The National Narcolepsy Expertise Center is being formed from a collaboration between the LUMC and the Sleep-wake Center SEIN in Heemstede, with a small branch in Zwolle. Gert Jan Lammers, neurologist, professor of Sleep Disorders and medical head of SEIN, works here together with Rolf Fronczek, neurologist and somnologist or sleep expert at the LUMC. Lammers works four days a week in Heemstede and one day a week in the LUMC. For Fronczek it’s the other way around. Together they form a bridge between the sleep-wake center and the LUMC.
Waking quality is not good
Rare sleep disorders are related to neurological disorders of the brain and are characterized by an excessive tendency to sleep during the day rather than at night. That means that you have an increased tendency to sleep during the period you normally want to be awake. Or call it an inability to stay awake. It is also the case that the patients are not fully awake when they are awake. In other words, the quality of being awake is not good. Decreased attention, for example, is one of the problems. We only know a few rare sleeping diseases, namely: the Kleine-Levin syndrome, idiopathic hypersomnia and narcolepsy type 1 and 2. Narcolepsy is the most well-known sleeping disease.
“The fact that narcolepsy is best known of these rare diseases is due to the very special accompanying symptom cataplexy,” says Fronczek. “In addition to the daytime sleepiness associated with narcolepsy, these people experience a short-term and transient muscle relaxation of the skeletal muscles when they are clearly conscious. This usually happens with a positive emotion, but can also happen with a fright or anger. Random muscles in the body that you can normally control relax partially or completely. People can even land on the ground and stop moving. If the attack is limited to muscles in the face, neck or legs, it often only lasts a few seconds. By extension resulting in falling, it can take thirty seconds to a maximum of two minutes. But it is not sleep, because people are still awake. So they are conscious and can hear everything. That makes it very special. People who get this literally go limp with laughter. A special phenomenon that can also occur in animals. There are dogs that get an attack of cataplexy when they get food or horses get it when they are allowed back into the pasture.”
From examination to treatment
In the Netherlands, between 2,000 and 2,500 people have been diagnosed with narcolepsy. While it is estimated that at least 8,000 people should suffer from this sleep-wake disorder. Early recognition and treatment of narcolepsy is essential for normal childhood-onset cognitive and emotional development. On average, it takes eight years from the onset of the first symptoms before a diagnosis of narcolepsy is made. And often the disease is not recognized at all. If the diagnosis has been made, it is important that those around you understand what it means to have such a rare sleeping disorder as narcolepsy. The Expertise Center for Narcolepsy helps with this and is therefore of great value.
Fronczek: “If you look at exactly what we do from the center of expertise, we cover the entire palette. Very basic from a research point of view: we look at pieces of brain tissue, blood and cerebrospinal fluid (liquor) from patients. In addition, we conduct research in patients into the cause and effect of the disease. So we look at what changes when you have the disease and we also provide therapy. So we look at how to treat the disease. At the LUMC, we work together with our departments of immuno-haematology, neuro-immunology, pathology, endocrinology and the radiology department in Amsterdam. And for the pieces of brain tissue we work together with the Dutch Brain Bank in Amsterdam.”
A place where you are welcome
They mainly see patients with narcolepsy in Heemstede or Zwolle if the patient lives in the north of the country. There is a small branch there. Only if the patients participate in scientific research will they be asked to come to the LUMC. “We make sure that patients with this rare disease have a place where they are welcome and where they can go with their questions. That is in the SEIN sleep-wake center,” says Fronczek.
Lammers adds: “For the treatment of our patients, we mainly start from the perspective of the patient. So we ask the patient how he or she lives and what the obstacles of narcolepsy are. Then we focus on that. But we also ensure, for example, that sleeping places are set up at schools for children with narcolepsy in order to be able to be there better. Or that there is extra support at school and that information is provided about what exactly narcolepsy means. You get narcolepsy at a relatively young age. It often develops in childhood. We also have good cooperation with the patients’ association for narcolepsy, the NVN. For example, we always provide presentations on their national contact day.”
Conductor between sleep and wake
Years of research have shown that patients with narcolepsy lack the substance hypocretin in the brain. “Hypocretin is normally the conductor between your sleep and your wake. You have sleep and wake areas in the brain and hypocretin ensures that it is well distributed over the areas. That you are awake during the day and sleep at night. In a patient with narcolepsy, the sleep-wake distribution has become disturbed. We are investigating that. What is still a mystery to us, however, is where the cataplexy comes from,” says Fronczek.
The research into the disease narcolepsy is done, among other things, by looking at pieces of the brain. For example, the ‘hypothalamus’ is examined, a part of the brain where hypocretin is produced. Fronczek: “We then wonder what is going on with those cells in people with narcolepsy. And by administering an epidural to potential narcolepsy patients, we can see whether or not the substance is present in the spinal fluid, also known as cerebrospinal fluid. If not, we can solidify the diagnosis. We are the only center in the Benelux where this can be done. That also makes the LUMC unique in that we can measure the hypocretin in the liquor. And we do this together with the Central Clinical Chemical Laboratory (CKCL), our ‘liquor lab’ here in the LUMC.”
Internationale trials
The solution for the rare disease then seems very simple: administering hypocretin. Lammers: “If only it were that easy. Hypocretin is produced locally in the brain, does its work locally in the brain and, as far as we know, has no function for the rest of the body. But if you make that substance – and we can do that – it must then enter the brain via a tablet or by means of an injection via the bloodstream. And there we have a problem. It is a substance that is very difficult to cross the so-called blood-brain barrier. This only works when administering extremely high doses. However, that gives serious side effects and, moreover, it does not get where it should be.”
Nevertheless, progress has been made. Over the past 20 years, research has been done to develop this replacement for the substance hypocretin. This substance must have the same properties as hypocretin and, as Lammers previously indicated, must be able to pass easily from the bloodstream to the brain. They are now so far in development that the first major international studies will soon start.
Placebo-controlled study
Lammers: “The great thing is that we are going to participate in that. Not only as a center of expertise, but also many of our patients will participate in the studies. That’s going to be a pretty exciting time. For us as researchers, but especially for our patients. Many patients immediately wanted to participate when it became known. However, the study is placebo controlled. So you have a chance that you will receive a placebo for more than two months and you will have to stop your current medication. This may mean that if you stop your current treatment, which is quite effective, you will hardly function for the months in which the study is running. Of course they have to think very carefully about that. And if you do get the material, it remains to be seen whether it helps. There are short-term studies that show spectacular states, but of course you never know if you use it for weeks on end whether those effects will indeed last and how that will go. It is true that after the study, the participating patients have the opportunity to get the real substance in a follow-up process. They can then use it for at least a year.”
Lammers and Fronczek are both very excited about the upcoming international trials. Fronczek: “These studies are truly unique. What we’ve done so far is just treating the symptoms. Which, by the way, helps the patients well. It’s exciting because theoretically, if all goes well, the patients will return to ‘normal’ and that would of course be fantastic. We really hope to see that, but we still have to start testing in these international trials. If good results come out and it works for classic narcolepsy, the question arises whether it will also work for other forms. And if this works for those patients, the whole field will change.”
Recognition from the Ministry of VWS
Thanks to the collaboration with the LUMC, the SEIN sleep-wake center has taken over the role of the academic centre. This created the opportunity for Lammers and Fronczek to expand patient care, patient-related science and collaboration in international science related to narcolepsy. And that ultimately resulted in the recognition of the Expertise Center for Narcolepsy by both the Dutch Federation of University Medical Centers (NFU) and the Ministry of Health, Welfare and Sport.
This expertise center is one of the 38 expertise centers for rare disorders (ECZA) at the LUMC. Each center has its own specialization. By bundling knowledge and expertise about a rare disorder in a center of expertise, patients can be treated more quickly. In addition to the expertise center where Lammers and Fronczek passionately carry out their work, we have another expertise center in the Netherlands focused on narcolepsy. That is Kempenhaeghe’s Expertise Center for Sleep Medicine in Heeze. The two centers of expertise work together in many areas.
In the case of a rare disease, the right, tailor-made care is needed in the right place. Unfortunately, not every hospital can offer that. Centers of expertise for rare disorders are therefore tested and recognized by the Ministry of Health, Welfare and Sport. The LUMC has a total of 38 recognized expertise centers for rare disorders. Patients with rare diseases have access to the specialist care they need within these centers of expertise. In addition, patient care and research are strongly connected within these centers of expertise. There are also virtual knowledge networks at European level for rare diseases, the so-called European Reference Networks (ERNs). The LUMC participates in 14 of the 24 existing ERNs.