Narcolepsy: Knocked out by the Sandman

4. February 2013

People with narcolepsy even on the brightest of days fall into a deep sleep in a flash. Those working in medicine can't heal the socially burdensome underlying disease at all, but there are effective drugs for treating the symptoms.

Chronic fatigue syndrome: depression and anxiety disorders are often concealed behind it. In rare cases, however, narcolepsy is at the heart of the matter: from among 100,000 people epidemiologists on average find 25 to 50 to be affected, with a high number of unreported cases. Ten years or more can pass from first symptoms to treatment. This need not be the case. In order to distinguish a narcolepsy case from other diseases, help is obtained, for example, by the Epworth Sleepiness Scale (ESS). Other questionnaires such as the Stanford Narcolepsy Questionnaire or the Ullanlinna Narcolepsy Scale specify the matching indicators.

Waking up exhausted

Patients with narcolepsy describe their biggest problem as daytime sleepiness with the compulsion to go to sleep. Attacks lead in fewer than five minutes to REM sleep, whereas healthy people require an hour or more. With narcoleptics there are thus important deep sleep waves missing. The sufferer feels the next morning, despite having had adequate sleep, tired and exhausted. In 80 to 90 percent of all cases, patients suffer in addition from cataplexy. For them, emotion such as laughter, fear, anger or fright lead to the brief loss of muscle tone and they get hurt by falling. The respiratory muscles and the muscles of the tongue and pharynx remain fortunately spared from such events. Narcolepsy has from a statistical perspective no effect at all on life expectancy. Professionally and personally however, patients suffer immensely, not to mention their increased risk of accidents.

Treacherous Orexin

Why patients suffer from narcolepsy has not yet been explained with certainty. Researchers however know that in those affected the sleep-wake regulation no longer works. Blame is attributed to Orexin A and B, two neuropeptides from the hypothalamus. They control among other things the sleep cycle. As such, there are two causal models: mutations in the HCRT gene cause significant loss of function of important orexin receptors. Among mice without the relevant control points, REM sleep phases in fact are increased – as they are with narcoleptics. Another cause debated by scientists is lack of orexin. In the cerebrospinal fluid of patients they have found abnormally low levels of these neurotransmitters. In mice, neurons were successfully destroyed that normally secrete these peptides. When the “alarm-clock” protein orexin was lacking, narcolepsy promptly occurred. Similar symptoms appeared if the rodent were injected with antibodies from narcoleptic patients.

Self-destruction in the body

Therefore a strong case for autoimmune disease exists. One trail here leads to the genome: human genome researchers have found in neuroleptics with cataplexy in up to 98 percent of total cases the genotype (HLA) DQB1 * 0602. For family members of patients this increases the risk of developing the disease by a factor of 38 to 40, if they should carry this allele. The HLA complex encodes for leucocyte antigens, mutations lead to an autoimmune reaction against protein-secreting neurons. What’s more characteristic polymorphisms can be found in the locus of T-cell receptors. Normally, the appropriate binding sites recognise foreign materials, but they suddenly direct their actions against human cells.

Genetics alone is only part of the truth. Rather, it is environmental factors that trigger the disease. Researchers suspect that – in a way similar to Guillain-Barré Syndrome – viral or bacterial infections could be the culprits. What strengthens this view is that in China after flu outbreaks the number of narcoleptic patients also increased. Many instances of illness occurred in April, after dissipation of seasonal influenza; the fewest cases were recorded in November. A statistical relationship with influenza vaccines has not emerged there – in contrast to Northern Europe.

Today vaccination, tomorrow narcolepsy?

During the influenza season 2009/2010, a pathogen by the name A /California/ 7/2009 (H1N1), more commonly known as “Swine ‘flu” or “New ‘flu”, spread fear and dread. Doctors reached for, among other things, Pandemrix® as a vaccine. This subunit vaccine was injected together with AS03, an adjuvant, an oil-in-water emulsion derived from squalene and tocopherol. Evidence that squalene triggers autoimmune diseases has existed for more than ten years. Pandemrix® itself resulted in, among a total of 31 million vaccinations, 161 documented cases of narcolepsy, especially among children and adolescents. If there were initially doubts, the relationship can today no longer be scientifically denied. Astonishingly: more than 70 percent of all cases occurred in Sweden, Finland and Ireland. Vaccinated children and adolescents in Sweden have a seven times higher incidence of narcolepsy than a comparison group. In Finland and Ireland the incidence increased by a factor of 13. French epidemiologists found evidence that not only children but also adults are affected.

Looking at Germany, the Paul-Ehrlich-Institute reported only 33 recorded cases, involving 21 children and twelve adults. The attempt to scientifically reconcile all European data under VAESCO (Vaccine Adverse Event Surveillanceand Communication) was, however, only partially successful. Despite a common study protocol, standardised data was not successfully collected in all EU countries. In addition further cases were added after the “Data Lock Point”. This is the point in time by which the relevant information has to actually be present. The cause cannot lie with vaccines alone, this has already been shown by the large fluctuations in Europe. Researchers from the World Health Organization on the contrary see an association with risk factors in the genome. Again they found a link to the known allele (HLA) DQB1* 0602. For its patients, narcolepsy is nonetheless not a death sentence.

Treatment according to guideline

Patients at present cannot expect a cure. Nevertheless, there are many medications for controlling the symptoms. Mentioned in the current guideline in first place is Modafinil, followed by methylphenidate. Sodium oxybate is a potent drug used against cataplexy, but it also has its downsides. At the end of December, the U.S. Food and Drug Administration published on this ground a warning about possible interactions with alcohol and other CNS depressants. Dangerous respiratory depression can occur via interactions. Sodium oxybate can be combined with Modafinil, which leads to better results, but also to an increase in side effects. Should the medically sought effect not be sufficient, there remain drugs such as ephedrine, dextroamphetamine or MAO inhibitors as a second choice. For patients who suffer from cataplexy, sleep paralysis or hallucinations while falling asleep, antidepressants can improve the overall clinical picture.

The available data on intravenous immunoglobulins is comparatively poor. There is evidence that patients benefit in the early stages of their disease from immunomodulatory effects, further studies however need to follow as yet. In parallel, patients are required to develop coping strategies in order to manage their lives despite the disease. Medical staff can give valuable assistance here.

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Internal medicine, Medicine

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