Dr. Gert Jan Lammers

Neurologist. Leiden University Hospital. President of the Narcolepsy-Cataplexy European Group

Question. What is the proposed mechanism for the development of obesity in hypocretin deficient narcolepsy?
Answer. It has been known for around 90 years that narcolepsy with cataplexy is associated with obesity. In the early years it was thought that narcoleptic patients just spent less energy because they were asleep during a large part of the day. However, investigations in the 1980s already showed that over the 24 hours of the day narcoleptic patients don’t usually sleep more than subjects without narcolepsy. Moreover, many patients explain that they combat their sleep attacks by trying to be active. Intrigued by the relation with obesity, and far from convinced that it could simply be explained by decreased energy expenditure, we performed a study on BMI in narcolepsy. We compared the BMI of subjects suffering from narcolepsy with cataplexy with the BMI of patients suffering from idiopathic hypersomnia (IH) with short sleep time who have a comparable phenotype as far as daytime sleep is concerned, and with recent data from the population. What we found was that narcoleptic patients had a significantly higher BMI (about 10%) when compared to the normal population and the IH patients. The IH patients showed a trend towards a higher BMI when compared to the normal population. From these data we had to conclude that the cause of the propensity for obesity is not the sleep phenotype but hypocretin deficiency. You may be interested to know that we recently analyzed the European data and found clear evidence that in Spain narcolepsy is also associated with an increased BMI.The mechanism by which this is mediated is still a matter of speculation. In the normal population, there is an association between short nocturnal sleep and increased BMI. Moreover, experimental studies show that not only sleep deprivation but also sleep disruption lead to hormonal changes that predispose for obesity. In narcolepsy we have found comparable hormonal changes, particularly in leptin. So it might be that the (nocturnal) sleep disruption that accompanies narcolepsy predisposes for obesity.
An alternative explanation might be that hypocretin deficiency leads to an alteration in the basal metabolic rate mediated through the autonomic nervous system. Our current research focuses on these issues.

Q. Narcolepsy has been proposed to be an autoimmune disease, what is your opinion?
A. This is a hot issue. Since the discovery, in the 1980s, that over 90% of the patients suffering from narcolepsy with cataplexy carry the HLA DQB1*0602 haplotype, it has been suggested that narcolepsy is an autoimmune disorder. However, blood and CSF studies never gave support to this suggestion. In those days the problem was that nobody knew what the presumed autoimmune attack would be directed against. Only since 2000 do we know that narcolepsy is caused by a selective loss of hypocretin cells in the hypothalamus. With this new knowledge it was possible to perform studies focusing on antibodies against hypocretin and components of hypocretin cells. Unfortunately, the search for antibodies against hypocretin showed disappointing results. However, very recently and as a result of European collaboration, antibodies against Trib2, a co-localizing peptide in hypocretin cells, have been identified. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. Moreover, high Trib2-specific antibody titers correlated with the severity of cataplexy. These findings provide evidence, but not yet the final proof, that narcolepsy is indeed an autoimmune disorder. See also the March issue of the Journal of Clinical Investigation: Cvetkovic-Lopes V, Bayer L, Dorsaz S, Maret S, Pradervand S, Dauvilliers Y, et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. J Clin Invest 2010; 120: 713-9.

Q. Can hypocretin be a final pathway for the occurrence of sleep disorders in degenerative brain diseases?
A. Indeed decreased numbers of hypocretin cells have been found in post mortem brain studies of various degenerative brain disorders, particularly in Morbus Parkinson. Since Parkinson’s disease is often accompanied by narcolepsy-like sleep complaints, it is tempting to speculate that the degeneration of hypocretin cells could be a common final pathway. In my opinion, the degeneration of the hypocretin cells is definitely of major importance for the development of the sleep complaints in Parkinson’s disease. But, since lower numbers of other cell groups involved in (REM) sleep regulation such as MCH cells have also been found, it seems not to be just a matter of hypocretin deficiency.

Q. What are the main goals of the EU-NN?
A. The European Narcolepsy Network (EU-NN), founded in 2008, consists of a group of European clinical and scientific experts in the field of narcolepsy. The objectives of the EU-NN are the promotion of European scientific research of narcolepsy and its borderland, and the optimization of medical care in this field in the broadest sense.
Europe and the individual European centers can only achieve a leading position in this field through close collaboration. Experts, clinicians as well as basic researchers, are spread all over Europe. On their own they see too few patients or may have too limited facilities to perform research with a significant impact. Adequate patient number and application of cutting-edge techniques can only be achieved through collaboration. Up to now such collaboration has been hampered by the lack of guidelines for standardized assessment of clinical phenomena, and for standardized procedures to collect and store biosamples.
The EU-NN provides the opportunity to solve these issues and facilitates ‘cross fertilization’ and synergistic collaboration, which will also increase the chances of funding. The core tools are the available database and biosample bank. Guidelines for the entry of data guarantee its standardization and quality, and its modular structure enables the collection of prospective data.
Close collaboration is also important from a clinical point of view, as it facilitates the timely and smooth implementation of relevant new findings in patient care.

Q. How about the EU-NN database? How is it developing?
A. We already started a retrospective database in 2008, but the prospective database will be launched on March 18 as well!

Dra. Rosa Peraita-Adrados
Unidad de Sueño-Neurofisiología Clínica
Hospital General Universitario Gregorio Marañón

Prof. Dr. Juan V. Sánchez-Andrés
Depto. Médico, Viguera eds.

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