Pathophysiological Mechanisms Fostering Developmental and Epileptic Encephalopathies (DEE): a Complex Interplay between Genetics, Inflammation and Neurodegeneration.

A survey of adult caregivers of people with developmental and epileptic encephalopathies: A long-term care planning needs assessment.

We aimed to determine the population-based cumulative incidence and prevalence of developmental and epileptic encephalopathies (DEEs) and intellectual disability and epilepsy (ID+E) in children. We analyzed the cumulative incidence of specific epilepsy syndromes. Children younger than 16 years with a DEE or ID+E were ascertained using EEG records from 2000 to 2016 in the Wellington region of New Zealand. Epilepsy syndromes were diagnosed on medical record and EEG review. Point prevalence and cumulative incidence for children with epilepsy and developmental impairment, DEE and ID+E were calculated. Cumulative incidence for each epilepsy syndrome was calculated. The cohort comprised 235 children (58% male) with developmental impairment and epilepsy, including 152 (65%) with DEE and 83 (35%) with ID+E. The median age of seizure onset was 15.4 months (range day 1-15 years). The median follow-up from seizure onset was 7.9 years (range 0-18.2 years). Point prevalence for the broad group of children with epilepsy and developmental impairment was 175/100,000 children (95% CI 149-203; DEE 112 and ID+E 63/100,000 children). Cumulative incidence for DEE was 169/100,000 children (95% CI 144-199) and that for ID+E was 125/100,000 children (95% CI 95.4-165). Cumulative incidence per 100,000 children was as follows: infantile epileptic spasms syndrome 58.2 (95% CI 45.0-75.3), epilepsy with myoclonic-atonic seizures 16.4 (95% CI 9.69-27.7), Lennox-Gastaut syndrome 13.2 (95% CI 4.1-41.9), and Dravet syndrome 5.1 (95% CI 2.1-12.2). Fifty/152 (33%) of children with DEE and 70/83 (84%) with ID+E could not be diagnosed with a known epilepsy syndrome. Epilepsy and developmental impairment before the age of 16 years occurs in 1 in 340 children, with 1 in 590 having a DEE and 1 in 800 having ID+E. These individuals require significant health and community resources; therefore, these data will inform complex health service and education planning. Epidemiologic studies have focused on early childhood-onset DEEs. These do not fully reflect the burden of these disorders because 27% of DEEs and 70% of ID+E begin later, with seizure onset after the age of 3 years. Understanding the cumulative incidence of specific syndromes together with the broad group of DEEs is essential for the planning of therapeutic trials. Given trials focus on specific syndromes, there is a risk that effective therapies will not be developed for one-third of children with DEE.

Highly purified cannabidiol (CBD) is approved as adjunctive therapy for seizures associated with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC), although its role in other developmental and epileptic encephalopathies (DEEs) remains unexplored. The aim of this study was to assess the real-world use, efficacy, and safety of CBD across a broad cohort of patients with DEEs, including off-label indications. In this retrospective study, we evaluated 107 patients with DEEs treated with CBD for ≥3 months between 2020 and 2024. Data on seizure frequency, tolerability, retention, and non-seizure outcomes were collected. Efficacy was defined as ≥50% or ≥75% seizure reduction. Statistical analyses explored predictors of response. Patients had LGS (55.1%), DS (16.8%), TSC (8.4%), or other DEEs (19.6%), with a genetic etiology in 56.1%. At a median follow-up of 20 months, 69% achieved ≥50% seizure reduction, and 21% achieved ≥75% reduction. Patients with LGS, TSC, and other DEEs showed higher efficacy and retention rates compared to DS. Genetic or unknown etiology was associated with better outcomes (p = 0.011). Combination with valproate was associated with reduced efficacy (p = 0.006), while combination with clobazam had no significant effect on efficacy nor safety. Non-seizure improvements included increased alertness (56%), improved sleep quality (25%), and enhanced motor performance (14%). Adverse events occurred in 33.6%, mostly mild and transient; 9% discontinued due to side effects. This study confirms the effectiveness and good tolerability of CBD in a real-world DEE population, including off-label use. These findings support expanding CBD indications and underscore the need for prospective studies targeting both seizure and developmental outcomes. This study looked at the use of cannabidiol (CBD), a cannabis-based medicine, in 107 people with severe forms of epilepsy called developmental and epileptic encephalopathies (DEEs). With CBD add-on, about two-thirds of patients had fewer seizures, and some caregivers noticed improvements in alertness, sleep, or movement. Most patients tolerated the treatment well, but some experienced side effects, and a few had to stop taking it. While the results are promising, more research is needed to confirm how effective and safe CBD is for different types of DEEs, especially those not currently approved for treatment with CBD.

Developmental and epileptic encephalopathies: From current care to future perspectives - insights from epilepsy centres in Lombardy, Italy.

Developmental and epileptic encephalopathy (DEE) is epilepsy related to developmental impairment that may be caused by both the underlying etiology (developmental encephalopathy) and superimposed epileptic activity (epileptic encephalopathy). The origin of DEE and the causes of its variations remain unknown. Owing the lack of clarity regarding the role of genetic variables in DEE, we conducted a scoping review to qualitatively identify the genes most important in the development of DEE to provide an up-to-date review. We searched all published studies related to the genetic factors of DEE. The identified publications were screened and selected by the authors on basis of on inclusion and exclusion criteria and assessed for methodological quality. Eighteen articles were included. The extracted data included age of onset, sex, gene mutations and inheritance (e.g. nucleotide change, protein change, and family testing), clinical manifestation, electroencephalogram, imaging, medication, and outcomes. A total of 18 studies were included in this scoping review. The most frequently reported gene variants were STXBP1 in Ohtahara Syndrome, SLC1A2 in Early Myoclonic Encephalopathy (EME), CDKL5 in West Syndrome, SCN1A in Dravet Syndrome, and KCNT1 in Epilepsy of Infancy with Migrating Focal Seizures (EIMFS). Each gene was associated with distinct electroclinical features, including differences in age of onset, seizure type, EEG patterns, and developmental outcomes. While genotype and phenotype associations were heterogeneous, certain variants showed consistent patterns indicative of more severe disease courses. This review identified key gene variants commonly associated with early-onset DEE in infants, particularly STXBP1, SLC1A2, CDKL5, SCN1A, and KCNT1, each linked to unique clinical presentations and outcomes. These findings support the clinical utility of next-generation sequencing (NGS) for early diagnosis and tailored treatment planning in DEE. Understanding genotype-phenotype correlations may enhance prognostication and highlight potential avenues for targeted therapy in future research.

Developmental and epileptic encephalopathies (DEEs) cause disability and dependence affecting both children and the family. The aim of the study was to describe the perspective of parents of children with DEEs regarding the impact of the disease on the family. We carried out a qualitative study based on the interpretivist paradigm. Twenty-one participants were selected using purposive sampling. Parents of children with DEEs of SCN1A, KCNQ2, CDKL5, PCDH19, and GNAO1 variants were included. In-depth interviews and researcher notes were used for data collection. A thematic analysis was performed on the data. Three themes were identified in the results: (a) Assuming conflicts and changes within the couple, causing them to distance themselves, reducing their time and intimacy and leading them to reconsider having more children; (b) impact of the disorder on siblings and grandparents, where siblings perceived DEE as a burden in their lives, felt neglected, and needed to grow and mature alone; conversely, the grandparents suffered for their grandchildren and the parents, in addition to perceiving that their health worsened, and (c) reconciling the care of the child with family life and work; this led the parents to share tasks, abandon or reduce working hours and ask for help.Conclusions: Caring for a child with DEE can result in neglect of social, psychological, emotional, recreational, educational, or occupational needs and obligations that ultimately impact all family members. What is Known: • Children with DEE may develop seizures and experience developmental and cognitive problems. • Caring for a child with DEE has a social and psychological impact on the entire family.<div class="NodiCopyInline">Caring for a child with DEE has a social and psychological impact on the entire family.</div> What is New: • Within the couple, there are tensions due to a lack of time, which could be alleviated by alternating childcare duties. • It is necessary to implement programs that address the physical and mental needs of the couple, as well as cater to the needs of siblings and alleviate the suffering of grandparents.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of several rare neurodevelopmental disorders characterized by early-onset refractory seizures, specific EEG abnormalities, developmental delay or regression, and intellectual disability (ID).1 DEEs are classically considered pediatric disorders because most of the literature defines their phenotype in children. With recent advances of symptomatic and supportive treatments, many patients with DEE can now survive into adulthood and exhibit unique abnormalities not seen in children. In 2008, Saitsu et al.2 described de novo STXBP1 sequence variants in 5 children with Ohtahara syndrome. During the past decade, the phenotypic spectrum of STXBP1 -DEE was broadened to include West syndrome, nonsyndromic epilepsy with ID, autism, and movement disorders such as ataxia, spasticity, dyskinesia, and dystonia. Although STXBP1 -DEE is one of the most frequent DEEs, there are very limited studies describing its adult phenotype.

Developmental and epileptic encephalopathy (DEE) is characterized by refractory seizures, developmental delay or intellectual disability, which may be caused by gene mutation. In this study, we explored the clinical phenotype and long-term outcome in children with genetic early-infantile-onset DEEs. Next-generation sequencing was performed on 470 patients diagnosed with early-infantile-onset DEE between 2010 and 2020. The genetic variation in all cases was classified and evaluated to identify pathogenic variants. The identified variants were further verified by Sanger sequencing. A total of 118 and 10 patients were found to have putative disease-causing gene mutations and copy number variations, respectively. SCN1A mutations were detected in 38 patients (38/118, 32.2%), representing the largest proportion. In patients with early-infantile-onset DEE with burst suppression, KCNQ2 mutation was found in six patients, and the remaining mutations were reported in SCN2A (n=2) and STXBP1 (n=1). Seven patients with dyskinesia were described. In patients with non-syndromic genetic early-infantile-onset DEEs, we detected possible rare pathogenic variants in SETBP1, DPYD, CSNK2B, and H3F3A. With regards to inheritance pattern, de novo heterozygous mutations accounted for the majority (104/118; 88.1%). Three patients with SMC1A mutations responded well to ketogenic diet add-on therapy. Addition of valproic acid showed good therapeutic effects against KCNB1 and PACS2 encephalopathy. We detected four possible rare pathogenic gene variants as non-syndromic genetic causes of early-infantile-onset DEEs. Although early-infantile-onset DEEs responded poorly to antiseizure medication treatment, we found that specific antiseizure medications showed good therapeutic effects in some patients with early-infantile-onset DEEs harbouring gene variants.

Loss of function variants of SCN1B are associated with a range of developmental and epileptic encephalopathies (DEEs), including Dravet syndrome. These DEEs feature a wide range of severe neurological disabilities, including changes to social, motor, mood, sleep, and cognitive function which are notoriously difficult to treat, and high rates of early mortality. While the symptomology of SCN1B-associated DEEs indicates broad changes in neural function, most research has focused on epilepsy-related brain structures and function. Mechanistic studies of SCN1B/Scn1b have delineated diverse roles in development and adult maintenance of neural function, via cell adhesion, ion channel regulation, and other intra- and extra-cellular actions. However, use of mouse models is limited as knockout of Scn1b, globally and even in some cell-specific models (e.g., Parvalbumin+ interneuron-specific knockout) in adult mice, leads to severe and progressive epilepsy, health deterioration, and 100% mortality within weeks. Here, we report findings using male and female mice of a novel transgenic line in which Scn1b was specifically deleted in cerebellar Purkinje cells. Unlike most existing models, these mice survive and thrive. However, we quantified marked decrements to Purkinje cell physiology as well as motor, social, and cognitive dysfunction. Our data indicates that cerebellar Purkinje cells are an important node for dysfunction and neural disabilities in SCN1B-related DEEs, and combined with previous work identify this as a potentially vital site for understanding mechanisms of DEEs and developing therapies that can treat these disorders holistically.Significance Statement Developmental and epileptic encephalopathies (DEEs), caused SCN1B or other gene variants, cause neuropsychiatric disabilities including movement, social, and cognitive dysfunction. Because global Scn1b knockout mice die in the third week of life and many DEE disabilities localize to cerebellar function we crossed a conditional Scn1b knockout mouse model with a cerebellar Purkinje cell-specific Cre line to study post-developmental neurological function. We found that Purkinje cell-specific Scn1b knockout mice survived into adulthood but had severe loss of Purkinje cell excitability, ataxia, decreased social interest, and disrupted cognitive performance. Our study shows that Scn1b is vital to the function of cerebellar neurons and loss of this gene isolated to Purkinje cells is sufficient to cause multiple disabilities that mirror SCN1B-associated DEEs.

Epilepsy and autism often co-occur in genetic developmental and epileptic encephalopathies (DEEs), but their underlying neurobiological processes remain poorly understood, complicating treatment. Advances in molecular genetics and understanding the neurodevelopmental pathogenesis of the epilepsy-autism phenotype may lead to mechanism-based treatments for children with DEEs and autism. Several genes, including the newly reported PPFIA3, MYCBP2, DHX9, TMEM63B, and RELN, are linked to various neurodevelopmental and epileptic disorders, intellectual disabilities, and autistic features. These findings underscore the clinical heterogeneity of genetic DEEs and suggest diverse neurobiological mechanisms influenced by genetic, epigenetic, and environmental factors. Mechanisms linking epilepsy and autism include γ-aminobutyric acidergic (GABAergic) signaling dysregulation, synaptic plasticity, disrupted functional connectivity, and neuroinflammatory responses. GABA system abnormalities, critical for inhibitory neurotransmission, contribute to both conditions. Dysregulation of the mechanistic target of rapamycin (mTOR) pathway and neuroinflammation are also pivotal, affecting seizure generation, drug resistance, and neuropsychiatric comorbidities. Abnormal synaptic function and connectivity further underscore the epilepsy-autism phenotype. New treatment options targeting specific mechanisms linked to the epilepsy-autism phenotype are emerging. Genetic variants in potassium channel genes like KCNQ2 and KCNT1 are frequent causes of early onset DEEs. Personalized treatments like retigabine and quinidine have been explored with heterogeneous responses. Efforts are ongoing to develop more effective KCNQ activators and KCNT1 blockers. SCN1A genetic variants, particularly in Dravet syndrome, show potential for treatment of autistic symptoms with low-dose clonazepam, fenfluramine, and cannabidiol, although human trials have yet to consistently replicate animal model successes. Early intervention before the age of 3 years, particularly in SCN1A- and tuberous sclerosis complex-related DEEs, is crucial. Additionally, targeting the mTOR pathway shows promise for seizure control and managing epilepsy-associated comorbidities. Understanding the distinct autism spectrum disorder phenotype in DEEs and implementing early behavioral interventions are essential for improving outcomes. Despite genetic advances, significant challenges persist in diagnosing and treating DEE-associated epilepsy-autism phenotypes. Future clinical trials should adopt precision health approaches to improve neurodevelopmental outcomes.

We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association "KCNB1 France." Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the long-term outcome in patients older than 12years from our series and from literature. Our series included 36 patients (21 males, median age = 10years, range = 1.6months-34years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10months, range = 10days-3.5years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5years, range = 18months-25years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n=41/61) and autistic features in 56% (n=32/57). Long-term outcome in 22 individuals older than 12years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

To determine whether functional impairments and autonomic symptoms are correlated in young people with developmental and epileptic encephalopathies (DEEs). Cross-sectional, online surveys (2018-2020) of parents recruited from family groups obtained information on several aspects of children's conditions including functional abilities (mobility, hand use, eating, and communication), 18 autonomic symptoms in six groups (cardiac, respiratory, sweating, temperature, gastrointestinal, and other), and parental stress. Bivariate and multivariable logistic regression analyses examined associations of dysautonomias with functional impairment, adjusted for type of DEE and age. Of 313 participants with full information on function and dysautonomias, 156 (50%) were females. The median age was 8 years (interquartile range 4-12y); 255 (81%) participants had symptoms in at least one autonomic symptom group; 283 (90%) had impairment in at least one functional domain. The number of functional impairment domains and of autonomic symptom groups varied significantly across DEE groups (both p<0.001). The number of functional impairment domains and of autonomic symptom groups were correlated (Spearman's r=0.35, p<0.001) on bivariate and multivariable analysis adjusted for DEE group and age. Parental stress was also independently correlated with dysautonomias (p<0.001). Parent-reported dysautonomias are common in children with DEEs. They correlate with extent of functional impairment and may contribute to caregiver stress. What this paper adds Dysautonomic symptoms are common in young people with developmental and epileptic encephalopathies (DEEs). Burden of dysautonomias is strongly correlated with burden of functional impairments. Aspects of dysautonomic function may provide biomarkers of DEE disease severity.

Within the spectrum of developmental and epileptic encephalopathy (DEE), there are a group of infants with features that are distinct from the well-recognized syndromes of early infantile developmental and epileptic encephalopathy (EIDEE), infantile epileptic spasm syndrome (IESS), and Lennox-Gastaut syndrome (LGS). We refer to this condition as late infantile epileptic encephalopathy (LIEE). Our objective was to highlight the characteristics of this group by analyzing patients who exhibit prototypical features. From July 2022 to May 2023, we searched for LIEE features in pediatric patients who underwent epilepsy follow-up at the University of Chicago Comer Children's Hospital. Out of 850 patients evaluated, thirty patients (3.5%) were identified with LIEE based on electroclinical characteristics. These patients had an average onset of epilepsy at 6.8 months and an average onset of LIEE features at 18.1 months. The epilepsy etiology was most commonly genetic and metabolic (50%), followed by congenital cortical malformations (23%), acquired structural abnormalities (20%), and unknown (7%). The predominant seizure types were myoclonic-tonic (70%), spasm-tonic (50%), epileptic spasms (47%), tonic (43%), and myoclonic (43%) seizures. All patients reported a history of either spasm-tonic or myoclonic-tonic seizures in addition to other types. All patients had EEGs showing discontinuity, electrodecrements, or both along with diffuse slowing, background voltages between 100 and 300 μV, and superimposed multifocal, diffuse epileptiform discharges. Every patient, except one, fulfilled the definition of drug-resistant epilepsy, and all reported either moderate-to-severe or severe developmental delay. Late infantile epileptic encephalopathy (LIEE) is characterized by several unique clinical and electrographic features. Typically, LIEE manifests in patients during the second year of life and occurs before two years of age, hence late infantile onset. The condition is commonly observed in infants with symptomatic epilepsy. Myoclonic-tonic and spasm-tonic seizures are the quintessential seizure types. The inter-ictal EEG exhibits more organization and lower voltages than seen with hypsarrhythmia and lacks the defining EEG characteristics of EIDEE, IESS, or LGS. We propose that LIEE is a distinct electroclinical syndrome within the spectrum of developmental and epileptic encephalopathies.

Motor phenotyping in a Greek cohort of patients with neonatal and infantile onset developmental and epileptic encephalopathy.

Heterozygous de novo variants in the autophagy gene, WDR45, are found in beta-propeller protein-associated neurodegeneration (BPAN). BPAN is characterized by adolescent onset dementia and dystonia; 66% patients have seizures. We asked whether WDR45 was associated with developmental and epileptic encephalopathy (DEE). We performed next generation sequencing of WDR45 in 655 patients with developmental and epileptic encephalopathies. We identified 3/655 patients with DEE plus 4 additional patients with de novo WDR45 pathogenic variants (6 truncations, 1 missense); all were female. Six presented with DEE and 1 with early onset focal seizures and profound regression. Median seizure onset was 12 months, 6 had multiple seizure types, and 5/7 had focal seizures. Three patients had magnetic resonance susceptibility-weighted imaging; blooming was noted in the globus pallidi and substantia nigra in the 2 older children aged 4 and 9 years, consistent with iron accumulation. We show that de novo pathogenic variants are associated with a range of developmental and epileptic encephalopathies with profound developmental consequences.