A Case of CDKL5 Deficiency Due to an X Chromosome Pericentric Inversion: Delineation of Structural Rearrangements as an Overlooked Recurrent Pathological Mechanism.

CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.

Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation.

There are more than 70 million people worldwide living with epilepsy, with most experiencing the onset of epilepsy in childhood. Despite the availability of more than 20 anti-seizure medications, approximately 30% of epilepsy patients continue to experience unsatisfactory treatment outcomes. This situation places a heavy burden on patients' families and society. Childhood epilepsy is a significant chronic neurological disease that is closely related to genetics. Col4a2, the gene encoding the α2 chain of type IV collagen, is known to be associated with multiple diseases due to missense mutations. The Col4a2 variant of collagen type IV is associated with various phenotypes, including prenatal and neonatal intracranial hemorrhage, porencephaly, porencephaly with cataracts, focal cortical dysplasia, schizencephaly, strokes in childhood and adolescence, and sporadic delayed hemorrhagic stroke. Although epilepsy is recognized as a clinical manifestation of porencephaly, the specific mechanism of Col4a2-related epileptic phenotypes remains unclear. A total of 8 patients aged 2 years and 2 months to 18 years who were diagnosed with Col4a2-related infantile epileptic spasm syndrome were analyzed. The seizure onset age ranged from 3 to 10 months. Initial EEG results revealed hypsarrhythmia or multiple and multifocal sharp waves, spike waves, sharp slow waves, or spike slow waves. Elevated levels of the cytokines IL-1ß (32.23±12.58 pg/ml) and IL-6 (45.12±16.03 pg/ml) were detected in the cerebrospinal fluid of these patients without any signs of infection. Following antiseizure treatment, decreased IL-1ß and IL-6 levels in the cerebrospinal fluid were noted when seizures were under control. Furthermore, we aimed to investigate the role of Col4a2 mutations in the development of epilepsy. Through the use of immunofluorescence assays, ELISA, and Western blotting, we examined astrocyte activity and the expression of inflammatory cytokines such as IL-1ß, IL-6, and TNF-α after overexpressing an unreported Col4a2 (c.1838G>T) mutant in CTX-TNA cells and primary astrocytes. We found that the levels of the inflammatory factors IL-1ß, IL-6, and TNF-α were increased in both CTX-TNA cells (ELISA: p = 0.0087, p<0.001, p<0.001, respectively) and primary astrocytes (ELISA: p = 0.0275, p<0.001, p<0.001, respectively). Additionally, we conducted a preliminary investigation of the role of the JAK/STAT pathway in Col4a2 mutation-associated epilepsy. Col4a2 mutation stimulated astrocyte activation, increasing iNOS, COX-2, IL-1ß, IL-6, and TNF-α levels in both CTX-TNA cells and primary astrocytes. This mutation also activated the JAK/STAT signaling pathway, leading to increased phosphorylation of JAK2 and STAT3. Treatment with the JAK/STAT inhibitor WP1066 effectively counteracted this effect in primary astrocytes and CTX-TNA cells. To date, the genes who mutations are known to cause developmental and epileptic encephalopathies (DEEs) are predominantly grouped into six subtypes according to function. Our study revealed that an unreported mutation site Col4a2Mut (c.1838G>T) of which can cause neuroinflammation, may be a type VII DEE-causing gene.

Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder.

BACKGROUND: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5-/y rats. METHODS: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. RESULTS: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. CONCLUSIONS: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. LIMITATIONS: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

Evaluating bexicaserin for the treatment of developmental epileptic encephalopathies.

INTRODUCTION: Developmental epileptic encephalopathies (DEEs) pose significant challenges due to their refractory nature and limited treatment options. Despite advancements in genetic understanding, effective therapies targeting underlying pathophysiology are lacking. Serotoninergic dysfunction has been implicated in epilepsy, sparking interest in serotonin as a therapeutic target. AREA COVERED: This article explores the potential of bexicaserin, a selective 5-HT2C receptor agonist, as an adjunctive antiseizure medication in DEEs. Bexicaserin is thought to modulate GABAergic neurotransmission, suppressing central hyperexcitability. Preclinical studies demonstrate its efficacy across various seizure models. Clinical trials, including the Pacific Study, reveal promising results in reducing motor seizures. However, challenges such as adverse effects and treatment discontinuation underscore the need for further investigation. EXPERT OPINION: The efficacy of 5-HT2C serotoninergic agonists, validated in preclinical and clinical studies, highlights serotonin's role in DEEs. Bexicaserin offers new therapeutic possibilities, potentially synergizing with existing antiseizure medications. Polypharmacotherapy, targeting distinct pathways, may enhance therapeutic outcomes. Monitoring pharmacological interactions and addressing central nervous system comorbidities are crucial for optimizing treatment strategies. Further research is needed to elucidate bexicaserin's mechanisms and potential antiepileptogenic effects.

Expanding the clinical phenotype and genetic spectrum of GEMIN5 disorders: Early-infantile developmental and epileptic encephalopathies.

BACKGROUND: Several biallelic truncating and missense variants of the gem nuclear organelle-associated protein 5 (GEMIN5) gene have been reported to cause neurodevelopmental disorders characterized by cerebellar atrophy, intellectual disability, and motor dysfunction. However, the association between biallelic GEMIN5 variants and early-infantile developmental and epileptic encephalopathies (EIDEEs) has not been reported. PURPOSE: This study aimed to expand the phenotypic spectrum of GEMIN5 and explore the correlations between epilepsy and molecular sub-regional locations. METHODS: We performed whole-exome sequencing in two patients with EIDEE with unexplained etiologies. The damaging effects of variants were predicted using multiple in silico tools and modeling. All reported patients with GEMIN5 pathogenic variants and detailed neurological phenotypes were analyzed to evaluate the genotype-phenotype relationship. RESULTS: Novel biallelic GEMIN5 variants were identified in two unrelated female patients with EIDEE, including a frameshift variant (Hg19, chr5:154284147-154284148delCT: NM_015465: c.2551_c.2552delCT: p.(Leu851fs*30)), a nonsense mutation (Hg19, chr5:154299603-154299603delTinsAGA: NM_015465: c.1523delTinsAGA: p.(Leu508*)), and two missense variants (Hg19, chr5:154282663T > A: NM_015465: c.2705T > A: p.(Leu902Gln) and Hg19, chr5:154281002C > G: NM_015465: c.2911C > G: p.(Gln971Glu)), which were inherited from asymptomatic parents and predicted to be damaging or probably damaging using in silico tools. Except p.Leu508*, all these mutations are located in tetratricopeptide repeat (TPR) domain. Our two female patients presented with seizures less than 1 month after birth, followed by clusters of spasms. Brain magnetic resonance imaging suggests dysgenesis of the corpus callosum and cerebellar hypoplasia. Video electroencephalogram showed suppression-bursts. Through a literature review, we found 5 published papers reporting 48 patients with biallelic variants in GEMIN5. Eight of 48 patients have epilepsy, and 5 patients started before 1 year old, which reminds us of the relevance between GEMIN5 variants and EIDEE. Further analysis of the 49 GEMIN5 variants in those 50 patients demonstrated that variants in TPR-like domain or RBS domain were more likely to be associated with epilepsy. CONCLUSIONS: We found novel biallelic variants of GEMIN5 in two individuals with EIDEE and expanded the clinical phenotypes of GEMIN5 variants. It is suggested that the GEMIN5 gene should be added to the EIDEE gene panel to aid in the clinical diagnosis of EIDEE and to help determine patient prognosis.

Identification and treatment of surgically-remediable causes of infantile epileptic spasms syndrome.

INTRODUCTION: Infantile epileptic spasms syndrome (IESS) is a common developmental and epileptic encephalopathy with poor long-term outcomes. A substantial proportion of patients with IESS have a potentially surgically remediable etiology. Despite this, epilepsy surgery is underutilized in this patient group. Some surgically remediable etiologies, such as focal cortical dysplasia and malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE), are under-diagnosed in infants and young children. Even when a surgically remediable etiology is recognised, for example, tuberous sclerosis or focal encephalomalacia, epilepsy surgery may be delayed or not considered due to diffuse EEG changes, unclear surgical boundaries, or concerns about operating in this age group. AREAS COVERED: In this review, the authors discuss the common surgically remediable etiologies of IESS, their clinical and EEG features, and the imaging techniques that can aid in their diagnosis. They then describe the surgical approaches used in this patient group, and the beneficial impact that early epilepsy surgery can have on developing brain networks. EXPERT OPINION: Epilepsy surgery remains underutilized even when a potentially surgically remediable cause is recognized. Overcoming the barriers that result in under-recognition of surgical candidates and underutilization of epilepsy surgery in IESS will improve long-term seizure and developmental outcomes.

Surgical treatment of epileptic encephalopathy with spike-and-wave activation in sleep: A systematic review and meta-analysis.

OBJECTIVE: Epileptic Encephalopathy / Developmental Epileptic Encephalopathy with spike-and-wave activation during sleep (EE/DEE-SWAS) is a self-limiting childhood epilepsy syndrome but may cause permanent neurocognitive impairment. Surgical interventions have been controversial in the treatment of EE/DEE-SWAS. This systematic review aims to evaluate the efficacy of various surgical procedures on the outcomes of EE/DEE-SWAS. METHODS: A systematic review was performed per the PRISMA guidelines. A total of 14 retrospective studies were identified, comprising 131 cases of EE/DEE-SWAS treated with epilepsy surgery. The review analyzed presurgical data, surgical interventions, as well as outcomes related to seizures, EEG, and neuropsychological assessments. RESULTS: Epilepsy surgery was successfully performed in 131 cases with minor complications. The average age was 2.6 years at seizure onset and 5.0 years at diagnosis of SWAS. Excellent seizure control (Engel I and II) was achieved in 80.6 %, 78.6 %, 77.4 % and 27.2 % of patients receiving hemispherectomies, focal resections, multiple subpial transections (MSTs), and corpus callosotomies (CCTs), respectively. EEG SWAS resolution was seen in 79.7 % of hemispherectomy cases, 78.6 % in focal resections, 63.9 % in MSTs, and 8.3 % in CCTs. Neurocognitive and behavioral improvement was noted in 58.0 %, 71.4 %, 58.3 % and 16.7 % for patients receiving hemispherectomies, focal resections, MSTs, and CCTs, respectively. A correlation between improved seizure control and SWAS resolution was observed with improved neuropsychological outcomes. CONCLUSION: Epilepsy surgery is a safe and effective treatment for carefully selected children with drug-resistant EE/DEE-SWAS. Patients who underwent epilepsy surgery had reduction of seizure burden, SWAS resolution and improvements in neurocognitive and behavioral function.

Computational EEG attributes predict response to therapy for epileptic spasms.

OBJECTIVE: We set out to evaluate whether response to treatment for epileptic spasms is associated with specific candidate computational EEG biomarkers, independent of clinical attributes. METHODS: We identified 50 children with epileptic spasms, with pre- and post-treatment overnight video-EEG. After EEG samples were preprocessed in an automated fashion to remove artifacts, we calculated amplitude, power spectrum, functional connectivity, entropy, and long-range temporal correlations (LRTCs). To evaluate the extent to which each feature is independently associated with response and relapse, we conducted logistic and proportional hazards regression, respectively. RESULTS: After statistical adjustment for the duration of epileptic spasms prior to treatment, we observed an association between response and stronger baseline and post-treatment LRTCs (P = 0.042 and P = 0.004, respectively), and higher post-treatment entropy (P = 0.003). On an exploratory basis, freedom from relapse was associated with stronger post-treatment LRTCs (P = 0.006) and higher post-treatment entropy (P = 0.044). CONCLUSION: This study suggests that multiple EEG features-especially LRTCs and entropy-may predict response and relapse. SIGNIFICANCE: This study represents a step toward a more precise approach to measure and predict response to treatment for epileptic spasms.

Early Response, Long-Term Seizure Outcome, and Very-Low-Dose Adrenocorticotrophic Hormone Therapy for Infantile Epileptic Spasms Syndrome With Down Syndrome.

BACKGROUND: Infantile epileptic spasms syndrome (IESS) with Down syndrome has good treatment response and good seizure outcomes with high-dose adrenocorticotrophic hormone (ACTH) therapy. We investigated the early treatment response of epileptic spasms (ES), long-term seizure outcome, and efficacy of very-low-dose ACTH therapy for IESS with Down syndrome. METHODS: We retrospectively investigated patients with Down syndrome and IESS between April 1983 and January 2023. We defined response to treatment as clinical remission and electrographic resolution of hypsarrhythmia after treatment for more than one month and early treatment as any treatment for ES within three months of initiation of treatment. Long-term seizure outcomes were determined by the presence of any type of seizure within one year of the last visit. We investigated the dosage and efficacy of very-low-dose ACTH therapy. RESULTS: Thirty patients were enrolled with a median follow-up period of 7.7 years (range: 1.3 to 19.1). The response and relapse rates in the early treatment were 83.3% and 16.0%, respectively. The seizure-free rate of long-term seizure outcomes was 80.0%. Long-term seizure outcomes correlated with early treatment response to ES. The response rate of very-low-dose ACTH therapy was 59.3%. The efficacy of ACTH therapy tended to be dose-dependent (P = 0.055). CONCLUSIONS: Early treatment response to ES may be useful in predicting long-term seizure outcomes of IESS with Down syndrome. Very-low-dose ACTH therapy was the most effective treatment for ES and could exhibit dose-dependent efficacy. Depending on the IESS etiology, the ACTH dose could be reduced to minimize its side effects.

[Clinical and genetic analysis of a child with West syndrome due to a de novo variant of NEXMIF gene].

OBJECTIVE: To investigate the clinical features and genetic variant of a child with West syndrome due to a variant of NEXMIF gene. METHODS: A child who was admitted to the First Medical Center of Chinese PLA General Hospital in March 2021 was selected as the study subject. Clinical data of the patient was collected. The child and his parents were subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing and pathogenicity analysis. RESULTS: The child, a 4-month-old boy, had presented with spastic seizures with no obvious cause. Abnormal EEG, severe hypsarrhythmia, and multiple spastic seizures were discovered. Cranial MRI revealed widening of the extracerebral space at the top of the frontal lobe. Physical examination revealed that the child could not hold his head up, and could not respond to sounds or follow objects with his eyes. He also has microcephaly, with height < 1 s. The child was diagnosed with West syndrome at a local hospital, and was given prednisone orally for 3 months, with seizures under control. Topiramate tablets were taken orally for maintenance treatment, and he has been seizure-free for 7 months. DNA sequencing revealed that he has harbored a de novo nonsense variant of c.982_c.983delTT (p.L328Dfs*23) in the NEXMIF gene. CONCLUSION: For children with West syndrome with severe developmental delay or even regression as the first symptoms, uncontrollable seizures and abnormal facial appearance, mutations of the NEXMIF gene should be suspected, and genetic testing can facilitate early diagnosis and treatment.

Neurophysiological and brain structural insights into cyclin-dependent kinase-like 5 deficiency disorder: Visual and auditory evoked potentials and MRI analysis.

OBJECTIVE: CDKL5 deficiency disorder (CDD), an epileptic encephalopathy for which novel therapeutics are under development, lacks valid and reliable measures of therapeutic efficacy. We aimed to elucidate the neurophysiological and brain structural features of CDD patients and identify objective indicators reflecting the clinical severity. METHODS: Twelve CDD patients and 12 healthy controls (HCs) participated. The clinical severity of CDD was scored using the CDD severity assessment (CDD-SA). The participants underwent visual evoked potential (VEP), auditory brainstem response (ABR), structural MRI, and diffusion tensor imaging (DTI) analyses. Measurements from each modality were compared with normal values of age-matched cohorts (VEP and ABR) or statistically compared between CDD patients and HCs (MRI). RESULTS: VEP showed a significant correlation between P100 latency and CDD-SA in CDD patients. ABR showed abnormalities in six patients (50%), including prolonged V-wave latency (n = 2), prolonged inter-peak latency between waves I and V (n = 3), and mild hearing loss (n = 4). Structural MRI showed a significant reduction in cortical volume in the left pars triangularis and right cerebellum compared with HCs. DTI showed a widespread decrease in fractional anisotropy and an increase in mean and radial diffusivity compared with HCs. CONCLUSION: CDD patients had reduced cortical volume in the left pars triangularis, a brain region crucial for speech, and one-third of patients had mild hearing loss. These changes may be involved in language impairments in CDD patients. Additionally, P100 latency significantly correlated with the clinical severity. These features can be used to assess the clinical severity of CDD.

X-Linked Epilepsies: A Narrative Review.

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype-phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

Modulation index predicts the effect of ethosuximide on developmental and epileptic encephalopathy with spike-and-wave activation in sleep.

PURPOSE: In developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis. METHODS: We retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40-80 Hz; ripples, 80-150 Hz) and one of five slow-wave bands (delta, 0.5-1, 1-2, 2-3, and 3-4 Hz; theta, 4-8 Hz), and compared it between ESM responders and non-responders. RESULTS: We identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5-1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5-1, 3-4, and 4-8 Hz slow waves in the frontal region, 3-4 Hz slow waves in the parietal region, 0.5-1, 2-3, 3-4, and 4-8 Hz slow waves in the occipital region, and 3-4 Hz slow waves in the anterior-temporal region. SIGNIFICANCE: High MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.

Electrographic screening for infantile epileptic spasms syndrome in a single sleep-wake cycle.

OBJECTIVE: Infantile epileptic spasms syndrome (IESS) is a common and urgent diagnosis with seizure and nonseizure mimics. Evaluation with prolonged video-electroencephalography (EEG) can be time-consuming and costly. This study investigated the use of EEG review of a single sleep-wake cycle to exclude IESS. METHODS: We retrospectively reviewed video-EEG studies to rule out IESS in children between the ages of 2 months and 2 years in the period from January 2019 through June 2020. EEG studies were reviewed from the start of the recording through the first sleep-wake cycle and scored as "normal," "consistent with IESS," or "abnormal but not diagnostic of IESS." Scores were compared to the clinical report created by analysis of the entire video-EEG. RESULTS: Inclusion criteria were met in 238 EEG studies. The mean patient age was 7.6 months. The median duration of the full study was 908 min, compared to 107.5 min for the first sleep-wake cycle only. The median difference in recording time was 801 min, p-value < .01. Scored outcomes were similar. Sixty-eight percent of EEG studies were scored as "normal" on first sleep-wake cycle review as compared to 63% on full study review, 13% scored as "consistent with IESS" compared to 16% and 19% scored as "abnormal but not diagnostic of IESS" compared to 21%. Sensitivity and specificity of the first sleep-wake cycle review for studies "consistent with IESS" was 84% and 100%, respectively. No cases of IESS were scored as normal on first sleep-wake cycle review. SIGNIFICANCE: A single sleep-wake cycle captured on EEG can triage studies when IESS is suspected. A normal first sleep-wake cycle did not miss cases of IESS and could result in reduced EEG recording time. Because most of these cases presented to an emergency department, a normal first sleep-wake cycle may help providers determine the acuity, or necessity, of further testing.

Epileptic spasms relapse is associated with response latency but not conventional attributes of post-treatment EEG.

OBJECTIVE: Relapse of epileptic spasms after initial treatment of infantile epileptic spasms syndrome (IESS) is common. However, past studies of small cohorts have inconsistently linked relapse risk to etiology, treatment modality, and EEG features upon response. Using a large single-center IESS cohort, we set out to quantify the risk of epileptic spasms relapse and identify specific risk factors. METHODS: We identified all children with epileptic spasms at our center using a clinical EEG database. Using the electronic medical record, we confirmed IESS syndrome classification and ascertained treatment, response, time to relapse, etiology, EEG features, and other demographic factors. Relapse-free survival analysis was carried out using Cox proportional hazards regression. RESULTS: Among 599 children with IESS, 197 specifically responded to hormonal therapy and/or vigabatrin (as opposed to surgery or other second-line treatments). In this study, 41 (21%) subjects exhibited relapse of epileptic spasms within 12 months of response. Longer duration of IESS prior to response (>3 months) was strongly associated with shorter latency to relapse (hazard ratio = 3.11; 95% CI 1.59-6.10; p = 0.001). Relapse was not associated with etiology, developmental status, or any post-treatment EEG feature. SIGNIFICANCE: This study suggests that long duration of IESS before response is the single largest clinical predictor of relapse risk, and therefore underscores the importance of prompt and successful initial treatment. Further study is needed to evaluate candidate biomarkers of epileptic spasms relapse and identify treatments to mitigate this risk. PLAIN LANGUAGE SUMMARY: Relapse of infantile spasms is common after initially successful treatment. With study of a large group of children with infantile spasms, we determined that relapse is linked to long duration of infantile spasms. In contrast, relapse was not associated with the cause of infantile spasms, developmental measures, or EEG features at the time of initial response. Further study is needed to identify tools to predict impending relapse of infantile spasms.

Three Patients of the Early Onset Epileptic Spasms without Hypsarrhythmia.

Epileptic spasms without hypsarrhythmia occur when patients do not display hypsarrhythmia on electroencephalogram (EEG) at the onset and throughout the clinical course. We report three patients of epileptic spasms in patients with early onset, all of whom experienced other types of seizures.We detail three patients (two boys and one girl) of epileptic spasms without hypsarrhythmia, occurring between 1 and 3 months of age, with no abnormalities detected on neurometabolic analysis and brain magnetic resonance imaging. Long-term video-EEG monitoring revealed epileptic spasms with focal onset seizures in two patients, and epileptic spasms followed by generalized tonic-clonic seizures in one patient. Hypsarrhythmia was never observed in repeated EEG examinations. Two patients achieved seizure freedom and improved development through treatment with topiramate alone or in combination with valproate, without requiring hormonal therapies or vigabatrin. The remaining patient achieved seizure freedom following administration of antiseizure medications, including topiramate, after a trial of adrenocorticotropic hormone therapy.We report the cases of three patients with early onset epileptic spasms without hypsarrhythmia. All patients achieved seizure freedom after topiramate treatment. Topiramate may be considered as a relatively effective antiseizure medication for early onset epileptic spasms without hypsarrhythmia.

Identification of a Novel Homozygous GLS Gene Variant Associated with Developmental and Epileptic Encephalopathy (DEE) Type 71.

Developmental and epileptic encephalopathy (DEEs) (OMIM#618,328) is characterized by seizures, hypotonia, and brain abnormalities, often arising from mutations in genes crucial for brain function. Among these genes, GLS stands out due to its vital role in the central nervous system (CNS), with homozygous variants potentially causing DEE type 71. Using Whole Exome Sequencing (WES) on a patient exhibiting symptoms of epileptic encephalopathy, we identified a novel homozygous variant, NM_014905.5:c.1849G > T; p.(Asp617Tyr), in the GLS gene. The 5-year-old patient, born to consanguineous parents, presented with developmental delay, encephalopathy, frequent seizures, and hypotonia. Sanger sequencing further validated the GLS gene variant in both the patient and his family. Furthermore, our bioinformatics analysis indicated that this missense variant could lead to alteration of splicing, resulting in the activation of a cryptic donor site and potentially causing loss of protein function. Our finding highlights the pathogenic significance of the GLS gene, particularly in the context of brain disorders, specifically DEE71.