Distinct attentional and executive profiles in neurofibromatosis type 1: Is there difference with primary attention deficit-hyperactivity disorder?

PURPOSE: Attentional and executive dysfunctions are the most frequent cognitive disorders in neurofibromatosis type 1 (NF1), with a high prevalence of attention deficit-hyperactivity disorder (ADHD). We (i) compared attentional profiles between NF1 children with and without ADHD and children with primary ADHD criteria and (ii) investigated the possible relationship between attentional disorders and "unidentified bright objects" (UBOs) in NF1. METHODS: This retrospective study included 47 NF1 children, 25 with ADHD criteria (NF1+adhd group), matched for age, sex, and cognitive level with 47 children with primary ADHD (ADHD group). We collected computer task (sustained-attention, visuomotor-decision, inhibition, and cognitive-flexibility tasks) scores normalized for age and sex, and brain magnetic resonance imaging data. RESULTS: (i) Working memory was impaired in all groups. (ii) Omissions (p < 0.002) and response-time variability (p < 0.05) in sustained-attention and visuomotor-decision tasks and errors (p < 0.02) in the cognitive-flexibility task were lower for the NFI+adhd and ADHD groups than for the NF1-no-adhd group. (iii) The NF1+adhd group had slower response times (p ≤ 0.02) for inhibition and visuomotor-decision tasks than the other groups. (iv) We found no relevant association between cognitive performance and UBOs. CONCLUSIONS: NF1 children with ADHD have an attentional and executive functions deficit profile similar to that of children with primary ADHD, but with a slower response-time, increasing learning difficulties. The atypical connectivity of fronto-striatal pathways, poorer dopamine homeostasis, and increased GABA inhibition observed in NF1 renders vulnerable the development of the widely distributed neural networks that support attentional, working-memory, and executive functions.

New insights into CC2D2A-related Joubert syndrome.

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Bronchopulmonary Dysplasia and Risk of Developmental Delay: An EPIPAGE-2 Cohort Study.

BACKGROUND: Overall and respiratory management of preterm children are constantly evolving, which might have changed both the pathophysiology and neurodevelopmental consequences of bronchopulmonary dysplasia (BPD). OBJECTIVES: The objective of this study is to determine whether the previously shown association between BPD and risk of developmental delay persists. METHODS: The study population was children born before 32 weeks' gestation from the French prospective cohort EPIPAGE-2. The exposure was BPD assessed at 36 weeks' postmenstrual age. The main outcome was risk of developmental delay defined by an Age & Stages Questionnaires (ASQ) score below threshold at 24 months' corrected age. RESULTS: The analyzed population included 2,706 children. Among those with available ASQ score, 196/1,587 had BPD and 671/1,587 had an ASQ score below threshold. BPD was associated with an ASQ score below threshold (odds ratio 1.52, 95% confidence interval 1.11-2.08; p = 0.008). CONCLUSIONS: BPD was strongly associated with risk of developmental delay.

Non-invasive, multimodal analysis of cortical activity, blood volume and neurovascular coupling in infantile spasms using EEG-fNIRS monitoring.

Although infantile spasms can be caused by a variety of etiologies, the clinical features are stereotypical. The neuronal and vascular mechanisms that contribute to the emergence of infantile spasms are not well understood. We performed a multimodal study by simultaneously recording electroencephalogram and functional Near-infrared spectroscopy in an intentionally heterogeneous population of six children with spasms in clusters. Regardless of the etiology, spasms were accompanied by two phases of hemodynamic changes; an initial change in the cerebral blood volume (simultaneously with each spasm) followed by a neurovascular coupling in all children except for the one with a large porencephalic cyst. Changes in cerebral blood volume, like the neurovascular coupling, occurred over frontal areas in all patients regardless of any brain damage suggesting a diffuse hemodynamic cortical response. The simultaneous motor activation and changes in cerebral blood volume might result from the involvement of the brainstem. The inconstant neurovascular coupling phase suggests a diffuse activation of the brain likely resulting too from the brainstem involvement that might trigger diffuse changes in cortical excitability.

Vagus nerve stimulation in the treatment of drug-resistant epilepsy in 29 children.

BACKGROUND/PURPOSE: Vagus nerve stimulation (VNS) has been demonstrated to be safe and effective for adults and children with drug-resistant epilepsy and is able to improve most types of epilepsy. The aim of this study, in a paediatric population, was to assess the overall efficacy of vagus nerve stimulation on seizures, to assess tolerability and quality of life. METHODS: This single-centre, retrospective study reviewed the files of 29 children in whom a vagus nerve stimulator was implanted between 1995 and 2012. The response rate (greater than 50% reduction of the seizure frequency), antiepileptic efficacy according to the type of epilepsy or age at implantation or age at onset of epilepsy, the time-course of seizures, adverse effects, overall quality of life and number of hospitalisations were studied. RESULTS: In our population, vagus nerve stimulation achieved a significant reduction in the seizure frequency throughout follow-up (p = 0.015). Response rates were 59% at 3 months, and 66% at 6 months, and the response rate then remained stable at about 70%. Stimulation tended to be more effective in patients with non-idiopathic partial epilepsy than in patients with non-idiopathic and idiopathic generalised epilepsy (0.01 < p < 0.11). No other predictive factors of efficacy were identified. Patients, parents, caregivers reported improvement in overall quality of life in 38% of patients during clinical interviews. A significant reduction in the number of hospitalisations due to a reduction of seizure frequency was observed after implantation (p = 0.03). VNS was stopped because of complications or insufficient efficacy in 9 cases. CONCLUSION: Vagus nerve stimulation is a safe and effective treatment option in children with drug-resistant epilepsy who are not candidates for surgery.

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.