Treatment odyssey to epilepsy surgery in children with focal cortical dysplasia: Risk factors for delayed surgical intervention.

OBJECTIVE: To elucidate the patient's journey to epilepsy surgery and identify the risk factors contributing to surgical delay in pediatric patients with drug-resistant epilepsy (DRE) due to focal cortical dysplasia (FCD). METHODS: A retrospective review was conducted of 93 pediatric patients who underwent curative epilepsy surgery for FCD between January 2012 and March 2023 at a tertiary epilepsy center. The Odyssey plot demonstrated the treatment process before epilepsy surgery, including key milestones of epilepsy onset, first hospital visit, epilepsy diagnosis, MRI diagnosis, DRE diagnosis, and surgery. The primary outcome was surgical delay; the duration from DRE to surgery. Multivariate linear regression models were used to examine the association between surgical delay and clinical, investigative, and treatment characteristics. RESULTS: The median age at seizure onset was 1.3 years (interquartile range [IQR] 0.14-3.1), and at the time of surgery, it was 6 years (range 1-11). Notably, 46% experienced surgical delays exceeding two years. The Odyssey plot visually highlighted that surgical delay comprised a significant portion of the patient journey. Although most patients underwent MRI before referral, MRI abnormalities were identified before referral only in 39% of the prolonged group, compared to 70% of the non-prolonged group. Multivariate analyses showed that delayed notification of MRI abnormalities, longer duration from epilepsy onset to DRE, older age at onset, number of antiseizure medications tried, and moderate to severe intellectual disability were significantly associated with prolonged surgical delay. CONCLUSION: Pediatric DRE patients with FCD experienced a long journey until surgery. Early and accurate identification of MRI abnormalities is important to minimize surgical delays.

Epidemiological study on pediatric-onset dystonia in Japan: A questionnaire-based survey.

OBJECTIVE: This study aimed to investigate the clinical characteristics of pediatric-onset dystonia in Japan, addressing the diagnostic challenges arising from symptom variations and etiological diversity. METHODS: From 2020 to 2022, questionnaires were distributed to 1218 board certified child neurologists (BCCNs) by Japanese Society of Child Neurology. In the primary survey, participants were asked to report the number of patients with pediatric-onset dystonia under their care. Subsequently, the follow-up secondary survey sought additional information on the clinical characteristics of these patients. RESULTS: The primary survey obtained 550 responses (response rate: 45 %) from BCCNs for their 736 patients with dystonia. The predominant etiologies included inherited cases (with DYT10   being the most prevalent, followed by DYT5 and ATP1A3-related neurologic disorders), acquired cases (with perinatal abnormalities being the most common), and idiopathic cases. The secondary survey provided clinical insights into 308 cases from 82 BCCNs. Infancy-onset dystonia presented as persistent and generalized with diverse symptoms, primarily linked to ATP1A3-related neurologic disorders and other genetic disorders resembling acquired dystonia. Conversely, childhood/adolescent-onset dystonia showed paroxysmal, fluctuating courses, predominantly affecting limbs. The most common etiologies were DYT5 and DYT10 , leading to therapeutic diagnoses. CONCLUSION: Pediatric-onset dystonia in Japan was treated by 28 % of BCCNs. The majority of cases were inherited, with high prevalence rates of DYT5 and DYT10 . Infancy-onset dystonia exhibits diverse etiologies and symptoms, emphasizing the utility of various examinations, including genetic testing. These findings significantly contribute to our understanding of pediatric-onset dystonia in Japan, although this study has the limitation of questionnaire survey.

Intraventricular hemorrhage volume and younger age at surgery may be risk factors for postoperative hydrocephalus after hemispherotomy in children.

OBJECTIVE: Hemispherotomy is an effective treatment for intractable hemispheric epilepsy; however, hydrocephalus remains a common complication of the procedure. The causes of hydrocephalus following hemispherotomy have not been fully elucidated; therefore, the purpose of this study was to identify the risk factors associated with the condition. METHODS: The authors investigated the records of all patients aged < 18 years who underwent hemispherotomy at their institution between 2003 and 2020 and were monitored for hydrocephalus for at least 1 year after the procedure. To identify the risk factors for hydrocephalus, the following information about each patient was collected: sex, corrected age at surgery, body weight at surgery, previous intracranial surgery, etiology of epilepsy, results of PET for hypermetabolism, side of surgery, type of operation (vertical or horizontal approach), operation time, blood loss during surgery, use of intraventricular drainage, occurrence of intraventricular hemorrhage (IVH) on the 1st postoperative day, duration of postoperative fever of > 38°C, and maximum C-reactive protein level after the operation. Multivariate logistic regression analyses were performed. RESULTS: This study included 51 children who underwent hemispherotomies for drug-resistant epilepsy at our hospital. Seven patients (13.7%) experienced hydrocephalus and were treated with ventricular or subdural peritoneal shunts or fenestration. Multivariate logistic analysis using the Bayesian information criterion revealed that 3 factors were associated with the occurrence of hydrocephalus: age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C. CONCLUSIONS: This study showed that younger age at surgery, postoperative IVH volume, and duration of postoperative fever of > 38°C might be risk factors for hydrocephalus after hemispherotomy. The risk of hydrocephalus should be considered in cases of early surgical indication in children. Intraoperative hemostasis and postoperative use of anti-inflammatory measures may reduce the risk of hydrocephalus.

Double inversion recovery MRI of subcortical band heterotopia and its variations.

BACKGROUND AND PURPOSE: Subcortical band heterotopia (SBH) is a malformation of cortical development diagnosed via MRI. Currently, patients with SBH are classified according to Di Donato's classification. We aimed to show a variation of SBH and the usefulness of double inversion recovery (DIR) images. METHODS: We retrospectively reviewed the MRI findings of 28 patients with SBH. The patients were classified according to Donato's classification by using conventional MR images, and their DIR findings were reviewed. RESULTS: Of 28 patients, 20 were grade 1 and 8 were grade 2 according to Di Donato's classification. In 15 of 28 patients, the following four types of atypical MRI findings were detected: asymmetry distribution (four cases), coexistence of thin and thick SBH (five cases), and DIR faint abnormal signal intensity in subcortical white matter (five cases) and in deep white matter (five cases). The latter two types were detected on DIR alone and have not been reported. Additionally, these were identified only in the mild group (Di Donato's classification 1-1 or 1-2). CONCLUSION: DIR is a useful MRI sequence for detecting faint white matter signal abnormalities, and it can aid in the accurate classification of SBH and identification of its variations, which may reflect the pathology of SBH.

Duplication within two regions distal to MECP2: clinical similarity with MECP2 duplication syndrome.

BACKGROUND: X-linked methyl-CpG-binding protein 2 (MECP2) duplication syndrome is prevalent in approximately 1% of X-linked intellectual disabilities. Accumulating evidence has suggested that MECP2 is the causative gene of MECP2 duplication syndrome. We report a case of a 17-year-old boy with a 1.2 Mb duplication distal to MECP2 on chromosome Xq28. Although this region does not contain MECP2, the clinical features and course of the boy are remarkably similar to those observed in MECP2 duplication syndrome. Recently, case reports have described duplication in the region distal to, and not containing, MECP2. These regions have been classified as the K/L-mediated Xq28 duplication region and int22h1/int22h2-mediated Xq28 duplication region. The case reports also described signs similar to those of MECP2 duplication syndrome. To the best of our knowledge, ours is the first case to include these two regions. CASE PRESENTATION: The boy presented with a mild to moderate regressive intellectual disability and progressive neurological disorder. He developed epilepsy at the age of 6 years and underwent a bilateral equinus foot surgery at 14 years of age because of the increasing spasticity in lower extremities since the age of 11. Intracranial findings showed hypoplasia of the corpus callosum, cerebellum, and brain stem; linear hyperintensity in the deep white matter; and decreased white matter capacity. During his childhood, he suffered from recurrent infection. However, genital problems, skin abnormalities and gastrointestinal manifestations (gastroesophageal reflux) were not observed. CONCLUSIONS: Cases in which duplication was observed in the region of Xq28 that does not include MECP2 also showed symptoms similar to those of MECP2 duplication syndrome. We compared four pathologies: MECP2 duplication syndrome with minimal regions, duplication within the two distal regions without MECP2, and our case including both regions. Our results suggest that MECP2 alone may not explain all symptoms of duplication in the distal part of Xq28.

Synchronous heart rate reduction with suppression-burst pattern in KCNT1-related developmental and epileptic encephalopathies.

Suppression-burst (SB) is an electroencephalographic pattern observed in neonatal- and infantile-onset developmental and epileptic encephalopathies (DEEs), which are associated with high mortality in early life. However, the relation of SB electroencephalogram (SB-EEG) with autonomic function requires clarification. We investigated the relationship between heart rate (HR) and phasic transition during SB-EEG in DEEs to explore the mechanism of early death. Seven patients (two with KCNT1-DEE) with neonatal- and infantile-onset DEE who presented with SB-EEG were retrospectively identified. Five-minute SB-EEGs were analyzed with simultaneous recording of electrocardiograms. Mean HR, suppression duration, and burst period were calculated by measuring RR intervals. Two patients with KCNT1-DEE exhibited synchronous HR fluctuations, with an HR decrease during suppression and an increase during burst. The HR decrease was larger (-6.1% and -7.7%) and the median duration of suppression was longer (4.0 and 8.2 s) in patients with KCNT1-DEE than the other five (range: -2.9% to 0.9% and 0.7-1.7s, respectively). A strong negative correlation was confirmed between suppression duration and HR reduction rates in one patient with KCNT1-DEE. SB phases may influence HR regulation in patients with KCTN1-DEE.

Neurological insights on two siblings with GM3 synthase deficiency due to novel compound heterozygous ST3GAL5 variants.

BACKGROUND: ST3GAL5 encodes GM3 synthase (ST3 beta-galactoside alpha-2,3-sialyltransferase 5; ST3GAL5), which synthesizes GM3 by transferring sialic acid to lactosylceramide. GM3, a sialic acid-containing glycosphingolipid known as ganglioside, is a precursor to the biosynthesis of various more complex gangliosides that are active in the brain. Biallelic variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD), a rare congenital disorder of glycosylation. GM3SD was first identified in the Amish population in 2004. CASE: We report two siblings diagnosed with GM3SD due to novel compound heterozygous ST3GAL5 variants. The novel ST3GAL5 variants, detected by whole-exome sequencing in the patients, were confirmed to be pathogenic by GM3 synthase assay. The clinical courses of these patients, which began in infancy with irritability and growth failure, followed by developmental delay and hearing loss, were consistent with previous case reports of GM3SD. The older sibling underwent deep brain stimulation for severe involuntary movements at the age of 9 years. The younger sibling suffered from acute encephalopathy at the age of 9 months and subsequently developed refractory epilepsy. DISCUSSION: Reports of GM3SD outside the Amish population are rare, and whole-exome sequencing may be required to diagnose GM3SD in non-Amish patients. Since an effective treatment for GM3SD has not yet been established, we might select deep brain stimulation as a symptomatic treatment for involuntary movements in GM3SD.

Skeletal anomaly and opisthotonus in early-onset epileptic encephalopathy with KCNQ2 abnormality.

BACKGROUND: Heterozygous KCNQ2 variants cause benign familial neonatal seizures and early-onset epileptic encephalopathy in an autosomal dominant manner; the latter is called KCNQ2 encephalopathy. No case of KCNQ2 encephalopathy with arthrogryposis multiplex congenita has been reported. Furthermore, early-onset scoliosis and opisthotonus have not been documented as characteristics of KCNQ2 encephalopathy. CASE REPORT: A male infant born with scoliosis and arthrogryposis multiplex congenita developed intractable epilepsy on the second day of life. At 4 months of age, he developed opisthotonus. The opisthotonus was refractory to medication in the beginning, and it spontaneously disappeared at 8 months of age. Whole-exome sequencing revealed a novel de novo heterozygous variant in KCNQ2, NM_172107.4:c.839A > C, p.(Tyr280Ser). CONCLUSIONS: Early-onset scoliosis, arthrogryposis multiplex congenita, and opisthotonus may be related to KCNQ2 encephalopathy.

Impact of COVID-19 pandemic on epilepsy care in Japan: A national-level multicenter retrospective cohort study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study. METHODS: This study included monthly data on the frequency of (1) visits by outpatients with epilepsy, (2) outpatient electroencephalography (EEG) studies, (3) telemedicine for epilepsy, (4) admissions for epilepsy, (5) EEG monitoring, and (6) epilepsy surgery in epilepsy centers and clinics across Japan between January 2019 and December 2020. We defined the primary outcome as epilepsy-center-specific monthly data divided by the 12-month average in 2019 for each facility. We determined whether the COVID-19 pandemic-related factors (such as year [2019 or 2020], COVID-19 cases in each prefecture in the previous month, and the state of emergency) were independently associated with these outcomes. RESULTS: In 2020, the frequency of outpatient EEG studies (-10.7%, p<0.001) and cases with telemedicine (+2,608%, p=0.031) were affected. The number of COVID-19 cases was an independent associated factor for epilepsy admission (-3.75*10-3 % per case, p<0.001) and EEG monitoring (-3.81*10-3 % per case, p = 0.004). Further, the state of emergency was an independent factor associated with outpatient with epilepsy (-11.9%, p<0.001), outpatient EEG (-32.3%, p<0.001), telemedicine for epilepsy (+12,915%, p<0.001), epilepsy admissions (-35.3%; p<0.001), EEG monitoring (-24.7%: p<0.001), and epilepsy surgery (-50.3%, p<0.001). SIGNIFICANCE: We demonstrated the significant impact that the COVID-19 pandemic had on epilepsy care. These results support those of previous studies and clarify the effect size of each pandemic-related factor on epilepsy care.

Long-term changes in electroencephalogram findings in a girl with a nonsense SMC1A variant: A case report.

INTRODUCTION: Pathogenic truncating variants in SMC1A, which is located on chromosome Xp11.2, are known to cause infantile-onset epilepsy and severe intellectual disability in girls. Several studies have reported a correlation between SMC1A truncations and seizure clustering; however, the associated electroencephalogram (EEG) patterns remain largely unknown. CASE PRESENTATION: We investigated an 12-year-old girl who had developed epilepsy at the age of 4 months. The patient experienced unknown onset, tonic-clonic seizures that occurred in clusters several times a week. Her interictal EEG at the age of 2 years showed paroxysmal, generalized, high-amplitude slow waves, whereas epileptiform discharges were scarce. The patient's interictal EEG gradually deteriorated; at the age of 11 years, diffuse continuous spike-and-wave discharges were predominantly observed in the left temporal region and were particularly obvious in the awake state. Although the unknown onset, tonic seizures occurring weekly persisted under multiple antiepileptic medications, the patient did not experience seizure clustering since the age of 9 years. Whole-genome sequencing revealed a de novo known nonsense variant in SMC1A (c.2923C > T, p.R975*). CONCLUSION: Our patient presented with a mild abnormality in the interictal EEG during infancy and early childhood despite frequent seizure clustering. Notably, the patient's EEG findings gradually deteriorated over time, which was inconsistent with the amelioration of seizure clustering.

Low EEG Gamma Entropy and Glucose Hypometabolism After Corpus Callosotomy Predicts Seizure Outcome After Subsequent Surgery.

Background: Patients with generalized epilepsy who had lateralized EEG abnormalities after corpus callosotomy (CC) occasionally undergo subsequent surgeries to control intractable epilepsy. Objectives: This study evaluated retrospectively the combination of EEG multiscale entropy (MSE) and FDG-PET for identifying lateralization of the epileptogenic zone after CC. Methods: This study included 14 patients with pharmacoresistant epilepsy who underwent curative epilepsy surgery after CC. Interictal scalp EEG and FDG-PET obtained after CC were investigated to determine (1) whether the MSE calculated from the EEG and FDG-PET findings was lateralized to the surgical side, and (2) whether the lateralization was associated with seizure outcomes. Results: Seizure reduction rate was higher in patients with lateralized findings to the surgical side than those without (MSE: p < 0.05, FDG-PET: p < 0.05, both: p < 0.01). Seizure free rate was higher in patients with lateralized findings in both MSE and FDG-PET than in those without (p < 0.05). Conclusions: This study demonstrated that patients with lateralization of MSE and FDG-PET to the surgical side had better seizure outcomes. The combination of MSE and conventional FDG-PET may help to select surgical candidates for additional surgery after CC with good postoperative seizure outcomes.

Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.

Clinical and neuroimaging findings in patients with lissencephaly/subcortical band heterotopia spectrum: a magnetic resonance conventional and diffusion tensor study.

PURPOSE: To clarify brain abnormalities on magnetic resonance imaging (MRI) and its clinical implications in lissencephaly/subcortical band heterotopia (LIS/SBH) spectrum patients. METHODS: The clinical severity and classification according to Di Donato were retrospectively reviewed in 23 LIS/SBH spectrum patients. The morphological and signal abnormalities of the brainstem, corpus callosum, and basal ganglia were also assessed. The brainstem distribution pattern of the corticospinal tract (CST) was analyzed by diffusion tensor imaging (DTI) and categorized into two types: normal pattern, in which the CST and medial lemniscus (ML) are separated by the dorsal portion of the transverse pontine fiber, and the abnormal pattern, in which the CST and ML are juxtaposed on the dorsal portion of a single transverse pontine fiber. Correlations between MR grading score and potential additional malformative findings of the brain and clinical symptoms were investigated. RESULTS: All patients with grade 3 (n = 5) showed brainstem deformities, signal abnormalities of pontine surface and had a tendency of basal ganglia deformity and callosal hypoplasia whereas those abnormalities were rarely seen in patients with grade 1 and 2 (n = 18). For DTI analysis, the patients with grade 3 LIS/SBH had typically abnormal CST, whereas the patients with grade 1 and 2 LIS/SBH had normal CST. The classification was well correlated with CST and brainstem abnormalities and clinical severity. CONCLUSION: MR assessment including DTI analysis may be useful in assessing the clinical severity in LIS/BH spectrum and may provide insight into its developmental pathology.

Effect of anti-attention-deficit hyperactivity disorder (ADHD) medication on clinical seizures and sleep EEG: A retrospective study of Japanese children with ADHD.

AIMS: Patients with attention-deficit hyperactivity disorder (ADHD) often exhibit basic or paroxysmal wave abnormalities on electroencephalography (EEG). Methylphenidate (MPH), an anti-ADHD stimulant, has been reported to lower the seizure threshold. However, there have been no reports comparing EEG changes before and after administration of the central nervous system (CNS) stimulant MPH, or atomoxetine (ATX) hydrochloride, a non-CNS stimulant. In this study, we investigated changes in sleep EEG before and after the administration of ADHD treatment drugs. METHOD: With the approval of the ethics committee, the medical records of 28 children with ADHD (23 men and 5 women) who gave consent were retrospectively investigated. The appearance of sudden abnormal waves during a 10-minute sleep EEG recording was measured in 0.1-second units, and the duration of these waves was calculated as the paroxysmal index (PI). RESULTS: Paroxysmal index did not differ significantly between patients who received MPH and those who received ATX. In addition, there were no exacerbations of clinical seizures. CONCLUSION: It was concluded that ADHD medications do not have an adverse effect on epileptic seizures or abnormal sleep EEGs.

Single-subject gray matter networks in temporal lobe epilepsy patients with hippocampal sclerosis.

OBJECTIVE: Previous studies have demonstrated structural brain network abnormalities in patients with temporal lobe epilepsy (TLE) using cortical thickness or gray matter (GM) volume. However, no studies have applied single-subject GM network analysis. Here, we first applied an analysis of similarity-based single-subject GM networks to individual patients with TLE. MATERIALS AND METHODS: We recruited 51 patients with TLE and unilateral hippocampal sclerosis (22 left, 29 right TLE) and 51 age- and gender- matched healthy controls. Single-subject structural networks were extracted from three-dimensional T1-weighted magnetic resonance images for each subject. In this method, nodes were defined as small cortical regions and edges representing connecting regions that have high statistical similarity. The constructed graphs were analyzed using the graph theoretical approach. The following global and local network properties were calculated: betweenness centrality, clustering coefficient, and characteristic path length. In addition, small world properties (normalized path length λ, normalized clustering coefficient γ, and small-world network value σ) were obtained and compared with those for the controls. RESULTS: Although the small-world configurations were retained, impaired global clustering coefficient was observed in left and right TLE. At a regional level, patients with left TLE showed a widespread decrease of the clustering coefficient beyond the ipsilateral temporal lobe and a decreased characteristic path length in the ipsilateral temporal pole. On the other hand, patients with right TLE showed a localized decrease of the clustering coefficient in the ipsilateral temporal lobe. CONCLUSIONS: Our findings suggest that global and local network properties disrupted and moved toward randomized networks in TLE patients in comparison to controls. This network alteration was more extensive in left TLE than in right TLE patients. Single-subject GM networks may contribute to a better understanding of the pathophysiology of TLE.

Clinical profile of reading ability and reading and writing achievement of children with borderline full-scale intellectual quotient: a prospective study.

BACKGROUND: Poor reading ability is one of the common causes of low academic performance. In previous studies, children with dyslexia were found to demonstrate poor academic achievement due to poor reading ability. However, the relationship between academic achievement and reading ability in children with a borderline full-scale intellectual quotient (FSIQ) is unknown. This study aimed to clarify the clinical characteristics of children with borderline FSIQ and poor reading ability, and differentiate these characteristics from those of children with higher FSIQ and poor reading ability. METHODS: A total of 126 children (aged 6-15 years) identified as having low academic performance were enrolled. The reading ability of children was assessed through their performance on the hiragana (Japanese syllabary) reading task, while their reading and writing achievement was assessed through their reading and writing score on the Kaufman Assessment Battery for Children, Second Edition. Children were categorized into two groups based on their FSIQ score (FSIQ > 85 and 85 ≥ FSIQ ≥ 70). Reading ability in children was evaluated by referring to the linear relationship between FSIQ and the standard deviation value of reading tasks in typically developing children. A one-way analysis of variance (ANOVA) was performed to examine clinical characteristics between higher and lower FSIQ groups. Associations between reading and writing achievement, reading ability, and ages of children were assessed using Pearson's product-moment correlation coefficients for the higher and lower FSIQ groups. RESULTS: Poorer reading and writing achievement was associated with poorer reading ability in the higher FSIQ group. Conversely, poorer reading and writing achievement and poor reading ability were associated with older age in the lower FSIQ group. CONCLUSIONS: Poor reading and writing achievement were associated with older age, not with poor reading ability in the lower FSIQ group. Children with lower FSIQ need appropriate educational interventions based on independent assessments to further their academic achievement and reading ability. Moreover, they need more frequent evaluations of their academic achievement than do children with higher FSIQ and poor reading ability since they are more likely to be at a lower academic achievement level at an older age.

Epilepsy surgery in children under 3 years of age: surgical and developmental outcomes.

OBJECTIVE: Pediatric epilepsy surgery is known to be effective, but early surgery in infancy is not well characterized. Extensive cortical dysplasia, such as hemimegalencephaly, can cause refractory epilepsy shortly after birth, and early surgical intervention is indicated. However, the complication rate of early pediatric surgery is significant. In this study, the authors assessed the risk-benefit balance of early pediatric epilepsy surgery as relates to developmental outcomes. METHODS: This is a retrospective descriptive study of 75 patients who underwent their first curative epilepsy surgery at an age under 3 years at the authors' institution between 2006 and 2019 and had a minimum 1-year follow-up of seizure and developmental outcomes. Clinical information including surgical complications, seizure outcomes, and developmental quotient (DQ) was collected from medical records. The effects of clinical factors on DQ at 1 year after surgery were evaluated. RESULTS: The median age at surgery was 6 months, peaking at between 3 and 4 months. Operative procedures included 27 cases of hemispherotomy, 19 cases of multilobar surgery, and 29 cases of unilobar surgery. Seizure freedom was achieved in 82.7% of patients at 1 year and in 71.0% of patients at a mean follow-up of 62.8 months. The number of antiseizure medications (ASMs) decreased significantly after surgery, and 19 patients (30.6%) had discontinued their ASMs by the last follow-up. Postoperative complications requiring cerebrospinal fluid (CSF) diversion surgery, such as hydrocephalus and cyst formation, were observed in 13 patients (17.3%). The mean DQ values were 74.2 ± 34.3 preoperatively, 60.3 ± 23.3 at 1 year after surgery, and 53.4 ± 25.1 at the last follow-up. Multiple regression analysis revealed that the 1-year postoperative DQ was significantly influenced by preoperative DQ and postoperative seizure freedom but not by the occurrence of any surgical complication requiring CSF diversion surgery. CONCLUSIONS: Early pediatric epilepsy surgery has an acceptable risk-benefit balance. Seizure control after surgery is important for postoperative development.

Corpus callosotomy in pediatric patients with non-lesional epileptic encephalopathy with electrical status epilepticus during sleep.

Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is often refractory to medical treatment and leads to poor cognitive outcomes. Corpus callosotomy may be an effective treatment option for drug-resistant ESES with no focal etiology. We retrospectively identified three patients who underwent corpus callosotomy for drug-resistant ESES in our institution. Electroencephalography (EEG) findings and cognitive functions were evaluated before surgery, at 3 months, 6 months, 1 year, and 2 years after surgery. Age at surgery was 6 years 10 months, 7 years 9 months, and 8 years 4 months, respectively. Period between the diagnosis of ESES and surgery ranged from 7 to 25 months. All patients had no obvious structural abnormalities and presented with cognitive decline despite multiple antiseizure medications and steroid therapies. One patient showed complete resolution of ESES and an improvement of intelligence quotient after surgery. Epileptiform EEG was lateralized to one hemisphere after surgery and spike wave index (SWI) was decreased with moderate improvement in development and seizures in the other 2 patients. SWI re-exacerbated from 6 months after surgery, but without subsequent developmental regression in these 2 patients. Corpus callosotomy may become an important treatment option for drug-resistant ESES in patients with no structural abnormalities.

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.

Whole genome sequencing of 45 Japanese patients with intellectual disability.

Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.