The Association of Therapeutic Hypothermia With Seizure Burden in Neonates With Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To compare seizure burden between newborn infants treated with therapeutic hypothermia (TH) and those that were not and to compare the need for antiseizure medications (ASM) in a cohort of infants who were diagnosed with neonatal hypoxic-ischemic encephalopathy (HIE). METHODS: This was a retrospective cohort study on infants born after 35 weeks' gestation, diagnosed with moderate to severe HIE, monitored with amplitude-integrated electroencephalography (aEEG) and eligible for TH. Infants born before the implementation of TH in 2008 were compared with infants born thereafter who received TH. Seizure burden was assessed from aEEG as total time in minutes of seizures activity per hour of recording. Other clinical and demographic data were retrieved from a prospective local database of infants with HIE. RESULTS: Overall, 149 of 207 infants were included in the study: 112 exposed to TH and 37 not exposed. Cooled infants had a lower seizure burden overall (0.4 vs 2.3 min/h, P < 0.001) and were also less likely to be treated with ASM (74% vs 100%, P < 0.001). In multivariable regression models, not exposed to TH, having a depressed aEEG background, and having higher Apgar scores were associated with higher seizure burden (incidence rate ratio: 4.78 for noncooled infants, P < 0.001); also, not exposed to TH was associated with a higher likelihood of multidrug ASM (odds ratio: 4.83, P < 0.001). CONCLUSIONS: TH in infants with moderate to severe HIE is associated with significant reduction of seizure burden and ASM therapy.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

Real-Life Outcome After Gene Replacement Therapy for Spinal Muscular Atrophy: A Multicenter Experience.

BACKGROUND: Onasemnogene abeparvovec-xioi (OA) has been available since 2019 as a gene replacement therapy for individuals with spinal muscular atrophy (SMA) under age two years. We aim to expand upon the sparse knowledge about its safety and clinical efficacy. METHODS: The clinical outcome data of all the individuals with SMA who were treated with gene therapy in four tertiary hospitals in Israel were retrieved and analyzed. RESULTS: The study participants included 25 individuals who received the gene therapy between age 11 days and 23 months and whose median follow-up duration was 18.0 (interquartile range [IQR], 12.4 to 18.3) months. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores increased by a median (IQR) of 13 (8 to 20) points at the last follow-up compared with baseline. None of the patients experienced regression in motor abilities after gene therapy, which was generally well tolerated. There was gradual improvement in motor function, especially among presymptomatic patients (P ≤ 0.001) whose disease duration was shorter (≤8 months) before receiving gene therapy (P ≤ 0.001) and who did not experience recurrent infections and illnesses in the months following treatment (P ≤ 0.001). CONCLUSIONS: OA was well tolerated and led to favorable functional motor outcomes at six to 24 months after treatment initiation. Better progress in motor function was observed in individuals who received OA earlier and who were presymptomatic, irrespective of the SMN2 copy number or type. Our results further strengthen the clinical efficacy of OA and reinforce the importance of early recognition of SMA via newborn screening programs.

Neurologic Manifestations of Influenza in Children.

OBJECTIVE: We assessed the neurologic manifestation of influenza among hospitalized children with influenza (neuro-flu), comparing their demographic and clinical characteristics to hospitalized children without neurologic manifestation (classic-flu). METHODS: A retrospective, cohort study. All children with laboratory confirmed influenza (PCR), admitted to the Soroka University Medical Center (SUMC) between 2016 and 2019 were included. RESULTS: Overall, 951 patients were identified: 201 with neuro-flu, and 750 with classic-flu. Seizures (n = 125) were the most common neurological manifestation of neuro-flu (seizure-flu): 73 simple febrile seizures, 45 atypical febrile seizures, and 7 afebrile seizures. Neurological comorbidities rates were significantly higher in neuro-flu versus classic-flu (13.0% vs. 6.0%), while respiratory and cardiac comorbidities were less common in neuro-flu (4.5% and 0.5% vs. 8.0% and 4.5%, respectively). Neuro-flu (compared with classic-flu) was associated with leukocytosis (21.0% vs. 13.0%, P < 0.001) and lower C-reactive protein (CRP) levels (2.4 ± 4.1 vs. 3.3 ± 5.4, P = 0.03). Notably, patients with classic flu had a more prominent respiratory disease, as they had more chest radiographs (CXR) performed (60.5% vs. 45.0%, P < 0.001), higher rates of pneumonia (27.0% vs. 12.0%, P < 0.001), and antibiotic (antibacterial) treatment (60.0% vs. 42.0%, P < 0.001). CONCLUSIONS: Influenza can appear as a neurologic disease, manifested mainly with febrile seizures. Children with neuro-flu have more neurologic comorbidities, suggesting that neuro-flu is mainly driven by host-factors, rather than by pathogen-factors. The relatively lower rates of pneumonia in neuro-flu suggests that these patients are admitted in the early stage of the influenza infection, which triggers the neurologic response.

Adeno-associated virus serotype 9 antibody titers in patients with SMA pre-screened for treatment with onasemnogene abeparvovec -routine care evidence.

Spinal muscular atrophy (SMA) is characterized by progressive weakness of skeletal and respiratory muscles. This study aimed to evaluate the prevalence of pre-existing anti adeno-associated virus serotype 9 antibody (AAV9-Ab) titers among infantile-onset SMA diagnosed infants pre-screened for treatment with AAV9-based onasemnogene abeparvovec, and to explore whether clinical and/or demographic characteristics are correlated with AAV9 Ab test results. This is a retrospective multicenter study of children diagnosed with 5q SMA younger than two years of age. The obtained data included demographic data, SMA type, SMN2 gene copy number, onset date, and results of AAV9-Ab test and of SMA prior treatments. Thirty-four patients were enrolled; six patients had positive results of AAV9-Ab (titer > 1:50) in the initial screening, 15 patients were re-tested for AAV9-Abs, of whom, three patients had seroreverted [1.5-4.5 months] between the two AAV9-Abs tests. One patient had seroconverted (5.5 months after the first AAV9-Abs test). The remaining 11 patients presented matching titer results in the two tests. No demographic/clinical factors were correlated to high AAV9-Abs titers (P > 0.05).We recommend AAV9-Ab re-tests to be performed until the age of 8 months, or, if 1.5 months or more have passed after the initial AAV9-Abs test.

Delayed Neuropsychiatric Sequel Following Pediatric Carbon Monoxide Poisoning: A Case Report and Literature Review.

Carbon monoxide (CO) poisoning is a serious health problem. The main pathophysiological mechanism of acute CO poisoning is hypoxia due to the formation of carboxyhemoglobin (COHb). Delayed neuropsychiatric sequel (DNPS) occurs following an interval of several days to several weeks post-CO exposure and can present in many different manifestations, ranging from behavioral and mood disorders to encephalopathy and seizures and cause long-term neuropsychiatric sequel. The pathogenesis of DNPS following CO poisoning is a complex one that encompasses hypoxia-induced encephalopathy as well as inflammation, direct cellular changes and damage. The incidence varies and treatment is debated. We display a case of a previously healthy 13-year-old boy suffering from DNPS, presenting with seizures and encephalopathy and later developing optic nerve damage. Increased awareness to this condition might help diagnose future patients and aid in the understanding of the pathogenesis and treatment options for this poorly understood condition.

Using nirmatrelvir/ritonavir in patients with epilepsy: An update from the Israeli chapter of the International League Against Epilepsy.

Presented herein are recommendations for use of nirmatrelvir/ritonavir in patients with epilepsy, as issued by the Steering Committee of the Israeli chapter of the International League Against Epilepsy. The recommendations suggest that patients on moderate-to-strong enzyme-inducing antiseizure medications (ASMs) and everolimus should not be treated with nirmatrelvir/ritonavir; rectal diazepam may be used as an alternative to buccal midazolam; doses of ASMs that are cytochrome P450 (CYP3A4) substrates might be adjusted; and patients treated with combinations of nirmatrelvir/ritonavir and ASMs that are CYP3A4 substrates or lamotrigine should be monitored for drug efficacy and adverse drug reactions.

Not your usual drug-drug interactions: Monoclonal antibody-based therapeutics may interact with antiseizure medications.

Therapeutic monoclonal antibodies (mAbs) have emerged as the fastest growing drug class. As such, mAbs are increasingly being co-prescribed with other drugs, including antiseizure medications (ASMs). Although mAbs do not share direct targets or mechanisms of disposition with small-molecule drugs (SMDs), combining therapeutics of both types can increase the risk of adverse effects and treatment failure. The primary goal of this literature review was identifying mAb-ASM combinations requiring the attention of professionals who are treating patients with epilepsy. Systematic PubMed and Embase searches (1980-2021) were performed for terms relating to mAbs, ASMs, drug interactions, and their combinations. Additional information was obtained from documents from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Evidence was critically appraised - key issues calling for clinicians' consideration and important knowledge gaps were identified, and practice recommendations were developed by a group of pharmacists and epileptologists. The majority of interactions were attributed to the indirect effects of cytokine-modulating antibodies on drug metabolism. Conversely, strong inhibitors or inducers of drug-metabolizing enzymes or drug transporters could potentially interact with the cytotoxic payload of antibody-drug conjugates, and ASMs could alter mAb biodistribution. In addition, mAbs could potentiate adverse ASM effects. Unfortunately, few studies involved ASMs, requiring the formulation of class-based recommendations. Based on the current literature, most mAb-ASM interactions do not warrant special precautions. However, specific combinations should preferably be avoided, whereas others require monitoring and potentially adjustment of the ASM doses. Reduced drug efficacy or adverse effects could manifest days to weeks after mAb treatment onset or discontinuation, complicating the implication of drug interactions in potentially deleterious outcomes. Prescribers who treat patients with epilepsy should be familiar with mAb pharmacology to better anticipate potential mAb-ASM interactions and avoid toxicity, loss of seizure control, or impaired efficacy of mAb treatment.

Prenatal Exposure to Antibiotics and Development of Epilepsy in Children.

We aimed to confirm or reject previous reports on the association of prenatal antibiotic exposure and development of epilepsy in offspring by accounting for known and unidentified confounding factors. In a retrospective cohort investigation, we enrolled children aged 3-18 years born between 1998 and 2012 at a single regional hospital and their mothers. A computerized medication database was linked with hospital records. The exposed group included children whose mothers purchased 1 or more antibiotic medications for use during pregnancy. Epilepsy was defined by epilepsy diagnosis and/or by chronic dispensing of antiepileptic drugs. We analyzed maternal exposure to antibiotics 2 years after delivery (but not during pregnancy and/or the 2 years following delivery) as part of the specificity analysis. We enrolled 88 899 children and their 74 416 mothers. The group exposed prenatally to antibiotics comprised 36 622 children (41.2%). Of them, 326 (0.9%) developed epilepsy compared with 370 of 52 277 (0.7%) in the unexposed group (relative risk [RR], 1.24; 95% confidence interval [CI], 1.07-1.44: P = .004). Exposure during the first, second, and third trimesters was characterized by incidence of epilepsy in 0.8% (P = .943), 0.9% (P = .266), and 0.9% (P = .073) of children, respectively, compared with the unexposed group, with an RR of 1.01 (95%CI, 0.83-1.23), 1.12 (95%CI, 0.92-1.36), and 1.19 (95%CI, 0.98-1.45), respectively. Similarly, prenatal exposure by antibiotic class was associated with epilepsy. Nevertheless, the specificity analysis strongly suggested the possibility of confounding by indication. Our findings indicated that pregnant women should receive the indicated antibiotic treatment with no fear of the development of epilepsy in their children.

Treating Epilepsy Patients with Investigational Anti-COVID-19 Drugs: Recommendations by the Israeli Chapter of the ILAE.

BACKGROUND: The coronavirus disease-2019 (COVID-19) and its management in patients with epilepsy can be complex. Prescribers should consider potential effects of investigational anti-COVID-19 drugs on seizures, immunomodulation by anti-seizure medications (ASMs), changes in ASM pharmacokinetics, and the potential for drug-drug interactions (DDIs). The goal of the Board of the Israeli League Against Epilepsy (the Israeli Chapter of the International League Against Epilepsy, ILAE) was to summarize the main principles of the pharmacological treatment of COVID-19 in patients with epilepsy. This guide was based on current literature, drug labels, and drug interaction resources. We summarized the available data related to the potential implications of anti-COVID-19 co-medication in patients treated with ASMs. Our recommendations refer to drug selection, dosing, and patient monitoring. Given the limited availability of data, some recommendations are based on general pharmacokinetic or pharmacodynamic principles and might apply to additional future drug combinations as novel treatments emerge. They do not replace evidence-based guidelines, should those become available. Awareness to drug characteristics that increase the risk of interactions can help adjust anti-COVID-19 and ASM treatment for patients with epilepsy.

B4GALT1-congenital disorders of glycosylation: Expansion of the phenotypic and molecular spectrum and review of the literature.

A congenital disorder of glycosylation due to biallelic mutations in B4GALT1 has been previously reported in only three patients with two different mutations. Through homozygosity mapping followed by segregation analysis in an extended pedigree, we identified three additional patients homozygous for a novel mutation in B4GALT1, expanding the phenotypic spectrum of the disease. The patients showed a uniform clinical presentation with intellectual disability, marked pancytopenia requiring chronic management, and novel features including pulmonary hypertension and nephrotic syndrome. Notably, affected individuals exhibited a moderate elevation of Man3GlcNAc4Fuc1 on serum N-glycan analysis, yet two of the patients had a normal pattern of transferrin glycosylation in repeated analysis. The novel mutation is the third disease-causing variant described in B4GALT1, and the first one within its transmembrane domain.

Seizures in Premature Infants Born at Less than 28 Weeks' Gestation.

BACKGROUND: The incidence of seizures in the neonatal period is thought to be high due to a lower seizure threshold of the immature brain. Data on seizures in extremely premature infants are scarce. OBJECTIVES: The aim of this study was to determine whether seizures are an independent risk factor for in-hospital death and to determine the incidence of seizures in extremely premature infants. METHODS: This was a retrospective cohort study. Included were infants born under 28 weeks' gestation and monitored with amplitude-integrated electroencephalography (aEEG) over the first 3 days of life. The number and duration of seizures was retrieved from aEEG recordings together with clinical data. The association of seizures and other parameters with mortality was assessed using univariable analyses methods. Relevant parameters were used for a multivariable Cox regression analysis. RESULTS: Overall, 229 infants were included in the study. Forty-six infants had at least one seizure episode yielding an incidence of 20%. In univariable analyses, gestational age (p < 0.001), birthweight Z-score (p < 0.001), seizures (p = 0.025), suppressed background aEEG (p < 0.001), and severe intraventricular hemorrhage (IVH; p < 0.001) were associated with death before discharge. In multivariable analysis, gestational age (HR = 0.61, p < 0.001), background aEEG activity (HR = 0.30, p < 0.001), birth weight Z-score (HR = 0.51, p = 0.04), and severe IVH (HR = 2.60, p < 0.001) were found to be significant predictors of mortality while the presence of seizures in the first 3 days of life trended to significantly predict an increased risk of mortality (HR = 1.53, p = 0.09). CONCLUSIONS: Although seizure incidence was relatively high in this cohort of extremely preterm infants and infants with seizures were more likely to die, seizures alone are not a predictor for early death. However, they may be an important indicator of pathologies that are not immediately diagnosed yet could eventually lead to death among this vulnerable population.

Temporal lobe surgery for intractable epilepsy in children: What to do with the hippocampus?

PURPOSE: Resection of the hippocampus can cause verbal memory decline, especially in the pediatric population. Thus, preservation of the hippocampus can be crucial for the quality of life of children with intractable temporal lobe epilepsy (TLE) who are candidates for epilepsy surgery. We investigated techniques that determine whether the hippocampus is part of the epileptogenic zone and the outcomes of pediatric surgery aimed to spare the hippocampus. METHODS: We accessed data of children with normal hippocampus on MRI, who underwent surgery for medically refractory TLE. To identify epileptogenic areas, electrocorticography was performed in patients with space occupying lesions adjacent to the hippocampus, and long term invasive monitoring in patients with nonlesional TLE. Postoperative seizure control was classified according to Engel I-IV; Class I indicates seizure-free. RESULTS: Eleven females and 11 males met study inclusion criteria; the mean age at surgery was 11.3 years. Cortical and hippocampal electrocorticography was performed in 15 patients and long term invasive hippocampal monitoring in seven. The hippocampus was preserved in 16 patients (73%) while hippocampectomy was performed in 6 (27%). At the end of a mean follow-up of 3.5 years, 94% (15/16) of the patients who did not undergo hippocampectomy were classified as Engel I, compared to 50% (3/6) who underwent hippocampectomy. CONCLUSION: Sparing the hippocampus in temporal lobe epilepsy surgery is possible with excellent seizure outcome, while using the proper intraoperative technique.

Progressive hereditary spastic paraplegia caused by a homozygous KY mutation.

Twelve individuals of consanguineous Bedouin kindred presented with autosomal recessive progressive spastic paraplegia evident as of age 0-24 months, with spasticity of lower limbs, hyperreflexia, toe walking and equinus deformity. Kyphoscolisois was evident in older patients. Most had atrophy of the lateral aspects of the tongue and few had intellectual disability. Nerve conduction velocity, electromyography and head and spinal cord magnetic resonance imaging were normal in tested subjects. Muscle biopsy showed occasional central nuclei and fiber size variability with small angular fibers. Genome-wide linkage analysis identified a 6.7Mbp disease-associated locus on chromosome 3q21.3-3q22.2 (LOD score 9.02; D3S1290). Whole-exome sequencing identified a single homozygous variant within this locus, c.51_52ins(28); p.(V18fs56*) in KY, segregating in the family as expected and not found in 190 Bedouin controls. High KY transcript levels were demonstrated in muscular organs with lower expression in the CNS. The phenotype is reminiscent of kyphoscoliosis seen in Ky null mice. Two recent studies done independently and parallel to ours describe somewhat similar phenotypes in one and two patients with KY mutations. KY encodes a tranglutaminase-like peptidase, which interacts with muscle cytoskeletal proteins and is part of a Z-band protein complex, suggesting the disease mechanism may resemble myofibrillar myopathy. However, the mixed myopathic-neurologic features caused by human and mouse Ky mutations are difficult to explain by loss of KY sarcomere stabilizing function alone. KY transcription in CNS tissues may imply that it also has a role in neuromotor function, in line with the irregularity of neuromuscular junction in Ky null mutant mice.

Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis.

A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood-brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.

Genetic risk factors for antiepileptic drug-induced hypersensitivity reactions in Israeli populations.

The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.

New DSM-5 criteria for ADHD - Does it matter?

OBJECTIVE: The new Diagnostic Statistical Manual (DSM) requires the presence of fewer symptoms to make a diagnosis of adult ADHD while the criteria for diagnosis in childhood are unchanged as compared to previous editions. This study examines the prevalence of adults meeting the revised DSM-5 symptoms cutoff as compared to the previous DSM-IV symptoms cutoff. METHOD: This study is part of a larger nationwide study that evaluated the use of, and the attitudes toward, ADHD medications by university students. 445 students from four major university faculties were surveyed and filled out questionnaires for our study. RESULTS: The proportion of participants that met the minimum threshold of six out of nine current symptoms in either of the two DSM-IV symptom domains (inattentive presentation and hyperactive/impulsive presentation) for ADHD was 12.7% while the proportion that met the minimum threshold of five symptoms in either of the DSM-5 symptom domains was 21%. CONCLUSION: Since the new DSM requires fewer current symptoms for a diagnosis of ADHD, a significant increase (65%) was observed in the number of participants meeting the new cutoff as compared to the old DSM-IV symptoms cutoff. This increase in the number of adults meeting symptoms cutoff may affect the rates of adults diagnosed with ADHD. Using the new criteria may identify more adults with ADHD and fewer diagnoses will be missed. However, meeting the new symptoms cutoff should be considered within the overall clinical context to prevent over-diagnosis.