Data-Driven Phenotyping of Central Disorders of Hypersomnolence With Unsupervised Clustering

Background and ObjectivesRecent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers.MethodsWe used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups.ResultsWe included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters.DiscussionUsing a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features

Pharmacological management of narcolepsy in children and adolescents

Paroxysmal Cerebral Disorder

Evaluation of hypersomnolence: From symptoms to diagnosis, a multidimensional approach

Hypersomnolence is a major public health issue given its high frequency, its impact on academic/occupational functioning and on accidentology, as well as its heavy socio-economic burden. The positive and aetiological diagnosis is crucial, as it determines the therapeutic strategy. It must consider the following aspects: i) hypersomnolence is a complex concept referring to symptoms as varied as excessive daytime sleepiness, excessive need for sleep, sleep inertia, or drowsiness, all of which warrant specific dedicated investigations; ii) the boundary between physiological and abnormal hypersomnolence is blurred, since most symptoms can be encountered in the general population to varying degrees without being considered as pathological, meaning that their severity, frequency, context of occurrence and related impairment need to be carefully assessed; iii) investigation of hypersomnolence relies on scales/questionnaires as well as behavioural and neurophysiological tests, which measure one or more dimensions, keeping in mind the possible discrepancy between objective and subjective assessment; iv) aetiological reasoning is driven by knowledge of the main sleep regulation mechanisms, epidemiology, and associated symptoms. The need to assess hypersomnolence is growing, both for its management, and for assessing the efficacy of treatments. The landscape of tools available for investigating hypersomnolence is constantly evolving, in parallel with research into sleep physiology and technical advances. These investigations face the challenges of reconciling subjective perception and objective data, making tools accessible to as many people as possible and predicting the risk of accidents

[Adaptive radiotherapy Strategies and benefits depending on tumor localization]

National audienceAdaptive radiotherapy (ART) is a complexe image-guided radiotherapy modality that comprises multiple planning to account for anatomical variations occurring during irradiation. Schematically, two strategies of RTA can be distinguished and combined according to tumor locations. One or more replanning can be proposed to correct systematic variations such as tumor shrinkage. A library of treatment plans with day-to-day plan selection from cone-beam CT imaging can also be proposed to correct random variations such as uterine motion or bladder/rectum volume changes. Because of strong anatomical variations occurring during irradiation, RTA appears therefore particularly justified in head and neck, lung, bladder, cervical and rectum and pancreas tumors, and to a lesser extent for prostate tumors and other digestive tumors. For these tumor locations, ART provides a fairly clear dosimetric benefit but a clinical benefit not yet formally demonstrated. ART cannot be proposed in a routine practice but must be evaluated medico-economically in the context of prospective trials. A rigorous quality control must be associated

What do we need to deliver “online” adapted radiotherapy treatment plans?

International audienceDuring the joint SFRO/SFPM session of the 2019 congress, a state of the art of adaptive radiotherapy announced a strong impact in our clinical practice, in particular with the availability of treatment devices coupled to an MRI system. Three years later, it seems relevant to take stock of adaptive radiotherapy in practice, and especially the “online” strategy because it is indeed more and more accessible with recent hardware and software developments, such as coupled accelerators to a three-dimensional imaging device and algorithms based on artificial intelligence. However, the deployment of this promising strategy is complex because it contracts the usual time scale and upsets the usual organizations. So what do we need to deliver adapted treatment plans with an “online” strategy

État des lieux de la radiothérapie adaptative en 2019 : de la mise en place à l’utilisation clinique

National audienceIntensity modulated radiotherapy combined with image guided radiotherapy has led to increase the precision of external beam radiotherapy. However, intra or inter-fraction anatomical variations are frequent during the treatment course and can cause under-dosing of the target volume and/or over-dosing of the organs at risk. Several adaptive radiotherapy (ART) strategies can be defined to compensate these anatomical variations. The purpose of this article is to provide an overview of available ART strategies: offline, online, hybrid (library of treatment plans) or in real-time, while considering the arrival of MR-Linac devices in radiotherapy departments. The tools required to these ART strategies such as auto-segmentation, deformable image registration, calculation of the daily dose or dose accumulation, are also described. Implementing an ART strategy requires a rigorous quality assurance process, at each stage and on the entire workflow, as well as prior organization and training from of all the trades. A strong multidisciplinary involvement is finally required in order to ensure ART treatments

Absence of NMDA receptor antibodies in the rare association between Type 1 Narcolepsy and Psychosis

International audienceFrequency and mechanisms underlying the association between narcolepsy type 1 (NT1) and psychosis remain unclear with potential role for a common immune pathway. We estimated the frequency of psychosis and its characteristics in NT1 at two European sleep centers (France, n = 381; Spain, n = 161) and measured IgG autoantibodies that recognize the GluN1 subunit of the NMDAR in 9 patients with NT1 with psychosis, and 25 NT1 patients without psychosis. Ten NT1 patients (6 in France, 4 in Spain) were diagnosed with comorbid psychosis, a frequency of 1.8%. One patient reported psychotic symptoms few months before narcolepsy onset, two patients few months after onset, and one patient one year after onset but after modafinil introduction. The six remaining patients reported long delays between NT1 and psychosis onset. Half the patients, mostly male adults, reported onset or worsening of psychotic symptoms after medication. We found no IgG antibodies to NR1/NR2B heteromers of the NMDARs in patients with NT1 with or without psychosis. To conclude, psychosis is rare in NT1, with limited evidence for a key impact of stimulants, and no association with anti-NMDAR antibodies. However, dramatic NT1 and schizophrenia exists especially in early onset NT1, which may lead to inappropriate diagnosis and management

A density assignment method for dose monitoring in head-and-neck radiotherapy

International audienceBackground and purpose - During head-and-neck (H&N) radiotherapy, the parotid glands (PGs) may be overdosed; thus, a tool is required to monitor the delivered dose. This study aimed to assess the dose accuracy of a patient-specific density assignment method (DAM) for dose calculation to monitor the dose to PGs during treatment. Patients and methods - Forty patients with H&N cancer received an intensity modulated radiation therapy (IMRT), among whom 15 had weekly CTs. Dose distributions were calculated either on the CTs (CT), on one-class CTs (1C-CT, water), or on three-class CTs (3C-CT, water-air-bone). The inter- and intra-patient DAM uncertainties were evaluated by the difference between doses calculated on CT and 1C-CTs or 3C-CTs. PG mean dose (D) and spinal cord maximum dose (D) were considered. The cumulated dose to the PGs was estimated by the mean D of the weekly CTs. Results - The mean (maximum) inter-patient DAM dose uncertainties for the PGs (in cGy) were 23 (75) using 1C-CTs and 12 (50) using 3C-CTs (p ≤ 0.001). For the spinal cord, these uncertainties were 118 (245) and 15 (67; p ≤ 0.001). The mean (maximum) DAM dose uncertainty between cumulated doses calculated on CTs and 3C-CTs was 7 cGy (45 cGy) for the PGs. Considering the difference between the planned and cumulated doses, 53% of the ipsilateral and 80% of the contralateral PGs were overdosed by +3.6 Gy (up to 8.2 Gy) and +1.9 Gy (up to 5.2 Gy), respectively. Conclusion - The uncertainty of the three-class DAM appears to be clinically non-significant (<0.5 Gy) compared with the PG overdose (up to 8.2 Gy). This DAM could therefore be used to monitor PG doses and trigger replanning

Calcul de dose à partir d’images Cone Beam CT : état de l’art

National audienceIn external beam radiotherapy, the dose planning is currently based on computed tomography (CT) images. A relation between Hounsfield numbers and electron densities (or mass densities) is necessary for dose calculation taking heterogeneities into account. In image-guided radiotherapy process, the cone beam CT is classically used for tissue visualization and registration. Cone beam CT for dose calculation is also attractive in dose reporting/monitoring perspectives and particularly in a context of dose-guided adaptive radiotherapy. The accuracy of cone beam CT-based dose calculation is limited by image characteristics such as quality, Hounsfield numbers consistency and restrictive sizes of volume acquisition. The analysis of the literature identifies three kinds of strategies for cone beam CT-based dose calculation: establishment of Hounsfield numbers versus densities curves, density override to regions of interest, and deformable registration between CT and cone beam CT images. Literature results show that discrepancies between the reference CT-based dose calculation and the cone beam CT-based dose calculation are often lower than 3%, regardless of the method. However, they can also reach 10% with unsuitable method. Even if the accuracy of the cone beam CT-based dose calculation is independent of the method, some strategies are promising but need improvements in the automating process for a routine implementation

Validation of transit EPID and application for Head and Neck adaptive radiotherapy

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