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Interview with Prof. Markku Partinen for the 7th European Narcolepsy Day 2016

18/03/2016 ● Lecturas 25.120

Prof. Markku Partinen Director of the Helsinki Sleep Clinic, Vitalmed Research Centre, and Principal Investigator of Sleep Research at the Institute of Clinical Medicine, University of Helsinki, Finland.
He is leading the studies related to H1N1 pandemic influenza and narcolepsy conducted in the Nordic countries. He worked as a postdoc researcher at Stanford University, USA, in 1985-86. He has served on the Editorial Boards and as Assistant Editor of Sleep, Journal of Sleep Research and Sleep Medicine. He is the founder (1988) of the Finnish Sleep Research Society and the Finnish Sleep Federation (1998). He has been a member of the ESRS since 1978. He is also a long-term member of the SRS, AASM and WASM. He has held many international positions in different research societies, including Member of the Scientific Board and Vice-President of the European Sleep Research Society (ESRS), President of the Scandinavian Sleep Research Society, President Elect and President of the World Association of Sleep Medicine (WASM), Coordinating Secretary of the World Federation of Sleep Research Societies (WFSRS) and President and Member of the Board of the Scandinavian Sleep Research Society. He was President of the ESRS Congress in 1992 (Helsinki), the World Congress on Sleep Apnea in 2003 (Helsinki), and the WASM Congress in 2007 (Bangkok). In addition, he has organized several smaller meetings and symposia in the field of narcolepsy and different sleep disorders. Currently he is a Member of the Board in the ESRS EU-Narcolepsy Network (EU-NN) and Chair of the Scientific Board of the EU-NN.

Q. The Helsinki Sleep Clinic, Vitalmed Research Centre in Helsinki, is an international reference centre. Over the past years numerous specialists have been trained there and went on to generate excellent scientific publications. Could you explain the achievements and the goals of the current Vitalmed Research Centre that you direct?
A. The Vitalmed Research Centre works in close collaboration with the University of Helsinki. Currently the closest collaboration is with the Haartman Institute. We also work in collaboration with the Karolinska Institute in Stockholm, and Akademiska Sjukhuset at the University of Uppsala, Sweden. The Finnish Narcolepsy Research Centre is located at Vitalmed. The centre is the largest sleep clinic in Finland, where different problematic sleep disorder patients are treated. Most Finnish sleep clinics are focused only on sleep apnea. The largest diagnostic groups in Vitalmed are insomnia, narcolepsy, sleep apnea, parasomnias, restless legs, chronic fatigue syndrome, various neuropsychiatric disorders (ADHD, autism, Tourette, OCD), Parkinson’s disease and epilepsy.

Q. We are interested in your numerous articles dealing with H1N1 vaccination (ASO3-adjuvant vaccine). A sudden increase in the incidence of abrupt childhood narcolepsy with cataplexy was observed in Finland in 2010. You consider it likely that the Pandemrix vaccination contributed, perhaps together with other environmental factors, to this increase in genetically susceptible children. Could you explain the key aspects of your studies? What do you think are the factors that contributed to expand the risk in children?
A. Before 2010 about 30 to 60 patients had been diagnosed every year as having narcolepsy. Only a few of them were children below 10 years of age. During spring 2010 several young children and their parents consulted us because of excessive daytime odd sleep attacks involving, for example, falling or losing muscle power. By the end of July 2010 we had observed more children with narcolepsy than over the 10 or so previous years. This led us to investigate the matter in more depth. As previous studies, already before 2010, had shown, environmental factors are important. For example in identical twins most cases have been discordant. As the only environmental factor, which did not exist during previous years, was the H1N1 epidemic and the vaccination campaign, we suggested that either Swine flu or the vaccination may be associated with the onset of narcolepsy. Soon we had evidence that it was the vaccination rather than natural influenza, as almost no patients had caught an ILI (Influenza-like illness) but most of them had received vaccination. Different questions have been the focus of our own research and that of other Nordic teams:
1. Epidemiological studies based on registers to investigate changes in the incidence of narcolepsy. In Finland we have excellent patient registers from hospitals and outpatient services. We also have registered all subjects who have been vaccinated (place and date of vaccination, type of vaccination). This allows us to compute adequate hazard ratios. From the registers we can also know medications and possible sick leaves. Currently we are computing health economic costs of narcolepsy and investigating, for example, associations between previous usage of antibiotics and onset of narcolepsy.

2. Clinical and laboratory studies on narcolepsy. We have seen most patients with the Pandemrix-related narcolepsy. Blood samples (HLA-type, DNA, different antibodies, etc.) and CSF-samples (CSF-hypocretin and other studies) have been taken and investigated in collaboration with other researchers (University of Helsinki, Institute of Health and Welfare, Karolinska Institutet and Uppsala University, and also with Oxford University, for example). We also work in close collaboration with the European Narcolepsy Network on these issues.
a. One hypothesis has been that narcolepsy may, at least in some forms, be a 'synaptic disease'. In other words, for example, hypothalamic hypocretin secretion could be blocked by certain substances/factors/antibodies instead of being totally destroyed. Another hypothesis from the beginning was that narcolepsy might be an autoinflammatory/autoimmune disease with the presence of antibodies against some cells that are involved in narcolepsy. The molecular mimicry theory is behind these thoughts. As we know, the Stanford group published a study claiming to have evidence of molecular mimicry, but they had to withdraw the paper as the authors were not able to replicate their results. Thus, the question of molecular mimicry is still open. On the other hand, antibodies do not necessarily have to be directly the hypocretin cells. This has led to immunohistochemical studies as well as studies on, for example, T-cells.

b. There is evidence, based on the original descriptions (groups of De Lecea, Kilduff, Peyron, Nishino, Mignot, etc.), that narcolepsy is characterized by the selective destruction of hypocretin cells. There is also evidence of the genetic susceptibility. Therefore one logical question is, for example, how does this happen? What is the role of the cytotoxic T-cells? How do they enter the brain?

3. Why were children especially affected? Children are also at risk of developing other autoimmune diseases. The best example is juvenile diabetes type 1 and also many other diseases such as PANDAS (paediatric acute neuropsychiatric disease associated with streptococcal infection). No specific solutions have been found. The incidence of diabetes type 1 in Finland is among the highest and there is clear evidence in most countries that many autoimmune diseases are more common in children living in urban areas than in children living in the countryside, in less 'hygienic' environments. The so-called hygienic theory is therefore one possibility.

Q. You have published that Narcolepsy is an autoimmune disease (Lancet Neurology 2014, Duodecim, 2015) based on the fact that the incidence of narcolepsy clearly increased in countries where a vaccine with the AS03 adjuvant was used. Probably infections and perhaps often influenza may act as a trigger for narcolepsy. Are there any other hypotheses to explain narcolepsy as an autoimmune disorder? Do you think that prospective studies would contribute to clarifying these hypotheses?
A. We believe that narcolepsy is an autoimmune disease, but there is no final proof of that. Narcolepsy is no exception, however. There is no final proof for diabetes type 1 or for multiple sclerosis either. The role of the hypocretin system is certainly most important, but there are probably also other involvements. For this reason only a few subjects have shown antibodies against hypocretins. This is true for the Tribbles antibodies as well as other described antibodies. In one of our studies we did not find any antibodies against hypocretins but, in contrast, against some intermingled hypothalamic cells (Bergman et al. PNAS 2014). It is known, based also on the emerging findings from Spain (Peraita-Adrados et al.), that narcolepsy patients seem to be more common among subjects and in families with other autoimmune and/or allergic diseases. This also points towards the autoimmune hypothesis. We need prospective studies, as cross-sectional studies cannot prove or disapprove causality. These studies are laborious but we need large cohort studies. In such studies the baseline information should be as accurate as possible and unfortunately we do not have many large cohorts of, say, healthy infants and children (without any symptoms indicating possible narcolepsy at baseline), who have been followed up until they are adults.

Q. You co-authored a multicentre world study (Am J Hum Genet. 2015) with the interesting finding that new associations with HLA-DP alleles, but also in the HLA-class I region, suggest an independent role for these HLA alleles similar to other autoimmune diseases. HLA-class II molecules have never been detected in neurons, in contrast to HLA-class I. This supports the idea that cytotoxic CD8 T-cells play a central role: to damage cells, they must recognize an antigen presented by HLA-class I molecules (Degn and Kornum, 2015). Are there any other studies pointing in this direction?
A. The MHC group 2 (mainly DQB1*06:02) is strongly associated with narcolepsy type 1 (narcolepsy with loss of hypocretin). It seems to be almost a necessity for developing narcolepsy type 1, but it cannot explain the role of the cytotoxic cells as mentioned earlier. Therefore it is important to continue studies on other HLA systems. The Stanford group is continuing its studies and we also have some studies in Europe, together with the researchers of the EU-Narcolepsy Network and other European researchers, looking for HLA-class I. We aim to compare, for example, patients with the vaccination-related narcolepsy to patients with sporadic narcolepsy. I am not sure if that will yield anything, as most probably some environmental factors (most probably infections: streptococcal infection, influenza virus, other microbes) are often associated with the onset of narcolepsy – but very little is known about that.

Q. In reviewing your numerous publications, we found your work on the epidemiology of Narcolepsy interesting: the prevalence in the adult Finnish population (Sleep, 1994); the studies on twins in Finland (Sleep, 1994). Have these studies been replicated in other European populations? Don’t you think that epidemiological studies might be implemented due to the variations in the European populations and environmental factors, as well as in the epigenetic effects due to environmental factors?
A. Yes, similar figures have been published from Norway (Heier et al. Acta Neurol Scand, 2009), using a similar approach. Also the Hong-Kong group (Wing et al. Ann Neurol, 2002) has published very similar prevalence figures with a similar method using the Ullanlinna Narcolepsy scale as a screening tool. I suppose that the prevalence of around 30 per 10,000 inhabitants (in Finland 26/100,000) is quite close to the truth. A prevalence of 50 per 100,000 is often mentioned in the literature but I believe that it is too high. It is to be noted that all prevalence figures reflect only the most symptomatic narcolepsy patients, and even with those figures most narcolepsy (at least those with a less severe phenotype) remain undiagnosed. With a prevalence of 30/100,000 we should have about 1,500 diagnosed patients living in Finland but according to the registries (diagnostic registries, registries of narcolepsy medications used) we have not found more than 600. Similarly, there should be almost 14,000 diagnosed narcolepsy patients in Spain (ca 46 million inhabitants) but I am sure that there are so many diagnosed patients living in Spain. The genetic background for sure may explain some differences as well as different epigenetic factors. My guess is that the prevalence of narcolepsy could be lower in Spain than in Finland because of many reasons (immunogenetic susceptibility, much more sunlight, nutritional factors, etc.). This remains to be shown.

Q. You are the organizer of the 7th European Narcolepsy Day in Helsinki. You prepared a very attractive and interesting scientific programme for a large number of participants: scientists, sleep specialists, MDs, students and narcolepsy patients within the various European Narcolepsy Associations. Could you detail the main goals of the programme?
A. The aim of the programme is to gather together both patients and researchers interested in narcolepsy, and some experts outside the core group of European narcolepsy researchers. I hope that participants can have new ideas. We need open-minded thinking. Narcolepsy is a disease with many facets. One idea is also to work with evaluation of the disability caused by narcolepsy as well as to develop new methods of measuring functioning in narcolepsy. Most measures of quality of life and of functioning and disability work quite well in traumatic patients and in patients with, say, cardiovascular diseases. Narcolepsy patients have problems with sleepiness, poor nocturnal sleep and with cataplexy, which are not included in those scales. Also, most existing measures have been designed by experts. The idea is to also involve more and more the patient’s perspective. Patients are the best experts of their own disease. They read a lot from the Internet and we, physicians, may also learn a lot from the patients when we listen to them. I hope that the patients will learn too. Most European Narcolepsy patient associations will participate and hopefully they can learn some new things about the current best treatments and on-going developments. There is a lot of information on the Internet, but unfortunately also a lot of false, misleading information.

Q. Finally, you are a member of the European Narcolepsy Network (EU-NN) Board, could you summarize the achievements of the network over the past seven years and comment on what you think the future holds?
A. The aim of the EU Narcolepsy Network is to combine and enhance knowledge of narcolepsy. In a way, one of its roles is also to increase the impact of European narcolepsy research relative to the US and also Japanese narcolepsy research. In fact, the history of narcolepsy started from Europe (Westphal, Gélineau, Adie, Daniels, Roy, Parkes, Roth, Passouant, and later M. Billiard, Y. Dauvilliers, etc.). Interestingly, the two best known narcolepsy researchers at Stanford (Guilleminault and Mignot) are also originally European. In the very beginning the EU Narcolepsy Network focused perhaps too much on only a few centres inside Europe but it is opening up. Collaboration is getting better and better. We need everybody in Europe. I am quite sure that by joining together and through good collaboration Europe will soon be recognized as the most important place for narcolepsy research. I also believe that the next important breakthrough can be achieved in collaboration with the EU Narcolepsy Network.
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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