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This study aimed to determine the correlation between outcomes following adrenocorticotrophic hormone (ACTH) therapy and measurements of relative power spectrum (rPS), weighted phase lag index (wPLI), and graph theoretical analysis on pretreatment electroencephalography (EEG) in infants with non-lesional infantile epileptic spasms syndrome (IESS).Twenty-eight patients with non-lesional IESS were enrolled. Outcomes were classified based on seizure recurrence following ACTH therapy: seizure-free (F, n = 21) and seizure-recurrence (R, n = 7) groups. The rPS, wPLI, clustering coefficient, and betweenness centrality were calculated on pretreatment EEG and were statistically analyzed to determine the correlation with outcomes following ACTH therapy.The rPS value was significantly higher in the delta frequency band in group R than in group F (p 0.001). The wPLI values were significantly higher in the delta, theta, and alpha frequency bands in group R than in group F (p = 0.007,0.001, and0.001, respectively). The clustering coefficient in the delta frequency band was significantly lower in group R than in group F (p 0.001).Our findings demonstrate the significant differences in power and functional connectivity between outcome groups.This study may contribute to an early prediction of ACTH therapy outcomes and thus help in the development of appropriate treatment strategies.

Background Wolf–Hirschhorn syndrome (WHS) is caused by deletion of the terminal region of chromosome 4 short arm and is frequently associated with intractable epilepsy. Objective This article evaluates the clinical features of epileptic seizures in WHS and the therapeutic efficacy of oral antiseizure medications (ASMs) Methods Patients with WHS who were treated for epilepsy at the Saitama Children's Medical Center under 5 years of age were included. WHS was diagnosed based on genetic tests and clinical symptoms. Medical records regarding the age of onset of epilepsy, seizure type, treatment of status epilepticus (SE), and effectiveness of ASMs were retrospectively reviewed. Oral ASMs were considered effective when seizures were reduced by at least 50% compared with the premedication level. Results Eleven patients were included in the study. The median age at the onset of epilepsy was 9 months (range: 5–32 months). Unknown-onset bilateral tonic-clonic seizure was the most common type of seizure, occurring in 10 patients. Focal clonic seizures occurred in four patients. Ten patients exhibited recurrent episodes of SE, and its frequency during infancy was monthly in eight patients and yearly in two. SE occurrence peaked at 1 year of age and decreased after 3 years of age. The most effective ASM was levetiracetam. Conclusion Although WHS-associated epilepsy is intractable with frequent SE occurrence during infancy, improvement in seizure control is expected with age. Levetiracetam may be a novel ASM for WHS.

The impact of the coronavirus disease 2019 (COVID-19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study.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.In 2020, the frequency of outpatient EEG studies (-10.7%, p0.001) 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*10We 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.

Objective To evaluate whether serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels predict response to adrenocorticotropic hormone (ACTH) therapy in patients with infantile spasms. Methods We prospectively evaluated patients with infantile spasms who were referred to Saitama Children’s Medical Center from January 2011 to December 2020. We measured Q-albumin and serum MMP-9 and TIMP-1 levels before ACTH therapy. Patients were divided into three groups based on the etiology of their infantile spasms: those with an unknown etiology and normal development (unknown-normal group); those with a structural and acquired etiology (structural-acquired group); and those with a structural and congenital, genetic, metabolic, or unknown etiology with developmental delay (combined-congenital group). Responders were defined as those having complete cessation of spasms for more than 3 months with the resolution of hypsarrhythmia on electroencephalography during ACTH therapy. Results We collected serum from 36 patients with West syndrome and five patients with infantile spasms without hypsarrhythmia before ACTH therapy. Twenty-three of 41 patients (56.1%) were responders, including 8/8 (100%) in the unknown-normal group, 6/9 (66.7%) in the structural-acquired group, and 9/24 (37.5%) in the combined-congenital group. The serum MMP-9 level and MMP-9/TIMP-1 ratio were significantly higher in responders than in nonresponders (P = 0.001 for both). Conclusion A therapeutic response to ACTH was associated with a higher serum MMP-9 level and higher MMP-9/TIMP-1 ratio in patients with infantile spasms. Therefore, these biomarkers may predict responses to ACTH therapy in this patient population.

Background We evaluated zonisamide therapy in patients with paroxysmal kinesigenic dyskinesia (PKD). Methods We analyzed zonisamide therapy in 17 patients with PKD at Saitama Children’s Medical Center between November 1994 and April 2020. We collected information regarding family history, previous history, age at onset, age at zonisamide commencement, dyskinesia characteristics, brain magnetic resonance imaging, interictal electroencephalography, treatment lag, zonisamide efficacy, zonisamide dose, serum zonisamide concentration, and adverse effects. We evaluated PKD frequency at six months after zonisamide therapy commencement. Results Fourteen patients met the inclusion criteria. The median age at zonisamide therapy commencement was 12.8 (9.4 to 16.3) years. Zonisamide therapy was effective in 13 of 14 (92.9%) patients: complete remission for more than three months after zonisamide therapy (n = 7), decreased dyskinesia frequency by more than 90% (n = 4), dyskinesia frequency by 75% to 90% (n = 2), and no change of dyskinesia frequency (n = 1). The initial and maintenance zonisamide doses were 2.0 (1.4 to 3.8) and 2.0 (1.5 to 5.9) mg/kg/day, respectively. The median duration between zonisamide therapy commencement and dyskinesia decrease or cessation was 4 (1 to 60) days: 10 of 14 (71.4%) patients responded to zonisamide within one week after zonisamide therapy commencement. Regarding adverse effects, two patients experienced somnolence and one developed reduced perspiration. Conclusions We suggest that zonisamide monotherapy is effective for patients with PKD as a first-line treatment. We can evaluate the efficacy of zonisamide therapy within one week. Because zonisamide lacks the enzyme-inducing effects of carbamazepine and phenytoin, it may be useful for PKD treatment.

スパズムと他の焦点性発作を同時期に有する症例におけるVigabatrin（VGB）の有効性を検討した。当センターでスパズムに対しVGBを投与した症例のうち結節性硬化症を除き、同時期に焦点性発作を有した11例を対象とした。後方視的に各発作型へのVGBの有効性、VGB中止による発作変化、最終診察時の発作転帰について評価した。経過観察は1年～6年9カ月でVGB継続期間は2週間～1年3カ月、全例で焦点性発作がスパズムに先行発症した。VGBの発作型別の有効性は、スパズムは消失例がなく、焦点性発作は消失の5例を含め半減以上が9例だった。10例でVGBを中止し、VGB投与中焦点性発作が半減以上だった8例全例で再発又は増加した。発作転帰は、両発作型消失と焦点性発作のみ消失が各々1例、スパズムのみ消失が2例、両発作型残存が7例だった。両発作型を同時期に有する症例において、VGBはスパズムには無効でも焦点性発作に有効性を認めた。VGBは、スパズムと共に焦点性発作への有効性も考慮し、VGB継続ならびに再開を検討すべきである。また、難治性てんかんにおけるスパズム以外の発作型に対するVGBの適応拡大が望まれる。

Objective Absence status epilepticus (ASE) is a form of non-convulsive status epilepticus characterized by ongoing or intermittent epileptic activity accompanied by behavioral and cognitive changes. Herein, we assessed high-frequency oscillations in the ripple band in patients with ASE and typical absence seizures. Methods We enrolled five patients with ASE, 26 patients with childhood absence epilepsy (CAE), and 15 patients with juvenile absence epilepsy (JAE). We performed time–frequency analysis of electroencephalogram data for ictal absence seizures at each electrode to assess the high frequency activity (HFA) rate, peak frequency, and peak power. Results The average HFA rates were 60.7%, 20.8%, and 12.9% in ASE, CAE, and JAE patients, respectively. The average peak frequencies were 126.4 Hz, 120.9 Hz, and 126.1 Hz in ASE, CAE, and JAE patients, respectively. The average peak power values were 2,388.8 μV2, 120.9 μV2, and 126.1 μV2 in ASE, CAE, and JAE patients, respectively, and all epilepsy groups exhibited frontal-dominant ripple distribution. Conclusion ASE patients presented higher power and frontal dominant ripples of absence seizure, compared to CAE and JAE patients. Significance Future studies should utilize scalp-recorded ripples as a biomarker of absence epilepsy. This may aid in the development of novel treatment strategies for ASE.

Some pediatric patients with autoimmune encephalitis (AE) experience sequelae in spite of immunotherapy. In this study, we aimed to evaluate the association of serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels with the neurological prognosis of AE.We retrospectively included 13 patients with AE who had been referred to Saitama Children's Medical Center from February 2011 to May 2019. We compared serum MMP-9 levels, TIMP-1 levels, and MMP-9/TIMP-1 ratio in the acute period (within 30 days from the onset of AE) and subacute period (30-day period following the acute period). We also compared these biomarker levels between patients with (group A) and without sequelae (group B). Sequelae were evaluated at discharge or the last visit.Group A (median age, 7.8 years; range, 5.3-10.7 years) and group B (median age, 13.3 years; range, 11.1-15.4 years) had 6 patients each; 1 patient was excluded because the time of AE onset was unknown. In the acute period, there were no significant differences in MMP-9 levels, TIMP-1 levels, and MMP-9/TIMP-1 ratio between groups A and B. In the subacute period, serum MMP-9/TIMP-1 ratio was higher in group A than in group B (p 0.01). There were no significant differences in MMP-9 and TIMP-1 levels between groups A and B.Patients with sequelae of AE showed a high MMP-9/TIMP-1 ratio in the subacute period. Our study demonstrates that elevation of serum MMP-9/TIMP-1 ratio in the subacute period may be a predictive factor of sequelae of AE.

Perampanel is an antiepileptic drug. Some studies have documented the efficacy of perampanel in epileptic spasms. We aimed to evaluate the efficacy and safety of adjunctive perampanel therapy (PT) in patients with epileptic spasms.We retrospectively surveyed the efficacy and safety of adjunctive PT in 14 patients with epileptic spasms at the Saitama Children's Medical Center between June 2016 and September 2021. Seizure outcomes and safety were evaluated 12 months after commencing PT. Response to perampanel was defined as complete remission of epileptic spasms for more than 3 months.The median age at onset of epileptic spasms was 0.4 years (range, 0.1-1.3 years). The etiology was structural in 11 patients, genetic in two, and unknown in one. The median age at the commencement of PT was 3.2 years (1.5-10.3 years). The initial and maintenance doses of perampanel were administered at 0.04 (range, 0.02-0.05) mg/kg/day and 0.12 (range, 0.03-0.24) mg/kg/day, respectively. Five of the 14 patients (35.7%) showed remission of epileptic spasms for more than 3 months at 12 months after PT; these patients had a structural etiology. The median duration between commencement of perampanel and spasm remission was 2 months (range, 1-6 months). No serious adverse effects occurred.This is the first case series evaluating adjunctive PT for epileptic spasms. PT is worth investigating to treat epileptic spasms in patients with structural etiologies. As our study population primarily comprised children aged 2 years and older, PT may be useful for epileptic spasms beyond infancy.

OBJECTIVE To identify the risk factors for psychological distress in electroencephalography (EEG) technicians during the coronavirus disease 2019 (COVID-19) pandemic. METHOD In this national-level cross-sectional survey initiated by Japan Young Epilepsy Section (YES-Japan), which is a national chapter of The Young Epilepsy Section of the International League Against Epilepsy (ILAE-YES), a questionnaire was administered to 173 technicians engaged in EEG at four clinics specializing in epilepsy care and 20 hospitals accredited as (quasi-) epilepsy centers or epilepsy training facilities in Japan from March 1 to April 30, 2021. We collected data on participants' profiles, information about work, and psychological distress outcome measurements, such as the K-6 and Tokyo Metropolitan Distress Scale for Pandemic (TMDP). Linear regression analysis was used to identify the risk factors for psychological distress. Factors that were significantly associated with psychological distress in the univariate analysis were subjected to multivariate analysis. RESULTS Among the 142 respondents (response rate: 82%), 128 were included in the final analysis. As many as 35.2% of EEG technicians have been under psychological distress. In multivariate linear regression analysis for K-6, female sex, examination for patients (suspected) with COVID-19, and change in salary or bonus were independent associated factors for psychological distress. Contrastingly, in multivariate linear regression analysis for TMDP, female sex, presence of cohabitants who had to be separated from the respondent due to this pandemic, and change in salary or bonus were independent associated factors for psychological distress. CONCLUSION We successfully identified the risk factors associated with psychological distress in EEG technicians during the COVID-19 pandemic. Our results may help in understanding the psychological stress in EEG technicians during the COVID-19 pandemic and improving the work environment, which is necessary to maintain the mental health of EEG technicians.

Objective To evaluate the efficacy and safety of pyridoxal for treating West syndrome. Methods We retrospectively investigated pyridoxal’s efficacy and safety in 117 patients with West syndrome at Saitama Children’s Medical Center from July 1993 to May 2016. Pyridoxal was administered at doses of 10–50 mg/kg/day. We evaluated seizure outcomes and electroencephalographic findings at 4 weeks after pyridoxal therapy. The responders were those with complete cessation of spasms for more than 4 weeks and those with resolution of hypsarrhythmia on EEG at 1–4 weeks after pyridoxal therapy. Results Five of the 117 patients (4.3%) were responders. The median duration between pyridoxal therapy to spasm cessation was 6 (5–13) days. Among the responders, four had hypsarrhythmia resolution, no spasm relapse, and no other seizure types more than 2 years after pyridoxal therapy. One responder had partial seizures and spasm relapse. No serious adverse effects occurred. There were no significant differences in sex, etiologies, complication, other seizure types preceding the spasms, onset age of spasms, age of pyridoxal therapy, treatment lag, initial and maintenance doses of pyridoxal, and adverse effects between pyridoxal responders and non-responders. Conclusions The efficacy rate of pyridoxal monotherapy as first-line treatment for West syndrome was low. However, pyridoxal therapy showed a rapid response within 1 week and was safe. We consider pyridoxal therapy as a kind of challenge therapy during the evaluation period concerning differential diagnosis and etiologies of West syndrome and immunological risks before adrenocorticotrophic hormone therapy or vigabatrin therapy.

We aimed to evaluate choice and efficacy of intravenous antiepileptic drugs (AEDs) for status epilepticus (SE) in Dravet syndrome and to find predictable clinical features demonstrating the effectiveness of benzodiazepine (BZD) for SE.We retrospectively investigated the medical records in patients with Dravet syndrome and evaluated the effectiveness rate of intravenous AEDs and the rate of adverse effects. To find the clinical features of BZD-effective SE, we divided the SE episodes into the following two groups: BZD effective group and BZD non-effective group. The choice of treatment was dependent on physicians' discretion according to the protocol for SE in our institution.Sixty-eight SE episodes in 10 patients were assessed. The median age at SE was 31 months. Of 68 episodes, 42 episodes (61.8%) were in the BZD effective group and 26 (38.2%) in the BZD non-effective group. There were no significant differences in clinical features. In the BZD non-effective group, the effective rates of continuous midazolam, phenobarbital, phenytoin/fosphenytoin were 9/9 episodes (100%), 14/17 (82.4%), and 2/5 (40.0%), respectively. Adverse effects were identified in 19/68 episodes (27.9%), including 11/42 episodes in the BZD effective group and 8/26 in the BZD non-effective group, which was no statistical difference between the two groups. Respiratory suppression was found in all 19 episodes and the incidence of endotracheal intubation in the BZD non-effective group (15.4%) was higher than that in the BZD effective group (2.4%) (p = 0.046).BZD may be used as first choice, and phenobarbital prior to continuous midazolam as second choice for SE with Dravet syndrome. There might be no predictable clinical features showing that BZD will be effective.

Introduction Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation. Case Study A 3-year-old patient presented with nystagmus and muscle hypotonia in his neonatal period, followed by delayed psychomotor development. Brain magnetic resonance images showed delayed myelination. Wave III and subsequent components were not presented by his auditory brainstem response. These features were similar to those observed in Pelizaeus-Merzbacher disease (PMD). Methods Proteolipid protein 1 (PLP1) gene screening, Mendelian disease panel exome, and whole-exome sequencing (WES) were sequentially performed. Results After excluding mutations in either PLP1 or other known HLD genes, WES identified a mutation c.754G > A, p.(Asp252Asn) in TMEM106B, which appeared to occur de novo, as shown by Sanger sequencing and SalI restriction enzyme digestion of PCR products. Discussion This is the sixth case of HLD with a TMEM106B mutation. All six cases harbored the same variant. This specific TMEM106B mutation should be investigated when a patient shows PMD-like features without PLP1 mutation. Our PCR-SalI digestion assay may serve as a tool for rapid HLD diagnosis.

Background Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the N-methyl-D-aspartate receptor. Case The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid. Conclusion Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an N-methyl-D-aspartate receptor. Furthermore, the ketogenic diet may have modulated the excessive neurotoxic cascade through the N-methyl-D-aspartate receptor. Perampanel and ketogenic diet were effective for seizure control in our patient.

This study aimed to investigate the general presentation of epileptic spasms without hypsarrhythmia (ESwoH) and retrospectively determine whether there are differences in treatment effects related to ACTH therapy, long-term seizure outcome, and evolution of EEG features according to pre-treatment EEG patterns. According to the pattern of background activity, we divided our cohort into two groups: Group 1: normal background activity or with localized intermittent slow waves; Group 2: intermittent slow waves appearing generalized or in two or more lobes. Subjects included 22 children (Group 1: n=10; Group 2: n=12) diagnosed with ESwoH who received treatment from 2007 to 2017. The median age at onset of epileptic spasms was 5.5 months and the follow-up period lasted for 40.5 months. ACTH therapy was performed for seven patients from Group 1 and eight patients from Group 2. Only one patient from Group 2 responded to ACTH. Patients receiving effective treatments at early stages had excellent seizure outcome. Refractory cases included six patients in Group 1 and eight patients in Group 2; subsequent follow-up EEGs indicated hypsarrhythmia in one patient in Group 1 (17%) and six patients (75%) in Group 2, including one patient whose EEG pattern indicated progression to Lennox-Gastaut syndrome. Overall, ACTH is ineffective for patients with epileptic spasms without hypsarrhythmia. The EEG may indicate possible future development of hypsarrhythmia if epileptic spasms are resistant to treatment, especially in patients with diffuse slow waves on pre-treatment EEG. The efficacy of treatment introduced at early stages from onset may predict long-term seizure outcome.

Background Iodine 123 (I-123) iomazenil is a specific ligand of the central benzodiazepine receptor, which is a part of the postsynaptic gamma-aminobutyric acid A receptor complex. We performed statistical image processing of I-123 iomazenil single-photon emission computed tomography to elucidate maturational changes in the GABAergic system. Methods Thirty patients (18 boys and 12 girls, aged 17 days to 14 years) with cryptogenic focal epilepsy were enrolled and underwent I-123 iomazenil single-photon emission computed tomography. We used a semiquantitative analytical method consisting of brain surface extraction, anatomic normalization, and a three-parameter exponential model. We then assessed developmental changes in benzodiazepine receptor binding activity in 18 regions of interest in both hemispheres. Results The highest benzodiazepine receptor binding activity was observed during early infancy in all regions of interest. Benzodiazepine receptor binding activity then decreased exponentially across development. Benzodiazepine receptor binding in the primary sensorimotor cortex, primary visual cortex, cerebellar vermis, and striatum declined more rapidly than that in the cerebellar hemispheres and the frontal cortex. The pons and the thalamus had the lowest benzodiazepine receptor binding activities during the neonatal period, and benzodiazepine receptor binding in these areas declined gradually after infancy toward adolescence. There were no differences in adjusted benzodiazepine receptor binding activity according to laterality or sex. Conclusions Benzodiazepine receptor binding activity decreased exponentially during infancy in all regions of interest. Binding activity in the primary somatosensory and motor cortices (M1 and S1), the primary and association visual areas, the cerebellar vermis, and the striatum (caudate nucleus and putamen) tended to decline more rapidly than that in the cerebellar hemisphere and the frontal association cortex.

We retrospectively investigated whether perampanel (PER) could serve as an alternative for treating drug-resistant seizures in lissencephaly. We investigated the following data: age at onset of epilepsy, age at start of PER, etiology, brain MRI findings, seizure type, seizure frequency, adverse effects, and concomitant anti-epileptic drugs. There were 5 patients with lissencephaly, including 2 with Miller–Dieker syndrome. Four out of five patients exhibited ≥ 50% seizure reduction. Myoclonic seizures disappeared in 1 patient. PER was an effective adjunctive anti-seizure drug in our series of patients with lissencephaly., Highlights • PER could treat drug-resistant seizures of patients with lissencephaly. • PER could be effective against epileptic myoclonus in lissencephaly. • AMPA receptor phenotype in neuronal migration disorder may explain effects of PER.

A 3-year-old boy with normal development presented with acute cerebellitis at one year and 10 months of age. His truncal ataxia resolved without treatment. He experienced a relapse of truncal ataxia and atonic seizures at 2 years and one month of age. Five months later, he experienced myoclonic atonic seizures. By 3 years of age, the truncal ataxia had become severe, and the frequency of myoclonic atonic seizures increased. Compared to controls, we found higher levels of anti-C-terminal GluN2B and anti-N terminal GluD2 antibodies in the serum, and anti-N terminal GluN2B and anti-C terminal GluD2 antibodies in the cerebrospinal fluid (CSF). A cell-based assay revealed the presence of anti-NMDA-type glutamate receptor antibody in the serum, but absence in the CSF. Ictal EEG of myoclonic atonic seizures showed generalized spike and wave complexes. The patient was diagnosed with myoclonic atonic epilepsy. Adrenocorticotrophic hormone therapy resolved the truncal ataxia and myoclonic atonic seizures, along with the decreased serum anti-C-terminal GluN2B and anti-N-terminal GluD2 antibodies, and CSF anti-N-terminal GluN2B and anti-C-terminal anti-GluD2 antibodies. Our results suggest that the anti-GluN2B and anti-GluD2 antibodies may be associated with myoclonic atonic epileptic seizures and chronic cerebellitis.

Purpose Perampanel (PER) is a selective, non-competitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor. In Japan, PER is approved for patients with epilepsy who are at least 12 years old for the adjunctive treatment of primary generalised tonic-clonic seizures and partial-onset seizures (with or without secondary generalization). We surveyed the efficacy, adverse effects, and serum concentrations of PER, focusing especially on patients younger than 12 years of age. Methods We retrospectively surveyed the clinical information of patients treated with PER and assessed the efficacy at 6 months after treatment initiation. We compared efficacy, adverse effects, and serum concentration in patients younger or older than 12 years of age. Responders were defined as those who experienced a ≥50% seizure reduction. Results Eighty-four patients were enrolled. The average age of the younger group was 7.1 ± 3.3 (standard deviation) years compared to 16.4 ± 3.7 years in the older group. The responder rate was 42.9% (36/84). The responder rate did not differ between the two age groups ( 12 years, 16/40, 40.0%; p = 0.78). The younger age group had a significantly lower concentration-to-dose (CD) ratio than the older age group ( 12 years, 3076.3 ± 3352.2, p = 0.02). Treatment-emergent adverse events (TEAEs) were observed in 22.6% (19/84) of patients, with the most common being somnolence (8/84, 9.5%). Conclusion PER may be an alternative to treat seizures in paediatric drug-resistant epilepsy. Serum concentrations of PER might be lower in patients younger than 12 years than in older patients.

Pseudohypoaldosteronism type 1 (PHA1) is a rare disease characterized by congenital resistance to the action of aldosterone on epithelial tissue; PHA1 results in excessive salt wasting despite very high plasma aldosterone and renin levels (1,2,3). There are 3 types of PHA1. The systemic form of PHA1 is inherited in an autosomal recessive manner and manifests as severe life-long salt wasting caused by mineralocorticoid resistance in multiple target tissues (e.g., sweat glands, salivary glands, colonic epithelium, and lung). The renal form of PHA1 (adPHA1) is inherited in an autosomal dominant manner. In this form, mineralocorticoid resistance exists only in the kidney; moreover, salt wasting and other symptoms improve around 1–3 yr of age (1,2,3). The third type of PHA1 is the transient form, which is commonly seen in patients with urinary tract infection or obstructive uropathy. In the transient form, clinical symptoms disappear after treatment. adPHA1 is caused by a heterozygous mutation in NR3C2, which encodes the mineralocorticoid receptor (MR). Herein, we report the case of a young girl with adPHA1, a novel mutation in NR3C2, hyponatremia, and failure to thrive associated with urinary tract infection. We also describe a genetic analysis of her family.

Background Intravenous immunoglobulin (IVIG) therapy is used in the treatment of various diseases, and IVIG-related adverse effects (IVIG-AEs) vary from mild to severe. However, the mechanisms underlying IVIG-AEs and the potential predictive factors are not clear. This study investigated whether certain IVIG-AEs can be predicted before IVIG administration. Study design and methods This retrospective cohort study at the Division of Neurology, Saitama Children’s Medical Center included patients enrolled from 2008 to 2018 who were < 18 years old and received IVIG for the first time. IVIG-AEs were classified according to the Common Terminology Criteria for Adverse Events version 5.0. Results A total of 104 patients fulfilled the inclusion criteria. The rate of IVIG-AEs was 37.5% (39/104). The most frequent IVIG-AEs were fever (41.0% [16/39]) and headache (38.5% [15/39]). AEs were below grade 2 in all except one patient and there were no grade 4 AEs. High serum total protein (TP) level was significantly related to the occurrence of IVIG-AEs (odds ratio, 14.8; 95% confidence interval, 2.4–90.5; P < 0.01). The optimal cutoff TP level was 6.7 g/dL. Although low WBC count and immunoglobulin G level may be predictive risk factors of IVIG-AEs, it was not confirmed in this study. Conclusion IVIG-AEs occurred in 37.5% of cases, and most were mild. TP was the best predictive risk factor of IVIG-AEs before IVIG administration. These results may aid in elucidating the mechanism underlying IVIG-AEs.

Mutation of the gene encoding ubiquitin-like modifier-activating enzyme 5 (UBA5) causes autosomal recessive early-onset epileptic encephalopathy. UBA5 acts as an E1-activating enzyme in the ubiquitin-fold modifier 1 pathway, which is important for unfolded protein elimination and regulation of apoptosis, and has been linked to human diseases. We identified biallelic mutations in UBA5 in a Japanese boy with intractable West syndrome, profound failure to thrive, and severe cerebral and cerebellar atrophy. The boy presented with epileptic spasms and hypsarrhythmia at the age of three months. He was diagnosed with West syndrome, however, treatments with adrenocorticotropic hormone and several antiepileptic drugs were ineffective. MRI findings were initially normal, but subsequently showed a progression of cerebellar and cerebral atrophy. By the age of seven years, he had not achieved any developmental milestones; he had daily epileptic spasms and tonic seizures and profound failure to thrive. Gene analysis revealed novel compound heterozygous mutations in UBA5; a microdeletion encompassing the entire UBA5 gene and a putative disease-causing missense mutation in the catalytic domain. These biallelic variants may have caused loss of function, accounting for the observed clinical symptoms. Intractable infantile epileptic spasms, failure to thrive, and severe neurological impairment may be characteristic of patients with UBA5 mutations.

Objective: To elucidate the pathophysiology of West syndrome and mechanism of immunoglobulin therapy for this syndrome, we investigated serum and cerebrospinal fluid (CSF) cytokine levels before and after high-dose intravenous immunoglobulin (IVIG) therapy in patients with West syndrome. Methods: We measured serum and CSF cytokine levels of 11 patients with West syndrome who was referred to Saitama Children’s Medical Center from April 2010 to May 2014. All patients received IVIG, ranging from 200 to 500 mg/kg/day for 3 consecutive days (initial IVIG treatment), before adrenocorticotrophic hormone therapy. When spasms disappeared within 2 weeks after initial IVIG treatment, maintenance IVIG treatment was commenced. We measured cytokines level in patients before and after initial IVIG treatment. We compared the levels of cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17, Interferon γ, Granulocyte macrophage colony stimulating factor, IL-18, Tumor necrosis factor-α〔TNF-α〕) in serum and CSF, and between the seizure-free group and seizure-persisting group. Seizure free was defined as remission of spasms within 2 weeks after initial IVIG treatment and no relapse for at least 1 week after remission. Results: After IVIG therapy, 5 of 11 patients were in the seizure-free group (4 males, 1 cryptogenic) while 6 were in the seizure-persisting group (2 males, 1 cryptogenic). Levels of IL-1β, IL-10, IL-18, and TNF-α in serum were significantly higher than those in CSF before initiation of IVIG. Before IVIG treatment, the level of IL-8 in CSF was significantly higher than that in serum, while the serum IL-18 level in the seizure-free group was significantly lower than that in the seizure-persisting group. Alterations of serum IL-18 level and CSF IL-8 level were different between the seizure-free and seizure-persisting groups. Conclusions: Serum IL-18 and CSF IL-8 may be important factors for elucidating the pathophysiology of West syndrome and mechanism of IVIG therapy.

Objective To clarify changes in clinical practice for infantile spasms, including West syndrome, in Japan over the past two decades. Methods We investigated common treatment strategies for infantile spasms among 157 pediatric neurologists from a designated training facility for pediatric neurology and/or a designated training facility for epilepsy in Japan. A questionnaire was used to investigate use of adrenocorticotropic hormone (ACTH) therapy including daily dose, treatment duration, and tapering off period, and preferred first to fifth-line treatment choices. Results Among 119 responses (75.8%), 107 enabled analysis of ACTH therapy and 112 were used to determine preferred order of first to fifth-line treatments. Over 80% respondents reported an initial ACTH dose of ≤0.0125 mg/kg/day, with a treatment duration of 14 days and various tapering periods. Following an unfavorable response of seizures to ACTH, 80% respondents increased the dose and/or extended treatment duration. The same ACTH therapy regimen was performed for symptomatic and cryptogenic patients at 95 facilities (88.8%). Preferred orders of therapeutic agents were the same for both symptomatic and cryptogenic patients at 64 facilities (57.1%). Over half the respondents selected vitamin B6 or valproate as the first and second-line treatments instead of ACTH therapy, while ACTH therapy was the most frequently selected third-line treatment. Conclusions Current ACTH therapy regimens have lower doses and shorter durations than previously reported. However, treatment strategies for infantile spasms have not changed much in two decades. ACTH therapy should be the first/second-line treatment rather than third-line or later, especially for cryptogenic infantile spasms.

Introduction: We investigated serum matrix metalloprotease-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels in patients with acute phase hemiplegic migraine and migrainous infarction. Background: Migraine is a common disorder that is characterized by episodic headaches. Hemiplegic migraine and migrainous infarction are rare migraine-related conditions with unknown pathophysiology. Methods and Findings: We evaluated serum MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio in patients with migrainous infarction (patient 1), hemiplegic migraine (patient 2), cerebral infarction with other causes (group 3, n=4), and non-organic disease (group 4, n=5). Serum MMP-9 levels were significantly higher in patients 1 and 2 than in groups 3 and 4. The serum TIMP-1 level was significantly lower in patient 1 than in groups 3 and 4. MMP-9/TIMP-1 ratios were higher in patients 1 and 2 than in groups 3 and 4. Conclusion: MMP-9 levels and the MMP/TIMP-1 ratio may aid in the diagnosis of migraine, and therefore may provide a clue to the etiology of cerebral infarction.

To quantitatively evaluate regional cerebral blood flow (rCBF) and regional developmental changes during childhood usingWe retrospectively analyzed quantitative values of rCBF in 75 children (29 girls) aged between 16 days and 178 months (median: 12 months), whose brain images, including magnetic resonance imaging and SPECT data, were normal under visual inspection at Saitama Children's Medical Center between 2005 and 2015. The subjects had normal psychomotor development, no focal neurological abnormalities, and neither respiratory nor cardiac disease at the time of examination. Regions of interest were placed automatically using a three-dimensional stereotactic template.rCBF was lowest in neonates, who had greater rCBF in the lenticular nucleus, thalamus, and cerebellum than the cerebral cortices. rCBF increased rapidly during the first year of life, reaching approximately twice the adult levels at 8 years, and then fell to approximately adult levels in the late teenage years. Cerebral cortex rCBF sequentially increased in the posterior, central, parietal, temporal, and callosomarginal regions during infancy and childhood.rCBF changed dramatically throughout childhood and ranged from lower than adult values to approximately two times higher than adult values. It had different trajectories in each region during brain development. Understanding this dynamic developmental change is necessary for SPECT image evaluation in children.

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte aII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the alpha/beta spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. alpha II/beta II aggregates and aII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the alpha/beta spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B-and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the alpha/beta heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the alpha 20 repeat is important for alpha/beta spectrin heterodimer formation and/or alpha II spectrin function.

To evaluate factors influencing the efficacy and safety of intravenous immunoglobulins (IVIG) therapy for West syndrome.We investigated seizure outcomes in 70 patients who received IVIG treatment for West Syndrome during the first 3months after the onset of epileptic spasms. IVIG was administered for 3 consecutive days (initial IVIG treatment) at dosages ranging from 100 to 500mg/kg/day. If spasms disappeared within 2weeks of the initial treatment, maintenance IVIG treatment was commenced. We evaluated seizure outcomes at 2weeks (initial evaluation), at 2years (long-term evaluation), and the last visit (last follow-up evaluation) after the initial IVIG treatment. We analyzed dosages of IVIG, age at onset of spasms, treatment lag, and etiologies between responders and non-responders.Among the patients, 7/70 (10.0%) had cessation of spasms and resolution of hypsarrhythmia at the initial evaluation. Another 6/70 patients (8.6%) were found to have cessation of spasms at the long-term evaluations. The treatment lag in responders was shorter than that in non-responders (P0.01). There were no significant differences between responders and non-responders in IVIG dosages, age at onset of spasms, and etiologies. Two patients had relapse of partial seizures after cessation of spasms at the last follow-up evaluation. Adverse effects occurred in 2/70 patients.The efficacy of IVIG was so low that it should not be considered as first-line treatment in West syndrome. IVIG therapy has a good safety profile and we would recommend it for West syndrome cases with drug resistance, severe complications associated with profound brain damage, severe brain atrophy, and in immunocompromised patients.

We developed a simple and sensitive method using reversed-phase high-performance liquid chromatography (HPLC) for determining lamotrigine (LTG) plasma concentrations in infant patients with epilepsy undergoing polypharmacy.It involves a simple protein precipitation procedure that uses no solid-phase or liquid-liquid extraction.HPLC was carried out on a Cadenza CD-C 18 column (3μm,4.6 mm×150 mm) with phosphate buffer (pH 4.6;25 mM) containing a methanolacetonitrile mixture (4:3,v/v) as the mobile phase,by gradient elution at a 1.0 mL/min flow rate.LTG was detected using a UV detector at 215 nm.The quantification limit was 0.10μg/mL for 100μL of plasma sample.The intra- and interassay coefficients of variation were 1.18-6.87% and 1.65-7.07%,respectively.A specificity and selectivity study showed that there were no interfering peaks.In addition,correlation analysis conducted on LTG concentrations by the new method and a commercial HPLC method produced a correlation coefficient (r ) of 0.9974.

Purpose We investigated whether benign infantile seizures can be diagnosed in the acute phase. Methods We retrospectively analyzed the medical records of 44 patients initially diagnosed with acute phase benign infantile seizures. All patients were followed for more than 12 months, and we reviewed patients' psychomotor development and presence or absence of seizure recurrence at the last visit. Patients were divided into the following three groups according to the final diagnosis: benign infantile seizures, benign infantile seizures associated with mild gastroenteritis, and non-benign infantile seizures. We defined benign infantile seizures associated with mild gastroenteritis and benign infantile seizures as those associated with normal psychomotor development and no seizure recurrence 3 months after onset of the first seizure, whereas non-benign infantile seizures were associated with delayed psychomotor development and/or seizure recurrence after 3 months of onset of the first seizure. We analyzed the clinical features in the acute phase and compared them between the groups. Results The median age of seizure onset was 7.6 months. A final diagnosis of benign infantile seizures associated with mild gastroenteritis was made in three patients. In the remaining 41 patients, the final diagnosis was benign infantile seizures in 30 (73.2%) and non-benign infantile seizures in 11 (26.8%). In the non-benign infantile seizure group, intellectual disability was diagnosed in eight patients and seizure recurrence in six. There were no significant differences in clinical features between the groups in the acute phase, such as seizure type or seizure duration. Conclusion About 30% of patients initially diagnosed as having benign infantile seizures did not experience a benign clinical course. Our findings suggest that clinical features in the acute phase are not helpful for predicting benign outcomes in benign infantile seizures and that only long-term follow-up can discriminate benign infantile seizures from non-benign infantile seizures.

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors 150 or more kinds of proteins to the cell surface. There are at least 26 genes involved in the biosynthesis and transport of GPI anchored proteins (GPI-APs). In paroxysmal nocturnal hemogrobinuria (PNH), an acquired GPI deficiency, somatic mutation in X-linked PIGA accounts for most of the patients. A case with PNH due to a combination of inherited mutation in one allele and a somatic mutation in the other allele of autosomal gene PIGT was reported recently (Blood 2013 doi:10.1182/blood-2013-01-481499). On the other hand, many inherited GPI deficiencies (IGDs) were found recently using whole exome sequencing (Nat Genet 2010 vol.42 p827, Am J Hum Genet 2012 vol. 90 p295, p146, Am J Hum Genet 2012 vol. 91 p146, Am J Hum Genet 2013 vol. 92 p584). As the complete GPI deficiency causes embryonic death, these patients with IGD are partial deficiency. The major symptoms of IGDs include mental retardation, epilepsy, coarse facial features and multiple organ anomalies that vary in severity depending upon the degree of defect and/or position in the pathway of affected gene. We clarified a mechanism of hyperphosphatasia, an elevated release of tissue nonspecific alkaline phosphatase (TNAP, GPI-AP), seen in some of the patients with IGDs such as hyperphosphatasia mental retardation syndrome or Mabry syndrome caused by mutation in genes in the later stage of GPI biosynthesis (J Biol Chem. 2012 vol. 287 p6318) Here, we report four male patients with intellectual disabilities accompanied by seizures caused by the mutations in PIGA gene. These mutations were found by whole-exome sequencing using the Illumina HiSeq system. PIGA is X-linked gene which is involved in the first step of GPI biosynthesis pathway. These patients have germline hypomorphic mutations in PIGAgene and have completely different symptoms from patients with PNH, which is characterized by complement-mediated intravascular hemolysis. Patient 1 had a hemizygous nonsense mutation, and was diagnosed with Ohtahara syndrome (early infantile epileptic encephalopathy with suppression burst) with multiple congenital anomalies. The nonsense mutation is leaky and caused a partial deficiency. Patient 2 had a maternally inherited hemizygous missense mutation and was diagnosed with early-onset West syndrome (a severe epilepsy syndrome characterized by infantile spasm with hypsarrhythmia). Patients 3 and 4 are brothers, had maternally inherited hemizygous missense mutation and were suffering from severe intellectual disabilities with seizures but not with any anomalies. Analysis by flow cytometry of patients’ blood cells revealed that all four patients showed decreased expression of GPI-APs on the granulocytes but not in erythrocytes or lymphocytes, suggesting that FACS analysis of granulocytes is useful to screen patients with IGD. Interestingly, the FACS analysis of the granulocytes from the mother of patients 3 and 4 showed mosaic pattern in CD16 expression. The mother seemed to have no neurological symptom, raising the possibility that contribution of GPI-AP-deficient cells to neuronal system does not occur or is only limited. Although PNH and IGDs are different diseases, both are partial GPI deficiencies, the former affecting only hematopoietic cells, the latter having the hypomorphic mutations, which rescue the patients from lethality but cause the severe hematopoietic and developmental abnormalities, respectively. Disclosures: No relevant conflicts of interest to declare.