Prof. Yves Dauvilliers

Neurologist at the Department of Neurology, University Hospital Gui-de-Chauliac, Montpellier (France). Prof. Dauvilliers is the Head of the Sleep and Rare Hypersomnias Referral Centre. He is an internationally recognized expert on hypersomnias of ce

Question. The Sleep Centre at the Neurological Department of Montpellier is an international reference centre as a pioneer in sleep studies in Europe that started under the direction of Prof. P. Passouant. In July 1975, he organized the First International Symposium on Narcolepsy. His successor, Prof. M. Billiard has contributed to strengthen the tradition and hundreds of sleep specialists from around the world have been trained in Montpellier. Now, you are representing the 3rd generation. Can you explain the achievements and the goals of today’s Montpellier Sleep Centre?
Answer. It is a real pleasure for me to run the Montpellier Sleep Centre with a long tradition of narcolepsy research and sleep medicine in general.We aim to focus today on research in several sleep disorders but mostly on narcolepsy in different but complementary domains that include the genetic, environmental, immune system, consequences of hypocretin loss on brain and peripheral functions (cardiovascular, metabolism, addiction, decision-making, pain, etc.), but also on new strategies to manage the disease.

Q. We are interested in your numerous articles dealing with H1N1 vaccination (ASO3-adjuvant vaccine) and the increased incidence of narcolepsy-cataplexy in France in children and adolescents. Recently you have published in Brain (2013) with the Narcoflu-VF study group that you have also observed a robust increased risk in the adult population. The fact that adult cases had been reported only in France deserves an explanation. Can you explain the key aspects of this study? What do you think are the factors that contributed to expand the risk in adults?
A. We investigated the association between H1N1 vaccination and narcolepsy with cataplexy in children and adults in France compared with matched controls, and compared the phenotype of narcolepsy with cataplexy according to exposure to the H1N1 vaccination. The H1N1 vaccination was associated with narcolepsy-cataplexy with an odds ratio of 6.5 in subjects aged <18 years, and 4.7 in those aged 18 and over. A few differences were only found when comparing cases with narcolepsy-cataplexy exposed to H1N1 vaccination (mostly AS03-adjuvanted vaccine) to non-exposed cases. The associations appeared robust to sensitivity analyses, and a specific analysis focusing on ASO3-adjuvanted vaccine found a similar increase. I do believe that all this association exists in both adult and children populations but seems to be more sensitive in children potentially related to additional environmental factors such as comorbid infections.

Q. You are one of the authors of the European Federation of Neurological Societies (EFNS) Guidelines on Management of Narcolepsy (Eur J Neurol 2006), and the leader of the development of new treatments in Narcolepsy such as Pitolisant (Harmony study). Could you comment on this drug?
A. For the last 8 years we have been assessing the safety and efficacy of Pitolisant, a selective histamine H3 receptor inverse agonist that activates these neurons, in patients with narcolepsy. We performed a double-blind, randomized, parallel-group controlled trial in narcolepsy (Lancet Neurol. 2013). At doses up to 40 mg Pitolisant was efficacious on EDS on both subjective and objective measures compared with placebo and well tolerated compared with Modafinil. Pitolisant may also work on cataplexy frequency. Thus, Pitolisant could offer a new treatment option for patients with narcolepsy with a different mechanism of action and potential for combined medication.

Q. You have also been the first clinician to treat hypocretin-deficient narcolepsy patients with intravenous immunoglobulins with a clear improvement in the frequency and severity of cataplexy (Ann Neurol 2004, 2006, Neurology 2009). However, the results are controversial in the literature even if narcolepsy, an immuno-mediated disease, could have a chance of responding to immune-modulating therapies. Don’t you think that control studies in Europe are lacking?
A. We treated early-onset hypocretin-deficient narcolepsy patients with intravenous immunoglobulins and found a clear improvement in the frequency and severity of cataplexy. We reported its positive effect of normalizing both symptoms and CSF hypocretin-1 level in a single patient with narcolepsy. Our findings point to the importance of early diagnosis of narcolepsy, which, once treated quickly, may modify its long-term outlook. However some studies found no effect and we still need to do some RCT studies to prove these potential positive effects using IVIg or other immunomodulators close to disease onset.

Q. You are interested in hypersomnias, basically narcolepsy, and psychiatric comorbidities, as you recently published (BCM Medicine, 2013). Do you think that hypocretin-deficiency could be a contributing factor in this condition? Are there other studies pointing in this direction?
A. Mood symptoms are frequently reported in hypersomnia disorders of central origin, especially in narcolepsy. Due to its widely distributed CNS projections to specific targets such as amygdala, cingulum, dorsal raphe, hypocretin deficiency could be a contributing factor for the development of depression in narcolepsy-cataplexy.

Q. You are also interested in reward-based behaviours and emotional processing in human narcolepsy (Front Behav Neurosci 2013). What is the role of the hypocretin system in these behaviours and emotional processing in humans?
A. In addition to the role of hypocretin in the regulation of the sleep/wakefulness state, it also regulates reward processing, emotion and mood regulation, and addiction. Although studies on hypocretin-deficient mice have shown that hypocretin plays an essential role in reward-seeking, depression-like behaviour and addiction, results in human narcolepsy remain subject to debate. Most studies revealed that hypocretin-deficient narcolepsy patients who were either drug-free or medicated with a psychostimulant had preferences towards risky choices in a decision-making task under ambiguity. Narcoleptic patients may thus be vulnerable to impulsivity and gambling, but larger prospective studies are required to confirm these findings.

Q. Finally, you were a founder-member of EU-NN, could you summarize the achievements of the network over the last five years and comment on what you think the future holds?
A. We do need to advance further in understanding the pathophysiology, the major outcomes and the best management of narcolepsy. As narcolepsy is a rare disorder, an EU effort seems fully necessary: the EU-NN has been created with this end in mind. We need to work together on narcolepsy research all going in a similar direction. A nice database has been constituted that may help to answer several important clinical questions. In addition to the database, a nice GWA and a nice RCT on Pitolisant have been performed at the EU level. However, we still need more fruitful collaborations on important narcolepsy research projects at the EU level based on EU-NN guidelines.

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

Prof. Juan-Vicente Sanchez-Andrés
Director asociado de Revista de Neurología Departamento médico, Viguera eds.

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