[Michel Jouvet, from the discovery of paradoxical sleep and muscle atonia to the role of neuropeptides]. / Michel Jouvet, de la découverte du sommeil paradoxal et de l'atonie musculaire au rôle des neuropeptides.

This article focuses on the contributions made by Michel Jouvet about the neurons responsible for generating the muscle atonia of paradoxical sleep (REM sleep). He was the first to describe the neurons responsible for muscle atonia during paradoxical sleep using "pontine" cats (in which the forebrain has been removed down to the pons) and localized pontine lesions. Also discussed is the research going on in the 1980s, when Michel Jouvet was hunting for the hypnogenic factor. At that time, he thought that it was secreted by the hypophysis; but this factor finally turned out to be controlled by the hypocretin/orexin and melanin concentrating hormone neurones located in the lateral hypothalamus. Several unforgettable moments with Michel Jouvet are described which occurred between 1983 and his last moments with us.

TITLE: Michel Jouvet, de la découverte du sommeil paradoxal et de l'atonie musculaire au rôle des neuropeptides. ABSTRACT: Cet article porte sur les contributions que Michel Jouvet a apportées à la connaissance des systèmes responsables de l'atonie musculaire du sommeil paradoxal. Michel Jouvet a été le premier à décrire les structures du tronc cérébral responsables de l'atonie musculaire pendant le sommeil paradoxal à l'aide de chats dits « pontiques ¼ (dont le cerveau, après ablation, est réduit à sa partie postérieure à partir du pont de Varole) ou porteurs de lésions localisées au niveau du pont. Les recherches en cours dans les années 1980, alors que Michel Jouvet était à la recherche du facteur hypnogénique, sont également abordées. À cette époque, Jouvet pensait que ce facteur était sécrété par l'hypophyse mais il s'est finalement avéré que deux types de populations de neurones antagonistes, les neurones à hypocrétine/orexine et ceux à hormone de mélanoconcentration situés dans l'hypothalamus latéral, étaient impliqués. Plusieurs moments inoubliables avec Michel Jouvet sont décrits, qui se sont déroulés entre 1983 et ses derniers moments.

[Narcolepsy: From the discovery of a wake promoting peptide to autoimmune T cell biology and molecular mimicry with flu epitopes]. / Narcolepsie : une maladie auto-immune affectant un peptide de l'éveil liée à un mimétisme moléculaire avec des épitopes du virus de la grippe.

Narcolepsy-cataplexy was first described in the late 19th century in Germany and France. Prevalence was established to be 0.05 % and a canine model was discovered in the 1970s. In 1983, a Japanese study found that all patients carried HLA-DR2, suggesting autoimmunity as the cause of the disease. Studies in the canine model established that dopaminergic stimulation underlies anti-narcoleptic action of psychostimulants, while antidepressants were found to suppress cataplexy through adrenergic reuptake inhibition. No HLA association was found in canines. A linkage study initiated in 1988 revealed in hypocretin (orexin) receptor two mutations as the cause of canine narcolepsy in 1999. In 1992, studies on African Americans showed that DQ0602 was a better marker than DR2 across all ethnic groups. In 2000, hypocretin-1/orexin A levels were measured in the cerebrospinal fluid (CSF) and found to be undetectable in most patients, establishing hypocretin deficiency as the cause of narcolepsy. Decreased CSF hypocretin-1 was then found to be secondary to the loss of the 70,000 neurons producing hypocretin in the hypothalamus, suggesting immune destruction of these cells as the cause of the disease. Additional genetic studies, notably genome wide associations (GWAS), found multiple genetic predisposing factors for narcolepsy. These were almost all involved in other autoimmune diseases, although a strong and unique association with T cell receptor (TCR) alpha and beta loci were observed. Nonetheless, all attempts to demonstrate presence of autoantibodies against hypocretin cells in narcolepsy failed, and the presumed autoimmune cause remained unproven. In 2009, association with strep throat infections were found, and narcolepsy onsets were found to occur more frequently in spring and summer, suggesting upper away infections as triggers. Following reports that narcolepsy cases were triggered by vaccinations and infections against influenza A 2009 pH1N1, a new pandemic strain that erupted in 2009, molecular mimicry with influenza A virus was suggested in 2010. This hypothesis was later confirmed by peptide screening showing higher activity of CD4+ T cell reactivity to a specific post-translationally amidated segment of hypocretin (HCRT-NH2) and cross-reactivity of specific TCRs with a pH1N1-specific segment of hemagglutinin that shares homology with HCRT-NH2. Strikingly, the most frequent TCR recognizing these antigens was found to carry sequences containing TRAJ24 or TRVB4-2, segments modulated by narcolepsy-associated genetic polymorphisms. Cross-reactive CD4+ T cells with these cross-reactive TCRs likely subsequently recruit CD8+ T cells that are then involved in hypocretin cell destruction. Additional flu mimics are also likely to be discovered since narcolepsy existed prior to 2009. The work that has been conducted over the years on narcolepsy offers a unique perspective on the conduct of research on the etiopathogeny of a specific disease.

TITLE: Narcolepsie : une maladie auto-immune affectant un peptide de l'éveil liée à un mimétisme moléculaire avec des épitopes du virus de la grippe. ABSTRACT: La narcolepsie et la cataplexie sont décrites pour la première fois à la fin du XIXe siècle en Allemagne et en France. La prévalence de la maladie est établie à 0,05 % et un modèle canin est découvert dans les années 1970. En 1983, une étude japonaise révèle que les patients narcoleptiques sont porteurs d'un marqueur génétique unique, l'antigène leucocytaire HLA-DR2, suggérant l'auto-immunité comme cause de la maladie. Il faudra attendre 1992 pour qu'il soit montré, grâce à une étude chez des patients afro-américains, que DQ0602, un autre gène HLA, est la véritable cause de cette association. Des études pharmacologiques conduites sur le modèle canin établissent que la stimulation dopaminergique est le mode d'action des stimulants sur l'éveil, tandis que les antidépresseurs suppriment la cataplexie en inhibant la recapture adrénergique. Aucune association HLA n'est cependant mise en évidence chez les chiens, suggérant une cause distincte de la maladie humaine. Une étude de liaison génétique chez les chiens, initiée en 1988, révèle en 1999 que la narcolepsie canine est causée par des mutations du récepteur 2 de l'hypocrétine (orexine). En 2000, l'hypocrétine-1/orexine A est mesurée dans le liquide céphalo-rachidien (LCR) et on découvre qu'elle est indétectable chez la plupart des patients narcoleptiques, établissant qu'un déficit hypocrétinergique est la cause de la narcolepsie humaine. La diminution de l'hypocrétine-1 dans le LCR, secondaire à la perte des 70 000 neurones hypothalamiques produisant l'hypocrétine, est démontrée, ce qui, avec l'association au locus HLA, suggère qu'une destruction immunitaire de ces cellules est la cause de la maladie. D'autres études génétiques, notamment d'association à l'échelle du génome (GWAS), révèlent l'existence de nombreux facteurs génétiques prédisposant à la narcolepsie, la plupart étant également impliqués dans d'autres maladies auto-immunes. Une association forte et unique avec les loci des récepteurs lymphocytaires T (TCR) alpha et bêta est aussi observée, suggérant un rôle prépondérant des lymphocytes T. En dépit de nombreux efforts, toutes les tentatives visant à démontrer la présence d'auto-anticorps contre les cellules à hypocrétine dans la narcolepsie échouent, et la cause auto-immune présumée de cette maladie reste à l'état d'hypothèse. À la suite de la grippe pandémique influenza A pH1N1 en 2009, de nombreux cas de narcolepsie apparaissent, suggérant un mimétisme moléculaire avec le virus de la grippe qui pourrait déclencher la maladie auto-immune. Cette hypothèse est confirmée par un criblage peptidique montrant une plus grande réactivité des lymphocytes T CD4+ à un segment spécifique de l'hypocrétine (HCRTNH2) et une réactivité croisée des TCR correspondants à un segment d'hémagglutinine de pH1N1 qui partage une homologie avec HCRTNH2. De façon remarquable, le TCR le plus fréquent dans la population et qui reconnaît ces antigènes contient des séquences TRAJ24 ou TRVB4-2, segments modulés par des polymorphismes génétiques associés à la narcolepsie dans les études GWAS. Il est probable que les lymphocytes T CD4+ autoréactifs avec HCRTNH2 recrutent par la suite des lymphocytes T CD8+ qui détruisent les cellules à hypocrétine. On peut s'attendre à ce que d'autres séquences mimiques grippales inconnues soient découvertes prochainement puisque la narcolepsie existait avant 2009. Ces découvertes démontrent enfin la cause auto-immune de la narcolepsie. Les travaux menés au cours des années sur la narcolepsie offrent une perspective unique sur la conduite de la recherche sur l'étiopathogénie d'une maladie bien identifiée.

Dante's description of narcolepsy.

Sleep, sleepiness, and dreaming are expressed throughout Dante Alighieri's (1265-1321) the Divine Comedy from the start of his journey through the afterlife. In the book, Dante complains that he is "full of sleep," and he experiences sudden wake-dreaming transitions, short and refreshing naps, visions and hallucinations, unconscious behaviors, episodes of muscle weakness, and falls which are always triggered by strong emotions. Taken together these signs are highly reminiscent of narcolepsy, a term coined in 1880 by Gélineau to define a disease consisting of daytime irresistible sleep episodes with remarkable dream mentation, sleep paralysis, hallucinations, and cataplexy (falls triggered by strong emotions). Sleep, sleepiness, and episodes of sudden weakness triggered by emotions are Dante's literary fingerprints from his earliest works, pointing to a lifelong autobiographic trait. In the 19th century, Cesare Lombroso speculated that Dante had epilepsy, as he had suffered from frequent spells and hallucinations. However, the multiple emotionally triggered falls Dante experienced in the Divine Comedy contrast with the epileptic seizure he depicted in one of the damned individuals. It is possible that Dante may have intuitively grasped the main features of narcolepsy, but it also is plausible that Dante's sleep, dreams, hallucinations, and falls are clues to a lifelong pathologic trait and that Dante may have known of or had narcolepsy.

Narcolepsy and psychiatry: an evolving association of increasing interest.

Gélineau originally described narcolepsy as a disease with an organic cause. However, the disorder had undeniable emotional triggers and psychiatric-like expressions, and soon a psychiatric etiology of narcolepsy became a seriously considered option. In fact, the psychiatric view dominated scientific thinking for a long time, not necessarily to the benefit of patients. When hypocretin (orexin) defects were proven to be the cause of narcolepsy Gélineau's original disease model was shown to be right. However, the psychiatric symptoms of the disease were not forgotten afterwards, but gained a different significance: as psychiatric expressions of a brain disease. These symptoms, such as anxiety and eating disorders, can be highly debilitating and warrant clinical attention. Here, we describe the role of psychiatry in the history of narcolepsy, showing their evolving association.

Narcolepsia: diagnóstico diferencial nas síncopes não explicadas / Narcolepsy: differential diagnostics in the unexplained syncopes

A narcolepsia é uma doença com alta prevalência, frequentemente subdiagnosticada. Suas manifestações mais comuns, a hipersonolência e a cataplexia, muitas vezes podem simular episódios de síncope. Esta revisão tem o objetivo de esclarecer os mecanismos fisiopatológicos dessa patologia, assim como suas manifestações clínicas e seu manejo. Dessa forma, espera-se contribuir para que o médico a reconheça e a diferencie das causas mais frequentes de síncope.

English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and Gélineau in the late 19th century, with commentary.

STUDY OBJECTIVES: To publish the first English translations, with commentary, of the original reports describing narcolepsy and cataplexy by Westphal in German (1877) and by Gélineau in French (1880). METHODS: A professional translation service translated the 2 reports from either German or French to English, with each translation then being slightly edited by one of the authors. All authors then provided commentary. RESULTS: Both Westphal and Gélineau correctly identified and described the new clinical entities of cataplexy and narcolepsy, with recurrent, self-limited sleep attacks and/or cataplectic attacks affecting 2 otherwise healthy people. Narcolepsy was named by Gélineau (and cataplexy was named by Henneberg in 1916). The evidence in both cases is sufficiently convincing to conclude that they were likely each HLA-DQB1*0602 positive and hypocretin deficient. CONCLUSIONS: The original descriptions of narcolepsy and cataplexy are now available in English, allowing for extensive clinical and historical commentary.

[Narcolepsy: current view]. / Narcolepsie: le point actuel.

Narcolepsy is a primary sleep disorder which may or may not arise associated with catalepsy. It is a relatively frequent disease with 2 peaks of appearance in childhood and in young adulthood. It has genetic components which do not seem sufficient for its demonstration. It often depends on the environment and its clinical picture can be very variable, particularly in children. It is thus under-diagnosed and often confused with other diseases. In this short review of the literature we discuss: narcolepsy's history, clinical evaluation, diagnoses criteria, patient's history, clinical status and complementary examinations, clinical picture in the child and in the teenager, epidemiology, neurobiology, differential diagnoses, symptomatic narcolepsy, current treatments and internet sites of reference.

A brief history of hypocretin/orexin and narcolepsy.

The hypothalamic peptides named the orexins, or hypocretins, were discovered in 1998. In 1999 it was established that genetic narcolepsy could be caused by mutations in the genes synthesizing these peptides or their receptors. In September of 2000 it was found that most human narcolepsy is caused by loss of hypocretin cells, most likely as a result of a degenerative process. This paper reviews these events and their implications for our understanding of brain arousal and motor control systems.