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Objective The current study aimed to identify and compare the clinical characteristics of human parechovirus type 3 (HPeV3)-associated acute encephalitis/encephalopathy (HPeV3E/E) between infants with abnormal brain magnetic resonance imaging (MRI) findings (typical, or MRI-positive HPeV3E/E) and those with MRI-negative findings (MRI-negative HPeV3E/E). Methods This is a retrospective study on patients with HPeV3 infection, and a two-step questionnaire survey performed on 837 hospitals in Japan between 2014 and 2016. Results We identified 240 infants with HPeV3 infection, of which 34 had been clinically-diagnosed HPeV3E/E (cHPeV3E/E). However, detailed clinical data were provided by 32 of the 34 patients. Among these 32, 23 had undergone MRI and were categorized into two groups, MRI-positive (n = 17) and -negative (n = 6). There were no significant intergroup differences in clinical lab results or symptoms, except for gastrointestinal symptoms that were only present in the MRI-negative patients. The MRI-positive group showed white matter involvement on brain MRI during the acute phase, and 8 patients presented with lesions on follow-up MRI. Furthermore, 4 (50%) of the 8 patients had neurological sequelae. Conclusion Clinical characteristics of cHPeV3E/E patients with and without lesions on brain MRI showed no significant differences. Therefore, considering the difficulty in distinguishing febrile infants with cHPeV3E/E from those with a sepsis-like illness, during an HPeV3 infection epidemic, it is imperative to frequently perform brain MRI in febrile infants presenting with severe disease for the early diagnosis of HPeV3E/E presenting with brain lesions.

Aim To describe beneficial effects of callosotomy on KCNQ2-related intractable epilepsy. Case report Our patient was a 10-year-old girl who had developed epilepsy during the neonatal period, accompanied by a suppression-burst pattern on the electroencephalography (EEG). The patient showed profound psychomotor developmental delay since early infancy. Daily seizures of versive posturing and ocular deviation were transiently controlled by carbamazepine and valproate at the age of 1 year; however, the seizures gradually increased to up to 50 times per day. Ictal EEG and positron emission tomography revealed an epileptic focus in the left frontal lobe at age 5 years. Total callosotomy resulted in marked reduction of epileptic seizures thereafter, as well as improved responses to external auditory and visual stimuli. Whole exome sequencing at age 9 identified a de novo missense variant in KCNQ2 (NM_172107.3:c.563A > C:p.(Gln188Pro)). Conclusion This case supports that epilepsy surgery could benefit children with epileptic encephalopathy, even with the etiology of channelopathy.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10−6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders., Many causative genes are known for epileptic or developmental and epileptic encephalopathies (EE/DEE) yet a genetic diagnosis cannot be made for many patients. Here, the authors analyse whole exome sequencing data from a Japanese case−control cohort to identify common, rare and ultra-rare coding variants associated with EE/DEE.

Purpose To evaluate the long-term safety and seizure outcome in Japanese patients with Lennox–Gastaut syndrome (LGS) receiving adjunctive rufinamide therapy. Subjects and methods We conducted an open-label extension study following a 12-week multicenter, randomized, double-blind, placebo-controlled study of adjunctive rufinamide therapy in Japanese patients with LGS. Fifty-four patients participated in the extension study. Seizure frequency was evaluated until 52 weeks after the start of the extension study. Adverse events (AEs) were evaluated throughout both studies. Key findings Of the 54 patients, 41 (75.9%) completed the extension study. The median duration of exposure to rufinamide was 818.0 days in all 54 patients, and 38 patients (70.4%) received rufinamide for 2 years or more. The median percent change in the frequency of tonic–atonic seizures relative to the frequency at the start of the double-blind study was −39.3% (12 weeks), −40.6% (24 weeks), −46.8% (32 weeks), −47.6% (40 weeks), and −36.1% (52 weeks). Reduction of total seizure frequency was also maintained until 52 weeks. Frequent treatment-related AEs were somnolence (20.4%), decreased appetite (16.7%), transient seizure aggravation including status epilepticus (13.0%), vomiting (11.1%), and constipation (11.1%). Adverse events were mild or moderate, except for transient seizure aggravation in three patients. Adverse events resulting in discontinuation of rufinamide were decreased appetite, drug eruption, and worsening of underlying autism. When clinically notable weight loss was defined as a decrease ≥7% relative to baseline, 22 patients (40.7%) experienced weight loss at least once during long-term observation, although weight loss was reported as an AE in only three patients. Significance This study demonstrated a long-term benefit of rufinamide as adjunctive therapy for Japanese patients with LGS. Exacerbation of seizures and decreased appetite/weight loss should be monitored carefully.

Epileptic encephalopathy, which commences during early infancy, is a severe epileptic syndrome that manifests as age-dependent seizures and severe developmental delay. The syntaxin-binding protein 1 gene (STXBP1) is one of the genes responsible for epileptic encephalopathy. We conducted a cohort study to analyze STXBP1 in 42 patients with epileptic encephalopathy. We identified four novel mutations: two splicing mutations, a frameshift mutation, and a nonsense mutation. All of these mutations were predicted to cause loss-of-function. This result suggests loss-of-function is a common mechanism underlying STXBP1-related epileptic encephalopathy. The four patients showed epileptic features consistent with STXBP1-related epileptic encephalopathy, but showed variable radiological findings, including brain volume loss and myelination delay.

Objective Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD. Methods This open-label pilot study included five patients who received high-dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies. Results High-dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood–brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again. Interpretation Pharmacological chaperone therapy with high-dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.

Objective: We examined the short-term efficacy and safety of rufinamide (RFN) in patients with Lennox-Gastaut syndrome (LGS). Methods: We performed a retrospective review of clinical records of patients with LGS who started RFN treatment between July 2013 and June 2014 at the Hokkaido Medical Center for Child Health and Rehabilitation and Midorigaoka Ryo-iku-en. Efficacy and safety were evaluated when the patients had completed three months of treatment. Patients were classified into four categories according to percent seizure reduction : remission (seizure-free), response (seizure reduction≥50%), no change (seizure reduction50% or increase) and aggravation (seizure increase≥50%). Responder rate (RR) was the percentage of patients with≥50% decrease in seizure frequency. Results: Thirteen LGS patients (8 males, 5 females) were studied. The efficacy for tonic seizures (13 patients) was remission 1 patient, response 3 patients, no change 8 patients and aggravation 1 patient, with RR of 30.8%. Two patients discontinued LGS due to seizure aggravation. Four patients experienced transient remission. For generalized tonic clonic seizures (2 patients), 1 patient achieved remission and 1 patient showed no change. Two patients of atonic seizures showed no change. Of 2 patients of atypical absence, 1 patient showed response and 1 patient no change. Eight patients had adverse effects such as somnolence (6 patients), sleep disturbance (1 patient), and appetite loss (4 patients) including weight loss in 2 patients. There were no severe adverse effects and no discontinuation due to adverse effects. Conclusions: Short-term effectiveness for tonic seizures was observed when patients with LGS were treated with RFN, with transient remission in some patients. We consider that RFN is worth trying in patients with LGS due to its efficacy for tonic seizures and absence of severe adverse effects.

The purpose of this study was to identify the risk factors of cognitive impairment in pediatric epilepsy patients with focal cortical dysplasia (FCD).77 patients with histopathologically confirmed FCD were studied. The statistical relationship between cognition levels and clinical factors at presurgical evaluation was analyzed. Cognitive function was evaluated by development quotient or intelligence quotient (DQ-IQ).Ages at seizure onset were younger than 15 years (mean ± SD; 5.0 ± 4.2 years). Mean disease duration was 14.5 ± 8.5 years. Mean age at pre-surgical DQ-IQ evaluation was 34.8 ± 10.7 years. Mean DQ-IQ was 60.5 ± 20.5, and 41 of 77 (53.2%) patients had mental retardation (DQ-IQ 70). Younger seizure onset and seizure clustering were significantly associated with lower DQ-IQ (p 0.001). A multiple regression study identified higher seizure frequency pattern, a history of epileptic spasm and status epilepticus as aggravating factors of DQ-IQ decline (ROur study suggests that seizure characteristics including higher seizure frequency pattern, a history of epileptic spasm, status epilepticus, seizure clustering and early onset of seizure are risk factors of cognitive impairment in FCD patients.

SummaryPurposeTo evaluate the efficacy, safety, and pharmacokinetics of rufinamide as an adjunctive therapy for patients with Lennox–Gastaut syndrome (LGS) in a randomized, double-blind, placebo-controlled trial.MethodsWe conducted a multicenter clinical trial with a 4-week baseline, a 2-week titration, a 10-week maintenance, and either a follow-up visit or entry into an open-label extension. Patients with LGS (4 to 30 years old) taking between one and three antiepileptic drugs were recruited. After the baseline period, patients were randomly assigned to rufinamide or placebo. The primary efficacy variable was the percent change in the tonic–atonic seizure frequency per 28 days.Key findingsOf the 59 patients, 29 were randomized to the rufinamide group and 30 to the placebo group. The frequency of epileptic seizures was significantly decreased in the rufinamide group than in the placebo group; the median percent change in frequency of tonic–atonic seizures was −24.2% and −3.3%, respectively, (p=0.003) and that of total seizures was −32.9% and −3.1%, respectively (p

We describe two cases of refractory epilepsy with cerebral hemiatrophy and contralateral electroencephalographic (EEG) abnormalities, in which hemispherotomy of the atrophic hemisphere effectively controlled seizures. Case 1 was a 5-year-1-month-old girl with refractory bilateral asymmetrical tonic posturing seizures predominantly in the right arm. Magnetic resonance imaging showed left porencephaly corresponding to a left middle cerebral artery infarction. Case 2 was a 3-year-8-month-old boy with refractory bilateral asymmetrical tonic posturing seizures predominantly in the right arm due to atrophy of the left cerebral hemisphere after septic meningitis. Both patients had right hemiparesis and was incapable of pinching by the right hand. Contralateral interictal and ictal EEG abnormalities were observed. Interictal 99mTc-ethyl cysteinate dimer (99mTc-ECD) single photon emission computed tomography (SPECT) showed hypoperfusion and ictal 99mTc-ECD-SPECT showed hyperperfusion within the left cerebral hemisphere. Left hemispherotomy was performed. Cases 1 and 2 remained seizure-free at the last follow-up 18 months and 15 months, respectively, after surgery, and contralateral interictal EEG abnormalities disappeared. In patients with cerebral hemiatrophy and contralateral EEG abnormalities, epilepsy surgery may be considered when the laterality of seizure semiology, functional imaging findings and motor deficits were concordant with the atrophic side. Ictal SPECT is effective to confirm the epileptogenic hemisphere.

Subependymal giant cell astrocytomas are benign tumors often observed with tuberous sclerosis complex. These tumors are rarely diagnosed during fetal life or early infancy. Until recently, the only available treatment has been surgical resection. Current clinical research has demonstrated that everolimus can induce these tumors’ regression. We report a 19-month-old boy with tuberous sclerosis complex. At 2 months of age, he presented with congenital subependymal giant cell astrocytoma that was complicated by refractory epilepsy and severe mental retardation. Treatment with everolimus was started when he was 10 months old. Three months after initiating everolimus, the tumor was significantly reduced in size, and the reduction was subsequently maintained. His seizures decreased and he showed cognitive and developmental improvement. No severe adverse events have been observed to date. Everolimus has promise as an effective alternative to surgery for subependymal giant cell astrocytomas during early infancy.

The hallmark of neuronopathic Gaucher disease (GD) is oculomotor abnormalities, but ophthalmological assessment is difficult in uncooperative patients. Chromatic pupillometry is a quantitative method to assess the pupillary light reflex (PLR) with minimal patient cooperation. Thus, we investigated whether chromatic pupillometry could be useful for neurological evaluations in GD. In our neuronopathic GD patients, red light-induced PLR was markedly impaired, whereas blue light-induced PLR was relatively spared. In addition, patients with non-neuronopathic GD showed no abnormalities. These novel findings show that chromatic pupillometry is a convenient method to detect neurological signs and monitor the course of disease in neuronopathic GD.

The aims of this study were to identify the factors influencing the metabolism of clobazam (CLB) and its active metabolite [N-desmethyl clobazam (NCLB)] and to evaluate the NCLB concentration as an indicator for CYP2C19 polymorphism in epileptic patients.A total of 302 serum samples from 238 Japanese patients were evaluated. The ratios of the serum CLB and NCLB concentrations to the CLB dose (CD ratios) were calculated and compared with CYP2C19 phenotypes.The mean CD ratio of NCLB in extensive metabolizers (EM: *1/*1), intermediate metabolizers (IM: *1/*2 or *1/*3), and poor metabolizers (PM: *2/*2, *3/*3, or *2/*3) was 3.1, 4.9, and 21.6 (μg/mL)/(mg/kg), respectively. In the EM and IM groups, the concomitant use of hepatic enzyme inducers (phenytoin and carbamazepine) reduced the CD ratio of CLB and increased that of NCLB. In the PM group, these inducers also decreased the CD ratio for CLB but did not elevate the CD ratio for NCLB. Using multiple regression analysis, body weight showed a positive correlation with an increased CD ratio for NCLB. The concomitant use of zonisamide and stiripentol also elevated the CD ratio for NCLB in the EM and IM groups, but that of the PM group was almost unchanged. When the cut-off value of the CD ratio for NCLB was set as 10.0 (μg/mL)/(mg/kg) for predicting the CYP2C19 PM status, the sensitivity and specificity were 94.4% and 95.7%, respectively.The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes. Measurement of the serum NCLB concentration is clinically useful for identifying the PM phenotype.

In 32 patients with prolonged central nervous system symptoms after human papillomavirus (HPV) vaccination, we measured conventional and immunological markers in cerebrospinal fluid (CSF) and compared with the levels in disease controls. Our studies revealed significantly decreased chloride and neuron-specific enolase (NSE) levels in CSF of patients with CNS symptoms after HPV vaccination compared to disease controls. IL-4, IL-13, and CD4(+) T cells increased significantly in patients, and IL-17 increased significantly from 12 to 24months after symptom onset. Chemokines (IL-8 and MCP-1) were also elevated, but CD8(+) T cells, PDGF-bb and IL-12 were reduced. Antibodies to GluN2B-NT2, GluN2B-CT and GluN1-NT increased significantly. These results suggest biological, mainly immunological, changes in the CSF of patients after HPV vaccination.

Patients with epilepsy after encephalitis/encephalopathy (EAE) often have refractory seizures, resulting in polytherapy with the risk of adverse reactions due to anti-epileptic drugs (AEDs). We focused on the characteristics of cutaneous adverse reaction (CAR). In this retrospective study, the medical records of 67 patients who were diagnosed as having EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1 (s-TNFR 1), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured in 22 patients. CARs attributed to AEDs were observed in 16 of 67 EAE patients (23.9%) (CAR group). High CAR rates were observed with phenytoin, lamotrigine, phenobarbital, and carbamazepine. Severe CARs were found in three of 67 patients (4.5%). The frequencies of CARs were significantly higher in patients with encephalitis onset older than five years of age. CAR occurred only in patients who had onset of EAE within 6 months after encephalitis. The durations from acute encephalitis to CARs were within one year for almost all AEDs, except lamotrigine. The proportion of patients with serumregulated on activation normal T cell expressed and secreted (RANTES) levels higher than the upper limit of normal range was significantly higher in CAR group than in non-CAR group. Patients in the early stage of EAE and patients with encephalitis onset older than five years of age may be at higher risk of CARs to AEDs, especially to phenytoin, lamotrigine, phenobarbital, and carbamazepine. RANTES may be a biomarker for susceptibility to CARs in EAE patients.

The cyclin-dependent kinase-like 5 gene (CDKL5) is recognized as one of the genes responsible for epileptic encephalopathy. We identified CDKL5 mutations in five Japanese patients (one male and four female) with epileptic encephalopathy. Although all mutations were of de novo origin, they were located in the same positions as previously reported pathogenic mutations. These recurrent occurrences of de novo mutations in the same loci may indicate hot spots of nucleotide alteration.

Summary Purpose: Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. Methods: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. Key Findings: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. Significance: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.

Summary Purpose: A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome. Methods: A questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and their prevalence of early death. Key Findings: Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome died. Data from 59 of these patients were analyzed. The patients’ ages at death ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The analysis showed that the risk of mortality remained high up to approximately 12 years of age. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and acute hepatopathy in one patient (1%). The incidence of sudden death reached a first peak at 1–3 years of age and reached a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a sharp peak at 6 years of age. Seven of 10 patients who underwent an SCN1A mutation analysis exhibited positive mutations without a specific mutation site. Significance: In the present study, the prevalence of Dravet syndrome–related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was the highest in infancy (1–3 years) and at early school ages (with a peak at 6 years), respectively. After approximately 12 years of age, the risk of mortality declined sharply. Neither the treatment nor the number of seizures was associated with any cause of mortality. In addition, it is difficult to predict which factors lead to a fatal outcome.

A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome. The questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and the prevalence of early death due to the disorder. Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome had died. Data from 59 of these patients were analyzed. The age at death for these patients ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and other causes in one patient (1%). The incidence of sudden death reached a first peak at 1-3 years of age and a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a peak at 6 years of age. Seven of the 10 patients who underwent SCN1A mutation analysis exhibited positive mutations but exhibited no consistent phenotype. The prevalence of Dravet syndrome-related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was higher in infancy (1-3 years) and at early school ages (with a peak at 6 years), respectively. Neither the treatment nor the number of seizures was associated with any cause of mortality. Factors leading to a fatal outcome are difficult to predict.

Polyoma BK virus (BKV) is frequently found in the urine of stem cell transplantation (SCT) patients with hemorrhagic cystitis (HC), but also occurs in SCT patients without HC. How BK viruria relates to the development of HC in SCT patients, especially in children, has not yet been fully evaluated. In the present study, we analyzed the relationship of several factors including urinary BKV load to HC development in children and adults undergoing SCT. We employed a quantitative PCR assay and evaluated 37 patients (aged 9 months-62 years) of whom 12 developed HC and 25 did not. Older age was a risk factor for the development of HC; however, other factors such as sex, primary disease, type of SCT, conditioning regimen and aGVHD were not. Peak urinary BKV values in HC patients were not higher than those in non-HC patients. Severity of HC also did not correlate with urinary BKV loads. However, in some patients who secreted higher urinary BKV loads, the peak loads were closely related with the onset of HC. Higher BKV loads may be a risk factor for the development of HC in conjunction with other coexisting factors.

Background Paroxysmal tonic upward gaze is a childhood oculomotor syndrome characterized by episodes of conjugate upward deviation of the eyes. Its pathogenesis is unknown, and the etiology is heterogeneous. Patient Description We describe a 2-year-old girl with Angelman syndrome who developed paroxysmal tonic upward gaze at 9 months of age. She presented with developmental delay, blond hair, jerky movements, ataxia, and epilepsy. Genetic testing revealed a maternal deletion of 15q11-13, confirming Angelman syndrome. Conclusions This is the first report of Angelman syndrome complicated by paroxysmal tonic upward gaze. Both transient paroxysmal tonic upward gaze and Angelman syndrome have been associated with dopaminergic neurons. We speculate that the dopaminergic abnormalities present in Angelman syndrome may cause paroxysmal tonic upward gaze.

The purpose of this study was to investigate the developmental outcome after surgery for early-onset epilepsy in patients with focal cortical dysplasia (FCD). Among 108 patients with histopathologically confirmed FCD operated between 1985 and 2008, we selected 17 patients with epilepsy onset up to 3 years of age. Development was evaluated by the developmental quotient or intelligence quotient (DQ-IQ) and mental age was measured by the Mother-Child Counseling baby test or the Tanaka-Binet scale of intelligence. Postsurgical development outcome was evaluated by the changes in DQ-IQ and mental age as well as rate of increase in mental age (RIMA) after surgery. RIMA was calculated as the increase in mental age per chronological year (months/year; normal average rate: 12 months/year). Age at epilepsy onset of 17 patients ranged from 15 days to 36 months (mean±SD, 11.0±10.0 months). Age at surgery ranged from 18 to 145 months (75.1±32.4 months). Evaluation just before surgery showed that 13 of 17 (76.4%) patients had DQ-IQ below 70. Ten patients (58.8%) were seizure-free throughout the postsurgical follow-up period. After surgery, DQ-IQ was maintained within 10 points of the presurgical level in 13 patients (76.4%), and increased by more than 10 points in one patient (5.9%). After surgery, RIMA in patients with Engel's class I (7.5±3.8) was higher than patients with Engel's class II-IV (2.6±3.4) (unpaired t-test with Welch's correction, t=2.99, df=15, p=0.0092). RIMA was particularly low in two patients with spasm. In four patients with presurgical DQ-IQ

We examined the effectiveness of repeated adrenocorticotropic hormone (ACTH) therapy in short-term and long-term seizure control in patients with intractable epileptic spasms.Twenty-five patients with intractable spasms, in whom epileptic seizures were not controlled or relapsed after the first ACTH therapy, were given repeated ACTH therapy. The short-term effect (seizure control longer than two months) of repeated ACTH therapy was analyzed, and the long-term effect was estimated by Kaplan-Meier method.Short-term seizure control by repeated ACTH therapy was achieved in 13 of 25 patients (52.0%), and in 5 of 13 patients, seizures were controlled by ACTH therapy at higher doses compared with the first ACTH therapy. Short-term effectiveness was obtained in 76.5% of patients who had epileptic spasms alone at the time of the second ACTH therapy, but was ineffective in all 8 patients who had multiple types of seizures, with relapses within 2 months. Short-term effectiveness was not associated with clinical factors such as onset age, age of repeated ACTH treatment, and EEG findings. Regarding the long-term effect of repeated ACTH therapy, the period until seizure relapse was significantly longer in patients with epileptic spasms alone compared to patients with multiple seizure types. Spasms were controlled in 5 of 25 cases (20.0%) at the final observation. In patients with multiple seizure types and patients with onset age older than eight months, seizure control was not obtained. Long-term outcome was good in patients with treatment lag within 2 months.In repeated ACTH therapy, seizure type seems to be one of the major determinants for short- and long-term seizure outcome.

We report a near-fatal case of cerebral edema associated with adenovirus type 2 infection in a previously healthy 19-month-old boy. After 3 to 4 d of high fever and a series of seizures, he developed persistent loss of consciousness and irreversible respiratory arrest. Adenovirus type 2 infection was diagnosed by virus isolation from his stool and serology.

Patients with epilepsy after encephalitis/encephalopathy (EAE) are often on polytherapy with anti-epileptic drugs (AEDs), and are at risk of adverse reactions. We examined the adverse effects of AEDs, especially sleepiness, in these patients.In this retrospective study, the medical records of 66 patients who were diagnosed with EAE in our hospital were reviewed and the clinical characteristics were analyzed. Immunological biomarkers including cytokines, chemokines, granzyme B, soluble tumor necrosis factor receptor 1, matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 were also investigated.The mean onset age of acute encephalitis was 9 years and 1 month and the mean interval from onset of acute encephalitis to onset of epilepsy was 6.4 months. Sleepiness induced by AEDs was observed in 26 of 66 patients (39.3%). The incidence of sleepiness was high in patients treated with clorazepate (75%), lamotrigine (66.7%), and ethosuximide (40%). Comparing the AEDs used by more than 20 patients, the incidence of sleepiness was high for clonazepam (30.4%) and phenytoin (25.8%). IgG, protein, and albumin levels in cerebrospinal fluid were significantly higher in patients affected by sleepiness than in those not affected. IL-8 in cerebrospinal fluid was significantly higher in the group with sleepiness compared to that without. Serum matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels were not different between the two groups.Long-lasting blood-brain barrier dysfunction and proliferation of immature vessels induced by IL-8 may contribute to the occurrence of sleepiness as an adverse effect of AEDs in patients with EAE. We recommend to assess for blood-brain barrier dysfunction when choosing AEDs for treating patients with intractable EAE.

Falling due to startle-induced seizures (SISs) often leads to injury. The triggers of SIS are mostly unexpected auditory stimuli, which are too common to avoid in daily life. As SISs are often refractory to conventional medications, effective therapeutic options have to be established. We report a small series of six patients treated with lamotrigine (LTG) as add-on therapy. Seizure control was improved greatly in three of the six patients, resulting in less restricted daily life, but no effect was observed in two and a skin rash developed in one. Patient 1 was a 19-year-old man. His seizure comprised of a sudden tonic extension of the extremities induced by auditory or visual stimulus. He fell down due to SISs, five to ten times a day, with frequent injuries. After adding LTG to treatment with valproate (VPA) and clobazam (CLB), SISs were reduced to once a month. Patient 2 was a 51-year-old woman. Sudden tonic extension of all limbs induced by unexpected sounds frequently threw her down onto the floor. Addition of LTG to treatment with CLB, zonisamide and phenytoin reduced her SISs from several to less than once a day. Patient 3 was a seven-year-old girl with post-encephalitic epilepsy. After adjunctive treatment of LTG to VPA, the severity of SISs became milder thus avoiding injury, although seizure frequency did not decrease. LTG is potentially effective for the treatment of SISs and may prevent falling. The addition of LTG treatment dramatically improved the lives of the patients presented here and should be considered as an option for startle-induced seizures.

A modified ketogenic diet was demonstrated to be remarkably effective in a child with intractable symptomatic focal epilepsy with combined seizures of focal seizures and epileptic spasms (ES) in a cluster (ESC). ES started at 8 months of age and disappeared with ACTH therapy. At the age of 13 months, the child began to have intractable focal seizures that, later, were followed by ESC 10 times a day. Brain MRI showed only a non-specific diffuse cerebral atrophy. Interictal EEG showed high amplitude diffuse disorganized slow waves with prominent sharp waves predominant over the bilateral occipital region. We started a modified ketogenic diet (mKD) treatment without fasting or a water/calorie limitation. Since the 20th day of mKD, the patient has been seizure free (6 months) without adverse effects. EEG showed remarkable improvement and he has some improvement in the developmental milestones. A modified ketogenic diet is easier to start and continue compared to the classic ketogenic diet, and should be tried in intractable epilepsies that are not treatable surgically early in life from the developmental prognosis point of view.

Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders.A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations.One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features.We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.

A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome.A questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and their prevalence of early death.Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome died. Data from 59 of these patients were analyzed. The patients' ages at death ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The analysis showed that the risk of mortality remained high up to approximately 12 years of age. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and acute hepatopathy in one patient (1%). The incidence of sudden death reached a first peak at 1-3 years of age and reached a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a sharp peak at 6 years of age. Seven of 10 patients who underwent an SCN1A mutation analysis exhibited positive mutations without a specific mutation site.In the present study, the prevalence of Dravet syndrome-related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was the highest in infancy (1-3 years) and at early school ages (with a peak at 6 years), respectively. After approximately 12 years of age, the risk of mortality declined sharply. Neither the treatment nor the number of seizures was associated with any cause of mortality. In addition, it is difficult to predict which factors lead to a fatal outcome.

A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome. The questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and the prevalence of early death due to the disorder. Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome had died. Data from 59 of these patients were analyzed. The age at death for these patients ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and other causes in one patient (1%). The incidence of sudden death reached a first peak at 1-3 years of age and a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a peak at 6 years of age. Seven of the 10 patients who underwent SCN1A mutation analysis exhibited positive mutations but exhibited no consistent phenotype. The prevalence of Dravet syndrome-related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was higher in infancy (1-3 years) and at early school ages (with a peak at 6 years), respectively. Neither the treatment nor the number of seizures was associated with any cause of mortality. Factors leading to a fatal outcome are difficult to predict.

Here, we report a male child with Schinzel-Giedion syndrome associated with intramyelinic edema detected on brain magnetic resonance imaging (MRI) and persistent suppression-burst pattern on electroencephalography (EEG) with erratic myoclonus of the extremities and face. Similar to nonketotic hyperglycinemia, Schinzel-Giedion syndrome may be recognized as another causative genetic disease of early myoclonic encephalopathy and vacuolating myelinopathy.

N-methyl-D-aspartate (NMDA)-type glutamate receptor (GluR), is an important molecule, which contributes to the pathophysiological processes of various neurological diseases by various molecular mechanisms. Antibodies against NMDA-type GluR (NR) are detected by immunoblot analysis, enzyme-linked immunosorbent assay (ELISA), or immunocytochemical analysis (Dalmau's method). Immunoblot method uses whole molecules of GluRepsilon2 (NR2B), which are synthesized in NIH3T3 cells by using tetracycline system as antigens. In ELISA, synthesized peptides of each domain of GluRepsilon2 and GluRtheta1 (NR1) are used. Immunocytochemical method uses human embryonic kidney (HEK) cells transfected by expression vectors for NR1+NR2B/2A. In non-paraneoplastic, non-herpetic acute limbic encephalitis (NHALE), serum antibodies to GluRepsilon2 (NR2B) were detected in approximately 60% of the patients from acute to chronic stages further, these antibodies in the cerebrospinal fluid (CSF) were detected in 50% (acute stage), 40% (recovery stage), and 30% (chronic stage) of the patients. The antibodies against GluRepsilon2 seemed to increase in the sera after infection and infiltrate the central nervous system through the blood-brain barrier (BBB), which was damaged by cytokines, etc. The antibodies against GluRepsilon2 recognize broad regions of GluRepsilon2 as epitopes. In NHALE patients with ovarian teratoma, antibodies to NR recognize epitopes on GluRepsilon2 (NR2B) and GluRtheta1 (NR1). Pathophysiology of antibodies against NR is estimated to cause internalization of NR on surface of neurons, resulting in inhibition of NR function.

BK polyomavirus (BKV) is ubiquitous among humans, usually infecting them asymptomatically during childhood. BKV persists in renal tissue of individuals and their progeny are excreted in urine, particularly in immunocompromised patients. JC virus, another human polyomavirus, has been considered to be transmitted from parents to children during prolonged cohabitation. However, BKV has been supposed to be transmitted not only within but also outside the family. In the present study, to clarify this possibility, we analyzed phylogenetically 35 BKV which were excreted in the urine by Japanese children and adults undergoing stem cell transplantation. Subtypes I, III and IV were detected in 15, two and one children and in 15, one and one adults, respectively. Among 15 subtype I isolates from children, three, four and eight belonged to subgroups Ia, Ib-1 and Ic, respectively. All the three children from whom Ia was detected were less than 9 years old. In contrast in the adults, three subtype I belonged to Ib-1 and the other 12 to Ic. These findings may reflect the recent transmission of BKV Ia strains to Japanese children.

Adenovirus infection during stem cell transplantation is associated with high morbidity and mortality. Adenovirus species B and C have been the main causes for these infections; however, epidemiological details about the species are still unclear. To clarify the contributions of species B and C adenovirus, the DNA was tested serially by quantitative real-time PCR in peripheral blood, stool and urine of 32 patients (16 adults and 16 children) undergoing stem cell transplantation. Adenovirus species B viremia was detected in 10 of 16 adult and 6 of 16 pediatric transplant recipients. Adenovirus species C viremia was also detected simultaneously in five adult and three pediatric recipients. The stool and urine of patients with adenovirus viremia were also positive for the same adenovirus species as in blood. In contrast, in none of 50 healthy adult controls was adenovirus species B or C viremia detected. Among patients who developed adenovirus viremia, one adult recipient developed disseminated disease and died from multiple organ failure. The remaining patients experienced fever of several degrees and/or diarrhea during the period of adenovirus viremia; however, they all recovered without antiviral therapy. The results indicated that stem cell transplantation was frequently associated with adenovirus species B or C viremia, although it did not always cause serious infectious complications.

A six month-old female infant developed dyspnea when she was treated with valproate sodium (VPA) and zonisamide (ZNS) for epileptic spasms. Two weeks after its onset, her dyspnea was exacerbated by respiratory syncytial virus (RSV) infection. We diagnosed interstitial pneumonitis (IP) based on her chest CT and high serum concentrations of KL-6 and surfactant protein D. Her dyspnea improved with the treatment which included steroids, neutrophil elastase inhibitor and discontinuation of VPA and ZNS. An allergic reaction probably explains the IP in our patient because steroids were effective. Her IP might have been exacerbated by several factors including the use of two anticonvulsants (VPA, ZNS), RSV infection, and physiological low serum IgA level of infants. Drug-induced interstitial lung disease should be remembered as a possible complication of anticonvulsant treatment, such as VPA and ZNS.

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.

Liver ultrasound elastography (LUE) is considered being one of the promising methods of non-invasive diagnostics of hepatic fibrosis (HF) stages in mucopolysaccharidoses (MPS), however data of using it in children in national and foreign literature are lacking. Objective:Detection of hepatic fibrosis severity stage in chidrenwith MPS with LUE. Materials and methods. We examined 20 children with MPS at the age from 1,5 to 17 (median age 8.0±4.8 years), of them 3 children with the I type, 11 —with the II, 4—with the III, and 2—with the VI type. All childrenwere performed LUE on “Fibroscan” (EchoSens, France). Results and their discussion: In 10 (50%) of 20 children median elasticity exceedance from 5.7 to 13.1 kPa was noted. Of them in 4 patients indices corresponded to minimal HF (F1), in 2 — to moderate fibrosis (F2), in 3 — to severe fibrosis (F3), and in 1 — to cirrhosis (F4). Besides, in 5 (50,0%) of 10 children having normal elasticity median (F0), up to LUE indexes, elevated indexes in separate measurements (from 6.1 to 23.4 kPa) were recorded, allowing us to identify them as the risk group because of diffuse sclerotic changes in the liver. Conclusion: According to LUE data results, 50% of children have fibrotic changes in the liver, of them in 40% of cases severe HF and cirrhosis is noted; and next 50% are in the risk group because of HF developing. LUE is informative non-invasive diagnostic method of HF severity stage in children with MPS.

We describe a 7-y-old boy who developed idiopathic intracranial hypertension (IIH) during the convalescent phase of Mycoplasma pneumoniae (M. pneumoniae) infection. Anti-M. pneumoniae antibody and cold hemagglutinin titer were extremely high during his course, and corticosteroid administration was noticeably effective. It supports an immunopathological mechanism for his intracranial hypertension.