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.

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.

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.

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.

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.

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.

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.