Comparison of time to positivity of pediatric blood cultures obtained within the first year of life and in later years.

The time to positivity (TTP) of blood culture has significant value for clinicians. However, almost all subjects of previous studies regarding TTP were adults and early infants. Therefore, careful attention is required when referring to previously published data, which might differ according to the age of subjects, as the tendency of infectious focus and pathogens identified from culture vary with age. In this study, we compared the TTP between two pediatric age groups (≤12 months and 13 months to 15 years [>12 months]) at a teaching hospital during a 5-year period. Of the 95 subjects, 41 and 54 were aged ≤12 and > 12 months, among whom true pathogenic bacteria were identified in 12 (29.3%) and 19 (35.2%), respectively. The median TTP for the younger group with pathogenic bacteria was 11.2 (interquartile range, 10.0-11.9) hours, which was significantly shorter than that for the older group (12.6 [interquartile range, 11.9-16.9] hours) (P = 0.01). At 12 h after the initiation of culture, the younger group with pathogenic bacteria had a significantly higher positivity rate (83.3%) than the older group (26.3%) (P < 0.01). The times required for the positivity to exceed 90% were 13.4 and 20.1 h for the younger and older pathogenic groups and 30.4 and 67.8 h for the younger and older contaminant groups, respectively. The range of TTP could be assessed more accurately by considering the effect of age on the infectious background.

Association between the frequency of bedwetting and late preterm birth in children aged ≥5 years.

AIM: We examined the associations between late preterm (LPT) birth children aged ≥5 years and the frequency of bedwetting. Moreover, those who were born full-term/low birthweight (BW), LPT/low BW, LPT/normal BW and LPT/low BW were compared. METHODS: In total, we evaluated 614 patients who underwent assessments for frequent bedwetting at the three hospitals from January 2014 to December 2016. Data at the initial visit were collected from the electronic medical records. We assessed the patients' bladder diaries and questionnaires containing detailed information on demographics and frequency of bedwetting per month. Neonatal data were collected from the Maternal and Child Health Handbook. RESULTS: Frequency of bedwetting in the LPT/low BW group was higher than in the term/low BW group (28 vs. 22.5, p < 0.05). However, the frequency between the LPT/normal BW group and the LPT/low BW group was not significantly different (28 vs. 28, p = 1.00). Multiple regression analyses were conducted to eliminate potential confounding factors, attention-deficit/hyperactivity disorder and intellectual disability, but results were not changed. CONCLUSION: This study revealed that LPT/low BW was associated with increased frequency of bedwetting in children. The results suggest that gestational age should be considered when examining patients with severe bedwetting.

Evaluation of Urinary Aquaporin 2 and Plasma Copeptin as Biomarkers of Effectiveness of Desmopressin Acetate for the Treatment of Monosymptomatic Nocturnal Enuresis.

PURPOSE: Desmopressin is a synthetic V2 specific analogue of antidiuretic hormone (arginine vasopressin) that is widely used as first line treatment for monosymptomatic nocturnal enuresis. However, no biomarkers to predict desmopressin effectiveness have yet been established. Because arginine vasopressin is unstable, we prospectively measured the major urine concentration factor aquaporin 2 and serum copeptin (as a surrogate marker for vasopressin) in patients with monosymptomatic nocturnal enuresis, and evaluated whether they are useful for predicting desmopressin treatment outcome. MATERIALS AND METHODS: The study included 32 children 6 to 11 years old with monosymptomatic nocturnal enuresis and nocturnal polyuria. Exclusion criteria were daytime urinary symptoms and underlying diseases causing nocturnal enuresis. Subjects were treated with 120 µg or 240 µg desmopressin oral disintegrating tablet and were divided into responders (at 120 or 240 µg) and nonresponders (at 240 µg). Day/night ratios of plasma copeptin and urinary aquaporin 2 were measured during desmopressin treatment. RESULTS: There was no significant difference in baseline day/night ratio of urinary aquaporin 2 between desmopressin responders and nonresponders. After 8 weeks of treatment there was a significant correlation between day/night ratio of aquaporin 2 and percentage of wet nights. In responders (but not nonresponders) there was a significant difference in the change in aquaporin 2 day/night ratio from before treatment to complete remission (p = 0.0004). For plasma copeptin the baseline day/night ratio for responders at 120 µg was significantly lower than in the 240 µg nonresponder group (p = 0.02). CONCLUSIONS: Urinary aquaporin 2 appears to be a biomarker of desmopressin treatment effectiveness during therapy, while plasma copeptin levels before treatment are predictive of desmopressin response.

Gradual tapering of desmopressin leads to better outcome in nocturnal enuresis.

BACKGROUND: Although desmopressin therapy is effective in treating polyuric monosymptomatic nocturnal enuresis (MNE), the relatively high rates of recurrence are problematic. To date, the treatment protocol on the discontinuation of oral desmopressin melt (ODM) tablet, MinirinMelt, has not been established. We tested two protocols of tapering ODM when the patients achieved full response on ODM, and compared the treatment outcomes. METHODS: One hundred and fifty-seven polyuric MNE children were newly treated with ODM at the authors' outpatient clinics (Juntendo Nerima Hospital and Musashi-Murayama Hospital). When the patients did not respond to the 8 week ODM therapy, we added another options such as alarm, anti-cholinergics, and imipramine (92 patients; 58.6%). Sixty-five patients (41.4%) achieved full response on ODM alone, and 49 of them accepted gradual tapering of ODM: group B (n = 25), 240 µg ODM per day → 120 µg ODM per day → 120 µg ODM per alternate day → cessation; and group C (n = 24), 240 µg ODM per day → 120 µg ODM per day → 60 µg ODM per day → 60 µg ODM per alternate day → cessation. RESULTS: Fourteen patients in group B (56%) and four in group C (17%) had relapses of enuresis after the discontinuation of ODM (P = 0.026). CONCLUSIONS: Gradual tapering of ODM therapy in MNE patients leads to better outcome.

Posterior quadrant disconnection surgery for Sturge-Weber syndrome.

OBJECTIVE: Some patients with Sturge-Weber syndrome (SWS) need epilepsy surgery for adequate seizure control and prevention of psychomotor deterioration. The majority of patients with SWS have leptomeningeal angioma located over the temporal, parietal, and occipital lobes. We applied posterior quadrant disconnection surgery for this type of SWS with intractable seizure. We evaluated the efficacy of this procedure in seizure control and psychomotor development. METHODS: Ten patients who were surgically treated using the posterior quadrantectomy (PQT) were enrolled in this study. Surgical outcome was analyzed as seizure-free or not at 2 years after surgery. Psychomotor development was evaluated by the scores of mental developmental index (MDI) and psychomotor developmental index (PDI) in the Bayley Scales of Infant Development II preoperatively, and at 6 and 12 months after the PQT. RESULTS: Eight of 10 patients were seizure-free. Patients without complete elimination of the angiomatous areas had residual seizures. Average MDI and PDI scores before the surgery were 64.8 and 71.6, respectively. Scores of MDI at 6 and 12 months after the PQT in seizure-free patients were 80.5 and 84.5, respectively (p < 0.01). PDI scores at these postoperative intervals were 87.3 and 86.4, respectively (p < 0.05). Patients with residual seizures did not improve in either MDI or PDI. SIGNIFICANCE: The PQT achieved good seizure control and improved psychomotor development in patients with SWS. The complete deafferentation of angiomatous areas is required for seizure-free results and psychomotor developmental improvement.

Traditional Japanese medicine, Yokukansan, for the treatment of nocturnal enuresis in children.

BACKGROUND: The major pathogenic factors involved in nocturnal enuresis are nocturnal polyuria, small bladder capacity and/or detrusor overactivity, and a high arousal threshold. Desmopressin is the first-line therapy for the patients with diuresis-dependent nocturnal enuresis. Yokukansan, a traditional Japanese medicine, has been used in Japan to treat patients with nervousness, insomnia, and children with night terrors and temper tantrums. We experienced the positive effect of Yokukansan in some of the patients who did not respond well to desmopressin therapy. METHODS: In total, 32 children with monosymptomatic nocturnal enuresis with nocturnal polyuria were treated with oral desmopressin melt tablets, which were approved for clinical use in Japan on 29 May 2012. This treatment was effective for 14 of them. For the rest (n = 18), Yokukansan was introduced in combination with desmopressin. RESULTS: Yokukansan was effective for 12 out of the 18 cases. CONCLUSIONS: Yokukansan should be a candidate for the medication of nocturnal enuresis.

Isolated growth hormone deficiency in two siblings because of paternal mosaicism for a mutation in the GH1 gene.

CONTEXT: Mutations in the GH1 gene have been identified in patients with isolated growth hormone deficiency (IGHD). Mutations causing aberrant splicing of exon 3 of GH1 that have been identified in IGHD are inherited in an autosomal dominant manner, whereas other mutations in GH1 that have been identified in IGHD are inherited in an autosomal recessive manner. OBJECTIVE: Two siblings born from nonconsanguineous healthy parents exhibited IGHD. To elucidate the cause, GH1 in all family members was analysed. RESULTS: Two novel mutations in GH1, a point mutation in intron 3 and a 16-bp deletion in exon 3, were identified by sequence analyses. The intronic mutation was present in both siblings and was predicted to cause aberrant splicing. The deletion was present in one of the siblings as well as the mother with normal stature and was predicted to cause rapid degradation of mRNA through nonsense-mediated mRNA decay. The point mutation was not identified in the parents' peripheral blood DNA; however, it was detected in the DNA extracted from the father's sperms. As a trace of the mutant allele was detected in the peripheral blood of the father using PCR-RFLP, the mutation is likely to have occurred de novo at an early developmental stage before differentiation of somatic cells and germline cells. CONCLUSIONS: This is the first report of mosaicism for a mutation in GH1 in a family with IGHD. It is clear that the intronic mutation plays a dominant role in the pathogenesis of IGHD in this family, as one of the siblings who had only the point mutation was affected. On the other hand, the other sibling was a compound heterozygote for the point mutation and the 16-bp deletion and it may be arguable whether IGHD in this patient should be regarded as autosomal dominant or recessive.

Does fever phobia cross borders? The case of Japan.

BACKGROUND: Undue parental fear of fever in children was termed "fever phobia" by Schmitt following a survey in the USA in 1980. In 2000, Crocetti et al. conducted the same survey and concluded that fever phobia existed even 20 years later. In this study, we explore differences in fever phobia between these two US populations and a Japanese sample, and determine whether parents of a single child or those whose child was previously hospitalized or had a febrile seizure report greater anxiety about fever. METHODS: A questionnaire was distributed to parents of children who visited a pediatric outpatient clinic in Juntendo University Nerima Hospital between 19 and 30 November 2007. RESULTS: Data was obtained from 211 parents who agreed to participate in the study. Compared with much smaller proportions reported in the two previous studies, 62% of caregivers considered a temperature below 37.8°C to be a fever, although less than half of parents reported that they were "very worried" about fever. Over 90% identified doctors and nurses as their primary information source. In contrast to 7% of parents in the US studies, almost no parents reported that temperatures could rise to or above 43.3°C if fever was left untreated; however, 63% of parents stated that they would visit a hospital. CONCLUSIONS: Fever phobia exists on both sides of the border, and while caregivers in Japan appear to have a more accurate understanding of fever, they are more likely to rely on health-care professionals to manage the condition.

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.

Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.

FKRP mutations cause congenital muscular dystrophy 1C and limb-girdle muscular dystrophy 2I in Asian patients.

Mutation in the fukutin-related protein (FKRP) gene causes alpha-dystroglycanopathies, a group of autosomal recessive disorders associated with defective glycosylated alpha-dystroglycan (α-DG). The disease phenotype shows a broad spectrum, from the most severe congenital form involving brain and eye anomalies to milder limb-girdle form. FKRP-related alpha-dystroglycanopathies are common in European countries. However, a limited number of patients have been reported in Asian countries. Here, we presented the clinical, pathological, and genetic findings of nine patients with FKRP mutations identified at a single muscle repository center in Japan. Three and six patients were diagnosed with congenital muscular dystrophy type 1C and limb-girdle muscular dystrophy 2I, respectively. None of our Asian patients showed the most severe form of alpha-dystroglycanopathy. While all patients showed a reduction in glycosylated α-DG levels, to variable degrees, these levels did not correlate to clinical severity. Fifteen distinct pathogenic mutations were identified in our cohort, including five novel mutations. Unlike in the populations belonging to European countries, no common mutation was found in our cohort.

Extent of Leptomeningeal Capillary Malformation is Associated With Severity of Epilepsy in Sturge-Weber Syndrome.

BACKGROUND: Individuals with Sturge-Weber syndrome (SWS) often expereince intractable epilepsy and cognitive decline. We hypothesized that the extent of the leptomeningeal capillary malformation (LCM) may correlate with the severity of neurological impairment due to SWS. We tested the hypothesis in a cross-sectional study of seizure severity and electroencephalographic (EEG) findings and a retrospective cohort study for surgical indications related to the extent of the LCM. METHODS: We enrolled 112 patients and classified them according to LCM distribution: (1) bilateral, (2) hemispheric, (3) multilobar, and (4) single lobe. Age at seizure onset, seizure semiology and frequency, and EEG findings were compared. Surgical indications were evaluated for each group by Fisher exact test, and predictors for surgery were evaluated by univariate and multivariate analyses. Therapeutic efficacy was evaluated by the SWS-Neurological Score (SWS-NS). RESULTS: The bilateral and hemispheric groups had early seizure onset (4.0 months old and 3.0 months old), frequent seizures (88.9% and 80.6% had more than one per month), focal-to-bilateral tonic-clonic seizures (88.9% and 74.2%), and status epilepticus (100% and 87.1%). The groups' EEG findings did not differ substantially. Surgical indications were present in 77.8% of the bilateral, 88.1% of the hemispheric, and 46.8% of the multilobar groups. Seizure more than once per month was a predictor of surgical treatment. Seizure subscore improved postoperatively in the hemispheric and multilobar groups. Even after surgical treatment, the bilateral and hemispheric groups exhibited higher SWS-NSs than members of the other groups. CONCLUSION: Our study demonstrated a strong association between extensive LCM and epilepsy severity. Surgical intervention improved seizure outcome in patients with SWS with large LCMs.

Autoimmune focal encephalitis shows marked hypermetabolism on positron emission tomography.

A 22-month-old toddler presented with involuntary movements, hemiparesis, and behavioral changes. Magnetic resonance imaging showed no abnormality, but positron emission tomography (PET) showed focal hypermetabolism. By immunohistochemical technique with the patient's sera in control brain sections, autoantibodies recognizing the same areas as found by PET scanning were identified and disappeared after intravenous immunoglobulin therapy. PET scanning may be useful in the diagnosis of autoimmune encephalitis.

The effect of the guidelines for management of febrile seizures 2015 on clinical practices: Nationwide survey in Japan.

OBJECTIVE: To investigate the effect of guidelines for management of febrile seizures on the clinical practice, we conducted a nationwide survey in Japan. METHODS: The Japanese guidelines for management of febrile seizures 2015 (GL2015) was released in 2015. In 2016, a questionnaire was sent to all 512 certified hospitals (3 pediatricians each) of the Japan Pediatric Society and all 47 prefecture Pediatric Associations (10 private pediatricians each) in Japan asking about management policies for febrile seizures (FSs) during 2013-2014 and 2016. The questionnaires were about the following procedures: (1) lumbar punctures, blood examinations, and diazepam suppositories for children after a first simple FS at emergency departments; and (2) prophylactic diazepam during febrile illnesses in children with two or three past simple FSs, with no known predictors of recurrence. RESULTS: A total of 1327 pediatricians (66.2%) answered the questionnaire. Numbers of pediatricians performing lumbar punctures and blood examinations, and giving diazepam suppositories after a first simple FS were less in 2016 than in 2013-2014 (1.2% and 2.0%, 53.1% and 61.3%, and 36.7% and 51.9%, respectively). Pediatricians recommending prophylactic diazepam for children with two and three FSs decreased from 45.7% and 82.4% in 2013-2014 to 31.0% and 65.0% in 2016, respectively. CONCLUSION: GL2015 had an effect on the clinical practices of pediatricians. On the other hand, 65% recommended prophylactic diazepam to children with three simple FSs even though GL2015 did not recommend use of diazepam based on number of previous FS. Anxiety about frequent seizures may affect pediatricians' clinical practice.

Depressive tendency in children with growth hormone deficiency.

AIM: This study assessed changes in depressive tendency of children with growth hormone deficiency. METHODS: The 41 children with growth hormone deficiency were assessed using the Depression Self-Rating Scale for Children. A score of 16 or more indicated a depressive tendency. The first assessment was carried out before growth hormone treatment, and the second one was carried out at 6 months or longer after the beginning of growth hormone treatment. RESULTS: The Depression Self-Rating Scale for Children improved significantly from 9.7 +/- 6.1 points before treatment to 6.9 +/- 4.6 points after treatment (P= 0.0013). A depressive tendency was observed in six patients (15%) before growth hormone treatment, and in two patients (5%) after treatment. No significant relationship was observed between the decrease in the score and the length of the treatment. A significant improvement was observed for 6 of the 18 items in the Depression Self-Rating Scale for Children. CONCLUSION: A depressive tendency was relatively common in children with growth hormone deficiency, and the Depression Self-Rating Scale for Children was decreased after growth hormone treatment. These results suggest that growth hormone treatment may have positive effects on the psychosocial aspects in children with growth hormone deficiency.

Parental knowledge and perceptions of fever in children and fever management practices: differences between parents of children with and without a history of febrile seizures.

OBJECTIVES: The aim of this study was to compare maternal knowledge and perceptions of fever, fever management practices, and information sources of mothers of children with and without a history of febrile seizures. METHODS: A questionnaire was used to survey mothers of children who visited health departments for a routine 18-month-old well baby check-up. RESULTS: A total of 386 responses were analyzed. More mothers of children with a history of febrile seizures than mothers of children without it stated that high fever caused febrile seizures and antipyretics prevented it. Fewer mothers of children with a history of febrile seizures than mothers in the other group thought that high fever caused brain damage and antipyretics prevented the disease from worsening and warmed the child's body during fever episode. Many mothers in both groups stated that they considered physicians to be their primary information source. Spouse and own parents were named as information sources among mothers of children with a history of febrile seizures, whereas books and the Internet were named in the other group. CONCLUSIONS: Mothers of children with a history of febrile seizures demonstrated a higher rate of accuracy in their knowledge of fever than those in the other group. Mothers of children with a history of febrile seizures used personal communication, whereas those in the other group relied on mass communication for health information. Providing accurate information to family members is essential to provide mothers with both accurate information and emotional support.

Treatments with midazolam and lidocaine for status epilepticus in neonates.

Status epilepticus (SE) occurs in children of all ages. Recent epidemiologic investigations of SE show heightened morbidity and mortality in newborns and young infants. However, the existing definition of SE in newborns is not precise and not easily applied in clinical investigations or in clinical practice. To evaluate the underlying conditions, clinical features and treatment of SE in neonates in Japan, a retrospective multi-center study was performed. In the initial investigation, questionnaires were sent to pediatric neurologists in 194 neonatal intensive care units of university hospitals, children's hospitals, and general hospitals throughout in Japan. The questionnaires sought information on the background of each case, types of seizures, etiology of SE, treatments, results and adverse effects of treatment for patients less than 1 week old who had prolonged or frequently repeated seizures lasting more than 15 min and who are refractory to treatment with conventional anticonvulsants, such as diazepam (DZP), phenobarbital (PB) or phenytoin (PHT). As a secondary investigation, 65 cases from nine institutes, which completely fulfilled these criteria and were treated with midazolam (MDL) or lidocaine (Lid) to stop seizures were examined more fully. Subtle seizure and generalized tonic-clonic seizure were the most frequent seizure types. Neonatal SE was most frequently associated with hypoxic-ischemic encephalopathy, followed by intraventricular hemorrhage, central nervous system infections, and cerebral infarction. The final treatment outcome was available for 72.7% and 81.3% of MDL- and Lid-treated patients, respectively. Adverse effects of MDL and Lid were identified in 7.3% and 6.3% of patients, respectively. To reveal electroclinical seizures, clinical seizures without ictal discharge or other non-epileptic movements in neonates was important for appropriate treatment. MDL and Lid were useful drugs for the treatment of neonatal SE.

New guidelines for management of febrile seizures in Japan.

In 2015, the Japanese Society of Child Neurology released new guidelines for the management of febrile seizures, the first update of such guidelines since 1996. In 1988, the Conference on Febrile Convulsions in Japan published "Guidelines for the Treatment of Febrile Seizures." The Task Committee of the Conference proposed a revised version of the guidelines in 1996; that version released in 1996 was used for the next 19years in Japan for the clinical management of children with febrile seizures. Although the guidelines were very helpful for many clinicians, new guidelines were needed to reflect changes in public health and the dissemination of new medical evidence. The Japanese Society of Child Neurology formed a working group in 2012, and published the new guidelines in March 2015. The guidelines include emergency care, application of electroencephalography, neuroimaging, prophylactic diazepam, antipyretics, drugs needing special attention, and vaccines. While the new guidelines contain updated clinical recommendations, many unsolved questions remain. These questions should be clarified by future clinical research.

Use of targeted next-generation sequencing for molecular diagnosis of craniosynostosis: Identification of a novel de novo mutation of EFNB1.

Craniofrontonasal syndrome (CFNS; MIM#304110) is characterized by asymmetric facial features with hypertelorism and a broad bifid nose due to synostosis of the coronal suture. CFNS shows a unique X-linked inheritance pattern (most affected patients are female and obligate male carriers exhibit a mild manifestation or no typical features at all) associated with the ephrin-B1 gene (EFNB1) located in the Xq13.1 region. In this study, we performed targeted, massively parallel sequencing using a next-generation sequencer, and identified a novel EFNB1 mutation, c.270_271delCA, in a Japanese female patient with craniosynostosis. Because subsequent Sanger sequencing identified no mutation in either parent, this mutation was determined to be de novo in origin. After obtaining molecular diagnosis, a retrospective clinical evaluation confirmed the clinical diagnosis of CFNS in this patient. Comprehensive molecular diagnosis using a next-generation sequencer would be beneficial for early diagnosis of the patients with undiagnosed craniosynostosis.