OBJECTIVE: Infantile seizures cause great concern for both doctors and parents. In addition to modern neuroimaging and genetics, clinical tools helpful in predicting the course of the disease are needed. We prospectively studied the incidence, electroclinical characteristics and etiologies of epilepsy syndromes with onset before the age of 12 months and looked for prognostic determinants of outcome by age 24 months.
METHODS: From February 2017 through May 2019, we recruited all eligible infants diagnosed with epilepsy at our unit. Data on electroclinical studies, genetic investigations and drug response were gathered prospectively. The infants were given a structured neurological examination (Hammersmith Infantile Neurological examination [HINE] and Griffiths scales) at predetermined intervals until age 24 months at which age neurocognitive evaluation with Bayley scales was performed.
RESULTS: Included were 60 infants (27 female). The mean onset age of epilepsy was 5.3 (±2.5 standard deviation) months. The incidence of epilepsy in the population-based cohort was 131 (95% confidence interval 99-172)/100 000. Epilepsy syndrome was identified in 80% and etiology in 58% of infants. Self-limited infantile epilepsy was the second most common syndrome (incidence 18/100 000) after infantile epileptic spasms syndrome. PRRT2 was the most common monogenic cause. At age 24 months, 37% of the infants had drug-resistant epilepsy (DRE) and half had a global developmental delay (GDD). Abnormal first HINE was the strongest predictor of GDD, followed by DRE and identified etiology. DRE was associated with structural etiology and GDD. Those with normal first HINE and good response to treatment had favorable outcomes, irrespective of the identified etiology.
CONCLUSIONS: Our results support a high incidence of self-limited epilepsy in infancy and PRRT2 as the genetic cause in the first year of life. Notwithstanding the advances in etiological discovery, we want to highlight the importance of clinical evaluation as standardized neurological examination with HINE proved a valuable tool in prognostication.
CONCLUSIONS: One in every 700-800 babies develop epilepsy within the first year after birth. Our study identified an epilepsy syndrome in 80% and the cause of epilepsy in 60% of the participants. By age 2 years, over one-third of the children still experienced seizures, and almost half faced significant developmental delay. Structural brain abnormalities increased the likelihood of difficult epilepsy and developmental challenges. Babies whose epilepsy was caused by a gene defect varied widely in development and response to medications. Babies with normal neurological examination at first visit, especially if their seizures stopped quickly, had favorable development.

BACKGROUND: Epilepsy has a high incidence among infants during their first year of life, yet the prognosis can vary significantly. Although considerable research has been conducted on infantile spasms, studies examining infantile-onset epilepsy, excluding infantile spasms, remain limited, particularly concerning the factors influencing outcomes. Therefore, our study aims to elucidate seizure control, developmental outcomes, and prognostic factors in infants with epilepsy during their first year of life, within a single-center study in Malaysia.
METHODS: We retrieved data from patients who experienced seizures before age 12 months and were followed for over two years, using electronic patient records at Hospital Raja Perempuan Zainab II in Kelantan, a state in Malaysia\'s east coast. We retrospectively reviewed these records and assessed clinical outcomes based on the last follow-up.
RESULTS: Of 75 patients, 61 (81.3%) achieved good seizure control or remission. At the last follow-up, 24 (32%) exhibited developmental delay, whereas 19 (25.3%) displayed abnormal neuroimaging. Patients with abnormal background electroencephalographic (EEG) activity, as well as abnormal radiological findings, were more likely to experience poor seizure control and unfavorable developmental outcomes (P < 0.05).
CONCLUSIONS: Our study underscores that most infants with epilepsy can achieve seizure remission. However, poor seizure control and developmental delay are associated with abnormal EEG background and characteristics, as well as neuroimaging abnormalities. The management of infantile-onset epilepsies may necessitate substantial resources and precise interventions to enhance overall outcomes.

Ketogenic diet Therapy (KDT) has been reported as a possible beneficial management strategy for controlling seizures in infants aged <2 years, but the safety and efficacy of this therapy remain to be investigated. We investigated the achievability, tolerability, efficacy, and safety of KDT for patients under 2 years old.
Infants younger than 2 years old with pharmacoresistant epilepsy were enrolled in this prospective study. We divided cases into three age groups: I) neonates; II) infants aged 1-12 months; III) infants aged 12-24 months. KDT initiation protocol were administration through parenteral route, enteral route or oral feeding. Seizure reduction rate, physical growth, and adverse effects were assessed at monthly visit.
Thirteen patients who completed 6 months of KDT were recruited. There was one neonate in group I, 9 infants in group II, and 3 infants in group III. Eleven of them (11/13, 84.6%) were responders to KDT. All infants with underlying genetic etiology were seizure free after treating with KDT. The starting keto ratio was 1.1 mmol/L in group I, 2.3 mmol/L in group II, and 2.8 mmol/L in group III, which gradually approached 3:1-4:1 over 5-7 days. There were no symptomatic adverse effects or growth retardation in any of the study subjects.
KDT is a promising alternative therapy with high feasibility, safety, and efficacy for pharmacoresistant epilepsy in infants under 2 years old, especially for those with genetic etiology. The starting keto ratio should be lower, and the keto ratio titration period should be longer than for children older than 2 years.

OBJECTIVE: Existing data suggest that epilepsy presenting in the first few years of life carries a worse prognosis than later onset. However, studies are few and methods differ, making interpretations of data uncertain. This study analyzes outcome at age 7 and potential prognostic factors in a well-characterized population-based cohort with epilepsy onset during the first 2 years of life.
METHODS: An incidence cohort of 116 prospectively identified cases of epilepsy with seizure onset before age 2 years was described in Stödberg et al. (2020). Cases were originally retrieved from the Stockholm Incidence Registry of Epilepsy (SIRE), which registered all cases with a first unprovoked epileptic seizure from September 1, 2001, in Northern Stockholm. Data on treatment and outcome at age 7 years were collected from electronic medical records and through interviews with parents. Outcome and potential prognostic factors were analyzed with descriptive statistics and multivariable log binomial regression analysis.
RESULTS: Eleven children (9.5%) died before age 7. Polytherapy was common. Epilepsy surgery was performed in two children. At age 7 years, 61 of 116 children (53%) had been seizure-free for the last 2 years or longer. Intellectual disability was diagnosed in 57 of 116 children (49%), autism spectrum disorder in 13 (11%), and cerebral palsy in 28 (24%). West syndrome had a similar seizure remission rate but a worse cognitive outcome. There was no difference in outcome between first and second year onset. Six predictors, including etiology, remained associated with two or more outcome variables after regression analysis.
CONCLUSIONS: About half of children with infantile-onset epilepsy will become seizure-free and half of them will have intellectual disability. Etiology was confirmed as a major independent predictor of outcome. Our study contributes to a more firm knowledge base when counseling parents of infants diagnosed with epilepsy.

Background: The nucleus accumbens associated 1 (NACC1) gene is a transcription factor member of the BTB/POZ family. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Case Presentation: We report a new case with a neurodevelopmental disorder characterized by severe intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Brain MRI reveals brain dysplasia. We observe a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 gene in this case. Now, the child regularly goes to the hospital for rehabilitation training (once a month). Sodium Valproate (10 mg/kg/day) and Clobazam (10 mg/kg/day) are used in the treatment of epilepsy. A total of three articles were screened, and two papers were excluded. The search revealed one article related to a syndrome caused by a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1; they screened the main clinical features of eight cases of a syndrome, which were summarized and analyzed. Conclusions: The NACC1 gene is a member of the BTB/POZ family of transcription factors. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. At present, there is no effective cure. In the future, we need more cases to determine the phenotype-genotype correlation of NACC1 variants. Many questions remain to be answered, and many challenges remain to be faced. Future transcriptional studies may further clarify this rare, recurrent variant, and could potentially lead to targeted therapies.

Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.

A child with a de novo STXBP1 heterozygous missense mutation, believed to be a pathogenic variant, presented with clustering focal seizures affecting both hemispheres. These had begun at the age of 10 months with a phenotype similar to that of PCDH19 encephalopathy. MRI suggested a similarity to focal cortical dysplasia, though further research is needed. There was no evidence of either suppression-bursts or infantile spasms. This new case adds to the few other cases of patients with STXBP1 mutation in whom imaging features of focal cortical dysplasia on MRI have been reported, implying a possible role of STXBP1 mutation in neuronal migration disorders. If such a mutation with focal seizures is suspected, the possibility of focal cortical dysplasia should be investigated. [Published with video sequences].

BACKGROUND: Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients.
METHODS: Patients with refractory seizures using ≥2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclusion criteria, were enrolled, and underwent WES.
RESULTS: Genetic diagnoses were confirmed in 24 patients. In the seizure group, KCNQ2, SCN1A, TBCID 24, GRIN1, IRF2BPL, MECP2, OSGEP, PACS1, PIGA, PPP1CB, SMARCA4, SUOX, SZT2, UBE3A, 16p13.11 microdeletion, [4p16.3p16.1(68,345-7,739,782)X1, 17q25.1q25.3(73,608,322-81,041,938)X3], and LAMA2 were identified. In the nonseizure group, SCN2A, SPTBN2, DMD, and FBN1 were identified. Ten novel mutations were identified. The recurrent genes included SCN1A, KCNQ2, and TBCID24. Male pediatric patients had a significantly higher (57% vs. 29%; p < 0.05, odds ratio = 3.18) yield than their female counterparts. Seventeen genes were identified from the seizure groups, of which 82% were rare genetic etiologies for childhood seizure and did not appear recurrently in the case series.
CONCLUSIONS: Wide genetic variation was identified for severe childhood seizures by WES. WES had a high yield, particularly in male infantile patients.

Population-based data on epilepsy syndromes and etiologies in early onset epilepsy are scarce. The use of next-generation sequencing (NGS) has hitherto not been reported in this context. The aim of this study is to describe children with epilepsy onset before 2 years of age, and to explore to what degree whole exome and whole genome sequencing (WES/WGS) can help reveal a molecular genetic diagnosis.
Children presenting with a first unprovoked epileptic seizure before age 2 years and registered in the Stockholm Incidence Registry of Epilepsy (SIRE) between September 1, 2001 and December 31, 2006, were retrieved and their medical records up to age 7 years reviewed. Children who met the epilepsy criteria were included in the study cohort. WES/WGS was offered in cases of suspected genetic etiology regardless of whether a structural or metabolic diagnosis had been established.
One hundred sixteen children were included, of which 88 had seizure onset during the first year of life and 28 during the second, corresponding to incidences of 139 and 42/100 000 person-years, respectively. An epilepsy syndrome could be diagnosed in 54% of cases, corresponding to a birth prevalence of 1/1100. Structural etiology was revealed in 34% of cases, a genetic cause in 20%, and altogether etiology was known in 65% of children. The highest diagnostic yield was seen in magnetic resonance imaging (MRI) with 65% revealing an etiology. WES/WGS was performed in 26/116 cases (22%), with a diagnostic yield of 58%.
Epilepsy syndromes can be diagnosed and etiologies revealed in a majority of early onset cases. NGS can identify a molecular diagnosis in a substantial number of children, and should be included in the work-up, especially in cases of epileptic encephalopathy, cerebral malformation, or metabolic disease without molecular diagnosis. A genetic diagnosis is essential to genetic counselling, prenatal diagnostics, and precision therapy.

Early infantile epileptic encephalopathy type 28 is a refractory epilepsy with early onset, poor prognosis, and hereditary causes. WW domain-containing oxidoreductase (WWOX) gene mutation can result in epileptic encephalopathy, but the mechanism remains unclear. We present the case of a patient with epilepsy and WWOX compound heterozygous mutations. The seizures manifested as tonic-clonic, convulsive and were refractory to drugs. Magnetic resonance imaging showed a widened subarachnoid space and thin corpus callosum. The patient died from asphyxia at the age of one year and 23 days. Peripheral blood was taken from the patient and his parents, and whole-exome sequencing was investigated to determine possible gene mutation. Two compound heterozygous mutations were identified: c.172+1G>C (with no amino acid change) and c.984C>G (amino acid change: p.Tyr328Ter). The pathophysiology of epileptic encephalopathy related to the WWOX gene remains to be determined, and further studies are required to elucidate possible mechanisms.