Short- and long-delay consolidation of memory accessibility and precision across childhood and young adulthood.

Childhood is a period when memory consolidation and knowledge base undergo rapid changes. The present study examined short-delay (overnight) and long-delay (after a 2-week period) consolidation of new information either congruent or incongruent with prior knowledge in typically developing 6- to 8-year-old children (n = 32), 9- to 11-year-old children (n = 33), and 18- to 30-year-old young adults (YA; n = 39). Both memory accessibility (cued recall of objects) and precision (precision of object placement) of initially well-learned object-scene pairs were measured. Our results showed that overnight, memory accessibility declined similarly in all age groups; memory precision improved more in younger children (YC) compared to older children (OC) and even declined in YA. After a 2-week period, both memory accessibility and precision became worse. Specifically, while age groups showed similar decline in memory accessibility, precision decline was less in YC than in OC and YA. The accessibility and precision of congruent and incongruent information changed similarly with consolidation in all age groups. Taken together, our results showed that, for initially well-learned information, YC have robust memory consolidation, despite their overall lower mnemonic performance compared to OC and YA, which is potentially crucial for stable and precise knowledge accumulation early on in development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The importance of routine genetic testing in pediatric epilepsy surgery.

Genetic variants in relevant genes coexisting with MRI lesions in children with drug-resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. Still, presurgical evaluation does not include genetic diagnostics routinely. Here, we report our presurgical evaluation algorithm that includes routine genetic testing. We analyzed retrospectively the data of 68 children with DRE operated at a mean age of 7.8 years (IQR: 8.1 years) at our center. In 49 children, genetic test results were available. We identified 21 gene variants (ACMG III: n = 7, ACMG IV: n = 2, ACMG V: n = 12) in 19 patients (45.2%) in the genes TSC1, TSC2, MECP2, DEPDC5, HUWE1, GRIN1, ASH1I, TRIO, KIF5C, CDON, ANKD11, TGFBR2, ATN1, COL4A1, JAK2, KCNQ2, ATP1A2, and GLI3 by whole-exome sequencing as well as deletions and duplications by array CGH in six patients. While the results did not change the surgery indication, they supported counseling with respect to postoperative chance of seizure freedom and weaning of antiseizure medication (ASM). The presence of genetic findings leads to the postoperative retention of at least one ASM. In our cohort, the International League against Epilepsy (ILAE) seizure outcome did not differ between patients with and without abnormal genetic findings. However, in the 7/68 patients with an unsatisfactory ILAE seizure outcome IV or V 12 months postsurgery, 2 had an abnormal or suspicious genetic finding as a putative explanation for persisting seizures postsurgery, and 3 had received palliative surgery including one TSC patient. This study highlights the importance of genetic testing in children with DRE to address putative underlying germline variants as genetic epilepsy causes or predisposing factors that guide patient and/or parent counseling on a case-by-case with respect to their individual chance of postoperative seizure freedom and ASM weaning. PLAIN LANGUAGE SUMMARY: Genetic variants in children with drug-resistant epilepsy (DRE) can negatively influence epilepsy surgery outcomes. However, presurgical evaluation does not include genetic diagnostics routinely. This retrospective study analyzed the genetic testing results of the 68 pediatric patients who received epilepsy surgery in our center. We identified 21 gene variants by whole-exome sequencing as well as deletions and duplications by array CGH in 6 patients. These results highlight the importance of genetic testing in children with DRE to guide patient and/or parent counseling on a case-by-case with respect to their individual chance of postoperative seizure freedom and ASM weaning.

The impact of microbiota and ketogenic diet interventions in the management of drug-resistant epilepsy.

AIM: Drug-resistant epilepsy (DRE) is a neurological disorder characterized by uncontrolled seizures. It affects between 10%-40% of the patients with epilepsy worldwide. Drug-resistant patients have been reported to have a different microbiota composition compared to drug-sensitive patients and healthy controls. Importantly, fecal microbiota transplantations (FMTs), probiotic and dietary interventions have been shown to be able to reduce seizure frequency and improve the quality of life in drug-resistant patients. The classic ketogenic diet (KD) and its modifications may reduce seizures in DRE in some patients, whereas in others they do not. The mechanisms mediating the dietary effects remain elusive, although it is known that gut microbes play an important role in transmitting dietary effects to the host. Indeed, specific commensal microbes differ even between responders and non-responders to KD treatment. METHODS: In this narrative mini-review, we summarize what is known about the gut microbiota changes and ketogenic diets with special focus on patients with DRE. RESULTS AND CONCLUSIONS: By highlighting unanswered questions and by suggesting future research directions, we map the route towards future improvement of successful DRE therapy.

Real-world experience with cenobamate: A systematic review and meta-analysis.

PURPOSE: Despite many new ASM, the rate of patients with drug-resistant epilepsy (DRE) has not changed. Cenobamate (CNB) is a novel ASM for the treatment of focal-onset seizures in adults with high seizure freedom rates in randomized controlled trials (RCT). Although CNB appears to be effective, it is not commonly prescribed to patients with DRE, resulting in a lack of "real-world data". METHODS: To evaluate the real-world effect of CNB and to assess the generalizability of RCT data, a systematic review and meta-analysis was conducted. Pooled proportions were calculated using a random intercept logistic regression model. RESULTS: The analysis included seven studies with a total of 229 patients with DRE, 77.3 % of whom were adults and 91.5 % had focal-onset seizures. Seizure reduction >50 % was achieved in 68 % of patients [54.54; 79.07], with seizure freedom in 16.2 % [8.38; 28.97]. There was no difference between pediatric and adult patients. CNB was discontinued in 10 % [6.74; 14.6] of patients, mostly due to lack of efficacy (39 %) or adverse effects (AE, 43 %). AE, observed in 57.3 % [39.7; 73.2] of patients, included fatigue and vertigo. A comparison of the rates calculated in this meta-analysis to the active arm of equivalent RCTs revealed no significant difference. CONCLUSION: CNB achieves a good treatment response in patients with DRE in real-world settings, like the effect reported in RCTs. The high heterogeneity between studies calls for studies focusing on specific DRE subpopulations.

Synapsin autoantibodies during pregnancy are associated with fetal abnormalities.

Anti-neuronal autoantibodies can be transplacentally transferred during pregnancy and may cause detrimental effects on fetal development. It is unclear whether autoantibodies against synapsin-I, one of the most abundant synaptic proteins, are associated with developmental abnormalities in humans. We recruited a cohort of 263 pregnant women and detected serum synapsin-I IgG autoantibodies in 13.3% using cell-based assays. Seropositivity was strongly associated with abnormalities of fetal development including structural defects, intrauterine growth retardation, amniotic fluid disorders and neuropsychiatric developmental diseases in previous children (odds ratios of 3-6.5). Autoantibodies reached the fetal circulation and were mainly of IgG1/IgG3 subclasses. They bound to conformational and linear synapsin-I epitopes, five distinct epitopes were identified using peptide microarrays. The findings indicate that synapsin-I autoantibodies may be clinically useful biomarkers or even directly participate in the disease process of neurodevelopmental disorders, thus being potentially amenable to antibody-targeting interventional strategies in the future.

Treatment of pediatric convulsive status epilepticus.

Status epilepticus is one of the most common life-threatening neurological emergencies in childhood with the highest incidence in the first 5 years of life and high mortality and morbidity rates. Although it is known that a delayed treatment and a prolonged seizure can cause permanent brain damage, there is evidence that current treatments may be delayed and the medication doses administered are insufficient. Here, we summarize current knowledge on treatment of convulsive status epilepticus in childhood and propose a treatment algorithm. We performed a structured literature search via PubMed and ClinicalTrails.org and identified 35 prospective and retrospective studies on children <18 years comparing two and more treatment options for status epilepticus. The studies were divided into the commonly used treatment phases. As a first-line treatment, benzodiazepines buccal/rectal/intramuscular/intravenous are recommended. For status epilepticus treated with benzodiazepine refractory, no superiority of fosphenytoin, levetirazetam, or phenobarbital was identified. There is limited data on third-line treatments for refractory status epilepticus lasting >30 min. Our proposed treatment algorithm, especially for children with SE, is for in and out-of-hospital onset aids to promote the establishment and distribution of guidelines to address the treatment delay aggressively and to reduce putative permanent neuronal damage. Further studies are needed to evaluate if these algorithms decrease long-term damage and how to treat refractory status epilepticus lasting >30 min.

Epilepsy surgery in early infancy: A retrospective, multicenter study.

Although epilepsy surgery is the only curative therapeutic approach for lesional drug-resistant epilepsy (DRE), there is reluctance to operate on infants due to a fear of complications. A recent meta-analysis showed that epilepsy surgery in the first 6 months of life can achieve seizure control in about two thirds of children. However, robust data on surgical complications and postoperative cognitive development are lacking. We performed a retrospective multicenter study of infants who underwent epilepsy surgery in the first 6 months of life. 15 infants underwent epilepsy surgery at a median age of 134 days (IQR: 58) at four centers. The most common cause was malformation of cortical development, and 13 patients underwent a hemispherotomy. Two thirds required intraoperative red blood transfusions. Severe intraoperative complications occurred in two patients including death in one infant due to cardiovascular insufficiency. At a median follow-up of 1.5 years (IQR: 1.8), 57% of patients were seizure-free. Three patients where reoperated at a later age, resulting in 79% seizure freedom. Anti-seizure medication could be reduced in two thirds, and all patients improved in their development. Our findings suggest that early epilepsy surgery can result in good seizure control and developmental improvement. However, given the perioperative risks, it should be performed only in specialized centers.

Pediatric de novo movement disorders and ataxia in the context of SARS-CoV-2.

OBJECTIVE: In the fourth year of the COVID-19 pandemic, mortality rates decreased, but the risk of neuropsychiatric disorders remained the same, with a prevalence of 3.8% of pediatric cases, including movement disorders (MD) and ataxia. METHODS: In this study, we report on a 10-year-old girl with hemichorea after SARS-CoV-2 infection and immunostained murine brain with patient CSF to identify intrathecal antibodies. Additionally, we conducted a scoping review of children with MD and ataxia after SARS-CoV-2 infection. RESULTS: We detected antibodies in the patient's CSF binding unknown antigens in murine basal ganglia. The child received immunosuppression and recovered completely. In a scoping review, we identified further 32 children with de novo MD or ataxia after COVID-19. While in a minority of cases, MD or ataxia were a symptom of known clinical entities (e.g. ADEM, Sydenham's chorea), in most children, the etiology was suspected to be of autoimmune origin without further assigned diagnosis. (i) Children either presented with ataxia (79%), but different from the well-known postinfectious acute cerebellar ataxia (older age, less favorable outcome, or (ii) had hypo-/hyperkinetic MD (21%), which were choreatic in most cases. Besides 14% of spontaneous recovery, immunosuppression was necessary in 79%. Approximately one third of children only partially recovered. CONCLUSIONS: Infection with SARS-CoV-2 can trigger de novo MD in children. Most patients showed COVID-19-associated-ataxia and fewer-chorea. Our data suggest that patients benefit from immunosuppression, especially steroids. Despite treatment, one third of patients recovered only partially, which makes up an increasing cohort with neurological sequelae.

Is There a Cognitive Decline in Pediatric Patients Following Epilepsy Surgery?

BACKGROUND: Epilepsy surgery is currently the only way to cure drug-resistant epilepsy (DRE). The loss of epileptic activity or its propagation in the developing brain may not only result in seizure freedom but also be associated with further positive effects. Here, we analyzed the cognitive development of children and adolescents with DRE after epilepsy surgery. METHODS: We evaluated retrospectively the cognitive development of children and adolescents before and after epilepsy surgery. RESULTS: Fifty-three children and adolescents underwent epilepsy surgery at a median age of 7.62 years. Overall seizure freedom was 86.8% at a current median observation period of 20 months. Presurgically, 81.1% had the clinical diagnosis of cognitive impairment, which was confirmed by standardized tests in 43 of 53 patients (76.7%). Further 10 patients had severe cognitive impairment rendering a standardized test impossible. The median intelligence quotient (IQ)/development quotient value was 74. After surgery, caretakers reported developmental progress in all patients, whereas the median IQ decreased slightly (P = 0.404). In eight patients the IQ points decreased after surgery; however, their individual raw scores increased in line with their reported increase in cognitive abilities. CONCLUSIONS: We did not detect any cognitive deterioration in children following epilepsy surgery. A loss of IQ points did not correspond to a real loss of cognitive abilities. These patients developed more slowly than age-matched peers with an average development speed but profited individually as seen in their raw scores. Therefore, an individual analysis of raw scores is relevant to assess the cognitive development after surgery.

Retrospective Pediatric Cohort Study Validates NEOS Score and Demonstrates Applicability in Children With Anti-NMDAR Encephalitis.

BACKGROUND AND OBJECTIVES: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis in children and adults. Although our understanding of the disease mechanisms has progressed, little is known about estimating patient outcomes. Therefore, the NEOS (anti-NMDAR Encephalitis One-Year Functional Status) score was introduced as a tool to predict disease progression in NMDARE. Developed in a mixed-age cohort, it currently remains unclear whether NEOS can be optimized for pediatric NMDARE. METHODS: This retrospective observational study aimed to validate NEOS in a large pediatric-only cohort of 59 patients (median age of 8 years). We reconstructed the original score, adapted it, evaluated additional variables, and assessed its predictive power (median follow-up of 20 months). Generalized linear regression models were used to examine predictability of binary outcomes based on the modified Rankin Scale (mRS). In addition, neuropsychological test results were investigated as alternative cognitive outcome. RESULTS: The NEOS score reliably predicted poor clinical outcome (mRS ≥3) in children in the first year after diagnosis (p = 0.0014) and beyond (p = 0.036, 16 months after diagnosis). A score adapted to the pediatric cohort by adjusting the cutoffs of the 5 NEOS components did not improve predictive power. In addition to these 5 variables, further patient characteristics such as the "Herpes simplex virus encephalitis (HSE) status" and "age at disease onset" influenced predictability and could potentially be useful to define risk groups. NEOS also predicted cognitive outcome with higher scores associated with deficits of executive function (p = 0.048) and memory (p = 0.043). DISCUSSION: Our data support the applicability of the NEOS score in children with NMDARE. Although not yet validated in prospective studies, NEOS also predicted cognitive impairment in our cohort. Consequently, the score could help identify patients at risk of poor overall clinical outcome and poor cognitive outcome and thus aid in selecting not only optimized initial therapies for these patients but also cognitive rehabilitation to improve long-term outcomes.

Family Burden and Epilepsy Surgery in Children with Drug-Resistant Epilepsy.

INTRODUCTION: Family burden (FB) in pediatric patients with drug-resistant epilepsy (DRE) is significantly higher than that in children with non-DRE. Epilepsy surgery is an established approach to treat DRE, and this study examines the impact of pediatric epilepsy surgery on FB. METHODS: We retrospectively analyzed data of families and pediatric patients with focal structural DRE treated with epilepsy surgery at our epilepsy center from April 2018 to November 2021. We examined the relationship between cognitive, behavioral, and epilepsy-specific data and the FB measured with the German version of the Impact on Family Scale before and after epilepsy surgery. RESULTS: The study cohort included 31 children with DRE at a mean age of 9 years at surgery (range = 0-16) and a mean epilepsy duration of 3 years (range = 0-14). Cognitive impairment correlated with FB in children with DRE prior to surgery. At the last assessment, 14.5 months (mean, range = 6-24) after epilepsy surgery, 87.2% of patients were seizure-free, FB values had decreased by 75.0%, and behavioral problems had decreased by 85,7%. Cognitive functions remained stable following epilepsy surgery. CONCLUSION: In children with DRE, epilepsy surgery reduces FB. Given the considerable impact of families on the development and wellbeing of their children, the impact of epilepsy surgery should be communicated to affected families.

Primidone improves symptoms in TRPM3-linked developmental and epileptic encephalopathy with spike-and-wave activation in sleep.

Developmental and epileptic encephalopathy with continuous spike-and-wave activation in sleep (CSWS) or DEE-SWAS is an age-dependent disease, often accompanied by a decline in cognitive abilities. Early successful treatment of CSWS is associated with a better cognitive outcome. We retrospectively analyzed the clinical, electrophysiological, radiological, and genetic data of children with DEE-SWAS associated with melastatin-related transient receptor type 3 gene (TRPM3) missense variants. We report two unrelated children with pharmacoresistant DEE-SWAS and developmental delay/regression and different heterozygous de novo missense variants in the TRPM3 gene (NM_001366145.2; c.3397 T > C/p.Ser1133Pro, c.2004G > A/p.Val1002Met). The variant p.Val1002Met (previously known as p.Val990Met or p.Val837Met) and p.Ser1133Pro were recently shown to result in a gain-of-function effect. Based on this finding, previous drug resistance, and the experimentally demonstrated inhibitory effect of primidone on TRPM3, we initiated an individualized therapy with this drug. In both children, developmental regression was stopped, psychomotor development improved, and CSWS was no longer detectable. To our knowledge, this is the first report of a treatment with primidone in TRPM3-associated CSWS. Our results highlight the importance of early genetic diagnosis in patients with epilepsy and the possibility of precision medicine, which should be considered in the future in individuals with a TRPM3-linked DEE-SWAS.

Corticosteroids in childhood epilepsies: A systematic review.

Corticosteroids have been used for the treatment of patients with epilepsy for more than 6 decades, based on the hypothesis of inflammation in the genesis and/or promotion of epilepsy. We, therefore, aimed to provide a systematic overview of the use of corticosteroid regimes in childhood epilepsies in line with the PRISMA guidelines. We performed a structured literature search via PubMed and identified 160 papers with only three randomized controlled trials excluding the substantial trials on epileptic spasms. Corticosteroid regimes, duration of treatment (days to several months), and dosage protocols were highly variable in these studies. Evidence supports the use of steroids in epileptic spasms; however, there is only limited evidence for a positive effect for other epilepsy syndromes, e.g., epileptic encephalopathy with spike-and-wave activity in sleep [(D)EE-SWAS] or drug-resistant epilepsies (DREs). In (D)EE-SWAS (nine studies, 126 patients), 64% of patients showed an improvement either in the EEG or in their language/cognition following various steroid treatment regimes. In DRE (15 studies, 436 patients), a positive effect with a seizure reduction in 50% of pediatric and adult patients and seizure freedom in 15% was identified; however, no recommendation can be drawn due to the heterozygous cohort. This review highlights the immense need for controlled studies using steroids, especially in DRE, to offer patients new treatment options.

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk.

OBJECTIVE: WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regard to survival. METHODS: We studied 13 patients from 12 families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method. RESULTS: All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day-10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n = 5), myoclonic (n = 2), epileptic spasms (n = 2), focal (n = 1), and migrating focal (n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value = .0085, log-rank test). SIGNIFICANCE: Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

Maternal synapsin autoantibodies are associated with neurodevelopmental delay.

Maternal autoantibodies can be transmitted diaplacentally, with potentially deleterious effects on neurodevelopment. Synapsin 1 (SYN1) is a neuronal protein that is important for synaptic communication and neuronal plasticity. While monoallelic loss of function (LoF) variants in the SYN1 gene result in X-linked intellectual disability (ID), learning disabilities, epilepsy, behavioral problems, and macrocephaly, the effect of SYN1 autoantibodies on neurodevelopment remains unclear. We recruited a clinical cohort of 208 mothers and their children with neurologic abnormalities and analyzed the role of maternal SYN1 autoantibodies. We identified seropositivity in 9.6% of mothers, and seropositivity was associated with an increased risk for ID and behavioral problems. Furthermore, children more frequently had epilepsy, macrocephaly, and developmental delay, in line with the SYN1 LoF phenotype. Whether SYN1 autoantibodies have a direct pathogenic effect on neurodevelopment or serve as biomarkers requires functional experiments.

Case report: Compound heterozygous NUP85 variants cause autosomal recessive primary microcephaly.

Nucleoporin (NUP) 85 is a member of the Y-complex of nuclear pore complex (NPC) that is key for nucleocytoplasmic transport function, regulation of mitosis, transcription, and chromatin organization. Mutations in various nucleoporin genes have been linked to several human diseases. Among them, NUP85 was linked to childhood-onset steroid-resistant nephrotic syndrome (SRNS) in four affected individuals with intellectual disability but no microcephaly. Recently, we broaden the phenotype spectrum of NUP85-associated disease by reporting NUP85 variants in two unrelated individuals with primary autosomal recessive microcephaly (MCPH) and Seckel syndrome (SCKS) spectrum disorders (MCPH-SCKS) without SRNS. In this study, we report compound heterozygous NUP85 variants in an index patient with only MCPH phenotype, but neither Seckel syndrome nor SRNS was reported. We showed that the identified missense variants cause reduced cell viability of patient-derived fibroblasts. Structural simulation analysis of double variants is predicted to alter the structure of NUP85 and its interactions with neighboring NUPs. Our study thereby further expands the phenotypic spectrum of NUP85-associated human disorder and emphasizes the crucial role of NUP85 in the brain development and function.

Gain-of-function variants in the ion channel gene TRPM3 underlie a spectrum of neurodevelopmental disorders.

TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo variants in TRPM3 were identified in individuals with developmental and epileptic encephalopathy, but the link between TRPM3 activity and neuronal disease remains poorly understood. We previously reported that two disease-associated variants in TRPM3 lead to a gain of channel function . Here, we report a further 10 patients carrying one of seven additional heterozygous TRPM3 missense variants. These patients present with a broad spectrum of neurodevelopmental symptoms, including global developmental delay, intellectual disability, epilepsy, musculo-skeletal anomalies, and altered pain perception. We describe a cerebellar phenotype with ataxia or severe hypotonia, nystagmus, and cerebellar atrophy in more than half of the patients. All disease-associated variants exhibited a robust gain-of-function phenotype, characterized by increased basal activity leading to cellular calcium overload and by enhanced responses to the neurosteroid ligand pregnenolone sulfate when co-expressed with wild-type TRPM3 in mammalian cells. The antiseizure medication primidone, a known TRPM3 antagonist, reduced the increased basal activity of all mutant channels. These findings establish gain-of-function of TRPM3 as the cause of a spectrum of autosomal dominant neurodevelopmental disorders with frequent cerebellar involvement in humans and provide support for the evaluation of TRPM3 antagonists as a potential therapy.

Real-world data on cannabidiol treatment of various epilepsy subtypes: A retrospective, multicenter study.

OBJECTIVE: Cannabidiol (CBD) is approved for treatment of Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC). Several studies suggest antiseizure effects also beyond these three epilepsy syndromes. METHODS: In a retrospective multicenter study, we analyzed the efficacy and tolerability of CBD in patients with epilepsy at 16 epilepsy centers. RESULTS: The study cohort comprised 311 patients with epilepsy with a median age of 11.3 (0-72) years (235 children and adolescents, 76 adults). Therapy with CBD was off-label in 91.3% of cases due to age, epilepsy subtype, lack of adjunct therapy with clobazam, and/or higher dose applied. CBD titration regimens were slower than recommended, with good tolerability of higher doses particularly in children. Of all patients, 36.9% experienced a reduction in seizure frequency of >50%, independent of their epilepsy subtype or clobazam co-medication. The median observation period was 15.8 months. About one third of all patients discontinued therapy within the observation period due to adverse effects or lack of efficacy. Adverse effects were reported frequently (46.9%). SIGNIFICANCE: Our study highlights that CBD has an antiseizure effect comparable to other antiseizure medications with a positive safety profile independent of the epilepsy subtype. Comedication with clobazam was not associated with a better outcome. Higher doses to achieve seizure frequency reduction were safe, particularly in children. These findings call for further trials for an extended approval of CBD for other epilepsy subtypes and for children <2 years of age.

PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients.

Hom ozygous variants in the peptidyl-tRNA hydrolase 2 gene (PTRH2) cause infantile-onset multisystem neurologic, endocrine, and pancreatic disease. The objective is to delineate the mechanisms underlying the core cerebellar phenotype in this disease. For this, we generated constitutive (Ptrh2LoxPxhCMVCre, Ptrh2-/- mice) and Purkinje cell (PC) specific (Ptrh2LoxPxPcp2Cre, Ptrh2ΔPCmice) Ptrh2 mutant mouse models and investigated the effect of the loss of Ptrh2 on cerebellar development. We show that Ptrh2-/- knockout mice had severe postnatal runting and lethality by postnatal day 14. Ptrh2ΔPC PC specific knockout mice survived until adult age; however, they showed progressive cerebellar atrophy and functional cerebellar deficits with abnormal gait and ataxia. PCs of Ptrh2ΔPC mice had reduced cell size and density, stunted dendrites, and lower levels of ribosomal protein S6, a readout of the mammalian target of rapamycin pathway. By adulthood, there was a marked loss of PCs. Thus, we identify a cell autonomous requirement for PTRH2 in PC maturation and survival. Loss of PTRH2 in PCs leads to downregulation of the mTOR pathway and PC atrophy. This suggests a molecular mechanism underlying the ataxia and cerebellar atrophy seen in patients with PTRH2 mutations leading to infantile-onset multisystem neurologic, endocrine, and pancreatic disease.

Distinct multivariate structural brain profiles are related to variations in short- and long-delay memory consolidation across children and young adults.

From early to middle childhood, brain regions that underlie memory consolidation undergo profound maturational changes. However, there is little empirical investigation that directly relates age-related differences in brain structural measures to memory consolidation processes. The present study examined memory consolidation of intentionally studied object-location associations after one night of sleep (short delay) and after two weeks (long delay) in normally developing 5-to-7-year-old children (n = 50) and young adults (n = 39). Behavioural differences in memory retention rate were related to structural brain measures. Our results showed that children, in comparison to young adults, retained correctly learnt object-location associations less robustly over short and long delay. Moreover, using partial least squares correlation method, a unique multivariate profile comprised of specific neocortical (prefrontal, parietal, and occipital), cerebellar, and hippocampal head and subfield structures in the body was found to be associated with variation in short-delay memory retention. A different multivariate profile comprised of a reduced set of brain structures, mainly consisting of neocortical (prefrontal, parietal, and occipital), hippocampal head, and selective hippocampal subfield structures (CA1-2 and subiculum) was associated with variation in long-delay memory retention. Taken together, the results suggest that multivariate structural pattern of unique sets of brain regions are related to variations in short- and long-delay memory consolidation across children and young adults.