Prof. Michel Billiard

Prof. Michel Billiard is Honorary Professor of Neurology at the School of Medicine, University Montpellier I and Honorary Chair of the Department of Neurology, Gui de Chauliac Hospital, Montpellier (France). He has been President of the European Sleep Research Society (1996-2000) and is the first Honorary member of the EU-NN, elected in the last European Narcolepsy Day in Helsinki (March 2016). He was the instigator of the European Collaborative Project on Genetic Susceptibility to Narcolepsy (1995). Over the past four decades, he has published numerous articles on narcolepsy with cataplexy and other hypersomnias of central origin, particularly Kleine-Levin Syndrome and Idiopathic hypersomnia.

Question. The Sleep and Wake Disorders Centre of the Department of Neurology, Gui de Chauliac Hospital, Montpellier, has been a pioneer in the study and treatment of sleep disorders in Europe. This centre was founded by Prof. Pierre Passouant. In July 1975, Prof. Passouant organized the First International Symposium on Narcolepsy. As Prof. Passouant’s collaborator and successor, you have contributed to maintain the tradition and hundreds of sleep specialists from all over the world were trained in Montpellier.
Answer. In 1971, at a time when there were very few sleep disorders centres in the world, Prof. P. Passouant opened a new department, referred to as Service de Physiopathologie des maladies nerveuses in the newly built Gui de Chauliac Hospital, in Montpellier. This department included a 28-bed clinical neurologic ward, an EEG unit, an EMG unit and a fully equipped 2-bed sleep disorders facility. The main interest of Prof. Passouant was then epilepsy and many epileptic patients were recorded throughout the night with the aim of studying the relationship between epileptic seizures and wakefulness, NREM sleep and REM sleep. Nevertheless, Prof. Passouant was also interested in sleep disorders, especially narcolepsy, and he attracted physicians interested in sleep, mainly clinical neurophysiologists, to his department. Meanwhile, Prof. Passouant sent Dr Billiard to Scotland (Prof. Oswald) and to California (Prof. Dement and Guilleminault). On returning from Stanford (1974) Dr Billiard developed the sleep disorders centre both in terms of number of beds and number of collaborators, and from that time on dozens and dozens of doctors from all over Europe, North Africa, the Middle East and Latin America came to Montpellier to be trained in sleep disorders medicine.

Q. Looking at your scientific production you published on A menstruation-linked periodic hypersomnia. Kleine-Levin Syndrome or a new clinical entity? (Neurology, 1975) and, more recently, Recurrent hypersomnia, a review of 339 cases (Sleep Med Rev 2011). Following the ICSD-3, the term 'menstrual related hypersomnia' has been replaced by the term 'menstrual related KLS' underlining the idea that this condition is part of KLS. I consider that these articles led to the diagnosis of hundreds of undiagnosed women with KLS' who were considered as depressive. Could you please comment on that aspect?
A. I am not sure that these articles led to the diagnosis of hundreds of undiagnosed women with Kleine-Levin syndrome who were considered as depressive. However, it is likely that the first paper drew attention to this rare condition, formerly referred to as menstrual-related hypersomnia, and the second, to female cases of Kleine-Levin syndrome initially considered as exceptional or non-existent (Critchley, 1962). Indeed, in our series of 293 patients with primary Kleine-Levin syndrome, 232 were male and 61 female (male/female ratio 4/1).

Q. You are the leading author of the Guidelines on Management of Narcolepsy (Eur J Neurol 2006) for the European Federation of Neurological Societies (EFNS), and the leader of the development of Modafinil in Europe since the early nineties. What do you think about the new treatments in Narcolepsy such as Sodium Oxybate (Xyrem) and Pitolisant (Wakix)? Could you comment on these drugs in the context of what we know about the disease?
A. Modafinil, used experimentally in France by Prof. Jouvet, starting in 1983, was a definite revolution in the treatment of narcolepsy due to its effectiveness and favourable adverse event profile. Following several open-label studies conducted in France in the years 1985-1990, a first multicenter, randomized, placebo-controlled trial was published (Sleep, 1994), later followed by large North American clinical trials. Although the awakening effect of modafinil is due to the dopamine reuptake inhibition, the precise mechanism of action is not totally known. Then came the sodium salt of gamma-hydroxybutyrate (sodium oxybate), recommended as early as 1975 by Canadian researchers, and approved in the USA for the treatment of cataplexy in 2002 and for the treatment of excessive daytime sleepiness in 2005. The introduction of this drug was another revolution due to its effectiveness on both REM sleep related symptoms and excessive daytime sleepiness, and its favourable adverse event profile when taken at the recommended dosage levels, in accordance with progressive titration and in the absence of significant OSAS and respiratory depressants. Sodium oxybate activates the gamma-aminobutyric acid receptor type B (GABA-B receptor), but the mechanism of action is not yet clearly elucidated. Pitolisant is an inverse agonist of the histamine H3 receptor which significantly decreases excessive daytime sleepiness versus placebo and is well tolerated. This medication is already used in France under temporary use authorization and is in the process of being approved by the European Medicines Agency. At this stage, it is too early to decide on the place of pitolisant in comparison with modafinil and sodium oxybate in the treatment of excessive daytime sleepiness.

Q. There is limited research to support the theory that the environmental risk factors are of major importance in the aetiology of narcolepsy with cataplexy. However, twin studies report 25–31% of concordance, suggesting a major contribution of environmental factors. Further studies, including prospective epidemiological studies in Europe are necessary for a better understanding of the implication of risk factors in the aetiopathogeny of narcolepsy. The control of many of these factors can prevent the disease. Do you think that epidemiological studies are lacking in Europe?
A. In Europe, epidemiological studies were carried out in the field of obstructive sleep apnoea syndrome and hypersomnias of central origin as early as 1980, by Lugaresi and his group in Italy, and then in several northern countries, including Finland, Sweden, Denmark and Iceland. Concerning the role of environmental factors in narcolepsy, we published a first study Life events in the year preceding the onset of narcolepsy (Sleep, 1994) showing that onset is frequently associated with various non-specific events such as an infection, psychic stress or an abrupt modification of the sleep-wake rhythm. This first study was followed by other valuable studies. Of more interest, however, have been various studies focused on seasonality of birth, specific infectious agents and head trauma. Infectious disorders commonly show seasonal variations that may be reflected in the temporal pattern of birth of affected individuals. In the case of narcolepsy several studies have revealed a March peak and a September trough in the birth pattern of patients with narcolepsy type 1. This seasonal predominance of birth suggests the role of early-life environmental factors, interacting with genetic susceptibility to cause damage to the hypocretin system. Upper airway infection such as Streptococcus pyogenes and influenza are now known to be triggers of narcolepsy onset, at least in children. Narcolepsy often follows strep throat and recent-onset narcolepsy subjects are often positive for antistreptolysine-O, a marker of streptococcus pyogenes. Moreover, in China and other countries, the number of children with new-onset narcolepsy increased threefold to fivefold over prior years in the spring and summer of 2010, peaking 4 to 6 months after the peak in H1N1 infection. Finally, head traumatism may lead to narcolepsy, but the generally mild to moderate character of head traumatism is more likely to relate narcolepsy onset to stress than to a neurological assault. Yet, environmental epidemiology systematically investigating the environmental exposures that contribute to or protect against narcolepsy is still warranted.

Q. You are interested in narcolepsy with and without cataplexy, idiopathic hypersomnia with and without long sleep time (Sleep Med, 2015; Sleep Med Rev, 2016). However, in the absence of biological markers, doubts have been raised as to the relevance of a division of idiopathic hypersomnia into two forms. However, you seem to be in favour of two entities. Are there other studies pointing in this direction?
A. Based on clinical studies, the distinction between idiopathic hypersomnia with and without long sleep time has been challenged by the absence of symptoms specific to one subgroup (e.g. great difficulty waking up or sleep drunkenness found in both subgroups). Moreover, the validity of the mean sleep latency during the multiple sleep latency test in diagnosing idiopathic hypersomnia has been brought into question following several studies. Thus, idiopathic hypersomnia can no longer be divided into two forms, with or without long sleep time (ICSD-3). We are not aware of any current study, with the exception of the cluster analysis that will be referred to later, supporting the division of idiopathic hypersomnia into two forms. However, Bedrich Roth, the great Czech neurologist and sleep specialist, who first coined the word idiopathic hypersomnia, distinguished two forms of idiopathic hypersomnia: polysymptomatic and monosymptomatic idiopathic hypersomnia. Moreover, the door remains open to two forms of idiopathic hypersomnia as it is pointed out in the ICSD-3 that 'Clinicians may wish to continue to note sleep duration as an important clinical feature' and that 'any further separation of idiopathic hypersomnia into distinct conditions must await advances in understanding the underlying biology'.

Q. Following with the same argument, differential diagnosis involves a number of diseases with hypersomnolence and it is not yet clear whether idiopathic hypersomnia and narcolepsy type 2 are not the same condition. What is the role of the hypocretin system in these diseases? Is there enough evidence to consider narcolepsy type 2, a hypocretin deficient disease?
A. Using a hierarchical cluster analysis (Sleep Med, 2015) based on patients with narcolepsy with cataplexy, patients with narcolepsy without cataplexy, patients with idiopathic hypersomnia with long sleep time and patients with idiopathic hypersomnia without long sleep time, we showed that patients with idiopathic hypersomnia with and without long sleep time belong to two different clusters, whereas patients with idiopathic hypersomnia without long sleep time and patients with narcolepsy type 2 belong to the same cluster. Up to now a hypocretin deficiency has not been demonstrated in narcolepsy type 2, except for a few cases. However narcolepsy type 2 is a heterogeneous condition.

Q. Finally, you are the first Honorary member of the EU-NN, could you summarize the achievements of the narcolepsy network in Europe over the last few years and comment on what you think the future holds?
A. When one considers the history of research on narcolepsy in Europe at its origin, it is clear that several groups were working separately. Then came the need for studies such as candidate gene association studies or genome-wide association studies requiring a great number of patients and controls, which pushed these groups to work together. Also, there was an incentive among European researchers not to depend exclusively on the Stanford narcolepsy group and to develop their own competence. Hence the launching of the European Narcolepsy Network and the wide body of data obtained so far. The next step, already initiated, is to develop common protocols of research using this set of data to improve the knowledge of the narcolepsy phenotype, the pathophysiology of the condition and the finding of new treatments.

Dra. Rosa Peraita Adrados
Unidad de Sueño y Epilepsia-Neurofisiología Clínica. Hospital Universitario Gregorio Marañón. Madrid

Profesor Juan-Vicente Sánchez-Andrés
Director asociado de Revista de Neurología
Departamento médico, Viguera eds.

Categorias
Sueño