Understanding neurodevelopmental trajectories and behavioral profiles in SCN1A-related epilepsy syndromes.

BACKGROUND: A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families. This study describes the profile and course of the behavioral phenotype in patients with SCN1A-related epilepsy syndromes, explores correlations between behavioral difficulties and potential risk factors. METHODS: Data were collected from questionnaires, medical records, and semi-structured interviews. Behavior difficulties were measured using the Adult/Child Behavior Checklist (C/ABCL) and Adult self-report (ASR). Other questionnaires included the Pediatric Quality of Life Inventory (PedsQL), the Functional Mobility Scale (FMS) and the Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP). To determine differences in behavioral difficulties longitudinally, paired T-tests were used. Pearson correlation and Spearman rank test were used in correlation analyses and multivariable regression analyses were employed to identify potential risk factors. RESULTS: A cohort of 147 participants, including 107 participants with DS and 40 with genetic epilepsy with febrile seizures plus (GEFS + ), was evaluated. Forty-six DS participants (43.0 %) and three GEFS + participants (7.5 %) showed behavioral problems in the clinical range on the A/CBCL total problems scale. The behavioral profile in DS exists out of withdrawn behavior, aggressive behavior, and attention problems. In DS patients, sleep disturbances (ß = 1.15, p < 0.001) and a lower age (ß = -0.21, p = 0.001) were significantly associated with behavioral difficulties. Between 2015 and 2022, behavioral difficulties significantly decreased with age (t = -2.24, CI = -6.10 - -0.15, p = 0.04) in DS participants aging from adolescence into adulthood. A decrease in intellectual functioning (ß = 3.37, p = 0.02) and using less antiseizure medications in 2022 than in 2015, (ß = -1.96, p = 0.04), were identified as possible risk factors for developing (more) behavioral difficulties. CONCLUSIONS: These findings suggest that, in addition to epilepsy, behavioral difficulties are a core feature of the DS phenotype. Behavioral problems require personalized management and treatment strategies. Further research is needed to identify effective interventions.

Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of Kv7.2.

Epileptic encephalopathy (EE) is characterized by seizures that respond poorly to antiseizure drugs, psychomotor delay, and cognitive and behavioral impairments. One of the frequently mutated genes in EE is KCNQ2, which encodes the Kv7.2 subunit of voltage-gated Kv7 potassium channels. Kv7 channels composed of Kv7.2 and Kv7.3 are enriched at the axonal surface, where they potently suppress neuronal excitability. Previously, we reported that the de novo dominant EE mutation M546V in human Kv7.2 blocks calmodulin binding to Kv7.2 and axonal surface expression of Kv7 channels via their intracellular retention. However, whether these pathogenic mechanisms underlie epileptic seizures and behavioral comorbidities remains unknown. Here, we report conditional transgenic cKcnq2+/M547V mice, in which expression of mouse Kv7.2-M547V (equivalent to human Kv7.2-M546V) is induced in forebrain excitatory pyramidal neurons and astrocytes. These mice display early mortality, spontaneous seizures, enhanced seizure susceptibility, memory impairment, and repetitive behaviors. Furthermore, hippocampal pathology shows widespread neurodegeneration and reactive astrocytes. This study demonstrates that the impairment in axonal surface expression of Kv7 channels is associated with epileptic seizures, cognitive and behavioral deficits, and neuronal loss in KCNQ2-related EE.

Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits.

CDKL5 deficiency disorder (CDD) is an early onset, neurodevelopmental syndrome associated with pathogenic variants in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5). CDKL5 has been implicated in neuronal synapse maturation, yet its postdevelopmental necessity and the reversibility of CDD-associated impairments remain unknown. We temporally manipulated endogenous Cdkl5 expression in male mice and found that postdevelopmental loss of CDKL5 disrupts numerous behavioral domains, hippocampal circuit communication, and dendritic spine morphology, demonstrating an indispensable role for CDKL5 in the adult brain. Accordingly, restoration of Cdkl5 after the early stages of brain development using a conditional rescue mouse model ameliorated CDD-related behavioral impairments and aberrant NMDA receptor signaling. These findings highlight the requirement of CDKL5 beyond early development, underscore the potential for disease reversal in CDD, and suggest that a broad therapeutic time window exists for potential treatment of CDD-related deficits.

Impact of epilepsy on language and discourse: Two self-limited focal epileptic syndromes of childhood.

Self-limited focal epilepsy with centro-temporal spikes, also known as Rolandic epilepsy (RE), is a well-established focal epilepsy of childhood, characterized with language impairment. To investigate the relationship between language deficits and clinical parameters of self-limited focal epilepsies of childhood (SFEC), 21 patients with RE, 10 patients with childhood occipital epilepsy of Gastaut type (COE-G) (another SFEC that is not typically associated with language impairment), and 31 healthy controls were recruited. A broad panel of language tests also including narration sample was administered, and clinical features were documented. The language was significantly impaired in both RE and COE-G. Patients with COE-G showed worse scores than patients with RE in subtests measuring semantic functions. Clinical parameters were not associated with impaired language domains. Language impairment is experienced in different types of SFEC, emphasizing the broad representation of the language network. In SFEC, recent activity of epilepsy does not affect the severity of language dysfunction.

Neurodevelopmental outcomes in paediatric immune-mediated and autoimmune epileptic encephalopathy.

Recognition of paediatric autoimmune/immune-mediated encephalitis and epileptic encephalopathy (e.g. NMDAR-Ab encephalitis) has rapidly increased over the last ten years. While we are succeeding in the diagnosis and identification and even early treatment of these encephalitidies, with studies describing >80% are making a "good" recovery, we are now recognising that a "good" medical outcome does not cover the cognitive, social and behavioural sequelae that can occur, particularly in paediatric patients. Basic measures of medical outcome, for example the modified Rankin Scale (MRS) or the Paediatric Cerebral Performance Category (PCPC), offer the advantage of being quick to use, but do not reveal the more complex difficulties that can impact the future of affected children. This article reviews the current literature on neurodevelopmental outcomes in children affected with autoimmune and immune-mediated encephalitis/epileptic encephalopathy and provides guidance on post-onset surveillance aimed at identifying those most likely to experience ongoing long-term difficulties.

Genetic attribution and perceived impact of epilepsy in multiplex epilepsy families.

OBJECTIVE: Studies have found that affected individuals who believe the cause of their disorder is genetic may react in various ways, including optimism for improved treatments and pessimism due to perceived permanence of the condition. This study assessed the psychosocial impact of genetic attribution among people with epilepsy. METHODS: Study participants were 165 persons with epilepsy from multiplex epilepsy families who completed a self-administered survey. Psychosocial impact of epilepsy was assessed with the Impact of Epilepsy Scale, containing items about relationships, employment, overall health, self-esteem, and standard of living. Genetic attribution was assessed using a scale derived from three items asking about the role of genetics in causing epilepsy in the family, the chance of having an epilepsy-related mutation, and the influence of genetics in causing the participant's epilepsy. We estimated prevalence ratios (PRs) for impact of epilepsy above the median using Poisson regression with robust standard errors, adjusting for number of lifetime seizures and time since last seizure. RESULTS: Participants' age averaged 51 years; 87% were non-Hispanic white, 63% were women, and 54% were college graduates. The genetic attribution scale was significantly associated with having a high impact of epilepsy (adjusted PR = 1.4, 95% confidence interval = 1.07-1.91, P = .02). One of the three genetic attribution questions was also significantly associated with a high impact of epilepsy (belief that genetics had a big role in causing epilepsy in the family, adjusted PR = 1.8). SIGNIFICANCE: These findings reflect an association between the psychosocial impact of epilepsy and the belief that epilepsy has a genetic cause, among people with epilepsy in families containing multiple affected individuals. This association could arise either because belief in a genetic cause leads to increased psychosocial impacts, or because a greater psychosocial impact of epilepsy leads some to believe their epilepsy is genetic.

Social cognition and psychopathology in childhood and adolescence.

There is a substantial body of research on social cognition in adults with epilepsy, and in broad categories such as focal and generalized epilepsies, but much less has been written about social cognition in children with epilepsy (CWE), and in childhood-onset epilepsy syndromes specifically. In several of these syndromes, autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), two disorders with social cognitive impairments, are reported. There is strong evidence for social cognitive deficits in juvenile myoclonic epilepsy (JME). There is also a considerable amount of evidence for such deficits in a number of syndromes that may be associated with ASD or ADHD, including West syndrome (WS), Dravet syndrome (DS), and the Landau-Kleffner syndrome (LKS). However, the evidence is of variable quality and incomplete across the range of childhood epilepsy syndromes. In some syndromes, childhood epilepsy substantially increases the risk of severe social cognitive impairment, which may persist after the seizures remit. This paper presents an overview of current research on social cognition in childhood epilepsy, with a particular focus on syndromes with a high prevalence of autistic and behavioral comorbidities. Social cognitive impairments represent a considerable additional challenge for patients and caregivers. Early diagnosis and intervention might significantly improve long-term social cognitive outcomes, highlighting the need for greater awareness among clinicians of this important topic. This article is part of the Special Issue "Epilepsy and social cognition across the lifespan".

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder.

Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.SIGNIFICANCE STATEMENT CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures. While synaptic dysfunction has been observed in mouse models of CDD, there is limited information on how synaptic alterations contribute to behavioral and functional changes in CDD. Here we reveal elevated hippocampal GluA2-lacking AMPAR expression in a novel mouse model of CDD that is accompanied by changes in synaptic AMPAR function and plasticity. We also show, for the first time, that acutely targeting GluA2-lacking AMPAR dysregulation rescues core synaptic and neurobehavioral deficits in CDD.

Clinical spectrum of STX1B-related epileptic disorders.

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Behavior problems and health-related quality of life in Dravet syndrome.

OBJECTIVE: Behavior problems in Dravet syndrome (DS) are common and can impact the lives of patients tremendously. The current study aimed to give more insight into (1) the prevalence of a wide range of specific behavior difficulties and aspects of health-related quality of life (HRQoL) in patients with DS compared with the general population (gp) and patients with epilepsy without DS, (2) the relations between these behavior problems and different aspects of HRQoL, and (3) the associations between seizure frequency, cognitive impairment (CI), behavior problems, and HRQoL, based on a conceptual model. METHODS: One hundred and sixteen patients (aged between 2 and 67 years), affected by SCN1A-related seizures, were included in the study. Eighty-five were patients with DS, 31 were patients with epilepsy without DS. Behavior problems were measured using the Child/Adult Behavior Checklist (C/ABCL), HRQoL was measured using the Pediatric Quality of Life Inventory (PedsQL) Measurement Model. Other characteristics were obtained by clinical assessments, medical records, and semi-structured telephone interviews with parents. Comparisons between patients with DS, patients without DS, and the gp were calculated by the exact goodness of fit χ2 analyses, relations between subscales were analyzed using Pearson's correlations, and the conceptual model was tested in a path analysis. RESULTS: (1) Patients with DS show significantly more behavior problems compared with the gp and patients with epilepsy without DS. A total of 56.5% of patients with DS scored in the borderline and clinical ranges for total behavior problems. Problems with attention were most prevalent; 62.3% of patients with DS scored in the borderline and clinical ranges. Health-related quality of life was significantly lower for patients with DS compared with the gp and patients without DS. Physical and social functioning scores were especially low and decreased even more in the older age categories. (2) Problems with attention, aggression, and withdrawn behavior were most related to social functioning. Somatic problems and anxiety/depression were most related to emotional functioning. (3) Cognitive impairment and behavior problems were both independent predictors of poorer HRQoL in patients with DS, with behavior problems being the strongest predictor. Seizure frequency was only indirectly related to HRQoL, mediated by cognitive impairment. IMPLICATIONS: The high prevalence of behavior problems in DS and the significant impact on quality of life (QoL), independent of epilepsy-related factors, emphasize the need for active management and treatment of these problems and should be considered as part of the management plan.

Memory in children with epilepsy: Utility of the WRAML-2 in generalized and focal epilepsy syndromes.

The material-specific model for memory impairment predicts that verbal memory deficits are seen with left temporal seizures, and visual memory deficits are seen with right temporal seizures (Henkin et al., 2005). In pediatric epilepsy, seizure pathology has not always yielded the expected material-specific memory profiles. This study used the Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) to assess memory functioning among pediatric patients with epilepsy. The WRAML-2 was administered to 180 youth with epilepsy during their neuropsychological evaluations. Memory and recognition scores correlated significantly with epilepsy severity variables. There were no significant differences in verbal and visual memory and recognition index scores among patients with generalized epilepsy or among those with lateralized or localized electroencephalography (EEG) patterns and lesions on imaging. However, clinically meaningful verbal versus visual discrepancy scores were significantly related to lateralized abnormalities on EEG and magnetic resonance imaging (MRI) results. Most patients with right hemisphere pathology showed the expected material-specific visual memory deficits, while fewer than 15% of the left hemisphere cases showed the expected verbal memory deficits. Over one-third of those with identified left-sided pathology showed clinically significant deficits in visual memory. Findings are incongruent with the material-specific memory model and reflect the fact that early developmental neurological insults can lead to functional reorganization/crowding effects in children with left hemisphere epilepsy. On exploratory analyses, there were no significant differences in discrepancy scores among participants with left, right, and bilateral languages on Wada and functional MRI (fMRI). However, those with right and bilateral language dominance were more likely to show discrepancies that were incongruent with the material-specific model.

Comparing Parental Well-Being and Its Determinants Across Three Different Genetic Disorders Causing Intellectual Disability.

Using the Short Form 12 Health Survey this cross-sectional study examined parental well-being in caregivers of children with one of three genetic disorders associated with intellectual disability; Down syndrome, Rett syndrome and the CDKL5 disorder. Data were sourced from the Western Australian Down Syndrome (n = 291), Australian Rett Syndrome (n = 187) and International CDKL5 Disorder (n = 168) Databases. Among 596 mothers (median age, years 43.7; 24.6-72.2), emotional well-being was poorer than general female populations across age groups. Multivariate linear regression identified the poorest well-being in parents of children with the CDKL5 disorder, a rare but severe and complex encephalopathy, and negative associations with increased clinical severity irrespective of diagnosis. These findings are important for those providing healthcare and social services for these populations.

[Epileptic encephalopathies]. / Encefalopatias epilepticas.

According to the International League Against Epilepsy's (ILAE) Commission on Classification and Terminology, the term 'epileptic encephalopathy' reflects the notion that epileptic activity in itself can contribute to the genesis of severe cognitive or behavioural disabilities, beyond what could be expected from the pathology underlying the epilepsy. However, in many cases it is difficult to define the boundary between the relative contribution of the epileptic seizures and the underlying cause in the genesis of cognitive deficits. Some epileptic syndromes, such as those of West, Lennox-Gastaut or Dravet, are associated to a high probability of encephalopathic traits. The most frequent causes of epileptic encephalopathy are hypoxic-ischaemic encephalopathy, brain malformations, including cortical dysplasias, chromosomal or genetic disorders, tuberous sclerosis and metabolic diseases.

TITLE: Encefalopatias epilepticas.Segun la Comision de Clasificacion y Terminologia de la Liga Internacional contra la Epilepsia (ILAE), el termino 'encefalopatia epileptica' refleja la nocion de que la actividad epileptica en si misma puede contribuir a la genesis de graves discapacidades cognitivas o comportamentales, mas alla de lo que seria de esperar de la patologia subyacente a la epilepsia. No obstante, en muchos casos resulta dificil deslindar la contribucion relativa de las crisis epilepticas y la causa subyacente en la genesis de los deficits cognitivos. Algunos sindromes epilepticos, como los de West, Lennox-Gastaut o Dravet, se asocian con una alta probabilidad de rasgos encefalopaticos. Las causas mas frecuentes de encefalopatia epileptica son la encefalopatia hipoxico-isquemica, las malformaciones cerebrales, incluyendo las displasias corticales, las alteraciones cromosomicas o geneticas, la esclerosis tuberosa y las enfermedades metabolicas.