clinical utility, defined as impact on clinical treatment, prognosis, or surveillance, are reported. Results: A total of 522 children (269 [51.5%] male; mean [SD] age at seizure onset, 1.2 [1.4] years) were enrolled, including 142 children (27%) with developmental epileptic encephalopathy and 263 children (50.4%) with intellectual disability. Of these, 100 participants (19.2%) had identifiable genetic explanations for their seizures: 89 participants had SNVs (87 germline, 2 somatic mosaic) involving 69 genes, and 11 participants had CNVs. The likelihood of identifying a genetic diagnosis was highest in patients with intellectual disability (adjusted odds ratio [aOR], 2.44; 95% CI, 1.40-4.26), early onset seizures (aOR, 0.93; 95% CI, 0.88-0.98), and motor impairment (aOR, 2.19; 95% CI 1.34-3.58). Among 43 patients with apparently de novo variants, 2 were subsequently determined to have asymptomatic parents harboring mosaic variants. Of 71 patients who received diagnostic results and were followed clinically, 29 (41%) had documented clinical utility resulting from their genetic diagnoses. Conclusions and Relevance: These findings suggest that pediatric-onset epilepsy is genetically heterogeneous and that some patients with previously unexplained pediatric-onset epilepsy had genetic diagnoses with direct clinical implications.

Rhythmic mid-Temporal Theta of Drowsiness Activated by Hyperventilation- Uncommon Trigger of a Rare Benign EEG Variant in Pediatrics. An Educational Review.

Distinguishing abnormal electroencephalogram (EEG) waveforms from benign variants is critical for accurate interpretation of EEG. Hyperventilation (HV) is one of the basic procedures during EEG to enable activation of epileptiform activity. Rarely, HV can activate benign EEG rhythms. Herein, we illustrate two pediatric cases with bursts of rhythmic mid-temporal theta of drowsiness (RMTD), activated by hyperventilation. Continued awareness of this EEG phenomenology and its variations in pediatrics is important in avoiding misdiagnosis of epilepsy.

Safety evaluation of perampanel as monotherapy or first adjunctive therapy in patients with epilepsy.

INTRODUCTION: There is a need for anti-seizure medications (ASMs) that are well tolerated and effective as monotherapy or first adjunctive therapy to reduce the need for adjunctive ASMs to treat newly diagnosed epilepsy, and to reduce the number of concomitant ASMs in patients with refractory epilepsy. Although the pivotal trials of perampanel evaluated its adjunctive use in patients with refractory seizures, open-label/real-world studies support its use in first/second-line settings. AREAS COVERED: This paper reviews the pharmacology, efficacy, and safety/tolerability of perampanel, focusing on its use as monotherapy or first adjunctive therapy. The safety of perampanel in special populations and its safety/tolerability compared with that of other ASMs is also discussed. EXPERT OPINION: Perampanel is a favorable candidate for initial or first adjunctive therapy due to its favorable efficacy and safety/tolerability as monotherapy and adjunctive therapy, its long half-life and ease of use, and its limited drug-drug interactions. The proposed mitigation strategies for managing the risk of serious psychiatric adverse events are appropriate patient selection, use of low doses, and slow titration. The growing body of evidence might shift current treatment strategies toward the early use of perampanel and its use at a low dose (4 mg/day).

Infantile spasms: Assessing the diagnostic yield of an institutional guideline and the impact of etiology on long-term treatment response.

OBJECTIVE: Neuroimaging and genetic testing have been proposed for diagnostic evaluation of infantile spasms (IS), establishing etiology in ~60% of multicenter IS cohorts. A retrospective analysis of the yield of diagnostic etiology following an institutionally established guideline for investigation/treatment of IS was conducted, and the association between etiological subgroups and sustained response to standard treatment was evaluated. METHODS: Etiology of IS, neuroimaging, and genetic results were extracted from clinical records. Etiology was categorized as acquired or nonacquired, the latter including syndromic patients, nonsyndromic patients with confirmed etiology, and unknown cases. Regression analyses, using clinical variables including subtypes of etiology, were conducted to determine which factors correlated with favorable (spasm freedom at last follow-up after two or fewer standard treatments) versus unfavorable treatment outcome (refractory spasms despite two standard treatments or relapse). RESULTS: We included 127 IS patients (60% males) with a follow-up of 2.4 years (range = .6-5 years). All patients had neuroimaging, and 95% of patients in the nonacquired category (103 of 108 patients) had genetic testing. Etiology was identified in 103 of 127 (81%, 95% confidence interval = .73-.86). At last follow-up, 42 (33%) patients had favorable treatment outcome. No difference in treatment response was observed between acquired and nonacquired etiologies. Among patients with nonacquired etiologies, developmental delay prior to spasms onset increased the odds of unfavorable treatment outcome (p = .014), whereas a clearly recognizable dysmorphic/syndromic etiology was associated with a lower risk for treatment failure (p = .034). In nonacquired etiology without a recognizable dysmorphic/syndrome but with a genetic etiology, unfavorable treatment outcome was more likely (p = .043). SIGNIFICANCE: Rigorous evaluation with neuroimaging and genetic testing yields an etiological diagnosis in most patients with IS. Among patients with a nonacquired etiology, those with recognizable dysmorphic/syndromic diagnosis had a higher likelihood of a favorable treatment outcome, whereas the absence of such a finding, when associated with an identifiable genetic diagnosis, was associated with unfavorable treatment outcomes.

Changes in the Functional Brain Network of Children Undergoing Repeated Epilepsy Surgery: An EEG Source Connectivity Study.

About 30% of children with drug-resistant epilepsy (DRE) continue to have seizures after epilepsy surgery. Since epilepsy is increasingly conceptualized as a network disorder, understanding how brain regions interact may be critical for planning re-operation in these patients. We aimed to estimate functional brain connectivity using scalp EEG and its evolution over time in patients who had repeated surgery (RS-group, n = 9) and patients who had one successful surgery (seizure-free, SF-group, n = 12). We analyzed EEGs without epileptiform activity at varying time points (before and after each surgery). We estimated functional connectivity between cortical regions and their relative centrality within the network. We compared the pre- and post-surgical centrality of all the non-resected (untouched) regions (far or adjacent to resection) for each group (using the Wilcoxon signed rank test). In alpha, theta, and beta frequency bands, the post-surgical centrality of the untouched cortical regions increased in the SF group (p < 0.001) whereas they decreased (p < 0.05) or did not change (p > 0.05) in the RS group after failed surgeries; when re-operation was successful, the post-surgical centrality of far regions increased (p < 0.05). Our data suggest that removal of the epileptogenic focus in children with DRE leads to a gain in the network centrality of the untouched areas. In contrast, unaltered or decreased connectivity is seen when seizures persist after surgery.

Insular Magnetoencephalography Dipole Clusters in Patients With Refractory Focal Epilepsy.

PURPOSE: The clinical significance of magnetoencephalography (MEG) dipole clusters in the insular region in patients with focal epilepsy, when present in conjunction with MEG dipole clusters in other regions of the brain is not known. METHODS: All patients (adult and pediatric) with MEG dipole clusters involving the insula were retrospectively evaluated. Patients who underwent any form of surgical intervention were included in the study. Data obtained included age, sex, seizure characteristics, MRI brain, EEG, MEG, intracranial EEG, type of intervention, and seizure outcomes. RESULTS: Twenty-four patients (12 adults and 12 pediatric) were included. Eight patients had one staged intervention and 16 had intracranial evaluation. Ten of 11 patients (91%) with insular coverage by stereotactic EEG had interictal insular spikes, and 5 of 11 patients (45%) had ictal onset from the insula. Combined Engel (I & II) outcomes were seen in five patients with resections/ablations involving the insula MEG dipole clusters as compared with eight patients where the insular MEG dipole clusters were not resected/ablated. CONCLUSIONS: Insular MEG dipole clusters identified on surface MEG correlated with interictal spikes in intracranial stereotactic electrode contacts in the insula. The presence of insular MEG dipole clusters, however, does not definitively imply a primary insular onset epilepsy.

Cognitive and functional status in late-onset Lennox-Gastaut syndrome: Variation on a classic phenotype.

Lennox-Gastaut syndrome (LGS) denotes a refractory epileptic encephalopathy of childhood onset with the triad of generalized slow spike-wave (GSSW) on interictal scalp electroencephalogram (EEG), multiple seizure types, and intellectual impairment. The neurobiology of LGS is said to sustain abnormal patterns of brain activity and connectivity that ultimately impair normal cerebral developmental mechanisms. However, we describe eight patients from our combined practice who presented with electroclinical findings consistent with LGS but without significant cognitive impairment. All patients fulfilled the other criteria of LGS with multiple seizure types (three or more of generalized tonic-clonic, atonic, tonic, myoclonic, and atypical absence) and GSSW activity on EEG. Four subjects completed high school, two completed some college, two acquired college degrees, and all performed basic and instrumental activities of daily living (ADL) independently. Magnetic resonance imaging (MRI) was normal in all patients. We speculate that a variation of the classic phenotype of LGS can present with preserved cognitive and functional status, often with onset in the second decade of life, and associated with normal brain imaging.

Expanding the Phenotypic Spectrum of CACNA1H Mutations.

BACKGROUND: The CACNA1H gene mutations encoding the α1H subunit of Cav3.2 T-type calcium channels have been associated with generalized epilepsy. Focal or multifocal epilepsy and systemic (immunologic and gastrointestinal) involvement associated with these mutations have not been described previously. We detail the clinical characteristics of five patients with CACNA1H mutations and expand its phenotypic spectrum. METHODS: A case series of five patients with pathogenic CACNA1H mutations was evaluated. The pathogenicity of the mutations was predicted by polymorphism phenotyping (Polyphen-2) and sorting-intolerant-from-tolerant analysis. RESULTS: Mean age of seizure onset was 8.2 ± 3.7 years. Three patients had de novo mutations in the CACNA1H gene, and two patients inherited the mutation from an asymptomatic parent. The patients experienced different types of seizures including absence, focal seizures without awareness, focal seizures with secondary generalization, and myoclonic, atonic, and generalized tonic-clonic seizures. Electroencephalography showed focal, multifocal, or generalized discharges. One patient had autism and global developmental delay. Two patients had failure to thrive and selective antibody deficiency. CONCLUSIONS: CACNA1H mutations can be associated with susceptibility to develop generalized epilepsy and focal or multifocal epilepsy of varying severity. Phenotypic features involving other organ systems (immune, gastrointestinal) can occur in addition to epilepsy, developmental delay, and autism.

An Infant Born to a Mother With Anti-N-Methyl-d-Aspartate Receptor Encephalitis.

BACKGROUND: Anti-N-Methyl-D-Aspartate receptor (NMDAR) encephalitis is an autoimmune disorder that often affects women of childbearing age, and maternal-fetal transfer of anti-NMDAR antibodies during pregnancy has been documented in both symptomatic and asymptomatic women. The effects of these antibodies on the fetus, however, are incompletely understood. PATIENT DESCRIPTION: This term infant exhibited depressed respiratory effort, poor feeding, and abnormal movements after birth. Magnetic resonance imaging revealed diffuse cerebral edema with ischemic and hemorrhagic injury. Her mother had experienced anti-NMDAR encephalitis secondary to an ovarian teratoma 18 months earlier. The baby's serum NMDAR antibody titer was elevated at 1:320. Intravenous immunoglobulin did not result in clinical improvement, and care was withdrawn on day of life 20. Her mother had an elevated serum NMDAR antibodies (1:80), positive CSF antibody titers, and a new ovarian teratoma. CONCLUSION: Routine testing of NMDAR antibodies in pregnant women with a previous history of anti-NMDAR encephalitis may be warranted. Infants born to these mothers should be closely monitored throughout pregnancy and after birth.

Involvement of Cerebellum in Leigh Syndrome: Case Report and Review of the Literature.

BACKGROUND: Leigh syndrome is an early-onset progressive neurodegenerative disorder typically involving lesions of the bilateral basal ganglia, thalami, and brainstem. Isolated involvement of the cerebellum is uncommon. PATIENT DESCRIPTION: We present a six-year-old boy with Leigh syndrome who presented with recurrent episodes of ataxia and dysarthria. He was diagnosed with Leigh syndrome at two years of age with bilateral basal ganglia lesions on brain magnetic resonance imaging (MRI). Genetic testing confirmed a diagnosis of Leigh syndrome secondary to a homoplasmic mitochondrial DNA mutation (m.9176T>C). He experienced regressive episodes (ages five and six years). Each regressive episode had a similar presentation with worsening of baseline ataxia and dysarthria. The first episode mimicked infectious cerebellitis, with elevated cerebral spinal fluid (CSF) protein and white blood cell count. No organisms were isolated from the CSF/blood during any of the regressive episodes. Brain MRI consistently showed cerebellar lesions, however cerebellar spectroscopy during the second episode found an elevated lactate peak, a decrease of the N-acetylaspartate peak, and elevation of the choline peak; consistent with an acute exacerbation of Leigh syndrome. CONCLUSIONS: Leigh syndrome can present primarily with involvement of the cerebellum, and it should be considered in the differential diagnosis for acute cerebellitis.

NICU admissions and maternal stress levels.

OBJECTIVE: To determine the stress levels among mothers of babies admitted in Neonatal Intensive Care Unit (NICU) and to identify demographic parameters that influence their stress levels. METHODS: Stress levels were assessed using Parental Stressor Scale: Neonatal Intensive Care Unit (PSS: NICU) questionnaire among 100 NICU mothers by doctors between 6 and 8 d of admission. Maternal stress was quantified using Likert scale as low (1-2.9), medium (3-3.9) and high (4-5). The data was analyzed using SPSS Ver.16. RESULTS: The mean scores for the subscales sights and sounds, looks and behaviour and alteration in the parental role were 2.55, 4.1 and 4.12 respectively. Increased maternal age, prematurity of baby, longer NICU stay and inability to directly breastfeed the baby were associated with higher stress levels. CONCLUSIONS: NICU mothers are under significant stress and appropriate counseling targeted towards specific stressors is required.

Stressors of NICU mothers and the effect of counseling-experience from a tertiary care teaching hospital, India.

OBJECTIVE: To determine the effect of counseling on stress levels of NICU mothers. METHODS: Stress levels were assessed using the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) questionnaire among 100 NICU mothers. After providing counseling including NICU educational support, the questionnaire was re-administered after 48 h. Coding of the responses was done and the data was analyzed using SPSS Ver.16. RESULTS: The mean pre intervention subscale stress score was highest for parental role alteration (4.12) followed by looks and behavior of the baby (4.10) and sights and sounds (2.55). There was significant reduction in the post-counseling stress levels among NICU mothers in all three sub scales of PSS:NICU. CONCLUSION: Counseling of mothers whose babies are admitted to the NICU with regards to various aspects of the infant`s environment and condition was significantly effective in reducing the stress levels of mothers.