Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Lipid and thyroid hormone levels in children with epilepsy treated with levetiracetam or carbamazepine: A prospective observational study.

Although previous studies have investigated the influence of antiepileptic drugs (AEDs) on lipid profiles and thyroid hormone levels, there is little evidence regarding the effects of levetiracetam (LEV). Therefore, we conducted a prospective longitudinal study to evaluate the effects of LEV and carbamazepine (CBZ) treatment on lipid profile and thyroid hormone levels in patients newly diagnosed with epilepsy. Inclusion criteria were as follows: (a) age between 4 and 15 years, (b) diagnosis of epilepsy with at least two focal seizures within a year, and (c) newly treated with LEV or CBZ monotherapy. Serum lipid profile and thyroid hormone levels were measured before and after 1 and 6 months of AED initiation. Among the 21 included patients (LEV: 13 patients, CBZ: 8 patients), all but one patient in the LEV group continued AED monotherapy during the study period. Although triglyceride (TG) levels tended to be increased in the CBZ group (baseline: 58.3 ±â€¯22.0 mg/dl, 1 month: 63.8 ±â€¯21.6 mg/dl, 6 months: 92.3 ±â€¯63.6 mg/dl, p = 0.22, analyses of variance (ANOVA)), there were no significant changes in total cholesterol (TC), TG levels, high-density lipoprotein cholesterol (HDL-C), or low-density lipoprotein cholesterol (LDL-C) in either group. Serum free thyroxine (fT4) levels were significantly decreased in the CBZ group (baseline: 1.15 ±â€¯0.06 ng/dl, 1 month: 1.00 ±â€¯0.16 ng/dl, 6 months: 0.98 ±â€¯0.14 ng/dl, p = 0.03, ANOVA). In contrast, there were no significant changes in fT4 or thyroid-stimulating hormone (TSH) levels in the LEV group. The results of the present study suggest that LEV monotherapy does not affect lipid profile or thyroid function while CBZ monotherapy may cause thyroid dysfunction.

[Risk of seizure recurrence after a first unprovoked seizure in childhood].

OBJECTIVE: To assess the risk of recurrence after a first unprovoked seizure in childhood. METHODS: This was a prospective study of 250 children aged 1 month to 16 years after a first seizure who presented between November 1, 2008 and October 31, 2012. None of the children was treated after the first seizure. Recurrence rates were calculated by Kaplan-Meier survival analysis, and univariate analyses for recurrence risk were performed using the Cox proportional hazards model. RESULTS: One hundred and thirty-five children (54%) had recurrence. Thirty-seven (27%) of the recurrences occurred in the first month, 71 (53%) within 3 months, 95 (70%) within 6 months, and 118 (87%) within 1 year. The risk of seizure recurrence was 38%, 47%, 54%, and 58% at 0.5, 1, 2, and 5 years, respectively. The risk factors for seizure recurrence were remote symptomatic etiology, abnormal electroencephalography, age ≥ 8 years, and a history of prior febrile seizure (partial seizure). CONCLUSIONS: Children should not be routinely treated after a first seizure, and it is important that we consider the recurrence rate and risk.

Treatment of preterm infants with West syndrome: differences due to etiology.

BACKGROUND: This study was conducted with a particular focus on preterm infants with West syndrome (WS) to evaluate differences in the first responses to oral medication based on etiology. METHODS: Medical records of 53 patients with WS, treated at five institutions between 2005 and 2009, were reviewed retrospectively. Patients were divided into six groups based on the time of brain insult, and evaluated for short-term outcomes using oral anti-epileptic agents and synthetic adrenocorticotropic hormone. RESULTS: The sample consisted of 15, six, 14, two, four, and 12 patients classified, on the basis of apparent time of acquisition of etiology, into the prenatal, term, preterm, postnatal, other, and no identified etiology groups, respectively. Average age of onset in the term group was 3.3 ± 1.0 months, significantly earlier than in the prenatal, preterm, postnatal and no identified etiology groups (P < 0.05). All patients in the term group had experienced seizures before the onset of WS. Only patients in the preterm group had only experienced neonatal seizures, and responded better to treatment. Patients in the preterm group had better responses to treatment, especially oral medication, compared with those in the prenatal and term groups. The prevalence of relapse of seizures in the preterm group (14%) was significantly lower than that in the prenatal group. CONCLUSIONS: Preterm WS patients responded well to treatment. Distinguishing WS patients on the basis of different etiologies is important for evaluating the effectiveness of treatment.

[Intravenous injection of phenobarbital for benign convulsions with mild gastroenteritis].

OBJECTIVE: We investigated the effectiveness of intravenous injection of phenobarbital (PB) in patients referred to Himeji Red Cross Hospital, Hyogo, Japan, with benign convulsions with mild gastroenteritis (CwG) between November 2009 and June 2011. METHODS: The patients who had a single seizure at the time of consultation were, in principle, followed without any treatment, and those with repeated seizures were treated with intravenous injection of 10 mg/kg PB. RESULTS: During the study, 24 of 33 patients with CwG were administered PB intravenously. PB was administered after a single seizure in one patient, and the remainder were treated after 2-7 seizures, no patient had repeated seizures. The side effects were temporary and mild, although somnolence was seen in five patients, and two also showed staggering. CONCLUSIONS: It was considered that intravenous injection of PB was effective for CwG. Intravenous injection of PB should be given to patients with CwG, regardless of whether they have vomiting and diarrhea.

Risk of seizure recurrence after a first unprovoked seizure in childhood.

OBJECTIVE: The aim of this study was to assess the risk of recurrence after a first unprovoked seizure in childhood and to explore the correlation between the first and second seizures in recurrent patients. METHODS: In a prospective study, we included 467 children aged 1 month to 16 years, who were attended to between November 1, 2008 and October 31, 2016 following a first seizure. Children who had been started on treatment with antiepileptic drugs were excluded. Recurrence rates were calculated using Kaplan-Meier survival analyses. Univariate and multivariate analyses for recurrence risk were performed using the Cox proportional hazards model. The kappa coefficient of correlation for categorical data was calculated. RESULTS: Recurrences occurred in 280 children (60.0%), of which 75 (26.8%) occurred in the first month, 184 (65.7%) within 6 months, and 256 (91.4%) within 2 years. None of the patients had new neurologic sequelae after their first or second seizure. The estimates of seizure recurrence risk were 39.5%, 48.1%, 55.1%, 60.8%, 61.8% and 61.8% at 0.5, 1, 2, 5, 8, and 10 years after the first seizure, respectively. Multivariate analysis showed that abnormal electroencephalogram and neuroimaging findings significantly increased the risk of recurrence. First and second seizures were significantly associated with state of arousal, status epilepticus, and multiple seizures in recurrent patients. CONCLUSION: Over half of untreated children had recurrence after a first unprovoked seizure, but prognosis was good overall.

STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern.

PURPOSE: De novo STXBP1 mutations have been found in individuals with early infantile epileptic encephalopathy with suppression-burst pattern (EIEE). Our aim was to delineate the clinical spectrum of subjects with STXBP1 mutations, and to examine their biologic aspects. METHODS: STXBP1 was analyzed in 29 and 54 cases of cryptogenic EIEE and West syndrome, respectively, as a second cohort. RNA splicing was analyzed in lymphoblastoid cells from a subject harboring a c.663 + 5G>A mutation. Expression of STXBP1 protein with missense mutations was examined in neuroblastoma2A cells. RESULTS: A total of seven novel STXBP1 mutations were found in nine EIEE cases, but not in West syndrome. The mutations include two frameshift mutations, three nonsense mutations, a splicing mutation, and a recurrent missense mutation in three unrelated cases. Including our previous data, 10 of 14 individuals (71%) with STXBP1 aberrations had the onset of spasms after 1 month, suggesting relatively later onset of epileptic spasms. Nonsense-mediated mRNA decay associated with abnormal splicing was demonstrated. Transient expression revealed that STXBP1 proteins with missense mutations resulted in degradation in neuroblastoma2A cells. DISCUSSION: Collectively, STXBP1 aberrations can account for about one-third individuals with EIEE (14 of 43). These genetic and biologic data clearly showed that haploinsufficiency of STXBP1 is the important cause for cryptogenic EIEE.

Combination of furosemide and fludrocortisone as a loading test for diagnosis of distal renal tubular acidosis in a pediatric case.

Renal tubular acidosis (RTA) is a rare disease caused by a defect of urinary acidification. The ammonium chloride loading test is the gold standard method for determining the type of RTA. However, because this test has some side effects (e.g., nausea, vomiting, and stomach discomfort), applying this test for pediatric cases is difficult. Recently, a loading test with the combination of furosemide and fludrocortisone was reported to be an alternative to the ammonium chloride loading test, with 100% sensitivity and specificity in adult's cases. We report the first pediatric case of distal RTA in a patient who was successfully diagnosed by a drug loading test with the combination of furosemide and fludrocortisone without any side effects. We also performed genetic analysis and detected a known pathogenic variant in the SLC4A1 gene. The combination loading test of furosemide and fludrocortisone is a useful and safe diagnostic tool for pediatric cases of RTA.

An infant with refractory cytomegalovirus-induced thrombocytopenia.

The present case underscores the importance of considering the association of severe thrombocytopenia or immune thrombocytopenia with cytomegalovirus (CMV) infection because CMV-induced thrombocytopenia occasionally requires antiviral therapy.

Efficacy of phenobarbital for benign convulsions with mild gastroenteritis: A randomized, placebo-controlled trial.

OBJECTIVE: This study was performed to evaluate the efficacy and safety of intravenous phenobarbital (PB) for benign convulsions with mild gastroenteritis (CwG). METHODS: A randomized, single-blind, placebo-controlled trial involving patients with CwG was conducted at the Japanese Red Cross Society Himeji Hospital. Patients with CwG who had experienced two or more seizures were eligible. Patients were excluded if any anticonvulsant was used before enrollment. Patients who were allocated to the PB group were administered 10 mg/kg of PB intravenously. Patients who were allocated to the placebo group were administered 20 ml of normal saline. RESULTS: From April 2016 to October 2018, 13 of 24 patients with CwG were randomized (PB group, n = 7; placebo group, n = 6; age, 1-3 years). Five of six patients in the placebo group had seizures after administration of placebo. However, patients in the PB group had no seizures after administration of PB, with a significant difference in efficacy between the two groups (P = 0.005). Five patients who had seizures after administration of normal saline were administered 10 mg/kg of PB, and no patients had a seizure thereafter. No significant differences were found in heart rate, blood pressure, or saturation of percutaneous oxygen between the two groups. CONCLUSION: This is the first randomized controlled trial to evaluate the efficacy of an anticonvulsant for CwG. Intravenous PB at 10 mg/kg is effective and well tolerated for CwG.

A Japanese case of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency who presented with severe metabolic acidosis and fatty liver without hypoglycemia.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mHS deficiency) is a rare autosomal recessive inborn error of ketogenesis caused by a mutation in the HMGCS2 gene, which is characterized by non-(hypo)-ketotic hypoglycemia, lethargy, and hepatomegaly during acute infection and/or prolonged fasting. Clinical presentations are similar to fatty acid oxidation defects; however, diagnosis of mHS deficiency is difficult because of poor biochemical markers. We report the case of a 12-month-old Japanese boy with mHS deficiency who presented with a coma, and hepatomegaly, but no hypoglycemia after a febrile episode and poor oral intake. Metabolic acidosis and severe fatty liver were observed. Serum acylcarnitine analysis revealed a slightly decreased free carnitine (C0) level and an increased acetylcarnitine (C2) level. Urinary organic acid analysis revealed hypoketotic dicarboxylic aciduria, and increased excretions of glutarate, and, retrospectively, 4-hydroxy-6-methyl-2-pyrone. Although the patient did not present with hypoglycemia, the severe fatty liver and elevated free fatty acids to total ketone bodies ratio strongly suggested an inborn error of ketogenesis. In the analysis of the HMGCS2 gene, compound heterozygous mutations of c.130_131ins C (L44PfsX29) and c.1156_1157insC (L386PfsX73) were identified, which led to the diagnosis of mHS deficiency. He had recovered without any complication by the therapy, including intravenous glucose infusion. Unlike the previously reported cases of mHS deficiency, our case did not present with hypoglycemia and the fatty liver lasted over several months. mHS deficiency should be taken into consideration when a patient has severe metabolic acidosis and fatty liver with no or subtle ketosis, even without hypoglycemia.

Clinical time course of pediatric acute disseminated encephalomyelitis.

The detailed clinical time course in acute disseminated encephalomyelitis (ADEM) from initial symptoms, through exacerbation, to remission has not been widely reported. Hence, this study aimed to investigate the clinical time course of pediatric ADEM. This was a multicenter retrospective study based on registry data from medical chart reviews. The study included children who met the international consensus diagnostic criteria for ADEM. The patients comprised 18 boys and 6 girls, with a mean age of 5.5 ±â€¯3.3 years at onset. From onset, the time until peak neurological symptoms, time until initial improvement, and time until full recovery was 3.1 ±â€¯3.7 days, 6.0 ±â€¯4.5 days, and 26 ±â€¯34 days, respectively. Twenty-three (96%) patients were treated with high-dose methylprednisolone (mPSL) with a mean duration of 4.1 ±â€¯4.0 days from onset. The condition of 15 patients (65%) improved within 3 days of high-dose mPSL initiation, whereas, that of four patients began to improve after >5 days of high-dose mPSL initiation. Only one patient (4%) did not achieve full recovery despite treatment with high-dose mPSL, intravenous immunoglobulin, and plasma exchange. This study presents the detailed clinical time course in pediatric ADEM in Japan. Progression of neurologic deficits typically lasts a few days, with initial improvement in 1 week leading to full recovery within 1 month.

High incidence of electrocardiogram abnormalities in young patients with duchenne muscular dystrophy.

Electrocardiogram abnormalities are reported to be complicated in Duchenne muscular dystrophy. Although Duchenne muscular dystrophy can be genetically diagnosed in young patients, extensive electrocardiogram studies have not been reported. Here, electrocardiogram abnormalities were examined in Duchenne muscular dystrophy cases with dystrophin gene mutations. Sixty-nine patients, aged

Clinical prediction rule for neurological sequelae due to acute encephalopathy: a medical community-based validation study in Harima, Japan.

OBJECTIVES: This study aimed to verify the screening performance of our clinical prediction rule for neurological sequelae due to acute encephalopathy (NSAE-CPR), which previously identified the following three variables as predictive of poor outcomes: (1) refractory status epilepticus; (2) consciousness disturbance and/or hemiplegia at 6 hours from onset and (3) aspartate aminotransferase >90 IU/L within 6 hours of onset. DESIGN: Medical community-based multicentre retrospective cohort study. SETTING: Six regional hospitals in Harima and one tertiary centre in Kobe, Japan, from 2008 to 2012. PARTICIPANTS: We enrolled a total of 1612 patients aged <16 years who met the diagnostic criteria for an initial diagnosis of complex febrile seizure. Patients with a history of neurological disease and those included in the derivation cohort were excluded. PRIMARY OUTCOME MEASURES: Univariate and multivariate analyses were performed to determine the association between each of the three predictor variables and poor AE outcome (Pediatric Cerebral Performance Category score ≥2). Receiver operating characteristic curve (ROC) analysis was also performed to assess the screening performance of the NSAE-CPR. RESULTS: The ROC analysis identified at least one of the three predictive variables as an optimal cut-off point, with an area under the curve of 0.915 (95% CI 0.825 to 1.000). The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios and Matthews correlation coefficient were 0.867, 0.954, 0.149, 0.999, 18.704, 0.140 and 0.349, respectively. CONCLUSIONS: Our findings indicate that the NSAE-CPR can be used for the screening and identification of patients with poor outcomes due to acute encephalopathy within 6 hours of onset.

Rituximab treatment for relapsed opsoclonus-myoclonus syndrome.

INTRODUCTION: Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder that is associated with paraneoplastic diseases. Because OMS can frequently relapse, patients may be inflicted with neurological problems for a long time. Recently, rituximab (RTX) was introduced as a drug to treat OMS. To assess RTX treatment, we studied a patient who experienced recurrence of OMS. CASE REPORT: A 2-year-old Japanese boy, who had left adrenal neuroblastoma, suddenly showed OMS symptoms, including ataxia and opsoclonus. Surgical resection of the tumor and subsequent steroid therapy ameliorated his symptoms. When OMS relapsed during the time when prednisolone was reduced, he was treated with full-dose RTX therapy (375 mg/m2/week) for 4 consecutive weeks. However, 1year later, he presented again with OMS symptoms. This time, we only administered an additional single dose of RTX treatment (375 mg/m2), allowing remission of OMS symptoms. During 2 years after the additional RTX treatment, OMS symptoms did not appear, even when prednisolone was reduced. He had no adverse events associated with RTX during the whole treatment period. CONCLUSIONS: An additional single-dose RTX therapy might be effective for relapsed OMS patients who were previously treated with full-dose RTX therapy.