Efficacy of intravenous clonazepam for paediatric convulsive status epilepticus.

AIM: To compare the efficacy of intravenous clonazepam (CLZ) for the initial management of convulsive status epilepticus (CSE) in children as a function of the first-line in-hospital dose used. METHOD: This monocentric retrospective study included children who received a first dose of CLZ for CSE at Montpellier University Hospital, France, between January 2016 and June 2019. Data from medical records (clinical, treatment, course) were collected and compared as a function of the first CLZ dose used. RESULTS: Among the 310 children treated for CSE, 105 received at least one CLZ dose (median age 3 years; quartile 1-quartile 3 [Q1-Q3] = 1 years 2 months-6 years 6 months). Among these 105 patients, 24 (22%) received a dose less than 0.03 mg/kg (low dose) and 69 (65%) received a dose of at least 0.03 mg/kg (high dose). Seizure cessation rate was not different between the low- and high-dose groups (62.5% vs 76%; odds ratio 0.53, 95% confidence interval [CI] 0.19-1.44, p = 0.29). The administration of a second dose of CLZ was more frequent in the low- than the high-dose group (37.5% vs 16%; odds ratio 3.2, 95% CI 1.1-9.1, p = 0.04). INTERPRETATION: Our study did not find any difference in seizure termination rate as a function of CLZ dose in children with CSE. However, a second CLZ dose was more frequently needed in the group receiving low (less than 0.03 mg/kg) CLZ.

Ryanodine receptor dysfunction causes senescence and fibrosis in Duchenne dilated cardiomyopathy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by progressive muscle weakness due to the absence of functional dystrophin. DMD patients also develop dilated cardiomyopathy (DCM). We have previously shown that DMD (mdx) mice and a canine DMD model (GRMD) exhibit abnormal intracellular calcium (Ca2+) cycling related to early-stage pathological remodelling of the ryanodine receptor intracellular calcium release channel (RyR2) on the sarcoplasmic reticulum (SR) contributing to age-dependent DCM. METHODS: Here, we used hiPSC-CMs from DMD patients selected by Speckle-tracking echocardiography and canine DMD cardiac biopsies to assess key early-stage Duchenne DCM features. RESULTS: Dystrophin deficiency was associated with RyR2 remodelling and SR Ca2+ leak (RyR2 Po of 0.03 ± 0.01 for HC vs. 0.16 ± 0.01 for DMD, P < 0.01), which led to early-stage defects including senescence. We observed higher levels of senescence markers including p15 (2.03 ± 0.75 for HC vs. 13.67 ± 5.49 for DMD, P < 0.05) and p16 (1.86 ± 0.83 for HC vs. 10.71 ± 3.00 for DMD, P < 0.01) in DMD hiPSC-CMs and in the canine DMD model. The fibrosis was increased in DMD hiPSC-CMs. We observed cardiac hypocontractility in DMD hiPSC-CMs. Stabilizing RyR2 pharmacologically by S107 prevented most of these pathological features, including the rescue of the contraction amplitude (1.65 ± 0.06 µm for DMD vs. 2.26 ± 0.08 µm for DMD + S107, P < 0.01). These data were confirmed by proteomic analyses, in particular ECM remodelling and fibrosis. CONCLUSIONS: We identified key cellular damages that are established earlier than cardiac clinical pathology in DMD patients, with major perturbation of the cardiac ECC. Our results demonstrated that cardiac fibrosis and premature senescence are induced by RyR2 mediated SR Ca2+ leak in DMD cardiomyocytes. We revealed that RyR2 is an early biomarker of DMD-associated cardiac damages in DMD patients. The progressive and later DCM onset could be linked with the RyR2-mediated increased fibrosis and premature senescence, eventually causing cell death and further cardiac fibrosis in a vicious cycle leading to further hypocontractility as a major feature of DCM. The present study provides a novel understanding of the pathophysiological mechanisms of the DMD-induced DCM. By targeting RyR2 channels, it provides a potential pharmacological treatment.

Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants.

BACKGROUND: Variants in GABRB2, encoding the ß2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants. METHODS: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. FINDINGS: Electrophysiological assessments of α1ß2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. INTERPRETATION: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. FUNDING: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

Clinical and Electrophysiological Characterization of Essential Tremor in 18 Children and Adolescents.

Background: Essential tremor (ET) is considered the most frequent abnormal movement in the general population, with childhood onset in 5 to 30% of the patients. Methods: A multicenter, descriptive cross-sectional study enrolled patients ⩽18 years with a definite diagnosis of ET according to the International Parkinson and Movement Disorders Society criteria. Demographic data, clinical and electrophysiological characteristics of the tremor, neurological examination and impact on quality of life were collected. Results: 9 males and 9 females were included (mean age of 13.9 years). Tremor was characterized by : upper limb onset at a mean age of 6.5 years; at enrollment, upper limbs localization, and involvement of an additional body region in 28% of the patients; kinetic tremor in all of the patients combined with postural tremor in 17 and rest tremor in 3; tremor mean frequency of 7.6 Hz, mean burst duration of 82.7 ms; identification of mild myoclonic jerks on the polymyographic recordings in 7 patients; altered quality of life with worse emotional outcomes in girls and when a disease duration >5 years was suggested. Discussion: Childhood-onset ET is associated with delayed diagnosis and remarkable functional impact. Electromyographic identification of additional mild myoclonus is a new finding whose significance is discussed. Highlights: ET onset involved upper limbs and at inclusion, 28% of the patients exhibited involvement of an additional body region.ET impacted quality of life for all patients.Girls and patients affected for >5 years reported worse emotional outcomes.Mild myoclonic jerks were identified on 7/17 polymyographic recordings.

Association of children's toothbrushing and fine motor skills: a cross-sectional study

Abstract Fine motor skills (FMS) allow for the control and coordination of the distal musculature of hands and fingers, a skill required to brush teeth. The objective of this study was to investigate the association between FMS and toothbrushing efficacy. This cross-sectional study included 42 low-income Latino children aged 5 to 9 years from Pasto, Colombia. Toothbrushing efficacy was determined by the children's dental plaque Quigley-Hein Index (QH-I) mean-score difference from before and after toothbrushing. FMS were evaluated using the 5-15R parent evaluation, the spiral drawing Archimedes test, and a neurodevelopmental assessment of movements and prehension patterns during toothbrushing. A descriptive analysis was performed to assess the characteristics of FMS and children's toothbrushing, and a generalized linear model was used to determine associations between these skills and toothbrushing efficacy. Eighty-six percent of the children had at least one difficulty with FMS, and in 7%, they interfered with daily activities. Fourteen percent presented a moderate pattern in the Archimedes test, and 43% had inefficient prehension patterns. Toothbrushing reduced the QH-I by a mean of 1.45 (SD = 0.78-2.12) (p < 0.001). Toothbrushing efficacy was only significantly associated with age (mean-difference = -0.315, 95%CI: -0.481 to -0.148, p < 0.001). FMS and toothbrushing efficacy were not significantly associated. Other components of fine motor control should be analyzed to understand the kinetics of toothbrushing.