Childhood Epileptic Encephalopathy Research Articles

Does the absence or presence of sleep spindles on EEG have prognostic value for cognitive outcome in children with infantile epileptic spasms syndrome? A systematic literature review.

Infantile Epileptic Spasms Syndrome (IESS) is an epileptic encephalopathy in childhood that affects infants under the age of two years. When spasm series occur, prognosis for cognitive outcome is poor in the majority of cases. The encephalopathy in IESS includes delayed maturation of normal sleep phenomena in the EEG, such as sleep spindles. Children with intellectual disabilities often have abnormal sleep, and children with sleep problems have difficulties learning at school. We examined whether there is evidence of prognostic value of detection of sleep spindles in the EEG of children with IESS on their future cognitive development. A systematic literature search yielded five studies touching this question. They were evaluated by two scorers independently. The lack of normal sleep patterns including lack of sleep spindles was used as a biomarker of poor cognitive outcome. Positive (PPV) and Negative (NPV) prognostic values were calculated. A summary of all five studies indicates a PPV of 82% and an NPV of 45%. Given the small amount of data, the retrospective quality of most studies, and the differences in the outcome parameters reported, it is prudent to say that currently available data do not allow us to conclude whether spindles have a specific and independent role in the cognitive prognosis of affected children. Since sleep spindles are needed for memory consolidation and demonstrate the active role of sleep for learning and memory, the hypothesis remains that their absence in the EEG may indicate an increased risk of cognitive delay, but more supporting data are needed to reach such a firm conclusion.

A-312 Segregation in Two Families of the PCDH19Gene Deletion Associated With Infantile Epileptic Encephalopathy of X-Linked Inheritance and Expression in Female Carriers

Abstract Background Developmental and epileptic encephalopathy-9 (DEE9) is an X-linked disorder characterized by seizure onset in infancy and mild to severe intellectual impairment. Autistic and psychiatric features have been reported in some individuals. The disorder affects heterozygous females only; transmitting males are unaffected. We described the segregation in two unrelated families where the proband was clinically affected as a female and another family where the proband was clinically unaffected as a male. Methods Array-CGH analysis was performed by a CGXTM HD v1,1 4-plex array 180 k (PerkinElmer), with an average resolution of 40 kb in the backbone and 20 kb in the regions of interest. Results In the first family a deletion of 809.93 Kilobases was detected in the chromosomal region Xq22.1, which includes the PCDH19 gene, in a 1 year old patient with very early onset seizures, 8 months old, inherited from an asymptomatic father. In the second family, a deletion that includes the entire PCDH19 gene was detected in a 5-year-old male patient referred to genetics for autism spectrum disorder (ASD) and not symptomatic for epilepsy; this deletion was inherited from a mother who had episodes of epilepsy in childhood. Conclusion The aCGH technique is currently the technique of choice to determine the presence of deletions/duplications in genes of interest with high reliability in patients with neurodevelopmental disorders such as epilepsy or ASD. The probands of these two families have been studied for different clinical pathology and in both the deletion of the complete PCDH19 gene has been detected. The PCDH19 gene is expressed in developing human and mouse central nervous system, including the hippocampus and cortex, suggesting a role in cognitive function. Malfunction of the protocadherin19 protein is the cause of epileptic seizures in early childhood, the seizures are mostly focal and cause serial seizures (many seizures that cluster together over a few days). It is a type of epilepsy that usually begins in early childhood. Onset may occur spontaneously or in association with fever. Mutations/deletions of the PCDH19 gene are described to cause Early Childhood Epileptic Encephalopathy, with high but incomplete penetrance. DEE9 affects only females heterozygous for the deletion and is characterised by childhood onset of seizures/epilepsy, usually with mild/severe intellectual disability, with males being healthy carriers. Although the cause is not known specifically, it is thought to be related to X-chromosome silencing that occurs in females heterozygous for this mutation. It causes an autosomal dominant X-linked disorder. Some cases of males with a mosaic PCDH19 mutation/deletion have been found to be affected and it has been suggested that the presence of both the normal gene and the mutated/deleted gene is necessary to develop for this epileptic encephalopathy.

Viral vector-mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome.

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is typically caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1, a 250-kDa voltage-gated sodium channel. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A open reading frame into the brain improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus and/or the thalamus of DS mice increased survival, reduced the occurrence of epileptic spikes, provided protection from thermally-induced seizures, corrected background electrocorticography activity and behavioral deficits, and restored hippocampal inhibition. Together, our results provide a proof-of-concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.

Heterozygous GABAA receptor β3 subunit N110D knock-in mice have epileptic spasms.

Infantile spasms is an epileptic encephalopathy of childhood, and its pathophysiology is largely unknown. We generated a heterozygous knock-in mouse with the human infantile spasms-associated de novo mutation GABRB3 (c.A328G, p.N110D) to investigate its molecular mechanisms and to establish the Gabrb3+/N110D knock-in mouse as a model of infantile spasms syndrome. We used electroencephalography (EEG) and video monitoring to characterize seizure types, and a suite of behavioral tests to identify neurological and behavioral impairment in Gabrb3+/N110D knock-in mice. Miniature inhibitory postsynaptic currents (mIPSCs) were recorded from layer V/VI pyramidal neurons in somatosensory cortex, and extracellular multi-unit recordings from the ventral basal nucleus of the thalamus in a horizontal thalamocortical slice were used to assess spontaneous thalamocortical oscillations. The infantile spasms-associated human de novo mutation GABRB3 (c.A328G, p.N110D) caused epileptic spasms early in development and multiple seizure types in adult Gabrb3+/N110D knock-in mice. Signs of neurological impairment, anxiety, hyperactivity, social impairment, and deficits in spatial learning and memory were also observed. Gabrb3+/N110D mice had reduced cortical mIPSCs and increased duration of spontaneous oscillatory firing in the somatosensory thalamocortical circuit. The Gabrb3+/N110D knock-in mouse has epileptic spasms, seizures, and other neurological impairments that are consistent with infantile spasms syndrome in patients. Multiple seizure types and abnormal behaviors indicative of neurological impairment both early and late in development suggest that Gabrb3+/N110D mice can be used to study the pathophysiology of infantile spasms. Reduced cortical inhibition and increased duration of thalamocortical oscillatory firing suggest perturbations in thalamocortical circuits.

Epilepsy-Related CDKL5 Deficiency Slows Synaptic Vesicle Endocytosis in Central Nerve Terminals.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe early-onset epileptic encephalopathy resulting mainly from de novo mutations in the X-linked CDKL5 gene. To determine whether loss of presynaptic CDKL5 function contributes to CDD, we examined synaptic vesicle (SV) recycling in primary hippocampal neurons generated from Cdkl5 knockout rat males. Using a genetically encoded reporter, we revealed that CDKL5 is selectively required for efficient SV endocytosis. We showed that CDKL5 kinase activity is both necessary and sufficient for optimal SV endocytosis, since kinase-inactive mutations failed to correct endocytosis in Cdkl5 knockout neurons, whereas the isolated CDKL5 kinase domain fully restored SV endocytosis kinetics. Finally, we demonstrated that CDKL5-mediated phosphorylation of amphiphysin 1, a putative presynaptic target, is not required for CDKL5-dependent control of SV endocytosis. Overall, our findings reveal a key presynaptic role for CDKL5 kinase activity and enhance our insight into how its dysfunction may culminate in CDD.SIGNIFICANCE STATEMENT Loss of cyclin-dependent kinase like 5 (CDKL5) function is a leading cause of monogenic childhood epileptic encephalopathy. However, information regarding its biological role is scarce. In this study, we reveal a selective presynaptic role for CDKL5 in synaptic vesicle endocytosis and that its protein kinase activity is both necessary and sufficient for this role. The isolated protein kinase domain is sufficient to correct this loss of function, which may facilitate future gene therapy strategies if presynaptic dysfunction is proven to be central to the disorder. It also reveals that a CDKL5-specific substrate is located at the presynapse, the phosphorylation of which is required for optimal SV endocytosis.

Lennox-Gastaut and Schizophrenia: Comorbidity or complication?

IntroductionLennox-Gastaut syndrome (LGS) belongs to the group of severe childhood epileptic encephalopathies and represents 1 to 2% of all childhood epilepsies.It is characterized by the occurrence of generalized epileptic seizures, characterized by a particular pattern of the electroencephalogram; slowed mental development and personality disorders.This syndrome appears between the ages of 2 and 7 years, and its management remains difficult, as it is generally refractory to conventional treatment.The long-term prognosis of this syndrome is poor, marked by the presence of periods of regression of cognitive functions, the appearance of frontal or even psychotic signs and extrapyramidal and cerebellar signs.ObjectivesWe will try trow a clinical case, to discuss the evolution of Lennox Gastaut syndrome towards schizophrenia, which remains an infrequent complication, and to determine what would be the adequate management of these patients?MethodsWe report the case of a 16-year-old patient,followed for Lennox Gastaut syndrome since the age of 03, who presented to the psychiatric emergency room for psychomotor agitation, geophagia and altered general condition. The admission interview showed a patient with motor instability, disorganized speech, delusional persecution syndrome, auditory and intrapsychic hallucinations, suicidal ideations in the context of mental automatism, impaired judgment and insight, and insomnia.The blood tests and the brain CT scan came back without any particularities.ResultsThe patient was put on Risperidone, Valproate sodium, Lamotrigine and Clobazam, with good clinical evolution.ConclusionsThe cognitive consequences are catastrophic, 85 to 92% of the patients have a progressive cognitive deterioration, in spite of the reduction of the frequency of the seizures and the improvement of the paroxysmal EEG anomalies.DisclosureNo significant relationships.

Detection of Deregulated miRNAs in Childhood Epileptic Encephalopathies.

The term "epileptic encephalopathy" is used to describe a possible relationship between epilepsy and developmental delay. The pathogenesis of developmental encephalopathies, independent of epilepsy, can be defined by genetic control mechanisms. The aim of this study was to investigate the use of miRNAs as serum biomarkers for the determination and discrimination of epileptic encephalopathies. Whole blood samples obtained from 54 individuals in 2 groups designated as epileptic encephalopathy patients' group (n = 24) and healthy controls (n = 30) were included in this study. The expression levels of 10 miRNAs were determined using qRT-PCR. After the determination of expression levels, the correlation of upregulated miRNA levels and Ki67 index was calculated using Pearson correlation test. The comparison of epileptic encephalopathy patients' group with healthy controls revealed the upregulation of one miRNAs (hsa-miR-324-5p) and downregulation of three miRNAs (hsa-miR-146a-5p, hsa-miR-138-5p, hsa-miR-187-3p). It has been determined that miRNAs with altered expression are an important factor in the formation of epileptic seizures and seizure-induced neuronal death. The fact that processes that play a key role in epiloptogenesis are under the control of miRNAs causes miRNAs to become meta-controllers of gene expression in the brain. We thought that further studies are needed to prove that especially hsa-miR-146a-5p, hsa-miR-138-5p, and hsa-miR-187-3p can be used as epileptic encephalopathy biomarkers. The detection of disease-specific miRNAs could contribute to the development of precision treatments.

Childhood Epileptic Encephalopathy in Sokoto, Northwestern Nigeria

Pediatric epileptic encephalopathies comprises a group of severe childhood epilepsy syndromes characterized by refractory seizures associated with progressive cerebral dysfunction, manifesting as cognitive or learning difficulties and behavioural or sensory impairments.

Longitudinal analysis of regional brain changes in anti-NMDAR encephalitis: a case report

BackgroundAnti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations.Case presentationA previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient’s clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402–18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient’s treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient’s clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain.ConclusionsOur results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.

Modeling genetic epileptic encephalopathies using brain organoids.

Developmental and epileptic encephalopathies (DEE) are a group of disorders associated with intractable seizures, brain development, and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain‐containing oxidoreductase (WWOX) are associated with a relatively mild autosomal recessive spinocerebellar ataxia‐12 (SCAR12) and a more severe early infantile WWOX‐related epileptic encephalopathy (WOREE). In this study, we generated an in vitro model for DEEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR‐engineered human ES cells and from patient‐derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt pathway and DNA damage response impairment. Furthermore, we provide a proof of concept that ectopic WWOX expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies.

Language regression as a manifestation of epilepsy

Introduction: Childhood epileptic encephalopathies are age-dependent brain disorders in which ictal and interictal epileptogenic activity is the apparent cause of progressive cognitive and neuro-psychological impairment. Case report: A previously healthy four-year-old boy presented to the Emergency Department with a history of receptive and expressive language regression with four days of evolution, associated with seizure onset. Clinical features and electroencephalographic findings led to diagnosis of Landau-Kleffner syndrome. The boy was treated with valproate, clobazam, and prednisolone, with language improvement. Discussion/Conclusion: Landau-Kleffner syndrome is a rare epileptic encephalopathy with pathognomonic sudden aphasia, epilepsy, and paroxysmal electroencephalographic abnormalities. The condition should be suspected in children with normal development who show a deterioration of established language skills. Early diagnosis and treatment are important to improve outcome.

Genomic Investigation of Infantile and Childhood Epileptic Encephalopathies in Kazakhstan: An Urgent Priority.

Objectives: Infantile and childhood epileptic encephalopathies are a group of severe epilepsies that begin within the first year of life and often portend increased morbidity. Many of them are genetically determined. The medical strategy for their management depends on the genetic cause. There are no facilities for genetic testing of children in Kazakhstan but we have a collection of data with already defined genes responsible for clinical presentations.Methods: We analyzed children with epileptic encephalopathies that began in the first 3 years of life and were accompanied by a delay/arrest of intellectual development, in the absence of structural changes in the brain. Such patients were recommended to undergo genetic testing using epileptic genetic panels in laboratories in different countries.Results: We observed 350 infants with clinical presentation of epileptic encephalopathies. 4.3% of them followed our recommendations and underwent genetic testing privately. In total 12/15 children became eligible for targeted treatment, 3/15 were likely to have non-epileptic stereotypies/movements, 2/15 were unlikely to respond to any therapy and all had a high chance of intellectual disability, behavioral and social communication disorders.Conclusion: The genetic results of 15/350 (4.3% of patients) have demonstrated the potential and enormous impact from gene panel analysis in management of epileptic encephalopathy. Availability of genetic testing within the country will improve management of children with genetic epilepsies and help to create a local database of pathogenic variants.

Fifteen-minute consultation: The efficient investigation of infantile and childhood epileptic encephalopathies in the era of modern genomics

The investigation of children presenting with infantile and childhood epileptic encephalopathies (ICEE) is challenging due to diverse aetiologies, overlapping phenotypes and the relatively low diagnostic yield of MRI, electroencephalography (EEG)...

Early surgical intervention for structural infantile spasms in two patients under 6\u2009months old: a case report

BackgroundInfantile spasms (IS) are the most common childhood epileptic encephalopathy. Focal cortical dysplasia (FCD) and gray matter heterotopias (GH) are common structural causes of IS. The recommended first-line treatment for IS patients with structural causes is surgical intervention, according to the International League Against Epilepsy (ILAE) commission guidelines. However, there is currently no consensus on appropriate timings of surgery.Case presentationsTwo structural IS cases are presented here: one was caused by FCD, and the other by GH. Both patients exhibited recurrent seizures at the age of 2 months, had poor responses to various antiepileptic drugs (AEDs) and displayed severe mental and motor developmental retardation. Seizure types included focal seizures and spasms. Brain magnetic resonance imaging showed abnormal gray signal or suspicious FCD lesions that coincided with the origin of the focal seizures. The patients underwent lesion resection before the age of 6 months. Follow-up observation showed that seizures of both patients were completely controlled several days after the surgery. All AEDs were gradually reduced in dosage within 1 year, and the mental and motor development almost returned to normal.ConclusionEarly resection of lesions in structural IS patients has benefits of effectively controlling convulsions and improving developmental retardation. Infants at several months of age can well tolerate craniotomy, and their cognitive development is more likely to return to normal after early surgery.

Convulsive seizures and some behavioral comorbidities are uncoupled in the Scn1aA1783V Dravet syndrome mouse model.

Dravet syndrome (Dravet) is a severe childhood epileptic encephalopathy. The disease begins with a febrile stage, characterized by febrile seizures with otherwise normal development. Progression to the worsening stage features recurrent intractable seizures and the presentation of additional nonepileptic comorbidities, including global developmental delay, hyperactivity, and motor deficits. Later in life, at the stabilization stage, seizure burden decreases, whereas Dravet-associated comorbidities persist. To date, it remains debated whether the nonepileptic comorbidities result from severe epilepsy or represent an independent phenotypic feature. Dravet mice (DS) faithfully recapitulate many clinical aspects of Dravet. Using wild-type (WT) and DS at different ages, we monitored multiple behavioral features as well as background electroencephalogram (EEG) activity during the different stages of Dravet epilepsy. Behavioral tests of WT and DS demonstrated that some deficits manifest already at the pre-epileptic stage, prior to the onset of convulsive seizures. These include motor impairment and hyperactivity in the open field. Deficits in cognitive functions were detected at the onset of severe spontaneous seizures. Power spectral analysis of background EEG activity, measured through development, showed that DS exhibit normal background oscillations at the pre-epileptic stage, a marked reduction in total power during the onset of severe epilepsy, and a subsequent smaller reduction later in life. Importantly, low EEG power at the stage of severe frequent convulsive seizures correlated with increased risk for premature death. Our data provide a comprehensive developmental trajectory of Dravet epilepsy and Dravet-associated comorbidities in mice, under controlled settings, demonstrating that the convulsive seizures and some nonepileptic comorbidities may be uncoupled. Moreover, we report the existence of an inverse correlation, on average, between the power of background EEG and the severity of epileptic phenotypes, suggesting that such measurements may potentially serve as a biomarker for Dravet severity.

Tumorous congenital calcinosis cutis associated with early childhood epileptic encephalopathy with a pathogenic FGF12 gene variant.

Calcinosis cutis is the deposit of insoluble calcium salts in the skin. It is classified according to its pathogenesis in dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Idiopathic calcinosis is asymptomatic, occurs in healthy patients, and includes scrotal calcinosis, Winer's nodular calcinosis or subepidermal calcified nodules, and familial tumor calcinosis. The latter is a rare condition characterized by periarticular calcium deposition in normocalcemic patients with no bone connection. The case of a 5-month-old male patient, who on the seventh day of life was hospitalized for multifactorial jaundice, late neonatal sepsis, and apnea with epileptic seizures is described. His evolution was torpid, with hospital admissions due to epileptic seizures that were difficult to manage with partial response to the use of diphenylhydantoin and electrolyte alterations. By means of exome sequencing directed, a pathogenic variant of wrong direction in FGF12 was detected and the diagnosis of early epileptic encephalopathy number 47 was confirmed. Also, the patient showed disseminated congenital dermatosis to lower extremities affecting thighs, asymptomatic, bilateral and symmetrical, constituted by hypopigmentation and fovea hard to deep palpation. The biopsy showed dystrophic calcification. The case of an infant with deep congenital cutis calcinosis associated with a pathogenic variant in the FGF12 gene with epileptic encephalopathy is described. To date, this clinical situation has not been previously reported in the literature.

Epileptic Encephalopathies of Childhood: The New Paradigm of Genetic Diagnosis

Epileptic encephalopathies of childhood are characterized by early seizure-onset and adverse neurological outcomes. The development of new genetic techniques has allowed an exponential identification of the genes that are involved. Over the last years, we have observed a revolution in the diagnostic paradigm. However, there are no international guidelines regarding the diagnosis of genetic epileptic encephalopathies. We aim to discuss the current knowledge about the genetic architecture of epileptic encephalopathies of childhood. review of the literature about infantile epileptic encephalopathies and the genetic tests currently available. A systematic approach and a diagnostic algorithm to use in clinical practice were proposed. Initially the patient's phenotype should be determined based on the seizure type, electroencephalogram pattern and neuroimaging. Patients with unclear etiology after brain magnetic resonance imaging should undergo an appropriate metabolic investigation to promptly exclude treatable conditions. Further studies should also include other genetic causes, mainly if associated with particular phenotypic features. Chromosomal microarray analysis should be firstly considered, particularly if dysmorphic or polymalformative abnormalities are present. If this is negative and/or there are no physical features, the next step should be next-generation sequencing multigene panels or whole-exome sequencing. Single gene study should only be considered when the patient's phenotype is highly suggestive of a specific syndrome. The revolution of the genetic knowledge about epileptic encephalopathies of childhood has led to a complex diagnostic approach. This new paradigm poses significant implications in genetic counselling, treatment and prognosis.

Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome

PurposeThis study aimed to investigate the genetic etiology of epilepsy in a cohort of Chinese children. MethodsTargeted next-generation sequencing (NGS) was performed for 120 patients with unexplained epilepsy, including 71 patients with early-onset epileptic encephalopathies, and 16 patients with Dravet syndrome (including three patients with a Dravet-like phenotype) but without SCN1A pathogenic variants. ResultsPathogenic variants of 14 genes were discovered in 22 patients (18%). A de novo KCND3 pathogenic variant (c.1174G > A, p.Val392Ile) was identified in a boy with refractory epilepsy, psychomotor regression, attention deficit, and visual decline. Pathogenic variants in other coding genes were excluded via whole exome sequencing. This KCND3 variant was previously confirmed to be pathogenic by Giudicessi, et al. However, the clinical profile was different: sudden death at 20 years old without any medical history of neurological disorders, nor with any diseases typically caused by KCND3 pathogenic variants such as Brugada syndrome, spinocerebellar ataxia type 19/22 or ataxia accompanied by epilepsy. This indicates that we have identified a new KCND3 phenotype. In addition, we also uncovered a GRIN1 pathogenic variant and a novel HCN1 pathogenic variant in the Dravet cohort. ConclusionOur study highlights the significant utility of NGS panels in the genetic diagnosis of pediatric epilepsy. Our findings indicate that KCND3 pathogenic variants may be responsible for a wider phenotypic spectrum than previously thought, by including childhood epileptic encephalopathy. Furthermore, this study provides evidence that GRIN1 and HCN1 are candidate genes for Dravet and Dravet-like phenotypes.

Modern approaches in the treatment of Lennox–gastaut syndrome (a review of literature)

Lennox–Gastaut syndrome (LGS) is a childhood epileptic encephalopathy characterized by frequent polymorphic seizures (including tonic axial seizures), pronounced cognitive impairment, typical changes in the electroencephalogram and drug resistance. Frequency of LGS accounts for approximately 4–10 % of all childhood epilepsy. The difficulties in the diagnosis and treatment of LGS are associated with the presence of various seizures that are frequently resistant to multiple antiepileptic drugs as well as with the disease evolution with age. This review covers the main principles of LGS therapy, analyzes the most common antiepileptic drugs used in LGS, and describes clinical trials evaluating the efficacy and tolerability of antiepileptic drugs in LGS. The article contains a detailed algorithm for the treatment of LGS, based on international guidelines and expert opinions.

Rufinamide (inovelon) in the treatment of Lennox–gastaut syndrome (a review of literature)

Lennox–Gastaut syndrome (LGS) is a childhood epileptic encephalopathy characterized by frequent polymorphic seizures (including tonic axial seizures), pronounced cognitive impairment, typical changes in the electroencephalogram and drug resistance. Since the disease is quite common (accounts for 4–10 % of all childhood epilepsy) and is characterized by various seizures that are frequently resistant to multiple antiepileptic drugs, great hopes are currently centered on the development of novel antiepileptic drugs with principally different mechanisms of action aimed to treat this severe form of epilepsy. Rufinamide (inovelon) is a promising antiepileptic drug for LGS therapy. In 2008, it was approved by the FDA as an adjunctive treatment of seizures associated with LGS in adults and children over 4 years of age. Rufinamide demonstrated its efficacy against both drop seizures (tonic/atonic) and generalized seizures (tonic, atonic and tonic-clonic) in LGS. In January 2015, the drug was approved for use in the Russian Federation for seizures associated with LGS in patients over 4 years of age. Multiple studies have demonstrated high efficacy and good tolerability of rufinamide in children and adults with epilepsy. In this article, we provide a systematic review of the currently available data on the use of rufinamide in the treatment of seizures associated with LGS.