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Interview with Prof. Karel Šonka for the 6th European Narcolepsy Day 2015

13/03/2015 ● Lecturas 25.289

Prof. Karel Šonka Neurologist at the Department of Neurology and Centre for Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital of Prague. He is also Director of the Sleep and Wake Disorders Centre, President of the Cze
Question. The Sleep Centre at the Prague Department of Neurology is an international reference centre as a pioneer in sleep studies in Europe, which started under the leadership of Prof. Bedřich Roth 60 years ago. Numerous specialists have been trained in the last two decades and have gone on to generate excellent scientific publications. Can you explain the achievements and current goals of the Sleep and Wake Disorders Centre that you run?
Answer. Thank you for your kind reference to the founder of our centre and our esteemed guru Bedřich Roth. Our aim is to develop his activities in the field of narcolepsy, in particular idiopathic hypersomnia. With regard to this latter issue, we repeatedly come back to Bedřich Roth’s original description of idiopathic hypersomnia, which, in his view, comprised prolonged nocturnal sleep and sleep drunkenness in the course of awakening, Bedřich Roth (1956, 1957). Thereafter, the definition of idiopathic hypersomnia went through a variety of changes. In the year 2005, the International Classification of Sleep Disorders (ICSD) defined two nosological entities: idiopathic hypersomnia with long nocturnal sleep, and the same disorder without long nocturnal sleep. However, in the year 2014, a new classification removed this division of idiopathic hypersomnia so that we now have only one idiopathic hypersomnia. This new entity seems to be defined negatively against narcolepsy and secondary and comorbid hypersomnias and encompasses perhaps a variety of different diseases. This step back in the definition of idiopathic hypersomnia led my second tutor Prof. Michel Billiard (Montpellier, France) and I to perform a cluster analysis of the salient symptoms of subjects suffering from idiopathic hypersomnia with and without long nocturnal sleep, idiopathic hypersomnia and narcolepsy with and without cataplexy (diagnosed according to the 2005 classification). As follows from our study, narcolepsy with cataplexy and idiopathic hypersomnia with long nocturnal sleep are two independent nosological entities. In contrast, idiopathic hypersomnia without long nocturnal sleep and narcolepsy without cataplexy are marked by similar symptoms so that, conceivably enough, they constitute a single nosological entity unless they make up a number of other conditions of so far unknown aetiopathogenesis. In a recent study, we drew attention to a multitude of nightmares in narcolepsy. Our distinguished colleague, Prof. Sońa Nevšímalová, has long been cooperating with Prof. Mignot on his molecular biological discoveries related to narcolepsy. Our centre is on record for successful scientific research into the genetic aspects of restless legs syndrome (Prof. David Kemlink) and for its part in the research of REM sleep behaviour disorder (RBD).

Q. You have published studies about the diagnosis and management of central hypersomnias (Ther Adv Neurol Disord, 2012). You are also a co-author of the 'European Federation of Neurological Societies (EFNS) Guidelines on the Management of Narcolepsy' (Eur J Neurol 2006). Could you comment on the current therapeutic issues of hypersomnias of central origin?
A. In the past few years, we have seen the appearance of new or newly tested molecules for the treatment of narcolepsy and daytime sleepiness (modafinil, gamma hydroxybutyrate-sodium oxybate, pitolisant), all of them drugs of great benefit for those affected. On the other hand, health care authorities are increasingly inclined to limit the use of medicines without the highest degree of efficiency and safety based on evidence-based medicine and to restrict off-label application. This presents a problem in drugs which have long been marketed without being tested according to recent requirements. Nor are there trials of modern medicaments designed for the management of rare disorders such as idiopathic hypersomnia. Last but not least, problems are encountered as to the legal availability of treatment for childhood patients. In many countries, including the Czech Republic, we have seen how drugs against sleepiness such as amphetamines and fenmetrazine have disappeared from the portfolio and are now restricted for prescription owing to abuse (by persons other than narcoleptics). As for methylphenidate, the EMEA has excluded it from the list of indications for narcolepsy despite its history of administration for narcolepsy going back to the 1960s, and despite it being fit for use in children. Off label are most of the antidepressants, which we routinely use to control cataplexy. I am greatly disappointed by the alibistic administrative restriction of indication of some drugs by the authorities, which, under the pretext of safety, drive our care of patients with narcolepsy and idiopathic hypersomnia almost to the brink of the law.

Q. Recently you coordinated an important study on Narcolepsy and pregnancy in Europe (J Sleep Res, 2013), the first related to this important issue. Can you summarise your findings in this study? Do you think that prospective studies would help make treatment during pregnancy clearer to specialists?
A. Together with my postgraduate student Eszter Maurovich-Horvat we organised a questionnaire investigation regarding pregnancy and delivery in narcoleptic women in sleep centres in 12 European countries. As follows from the results of the study, cataplexy during childbirth occurred in less than 1% of deliveries by women with narcolepsy and cataplexy. It should be added here that women with narcolepsy and cataplexy give birth by Caesarean section more often than is usual among the general population. Though we refrained from studying the reasons for this approach, we suppose that it was largely dictated by the obstetrician’s fear of cataplexy. Important for practical use was the discovery that after delivery, women with narcolepsy need greater family support with regard to their sleepiness, which may limit patient care. Our study has no comment to make on the effect of medication as only very few women in the cohort reported the use of drugs during their pregnancy.

Q. In reviewing your numerous publications, we found your work on Narcolepsy: clinical differences and association with other sleep disorders in different age groups (J Neurol, 2012) particularly interesting. Can you explain the key aspects of the study? Do you think that comorbidities with other sleep disorders are a challenging issue for treatment in narcolepsy?
A. Our centre has been studying age-related aspects of clinical manifestation for quite some time, and this is the first part of our study. The initial results suggest that children with narcolepsy without cataplexy may develop cataplexy later on. In addition, they also show that narcolepsy with cataplexy has more sleep comorbidities such as sleep apnoea, PLMS and RBD. As distinct from the general population, RBD in narcolepsy with cataplexy is already present from childhood. We are continuing this line of research, and at the Congress of the European Sleep Research in Tallinn we were able to show that hypnagogic hallucinations and sleep paralysis may occur from the onset of the disease for the rest of the patient’s life with the symptoms disappearing only in some of the patients. We are now exploring this condition and its comorbidities in our patients, since we think that not only the onset but, indeed, also the lifetime development of the patient’s state of health and social situation are of interest for research conducted on the disease.

Q. You are interested in the dynamics of the hypothalamus-pituitary-adrenal system, glucose metabolism and TNF-α in narcolepsy as you recently published (J Sleep Res, 2014). Do you think that hypocretin-deficiency could be a contributing condition? Are there any other studies pointing in this direction?
A. We studied this issue in conjunction with a group led by Prof. Thomas Pollmächer from Germany, who has long been interested in this field of sleep disorder pathophysiology. We found no disorder affecting glucose metabolism regulation, a fact corroborated in another recent study. All we found was subtle dysregulation of inflammatory cytokine production – in this respect, four other studies also produced results, although they were inconclusive. According to our findings, the hypothalamus-pituitary-adrenal gland axis is not altered. We conducted this study due to our suspicion that hypocretin may be involved in the control of the above-mentioned processes, but it appears that its deficit is not significant in this direction.

Q. You are also interested in MRI imaging in relation to the volume of the amygdala in patients with narcolepsy. Could you comment on these studies?
A. The amygdala plays a key role in the detection and processing of emotional signals – including laughter. Moreover, the amygdala is bidirectionally connected with the hypothalamus and obviously has a role to play in triggering off cataplexy. Our first measurement of the volume of the amygdala showed it to be smaller in patients with narcolepsy and cataplexy than in control subjects. We put this down to a reduced input either within the amygdala or to reduced connections from the hypothalamus. We resumed the subject and are now trying to verify our early results by using a more precise method of MRI acquisition in larger groups of patients and controls.

Q. Finally, you are an active member of the EU-NN, could you summarise the achievements of the network over the past six years and comment on what you think the future holds?
A. EU-NN is undoubtedly important as regards both research and the social and health situation of patients with excessive sleepiness and especially in those with narcolepsy. In Europe there are several quite exceptional centres engaged in research into narcolepsy, and more frequent meetings of specialists from those and other centres have of late certainly helped to accelerate cooperation in Europe, though some of it is merely bilateral. Obviously, the EU-NN has started joint research, and formed and goes on developing a large database, which is bound to lead to further progress in our knowledge of the disease. The EU-NN information-seeking activities are creating conditions that allow improvements to be made in the care and social situation of patients with narcolepsy, a condition which is still little known and insufficiently perceived as a significantly disabling disease.
Dra. Rosa Peraita Adrados
Unidad de Sueño y Epilepsia-Neurofisiología Clínica. Hospital Universitario Gregorio Marañón, Madrid

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