COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Le rôle du vermis cérébelleux dans les processus attentionnels : Étude de deux cas rarissimes avec Rhombecéphalosynapsis

National audienceLe rôle du vermis cérébelleux dans les processus attentionnels est très mal connu, la principale raison étant que ses lésions produisent des désordres cliniques importants dans lesquels les troubles attentionnels sont noyés. Il existe, cependant, des indices rares mais directs suggérant que le vermis fournit des influences modulatrices à des régions cérébrales impliquées dans des fonctions spécifiques. L'existence de connexions avec des aires impliquées dans l'attention (Middleton and Strick, 1998; Muggleton et al., 2003) appuie cette idée. Contrairement aux mouvements oculaires, l'orientation spatiale de l'attention n'est pas affectée par les lésions vermiennes (Machner et al., 2005; Yamaguchi et al., 1998; Golla et al., 2005), d'autres aspects de l'attention semblent touchés. Il s'agit surtout de la prise en compte des informations environnant une cible. En effet, les individus lésés manifestent une réactivité accrue à des cibles lorsque des distracteurs sont présents (Caston et al., 1998 ; Bobée et al., 2000 ; Michael et al., 2009), comme si ces derniers permettait de mieux appréhender les cibles. Il serait attendu, ainsi, que plus le nombre de distracteurs augmente, meilleure serait la détection d'une cible, et que l'absence de distracteurs n'affecte pas la performance. Nous avons directement testé cette hypothèse à l'aide d'un paradigme modifié de recherche visuelle auprès d'enfants normaux et de deux cas avec Rhombencéphalosynapsis (RS), une malformation congénitale rarissime caractérisée par l'absence de vermis et par une fusion médiane des hémisphères cérébelleux. Les deux cas sont d'autant plus rares que leurs fonctions intellectuelles sont intactes, contrairement à la très grande majorité de cas rapportés dans la littérature. Ce travail suggère que le vermis cérébelleux n'est pas impliqué dans les déplacements de l'attention dans l'espace, ni la recherche visuelle malgré la présence éventuelle de troubles oculomoteurs (Machner et al., 2005; Yamaguchi et al., 1998; Golla et al., 2005). Il semble impliqué dans la prise en compte des informations environnant une cible (Caston et al., 1998 ; Bobée et al., 2000 ; Michael et al., 2009). Ces conclusions sont d'autant plus valides que ces déficits semblent sélectifs, qu'ils sont présents dans les performances de deux cas ayant des pathologies identiques et spécifiquement concernant le vermis cérébelleux

Cognitive Abilities of Children With Neurological and Liver Forms of Wilson Disease

International audienceCognitive impairment in adult patients experiencing Wilson disease is now more clearly described, even in liver forms of the disease. Although this condition can appear during childhood, the cognitive abilities of children have not yet been reported in a substantial case series. This retrospective study included 21 children with Wilson disease who had undergone general cognitive assessment. The results argue in favor of a poor working memory capacity in the liver form of the disease, and more extensive cognitive impairments in its neurological form. Extensive neuropsychological investigations on all children experiencing Wilson disease are thus required

CNTNAP1-encephalopathy: Six novel patients surviving the neonatal period

International audienceCNTNAP1 encodes CASPR1, involved in the paranodal junction. Thirty-three patients, with CNTNAP1 biallelic mutations have been described previously. Most of them had a very severe neurological impairment and passed away in the first months of life. We identified four patients, from two unrelated families, who survived over the neonatal period. Exome sequencing showed compound heterozygous or homozygous variants. Severe hypotonia was a constant feature. When compared to previous reports, the most important clinical differences observed in our patients were the absence of antenatal problems and, in two of them, the lack of respiratory distress. Less commonly reported characteristics such as epileptic seizures, dystonia, and impaired communication skills were also observed. MRIs revealed hypomyelination or abnormal white matter signal, cerebral or cerebellar atrophy. The present observations support a wider than initially reported clinical spectrum, including survival after the neonatal period and additional neurological features. They contribute to better delineate the phenotype-genotype correlations for CNTNAP1. In addition, we report one more family with two sibs who carry a missense variant of uncertain significance which we propose could be associated with a milder phenotype

The blood copper isotopic composition is a prognostic indicator of the hepatic injury in Wilson disease

International audienceWilson disease (WD) is an autosomal recessive disorder of copper (Cu) metabolism. The gene responsible for WD, ATP7B, is involved in the cellular transport of Cu, and mutations in the ATP7B gene induce accumulation of Cu in the liver and ultimately in the brain. In a pilot study, the natural variations of copper stable isotope ratios (Cu-65/Cu-63) in the serum of WD patients have been shown to differ from that of healthy controls. In the present study, we challenged these first results by measuring the Cu-65/Cu-63 ratios in the blood of treated (n = 25), naive patients (n = 11) and age matched healthy controls (n = 75). The results show that naive patients and healthy controls exhibit undistinguishable Cu-65/Cu-63 ratios, implying that the Cu isotopic ratio cannot serve as a reliable diagnostic biomarker. The type of treatment (d-penicillamine vs. triethylenetetramine) does not affect the Cu-65/Cu-63 ratios in WD patients, which remain constant regardless of the type and duration of the treatment. In addition, the Cu-65/Cu-63 ratios do not vary in naive patients after the onset of the treatment. However, the Cu-65/Cu-63 ratios decrease with the degree of liver fibrosis and the gradient of the phenotypic presentation, i.e. presymptomatic, hepatic and neurologic. To get insights into the mechanisms at work, we study the effects of the progress of the WD on the organism by measuring the Cu concentrations and the Cu-65/Cu-63 ratios in the liver, feces and plasma of 12 and 45 week old Atp7b(-/-) mice. The evolution of the Cu-65/Cu-63 ratios is marked by a decrease in all tissues. The results show that Cu-63 accumulates in the liver preferentially to Cu-65 due to the preferential cellular entry of Cu-63 and the impairment of the Cu-63 exit by ceruloplasmin. The hepatic accumulation of monovalent Cu-63(+) is likely to fuel the production of free radicals, which is potentially an explanation of the pathogenicity of WD. Altogether, the results suggest that the blood Cu-65/Cu-63 ratio recapitulates WD progression and is a potential prognostic biomarker of WD

Attention and Executive Disorders in Neurofibromatosis 1: Comparison Between NF1 With ADHD Symptomatology (NF1 + ADHD) and ADHD Per Se

International audienceObjective: To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. Method: One group of children with NF1 + ADHD (N = 32), one group of children with ADHD (N = 31), and one group of healthy controls (N = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. Results: Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. Conclusion: ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1

The effect of methylphenidate on neurofibromatosis type 1: a randomised, double-blind, placebo-controlled, crossover trial

et Réseau NF1 Rhône Alpes Auvergne-FranceInternational audienceBackground: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an estimated prevalence of about 1/3000, independent of ethnicity, race, or gender. Attention Deficit Hyperactivity like Disorder (ADHD)-like characteristics are often reported in patients with NF1. We hypothesised that learning disabilities in NF1 children were related to ADHD symptoms. Treatment with methylphenidate (MPD) has improved learning disabilities in ADHD by acting on neurotransmitters. Our objective was to evaluate its efficacy on ADHD-like symptoms in neurofibromatosis type 1 children (7–12 years).Methods: This was a randomised, double blind, placebo controlled, and crossover trial comparing 0.5 to 0.8 mg/kg/d of MPD as it is indicated for ADHD to placebo in NF1 children with ADHD-like symptoms. Children aged 7 to 12 years were eligible when their IQ was between 80 and 120. The total follow-up was 9 weeks including 4 weeks for each period and 1 week wash out. Fifty subjects (25 for each period) were required for testing the primary study hypothesis. The main outcome was an improvement in scores on the simplified Conners' Parent Rating Scale.Results: Thirty-nine patients were included between April 2004 and December 2010. Twenty participants received MPD and 19 placebo during the first period. They all completed the trial. MPD decreased the simplified Conners by 3.9 points (±1.1, p = 0. 0003).Conclusions: This is the first randomised controlled trial showing the short-term benefit of MPD on simplified Conners scores in NF1 children