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Competing Interests: L. Barateau déclare avoir participé à des interventions ponctuelles pour les entreprises Bioprojet, Idorsia, Jazz Pharma, Takeda ; et avoir été prise en charge, à l’occasion de déplacements pour congrès, par Bioprojet, Idorsia, Jazz Pharmaceuticals. Y. Dauvilliers déclare avoir participé à des interventions ponctuelles pour les entreprises Bioprojet, Takeda, Avadel, Idorsia, Orexia et Jazz Pharmaceuticals. Q. Lorber déclare avoir été pris en charge, à l’occasion de déplacements pour congrès, par Vitalaire, Sos Oxygène.

Central disorders of hypersomnolence include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia and hypersomnia associated with medical or mental disorders. Treatment is both non-pharmacological and pharmacological, including wake enhancing drugs and stimulants. One of the first-line treatment (modafinil, MODIODAL®) was the subject of a health authority alert in 2019 concerning a risk of major congenital malformations when taken during organogenesis. Since this date, three epidemiological studies have presented contradictory results. Given their methodological weaknesses, it is not possible at this stage to confirm or deny such a risk for the embryo and its nature if there is one. In clinical practice, because of these uncertainties, it is preferable if possible to suspend the treatment of a pregnant woman during the first 10 weeks from last menstrual period (organogenesis). There is an unmet clinical need for research to clarify the potential teratogenic impact of modafinil., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Sleep is a physiological condition essential to life, present in all living organisms with a neuronal and glial network. Its functions, not fully understood, include the conservation of energy, the regulation of our immune system and brain function through the modulation of synaptic plasticity and the elimination of substances accumulated during wakefulness. Sleep in human is characterized by two exclusive states, the non-REM and the REM -paradoxical- sleep, whose occurrence is driven by a cyclic organi zation. Sleep and wakefulness result from complex mechanisms involving a hetero geneous transition of different brain structures from one physiological state to another. The sleep duration and distribution of sleep over 24 hours are regulated by complex interconnected mechanisms, involving both the need for sleep accumulated during wakefulness -homeostatic process- and biological rhythm -mainly the circadian process- under the influence of external synchronizers like light-dark cycle. The propensity to sleep at a given moment is regulated by a physiological signal, sleepiness, in connection with the level of vigilance. The characteristics of sleep are relatively stable for a given individual because of a strong genetic determinism, but varies in duration and architecture according to age, individual habits, sleep schedules and environmental constraints. An understanding of the physiology of sleep is important for the clinician, allowing a better understanding of sleep dysfunction, responsible for various and frequent sleep disorders equiring appropriate care., Competing Interests: R. Lopez déclare des liens ponctuels -conférences- avec UCB Pharma, et Shire. L. Barateau déclare n’avoir aucun lien d’intérêts. Y. Dauvilliers déclare des liens ponctuels avec UCB Pharma, Jazz, Theranexus, Flamel, Idorsia, Takeda, Harmony Biosciences, et Bioprojet.

Competing Interests: Y. Dauvilliers déclare des liens ponctuels (activité d’expertise, conférences, prise en charge lors de congrès) avec UCB Pharma, Jazz, Bioprojet, Theranexus, Avadel, Actelion, Takeda, GSK.

Competing Interests: Y. Dauvilliers déclare des liens ponctuels (activité d’expertise, conférences, prise en charge lors de congrès) avec UCB Pharma, Jazz, Bioprojet, Theranexus, Avadel, Actelion, Takeda, GSK. C. M. Morin déclare des liens ponctuels (activité de conseil et conférences) pour Merck, Cereve et Philips.

Competing Interests: Y. Dauvilliers déclare des liens ponctuels (activité d’expertise, conférences, prise en charge lors de congrès) avec UCB Pharma, Jazz, Bioprojet, Theranexus, Avadel, Actelion, Takeda, GSK.

Competing Interests: Y. Dauvilliers déclare des liens ponctuels (activité d’expertise, conférences, prise en charge lors de congrès) avec UCB Pharma, Jazz, Bioprojet, Theranexus, Avadel, Actelion, Takeda, GSK. C. M. Morin déclare des liens ponctuels (activité de conseil et conférences) pour Merck, Cereve et Philips...

Definitions and epidemiology of insomnia Complaints of poor sleep are numerous and frequent in the general population. One of the most important is insomnia. As it is a subjective complaint, it can be difficult to define and diagnose. Various nosologies propose a common definition even if no consensus has yet been reached. Insomnia may be associated to or be the consequence of various psychiatric and somatic comorbidities. The purpose of this article is to present various definitions used to diagnose insomnia and provide updated knowledge about its prevalence, incidence, determinants and consequences., Competing Interests: I. Jaussent déclare n’avoir aucun lien d’intérêts. C. M. Morin déclare des liens ponctuels (activité de conseil et conférences) pour Merck, Cereve et Philips. Y. Dauvilliers déclare des liens ponctuels (activité d’expertise, conférences, prise en charge lors de congrès) avec UCB Pharma, Jazz, Bioprojet, Theranexus, Avadel, Actelion, Takeda, GSK.

In the new international classification of sleep disorders (ICSD-3), narcolepsy is differentiated into two distinct pathologies: type 1 narcolepsy (NT1) and type 2 narcolepsy (NT2). NT1 is characterised by periods of an irrepressible need to sleep, cataplexy (a sudden loss of muscle tone triggered by emotion) and in some cases the presence of symptoms such as hypnagogic hallucinations, sleep paralysis and disturbed night-time sleep. Its physiopathology is based on the loss of hypocretin neurons in the hypothalamus, seemingly connected to an auto-immune process. By definition, cataplexy is absent and the hypocretin levels in the CSF are normal in NT2. Confirming the diagnosis requires polysomnography and multiple sleep latency tests. The choice of further investigations is based on the presence or absence of typical cataplexy. Further investigations include HLA typing, lumbar puncture to measure the hypocretin level in the CSF, or even brain imagery in the case of narcolepsy suspected to be secondary to an underlying pathology. In this consensus we propose recommendations for the work-up to be carried out during diagnosis and follow-up for patients suffering from narcolepsy., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Violent behaviors during sleep. Violent behaviors during sleep are probably underdiagnosed but frequent and disabling complaints. They refer to behaviors ranging from simple dream enactment to complex behaviors that may have serious or even lethal consequences for oneself or other individuals. After awakening, the subjects are often unaware of their actions and had partial or complete amnesia of the episode. The violent behaviors during sleep may have multiple aetiologies. The parasomnias, including the disorders of arousal and the rapid eye movement sleep behavior disorder are mainly involved. A carefully clinical interview may help the clinician to rule out the differential diagnoses (i.e. nocturnal frontal lobe epilepsy, sleep related dissociative disorder) and to address the patient for further investigations. This article provides a brief overview of the epidemiology, the diagnosis, the prognosis and the treatment of the main causes of violent behaviors during sleep., Competing Interests: R. Lopez déclare des liens ponctuels (conférences) avec UCB Pharma et Shire. E. Evangelista déclare n’avoir aucun lien d’intérêts. Y. Dauvilliers déclare des liens ponctuels (activité d’expertise et conférences) avec UCB Pharma, JAZZ, Bioprojet, Flamel, NLS Pharma, et Theranexus.

Competing Interests: Y. Dauvilliers déclare des liens ponctuels (activité d’expertise et conférences) avec UCB Pharma, JAZZ, Bioprojet, Flamel, NLS-pharma, et Theranexus.

Narcolepsy with cataplexy or narcolepsy type 1 in a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden less of muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, disturbed nighttime sleep, and weight gain. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document mean sleep latency below 8 min and at least two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. In contrast, a low hypocretin-1/orexin-A levels (values below 110 pg/mL) in the cerebrospinal fluid was highly specific for narcolepsy with cataplexy and was included in the recent diagnostic criteria for narcolepsy. The deficiency of the hypocretin system is well-established in human narcoleptics with a reduction of cerebrospinal fluid hypocretin levels in relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process in most probable acting on a highly genetic background with environmental factors such as streptococcal infections, and H1N1 AS03-adjuvanted vaccine named Pandemrix.

Central hypersomnias include narcolepsy type 1, type 2 and idiopathic hypersomnia with daytime sleepiness excessive in the foreground of the clinical symptoms. Despite major advances in our understanding of the mechanisms of the narcolepsy type 1 with a low level of hypocretin-1 in cerebrospinal fluid, its current management is only symptomatic. The current management is also only symptomatic for type 2 narcolepsy and idiopathic hypersomnia with an unknown pathophysiology. Treatment options may vary from a single drug targeting several symptoms or several drugs treating a specific symptom. The treatment of daytime sleepiness is based on modafinil in first intention. Other psychostimulants such as methylphenidate, pitolisant and exceptionally dextro-amfetamine may be considered. In narcolepsy type 1, antidepressants such as inhibitors of the reuptake of serotonin and noradrenaline will be considered to improve cataplexy. Sodium oxybate is an effective treatment on sleepiness, cataplexy and bad night sleep in narcolepsy. The management for other symptoms or comorbidities should be considered it necessary such as hallucinations, sleep paralysis, the disturbed nighttime sleep, unpleasant dreams, parasomnias, depressive symptoms, overweight/obesity, cardiovascular disease and obstructive sleep apnea syndrome. Important therapeutic perspectives are to be expected concerning new psychostimulant and anticataplectiques, but mainly on immune-based therapies administered as early as possible after disease onset and on hypocretin replacement therapy for patients with severe symptoms.

Excessive sleepiness or hypersomnolence is currently defined by two main symptoms: 1) the excessive amount of sleep, defined as a prolonged period of main sleep or the presence of naps; and 2) poor quality of awakening. Excessive sleepiness was reported by 27.8%. The presence of recurrent periods of irresistible sleep in the same day was found in 13.2%, recurrent naps in the same day in 1.9%, non-restorative sleep despite a nighttime sleep of more than 9 hours (0.7%), as well as a sleep drunkenness (4.4%). Adding criteria for duration and frequency (minimum of 3 times per week and duration of at least 3 months), having social or professional impairment and psychological distress, and after excluding significant associated comorbidities, the prevalence fall to 1.5%. These very important prevalence hypersomnolence figures constitute an excellent argument to educate doctors and health authorities on the need to identify and support the excessive sleepiness disorders.

Excessive 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.

Drug-induced adverse effects are one of the main avoidable causes of hospitalization in older people. Numerous lists of potentially inappropriate medications for older people have been published, as national and international guidelines for appropriate prescribing in numerous diseases and for different age categories. The present review describes the general rules for an appropriate prescribing in older people and summarizes, for the main conditions encountered in older people, medications that are too often under-prescribed, the precautions of use of the main drugs that induce adverse effects, and drugs for which the benefit to risk ratio is unfavourable in older people. All these data are assembled in educational tables designed to be printed in a practical pocket format and used in daily practice by prescribers, whether physicians, surgeons or pharmacists., (Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Narcolepsy type 1 (also named narcolepsy-cataplexy or hypocretin deficiency syndrome) is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, plus frequently hypnagogic hallucinations, sleep paralysis and nocturnal sleep disturbances. Narcolepsy type 1 is an immune system-associated disease linked with the destruction of 70.000-90.000 hypocretin neurons notably involved in wakefulness. Among narcoleptic patients, 98% are positive for HLA-DQB1*06:02, a HLA class II allele, against 20-25% in general population. Individuals carrying HLA-DQB1*06:02 have an extraordinary risk to develop narcolepsy (odd ratio: 251). Other genes involved in CD4+ T cells and immune system activation as T-cell receptor α are also associated with narcolepsy. The development of the disease is linked with environmental factors such as influenza and streptococcal infections. Narcolepsy type 1 incidence also increased in Europe following the use of Pandemrix, a 2009 H1N1 AS03-adjuvanted vaccine manufactured by GlaxoSmithKline. Interestingly, such increase was not observed with Arepanrix, another vaccine developed by GSK very similar to Pandemrix., (© 2014 médecine/sciences – Inserm.)

Narcolepsy (with or without cataplexy), idiopathic hypersomnia (with or without long sleep duration) and Kleine - Levin syndrome are the main central rare hypersomnias. They may be considered models to help us to better understand the mechanisms controlling sleep and waking regulation in humans. When creating the national centers for rare hypersomnias, the aims were: 1) screening and earlier treatment of patients with hypersomnia; 2) improving patient care with guidelines, a specific patient's card, coordination of treatments between centers and professionals, and the development of new treatments; 3) encouraging research studies into the epidemiology, pathophysiology and genotype/phenotype through the creation of clinical, DNA, sera and cerebrospinal fluid banks; 4) increasing public awareness among patients and their relatives, the general public and in the mass media of rare hypersomnias; and 5) regular evaluation of our activities. These goals appear to have been achieved over the past 5 years. However, there are now financial difficulties to be faced, given the increasing demands of patients and professionals while having to stay within the same limited budgets., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Aim: The purpose of this prospective study was to determine whether combined functional genioplasty and orthodontic treatment in patients with vertical mandibular growth can be beneficial not only in achieving an esthetic outcome and orthodontic stability but also for the multi-disciplinary management of oral ventilation., Methods: Twenty-five non-obese adolescents (mean age: 14.6 ± 1.4 years) with vertical excess of the lower third requiring genioplasty received surgery following orthodontic treatment. All were predominantly mouth-breathers despite ENT treatment and rehabilitation. The functional before-after impact of genioplasty was examined in a clinical setting using polysomnography., Results: Before genioplasty, 52% of the adolescents presented an upper airways resistance syndrome (UARS) with obstructive hypopnea and poor sleep quality. Three to 6 months after genioplasty, the mode of ventilation shifted from oral to nasal (p < 0.001). Lip seal was significantly restored with no contraction of the labio-mental muscles. All nighttime symptoms improved. The proportion of patients suffering from ronchopathy (pathological snoring), dry mouth and disturbed sleep dropped significantly (p = 0.08, p = 0.001, p = 0.0009, respectively). Respiratory events and sleep pattern became normal. Below, we present two clinical reports involving obstructive sleep apnea syndrome (OSAS)., Conclusions: Genioplasty performed during puberty promotes spontaneous lip closure and helps restore nasal ventilation. It improves the obstructive disorder and its manifestations during sleep., (Copyright © 2011 CEO. Published by Elsevier Masson SAS. All rights reserved.)

Aim: Genioplasty has been validated for the correction of mandibular vertical excess and is generally performed at the end of the growth period, either alone or in association with other forms of osteotomy. Our aim was to assess whether genioplasty performed at an earlier age can impact mandibular growth., Methods: This comparative prospective study included 25 high-angle, mouth-breathing adolescents following orthodontic and ENT treatment. Subjects were divided into two groups according to their stage of puberty, either early (group 1: Tanner's stage 3, n=12) or late stage (group 2: Tanner stage 4-5, n=13). Genioplasty was performed in both groups. Cephalometric comparison was made on the overall population and for each group, before and after genioplasty (at 1, 6, 12 and 18months)., Results: In the immediate postoperative period, significant variation of all the cephalometric measures was observed within each group showing reduction of the vertical dimension and sagittal augmentation. Eighteen months post-surgery, only group 1 exhibited a significant increase in SNPog. Augmentation of the SNB and anterior mandibular rotation were also significantly greater in group 1. The difference in the direction of growth of the mandible before genioplasty (18months of orthodontics) and postgenioplasty (18months of postoperative monitoring) was also significant., Conclusion: Early genioplasty permits redirection of mandibular growth conducive to orthopedic correction of high angle Class II., (Copyright © 2010 CEO. Published by Elsevier Masson SAS. All rights reserved.)

Excessive daytime sleepiness (EDS) is frequent in Parkinson's disease. It should be explored by an Epworth sleepiness scale, a nighttime sleep recording and multiple sleep latency tests. EDS can be secondary to disturbed nighttime sleep that should be explored first. The main reasons for nighttime sleep disturbances are pain, nocturia, restless legs syndrome, obstructive sleep apnea syndrome and depression. They should be treated step by step. EDS can also be secondary to antiparkinsonian dopaminergic treatments that can induce nighttime insomnia and/or daytime sleepiness sometimes with sleep attacks. Treatment modifications and, when indicated, deep brain stimulation can improve these symptoms. Furthermore, EDS can be secondary to the disease itself modifying the sleep wake regulation systems. When the treatment of disturbed nighttime sleep and adjustments of the dopaminergic treatments are not sufficient to improve EDS, wake promoting treatments can be used. Their efficacy is variable but new hopeful drugs are coming soon., (Copyright © 2010. Published by Elsevier Masson SAS.)

Restless legs syndrome (RLS) is characterized by an unpleasant sensation in the lower limbs and an urge to move, occurring during periods of rest, in the evening and during the night and improved by movement. There are two different phenotypes of RLS: an early-onset form, starting before 36 years old with mostly a familial history, being mostly severe and highly genetically determined, with a high dependence to iron brain levels; a delayed-onset form, starting after 36 years old, mostly secondary, without familial history, with a rapid evolution in two or three years, and with frequent low ferritine serum levels. The primary form of RLS is associated with a familial history in 40 to 92 % of the patients. Monozygotic twins have a 54 to 83 % concordance rate for RLS phenotype. Linkage association studies have identified eight loci involved in the familial transmission of the disease. Genetic association studies have identified allelic variants responsible for a 50 % increased risk to develop RLS in the general population. Proteins coded by some implicated genes are involved in the development of spinal motor neurons and spinal dorsal horns, and in brain iron homeostasis., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Introduction: Kleine-Levin syndrome is a rare neurological disorder (1-2 cases per million inhabitants) primarily affecting young subjects. It is characterized by relapsing-remitting episodes of hypersomnia in association with cognitive and behavioral disturbances. Case-reports, small series, meta-analysis and a recent large, prospective trio study are consistent with a homogeneous, genuine disease entity., State of the Art: Patients are mostly male (68-78%) and adolescents (81%), with mean onset at 15 years (range 4-82 years). The first episode is triggered by an infection in 72% of patients. Patients experience an average of 7-19 episodes of 10-13 days each, relapsing every 3.5 months. Episodes recur more quickly in patients with childhood onset. The median disease course is 8-14 years, with longer course in men, in patients with hypersexuality, and when onset is after age 20. During episodes, all patients have hypersomnia (with sleep lasting 15-21 heures per day), cognitive impairment (apathy, confusion, slowness, amnesia) and a specific feeling of derealization (dreamy state, altered perception). Less frequently, patients experience hyperphagia (66%), hypersexuality (53%, principally men) and depressed mood (53%, predominantly women). Patients are remarkably similar to controls between episodes regarding sleep, vigilance, mood, and eating attitude, but have increased body mass index. Structural brain imaging, evaluation of the cerebrospinal fluid and serological inflammatory markers are unremarkable. EEG slowing is notable in 70% of cases during episodes, without epileptic activity. Sleep structure varies from harmonious hypersomnia to hypo-arousal with low sleep efficiency. The brain scintigraphy may show hypoperfusion, mostly focused on the thalamic, hypothalamic and fronto-temporal areas, especially when contrasted to images obtained between episodes. Newly identified factors include increased birth and developmental problems, Jewish heritage, genetics (5% multiplex families, suggesting autosomal recessive transmission). The association of KLS with HLA-DQ2, found in a small series, is not replicated in a larger independent sample. There is no increased family history for neuropsychiatric disorders. Some stimulants (amantadine, but more rarely modafinil or amphetamins) and mood stabilizers (lithium, valproate, but not carbamazepine) have marginal efficacy. In the 10% KLS cases secondary to various genetic, inflammatory, vascular or paraneoplasic conditions, patients are older, have more frequent and longer episodes, but their clinical symptoms, disease course and treatment response are similar to primary cases., Perspective: The most promising findings are the familial clustering and a potential Jewish founder effect, supporting a role for genetic susceptibility factors., Conclusion: KLS is a puzzling and disabling disease. Until its cause will be identified, disease management should be primarily supportive and educational.

Narcolepsy is a rare, disabling sleep disorder, with a prevalence of 20 to 30 per 100,000. Its onset, from childhood to the fifties, peaks in the second decade. The main features are excessive daytime sleepiness and cataplexy or sudden loss of muscle tone triggered by emotional situations. Other less consistent symptoms include hypnagogic hallucinations, sleep paralysis, sleep maintenance insomnia, REM sleep behavior disorders, attention deficit and weight gain at disease onset. Narcolepsy with cataplexy remains a clinical diagnosis but nighttime and daytime polysomnography (multiple sleep latency tests) are useful to document a mean sleep latency below 8 min and at least two sleep-onset REM periods. HLA typing shows an association with HLA DQB1*0602 in more than 92% of cases but was not included in the new diagnostic criteria. In contrast, a low hypocretin levels (values below 110 pg/ml) in the cerebrospinal fluid (CSF) was highly specific for narcolepsy with cataplexy. The deficiency of the hypocretin system is well-established in animal models of narcolepsy (murine and canine narcolepsy) but also in human narcoleptics with a 90% reduction of CSF hypocretin levels in relation with an early loss of hypocretin neurons. The cause of human narcolepsy remains unknown, however an autoimmune process is most probable. The treatment of narcolepsy includes stimulants against sleepiness (modafinil, methylphenidate), anticataplectic drugs (antidepressants) and sodium oxybate. The current therapeutic target is oriented towards hypocretine agonists, histamine (an arousal system) H3 antagonists and immunosuppressants.

Narcolepsy with cataplexy is a rare but long lasting and disabling disorder where onset often occurs during childhood. Excessive daytime sleepiness, irresistible sleep attacks, partial or complete cataplexies leading to abrupt falls without loss of consciousness are the major symptoms of the disorder together with hypnagogic hallucinations and sleep paralysis. Narcolepsy cases with childhood onset are often severe. School and social life are affected in children suffering from this condition. Due to the permanence of the disorder, long-term treatment is often required targeting sleepiness. Anticataplectic treatments may be necessary early on in the course of the disease, when considering the potential handicap created by the cataplexies and the risk of falls. There is no medication available to this day to cure the disorder. Familial education, psychological and academic support play a crucial role in the management of the symptoms and in, combination with pharmacological treatment, the quality of life in children with narcolepsy and their outcome in adulthood should lead to an improvement.

Clinical Data: Narcolepsy is a poorly known disease, though not exceptional, with a prevalence of 25 to 35 per 100,000 according to various surveys. Its onset can be anytime from childhood to the fifties with a peak in the second decade. It is characterized by two cardinal symptoms, irresistible sleep episodes and cataplexy or sudden loss of muscle tone triggered by emotional situations. The other symptoms, referred to as accessory due to their inconstancy, are hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Its diagnosis relies on the identification of the cardinal symptoms. Laboratory tests are required to confirm the diagnosis before initiation of a life-long treatment. Theses test include: all-night and daytime polysomnography documenting sleep-onset REM periods, HLA typing, showing the association with HLA DQB1*0602, and, in unclear cases only, measurement of cerebro-spinal fluid (CSF) hypocretine-1 showing values below 110pg/ml, highly specific of narcolepsy with cataplexy. Pathophysiology owes a lot to the existence of a natural canine model, the narcoleptic dog. Irresistible sleep episodes and cataplexy exhibit different pharmacological control, the former depending on dopaminergic systems and the latter on noradrenergic systems. The most remarkable findings of the last twenty years are the close association with HLA DQB1*0602, the identification of a mutation of hypocretin receptor 2 in the narcoleptic dog and the absence of CSF hypocretin-1 in 90% of patients. An autoimmune mechanism is suggested but not evidenced. THREE-FOLD TREATMENT: First line treatment of irresistible sleep episodes in modafinil, Cataplexy or tricyclic antidepressants or sodium oxybate, and disturbed nocturnal sleep by hypnotics or sodium oxybate. Current therapeutic research is oriented towards hypocretin agonists and immunosuppressors.

Narcolepsy is a rare disabling sleep disorder whose main features are excessive daytime sleepiness and cataplexy. Human narcolepsy is most frequently a sporadic disorder with both genetic and environmental factors playing a role in its pathophysiology. Implication of the hypocretin system is well-established: as mutations in both canine and murine narcolepsies and as a consistent reduction in hypocretin neuron in human narcolepsy. The cause of human narcolepsy remains unknown. However degenerative, autoimmune and/or genetic processes are the most probable causes of the hypocretin neurons loss. Acting on a specific genetic background, an autoimmune process with hypocretin neuron degeneration, in response to environmental factors, is the most probable hypothesis for most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest association with a specific HLA antigen (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. Monoaminergic, immune (TNF alpha) and hypocretinergic systems seem to be involved and may interfere with the phenotype. Treatment has not evolved significantly over the last few years. However, new drugs, such as hypocretin agonists, are currently being developed.

Since the discovery of an almost 100 p. cent association of human narcolepsy with the HLA gene DQB1*0602, research has been focused on autoimmune mechanisms. Epidemiological data (age of onset, triggering factors, association with multiple sclerosis) would lend support to this hypothesis. However it has remained largely impossible to demonstrate immune abnormalities in blood or CSF by means of usual techniques. The canine form of the disease was supposed to be also immunologically mediated, since a linkage with a human immunoglobulin-related gene had been demonstrated. This was eventually demonstrated to be a pseudo-linkage, the real cause being a mutation in the closely related hypocretin receptor gene. This recently discovered neuropeptide is clearly involved in some aspects of sleep regulation. Soon thereafter, hypocretin deficiency was found in human narcoleptics, due to a severe neuronal loss in the hypothalamus; gliosis having been evidenced, it may be considered as the evidence of a prior inflammatory reaction, possibly due to an immune attack.

In 1976 Bedrich Roth coined the term "idiopathic hypersomnia" and described two forms of the disease, one monosymptomatic, manifested only by excessive daytime sleepiness, and one polysymptomatic, characterized by excessive daytime sleepiness, nocturnal sleep of abnormally long duration and signs of "sleep drunkenness" on awakening. In comparison with that of narcolepsy, the pathophysiology of idiopathic hypersomnia remains poorly known. There are two main reasons for that: the absence of clinical and polysomnographic criteria pathognomonic or at least characteristic of the condition, as the cataplexies and the sleep onset REM periods of narcolepsy, and also the absence of a natural animal model comparable with the canine model of narcolepsy. The first investigations have stressed the frequent familial pattern of idiopathic hypersomnia. Later on biochemical assays have been performed in the CSF with results in favour of a dysfunction of noradrenergic systems. In the light of the two process model of sleep regulation in which sleep propensity is determined by a homeostatic process S and a circadian process C and of the later three-process model of regulation in which sleepiness/alertness are simulated by the combined action of a homeostatic process, a circadian process and sleep inertia, we suggest that idiopathic hypersomnia is not a pathological entity in itself, but rather the consequence of chronic sleep deprivation in very long sleepers.