[18F]Fludeoxyglucose-Positron Emission Tomography Evidence for Cerebral Hypermetabolism in the Awake State in Narcolepsy and Idiopathic Hypersomnia

BackgroundChanges in structural and functional central nervous system have been reported in narcolepsy, with large discrepancies between studies. No study has investigated yet spontaneous brain activity at wake in idiopathic hypersomnia (IH). We compared relative changes in regional brain metabolism in two central hypersomnia conditions with different clinical features, namely narcolepsy type 1 (NT1) and IH, and in healthy controls.MethodsSixteen patients [12 males, median age 30 years (17–78)] with NT1, nine patients [2 males, median age 27 years (20–60)] with IH and 19 healthy controls [16 males, median age 36 years (17–78)] were included. 18F-fludeoxyglucose positron emission tomography (PET) was performed in all drug-free subjects under similar conditions and instructions to stay in a wake resting state.ResultsWe found increased metabolism in the anterior and middle cingulate and the insula in the two pathological conditions as compared to healthy controls. The reverse contrast failed to evidence hypometabolism in patients vs. controls. Comparisons between patient groups were non-significant. At sub-statistical threshold, we found higher right superior occipital gyrus glucose metabolism in narcolepsy and higher middle orbital cortex and supplementary motor area metabolism in IH, findings that require further confirmation.ConclusionThere is significant hypermetabolism in narcolepsy and IH in the wake resting state in a set of brain regions constitutive of the salience cortical network that may reflect a compensatory neurocircuitry activity secondary to sleepiness. Metabolic differences between the two disorders within the executive-control network may be a signature of abnormally functioning neural system leading to persistent drowsiness typical of IH

Gut microbiota composition is associated with narcolepsy type 1

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

BACKGROUND AND OBJECTIVES Recent 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 whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see if data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers. METHODS We 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. RESULTS We included 1078 unmedicated adolescents and adults. Seven clusters were identified, of which four clusters included predominantly individuals with cataplexy. The two most distinct clusters consisted of 158 and 157 patients respectively, were dominated by those without cataplexy and, amongst other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening and weekend-week sleep length difference. Patients formally diagnosed as narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these two clusters. DISCUSSION Using 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 rapid eye moment periods (SOREMPs) 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

Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.</p

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Narcolepsy has genetic and environmental risk factors, but the specific genetic risk loci and interaction with environmental triggers are not well understood. Here, the authors identify genetic loci for narcolepsy, suggesting infection as a trigger and dendritic and helper T cell involvement. Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix (R). Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix (R)

Orexin / hypocretin deficiency in humans : consequences and pathophysiology, Narcolepsy Type 1 as an experimental model

Les orexine-A (ORX) et -B (ou hypocrétines 1 et -2) sont des neuropeptides hypothalamiques découverts il y a tout juste 20 ans. Chez l’homme, la destruction sélective des neurones à ORX conduit à la narcolepsie type 1 (NT1), une maladie rare caractérisée par une somnolence diurne excessive, des cataplexies, un sommeil de nuit fragmenté, et une dysrégulation du sommeil paradoxal (SP). L’ORX joue un rôle majeur dans la régulation veille/sommeil, mais aussi autonomique et neuroendocrine, le contrôle moteur, la régulation des comportements motivés et le système de récompense. Cette thèse explore les conséquences et la pathophysiologie de la déficience en ORX chez l’homme, avec la NT1 comme modèle expérimental. La 1ère partie aborde la dysautonomie dans la NT1. Nous avons recherché de façon systématique des symptômes dysautonomiques, avec le questionnaire validé SCOPA-AUT (Clinical autonomic dysfunction in NT1, Sleep 2019). Nous avons utilisé la scintigraphie cardiaque au MIBG dans la NT1, et montré une absence de dénervation sympathique cardiaque (DSC) par rapport à des témoins, mais un lien avec la dérégulation du contrôle moteur en SP (Exploration of cardiac sympathetic adrenergic nerve activity in narcolepsy, Clinical Neurophysiology 2018). Le trouble du comportement en SP idiopathique (TCSPi) est une parasomnie associée à une DSC. Le TCSP est aussi présent chez la moitié des NT1, et nous avons montré une différence de recapture de MIBG entre les NT1 avec TCSP et les TCSPi (Cardiac sympathetic activity differentiates Idiopathic and symptomatic RBD, Scientific Reports 2018). La 2ème partie s’intéresse aux mécanismes physiopathologiques de la NT1 et les implications thérapeutiques. La NT1 est probablement d’origine auto-immune (AI), mais de pathophysiologie unique, et nous avons montré qu’il n’y a pas d’association avec d’autres maladies AI dans la NT1 contrairement aux autres maladies AI (Comorbidity between central disorders of hypersomnolence and immune-based disorders, Neurology 2017). La perte des neurones à ORX est irréversible, mais des thérapies immunomodulatrices pourraient prévenir cette destruction. Certaines pathologies neuroinflammatoires sont associées à l’activation microgliale (AM) dans le système nerveux central, qui peut être ciblée en imagerie TEP. Nous proposons un protocole de recherche pour identifier une AM chez certains NT1. Dans la 3ème partie, les liens complexes entre la NT1 et certaines pathologies psychiatriques sont étudiés. Nous avons montré que les patients NT1 ont très rarement des addictions (Smoking, alcohol, drug use, abuse and dependence in narcolepsy and idiopathic hypersomnia: a case-control study, Sleep 2016). Les troubles de l’humeur rapportés dans la NT1 pourraient être d’origine endogène, et nous avons évalué la symptomatologie dépressive et les idées suicidaires dans une large cohorte de NT1 (Depressive symptoms and suicidal thoughts in adults with NT1: systematic assessment and effect of medication, in prep). Dans la dernière partie, les aspects neurophysiologiques de la NT1 sont étudiés. Nous avons validé des critères de la NT1 pédiatrique (Validation of Multiple Sleep Latency Test for the diagnosis of pediatric NT1, Neurology 2019). Enfin nous avons exploré les liens entre les taux d’ORX-A dans le LCR et des marqueurs de fragmentation du sommeil nocturne à la polysomnographie, et découvert des biomarqueurs de la fragmentation du sommeil, fortement corrélés aux taux d’ORX, avec un effet dose-dépendant (Nocturnal sleep stability and CSF ORX-A levels: Sleep and Wake bouts, in prep).Orexin-A (ORX) and -B (or hypocretins 1 and -2) are hypothalamic neuropeptides discovered two decades ago. In humans, the selective destruction of ORX neurons leads to narcolepsy type 1 (NT1), a rare sleep disease characterized by excessive daytime sleepiness, cataplexy, fragmented nocturnal sleep, and abnormal expressions of rapid eye movement (REM) sleep. ORX plays a major role in sleep and wake regulation, but also neuroendocrine and autonomic functions, motor control, motivated behaviors, and reward seeking. This thesis explores the consequences and pathophysiology of ORX deficiency in humans, considering NT1 as an experimental model. The 1st part focuses on dysautonomia in NT1. We assessed systematically autonomic impairment, in a large cohort of NT1, using the SCOPA-AUT questionnaire (Clinical autonomic dysfunction in NT1, Sleep 2019). We explored MIBG cardiac scintigraphy in NT1, and showed an absence of cardiac sympathetic denervation (CSD), but a link with REM sleep motor deregulation (Exploration of cardiac sympathetic adrenergic nerve activity in narcolepsy, Clinical Neurophysiology 2018). Idiopathic REM sleep behavior disorder (iRBD) is a parasomnia associated with CSD. RBD is also reported in half of NT1, however MIBG uptake differences were found between NT1 with RBD and iRBD patients (Cardiac sympathetic activity differentiates Idiopathic and symptomatic RBD, Scientific Reports 2018). The 2nd part focuses on the pathophysiological mechanisms in NT1 and therapeutic implications. NT1 has a probable autoimmune (AI) origin, environmental factors interacting with susceptibility genes. However, its pathophysiology is unique, and we showed no specific association with other immune-based disorders in NT1 in contrast to many other AI diseases (Comorbidity between central disorders of hypersomnolence and immune-based disorders, Neurology 2017). The loss of ORX neurons is irreversible, but immune-based therapies could prevent their destruction if given close to disease onset. Some neuroinflammatory disorders are associated with activated microglia in the central nervous system, that can be targeted in PET imaging. We propose a research protocol, to identify a microglial activation in NT1 patients. In the 3rd part, the complex links between NT1 and some psychiatric disorders are studied. We showed that NT1 patients rarely exhibit addiction, possibly protected by ORX deficiency (Smoking, alcohol, drug use, abuse and dependence in narcolepsy and idiopathic hypersomnia: a case-control study, Sleep 2016). The psychological burden of NT1 is suspected to be endogenous, and we assessed depressive symptoms and suicidal thoughts, and effect of medication, in a large cohort of NT1 (Depressive symptoms and suicidal thoughts in adults with NT1: systematic assessment and effect of medication, in prep). The last part addresses neurophysiological aspects of NT1. We validated neurophysiological diagnostic markers for pediatric NT1, as no specific criteria existed so far (Validation of Multiple Sleep Latency Test for the diagnosis of pediatric NT1, Neurology 2019). Finally, we explored the relationships between CSF ORX-A levels and markers of nocturnal sleep fragmentation on polysomnography, and discovered reliable electrophysiological markers of sleep stability, strongly correlated to CSF ORX-A levels in a dose-dependent way (Nocturnal sleep stability and CSF ORX-A levels: Sleep and Wake bouts, in prep)

Recent advances in treatment for narcolepsy

International audienceNarcolepsy type 1 (NT1) is a chronic orphan disorder, caused by the selective and irreversible loss of hypocretin/orexin (ORX) neurons, by a probable autoimmune process. Little is known about NT2 etiology and prevalence, sharing with NT1 excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep, but without cataplexy and loss of ORX neurons. Despite major advances in our understanding of the neurobiological basis of NT1, management remains nowadays only symptomatic. The main and most disabling symptom, EDS, is managed with psychostimulants, as modafinil/armodafinil, methylphenidate, or amphetamines as a third-line therapy. Narcolepsy is an active area for drug development, and new wake-promoting agents have been developed over the past years. Pitolisant, a selective histamine H3 receptor inverse agonist, has been recently approved to treat patients with NT1 and NT2. Solriamfetol, a phenylalanine derivative with dopaminergic and noradrenergic activity will be soon a new therapeutic option to treat EDS in NT1 and NT2. Sodium oxybate, used for decades in adult patients with narcolepsy, was recently shown to be effective and safe in childhood narcolepsy. The discovery of ORX deficiency in NT1 opened new therapeutic options oriented towards ORX-based therapies, especially nonpeptide ORX receptor agonists that are currently under development. In addition, immune-based therapies administered as early as possible after disease onset could theoretically slow down or stop the destruction of ORX neurons in some selected patients. Further well-designed controlled trials are required to determine if they could really impact on the natural history of the disease. Given the different clinical, biological and genetic profiles, narcolepsy may provide a nice example for developing personalized medicine in orphan diseases, that could ultimately aid in similar research and clinical efforts for other conditions

Narcolepsy and Other Central Hypersomnias

International audiencePURPOSE OF REVIEW: This article focuses on the clinical presentation, pathophysiology, diagnosis, differential diagnosis, and management of narcolepsy type 1 and narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, and other central disorders of hypersomnolence, as defined in the International Classification of Sleep Disorders, Third Edition (ICSD-3). RECENT FINDINGS: In ICSD-3, the names of some central disorders of hypersomnolence have been changed: narcolepsy with cataplexy and narcolepsy without cataplexy have been renamed narcolepsy type 1 and narcolepsy type 2, respectively. A low level of hypocretin-1/orexin-A in the CSF is now theoretically sufficient to diagnose narcolepsy type 1, as it is a highly specific and sensitive biomarker. Conversely, other central hypersomnias are less well-defined disorders with variability in the phenotype, and few reliable biomarkers have been discovered so far. The epidemiologic observation that influenza A (H1N1) infection and vaccination are potential triggering factors of narcolepsy type 1 (discovered during the 2009 H1N1 pandemic) has increased interest in this rare disease, and progress is being made to better understand the process (highly suspected to be autoimmune) responsible for the destruction of hypocretin neurons. Treatment of narcolepsy remains largely symptomatic, usually initially with modafinil or armodafinil or with higher-potency stimulants such as methylphenidate or amphetamines. Several newer wake-promoting agents and psychostimulants have also been developed, including sodium oxybate, which has a role in the treatment of cataplexy and as an adjunctive wake-promoting agent, and pitolisant, a selective histamine H3 receptor inverse agonist that is currently only available in Europe. SUMMARY: Although far less common than many other sleep disorders, central hypersomnias are among the most severe and disabling diseases in the field of sleep medicine, and their early recognition is of major importance for patients, especially children, to maximize their quality of life and functioning in activities of daily living

Management of Narcolepsy

International audienceNarcolepsy type 1 (NT1) and type 2 (NT2) are two rare neurological diseases, classified as central disorders of hypersomnolence. The pathophysiology of NT1 is well known; it is caused by the selective destruction of hypocretin (Hcrt) neurons, by a highly suspected autoimmune process. On the contrary, little is known about NT2 etiology, sharing with NT1 somnolence and signs of dysregulation of rapid eye movement (REM) sleep, but not cataplexy. Management strategies are rather codified, at least in adults, with a lifelong treatment required in NT1, whereas no pharmacological study focused only on NT2 patients, with sometimes spontaneous improvement or disappearance of their symptoms. We recommend that medications and guidelines in NT2 should be the same as for NT1 (except for cataplexy), but the benefit risk ratio should be reassessed regularly. The main symptom in both diseases is a disabling excessive daytime sleepiness (EDS). First-line medications should be stimulants such as modafinil, armodafinil, or sodium oxybate, second-line methylphenidate and pitolisant, where available, and amphetamines as third-line therapy. Sodium oxybate has the advantage to be also effective to manage the fragmented nocturnal sleep, another common symptom in NT1. We advise to wait a few weeks with a stimulant drug before starting an anticataplectic treatment in NT1, except for severe cataplexy. Furthermore, cataplexy treatment should not be systematic. First-line strategy is the use of sodium oxybate, the only drug approved for cataplexy and EDS in adults. However, antidepressant agents such as venlafaxine are also commonly used, with few adverse effects and a good efficacy, although based on expert consensus only. A clinically relevant tool is required to quantify the severity of narcolepsy, subjective symptoms, and their consequences, to monitor the treatment efficacy, and to finally optimize narcolepsy management. In the future, Hcrt replacement or Hcrt agonists will certainly be options to treat NT1, but for now the different peptides do not cross easily the blood brain barrier. Immune-based therapies are other possibilities in NT1, at disease onset, with already some successful attempts to slow down or stop the autoimmune process

Consultation initiale, analyse de la plainte et enquête étiologique devant une hypersmnolence

International audienceExcessive sleepiness is a common problem, defined by a complaint of excessive daytime sleepiness almost daily with an inability to stay awake and alert dosing periods at sleep, with episodes of irresistible sleep need or drowsiness or non-intentional sleep, or by a night's sleep time overly extended often associated with sleep inertia. This sleepiness is variable in terms of phenotype and severity to be specified by the out-patient clinic. It is considered to be chronic beyond three months and often responsible for significant functional impairment of school and professional performance, of the accidents and cardiovascular risk. We need to decipher the causes of excessive sleepiness: sleep deprivation, toxic and iatrogenic, psychiatric disorders (including depression), non-psychiatric medical problems (obesity, neurological pathologies...), sleep disorders (as for example the sleep apnea syndrome), and finally the central hypersomnias namely narcolepsy type 1 and 2, idiopathic hypersomnia, and Kleine-Levin syndrome. If careful questioning often towards one of these etiologies, need most of the time a paraclinical balance with a sleep recording to confirm the diagnosis. Patients affected with potential central hypersomnia must be referred to the Sleep Study Centers that have the skills and the appropriate means to achieve this balance sheet