Research in narcolepsy and hypersomnia is continually evolving, with new diagnostic tools and treatment options in development.
As our understanding of the biology of narcolepsy and hypersomnia evolves, other diagnostic tests and treatment possibilities develop. Although it can take some time for these to come in to regular use in the clinic, understanding where research is at and where is it going helps get an idea of the direction things are heading.
Diagnosis:
Making a diagnosis of narcolepsy or hypersomnia often takes many years, as even people with typical symptoms including cataplexy often find. Often health care providers don’t recognise the symptoms of narcolepsy, so there is still a lot of work to be done educating health care providers about narcolepsy and hypersomnia.
Diagnosing narcolepsy on an overnight sleep study: Whilst typically a multiple sleep latency test (daytime napping test) is used to diagnose narcolepsy in the sleep laboratory, Prof Emmanuel Mignot and his group at Stanford have looked at the overnight sleep studies of people with narcolepsy. They found that if someone goes in to REM sleep within 15 minutes on their overnight sleep study that is diagnostic of narcolepsy as the likelihood of that person having narcolepsy is 99.4%. However, this isn’t a very sensitive way of diagnosing narcolepsy as they found only 51% of people with narcolepsy had this finding. This original research was published in JAMA Neurology in 2013, but has now been replicated by other groups and in children. The most recent study, which is not yet published shows results more like I see in clinical practice, with only 7% of people with narcolepsy having this finding, but 99.2% of people with this finding having narcolepsy.
Treatment:
Sodium Oxybate (Xyrem) – time to response: Sodium oxybate (Xyrem) has just become available for use in Australia, and people are asking me lots of questions about it’s use. Things like, how long do I need to trial it for to see if it is going to help? Research just published in the Journal of Clinical Sleep Medicine helps to answer that question. They looked at 86 people with narcolepsy who had used sodium oxybate in a clinical trial, and determined how long it took for people to get the maximum response with reductions in cataplexy and sleepiness symptoms. For cataplexy, by 25 days, 50% of people had a 50% reduction in the number of cataplexy attacks. For sleepiness, by 37 days, 50% of people had a 20% reduction in sleepiness, and as shown in the graph below, 50% of people had reached their maximum reduction in sleepiness by 106 days – just over 3 months.
Time to maximum sleepiness improvement with sodium oxybate (Xyrem)
JZP110: Jazz Pharmaceuticals are developing a new drug for the treatment of narcolepsy. It is a combined dopamine transporter (DAT)/norepinephrine transporter (NET) inhibitor, currently labeled JZP-110 (previously known as ADX-N05). So far, they have tested it in people with narcolepsy. In one trial presented at Sleep 2015, of 90 people with narcolepsy, 47% reported being either very much or much improved taking JZP110. Jazz also reported clinical trial data suggesting that the simultaneous antagonism of both DAT and NET may be more effective than drugs that have just one of these actions and don’t result in as much release of wake-promoting neurotransmitters.
Pitolisant: Histamine is thought to be one of the key neurotransmitters involved in the regulation of alertness and wakefulness. Pitolisant is a histamine 3 receptor (H3R) inverse agonist, and is the first agent that acts on histamine to be evaluated by health authorities for the treatment of sleepiness. So far, the majority of clinical trials have been in narcolepsy, but as histamine is thought to be important in idiopathic hypersomnia (IH), it may have a significant effect in people with IH. Final regulatory approval for the use of pitolisant in narcolepsy is pending in Europe, so it may be available in Europe soon as a narcolepsy treatment. Previous work published in The Lancet in 2013 had shown pitolisant had similar effects to modafinil on sleepiness in people with narcolepsy.
Orexin receptor structure and orexin receptor agonists: As narcolepsy with cataplexy is a disorder of orexin deficiency, with orexin secreting neurones being destroyed by an auto-immune process, the ideal treatment would be orexin replacement. However, this is difficult as the receptor structure hasn’t been well characterised and it is difficult to get the required drugs in to the brain, across the blood-brain barrier. However, recent work published in Nature has been able to work out the structure of the human orexin 2 receptor, and how to bind drugs to it that could then either stimulate or inhibit the receptor. Drugs that stimulate the orexin receptor (agonists), would be an ideal treatment for narcolepsy with cataplexy, that would address all of the symptoms by replacing the effects of missing orexin. From this research, other groups have now already developed orexin receptor agonists, and are moving on to looking at how to get these drugs in to the brain in the required concentrations. We hope that in 5-10 years we will have orexin receptor agonists available in the clinic as treatment for narcolepsy with cataplexy.
Related posts & links:
- What is narcolepsy?
- Managing narcolepsy as a team
- Narcolepsy Support Australia
- Stanford Center for Narcolepsy
- Julie Flygare’s blog on narcolepsy
- Hypersomnia info
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I agree that biomarkers for Idiopathic Hypersomnia are sorely needed. Without them people that have polysymptomatic hypersomnia (the patients that you mention that are significantly disabled) will continue to be mixed in with other patients and the problems this causes are be obvious. However I believe that distinguishing the severity should not be restricted by the lack of biomarkers and therefore objective measures. It would be helpful for doctors to give more consideration to the fact IH is a diagnosis of exclusion. Perhaps consideration should be given to the referral to a General Physician/Internist to assist in the exclusion process?
Above all I think consideration needs to be given to what IH actually is and I don’t believe the DSM5 or the ICSD3 do an adequate job of providing a criteria for IH. I agree with your comments about the DSM5. I was in San Francisco when the DSM5 was released and it was highly criticised by reviewers from all areas of medicine, including sleep medicine. There has been similar criticism of the ICSD3. While they were right to remove their inappropriate division of IH ie: “with and without long sleep”, by lumping all of IH under one umbrella the ICSD3 also fails to correctly identify IH. In a recent interview Prof Karel Šonka said that the ICSD3 new combined Idiopathic Hypersomnia “seems to be defined negatively against narcolepsy and secondary and comorbid hypersomnias and encompasses perhaps a variety of different diseases.” He explained that it was “this step back in the definition of idiopathic hypersomnia” that led him, Marek Šusta and Michel Billiard to produce the cluster analysis (Narcolepsy with and without cataplexy, idiopathic hypersomnia with and without long sleep time: a cluster analysis.) that determined Polysymptomatic Hypersomnia is not the same disorder as Monosymptomatic Hypersomnia. This analysis correlates very well with previous studies as well as the differences that I see in my work. Considering the findings of the cluster analysis, previous research, the data of over 200 patients diagnosed with IH in Australia and my discussions with Prof Sonka I believe the three clusters in his analysis best represent the different forms of Narcolepsy and Idiopathic Hypersomnia.
The analysis supports the findings of previous studies (and the data on Hypersomnolence Australia’s IH patient registry) that suggest Polysymptomatic Hypersomnia is in fact distinct and unique and is therefore an independent sleep disorder of Monosymptomatic Hypersomnia. The research also showed, which has been the long held belief of many researchers, that the clinical features of Monosymptomatic Hypersomnia are more closely related to those found in Narcolepsy without cataplexy (Type 2 Narcolepsy) and that those two disorders should be merged into one single condition (combined monosymptomatic hypersomnia). If sleep physicians approached Narcolepsy and Idiopathic Hypersomnia with these 3 clusters in mind I believe it would go a long way to resolving the problems that are created at the moment with the loose definitions and interpretations that are used when diagnosing IH and Narcolepsy.
It would certainly provide an adequate identity for the patients that fall under the umbrella of IH and Narcolepsy which is clearly lacking at present. At the moment what we see are patients with Polysymptomatic Hypersomnia that do not relate to patients with Monosymptomatic Hypersomnia and patients with Narcolepsy with cataplexy that do not relate to those without cataplexy. This indeed does make advocating for and supporting these patients extremely difficult. Of course educating doctors about these clusters would still be required however I don’t think the task would be anywhere near as complex as it is now considering the problems the DSM5 and ICSD3 have created.
http://www.hypersomnolenceaustralia.com/210919920/2745907/posting/research-confirms-idiopathic-hypersomnia-with-long-sleep-not-the-same-disorder-as-without-long-sleep
Thanks Michelle. I like that cluster analysis study and think it’s helpful. Not sure it’s the final answer as I still see a lot of people I couldn’t clearly fit in to one of those 3 clusters.
Regardless of what the DSM or ICSD have written this time round to describe IH and Narcolepsy neither of them have a history of being true to *the* definition of IH. IH was identified and described over 40 years ago by Bedrich Roth and the cluster analysis produced by Sonka, Susta & Billiard (students of Roth) is just fine tuning that initial definition so it would seem to me that if you have lots of patients that don’t fit into any of those 3 clusters it would suggest that those patients don’t have IH or Narcolepsy.
Unfortunately in clinical practice nothing is as clear cut as we wish it would be. Whilst some people fit fairly well within to one of the 3 clusters, some just don’t. What they have and what to call it I’m not sure, but they’re sleepy too and it significantly impacts on their life. So much we don’t know or have answers to.
Interesting discussion. I believe Dr. Rye’s team at Emory have developed a CSF test that can detect what they call a somnogen (an undiscovered neuropeptide?) that binds to GABA-A receptors or somehow alters their sensitivity. Flumazenil is being used in these patients. It only seems to work in the long sleeper IH group and KLS. Some develop a tolerance to it.
I am skeptical about hypocretin/orexin receptor agonists. I’m pretty sure the receptor expression diminishes after the peptide has been absent for so many years. Postmortem studies on a handful of narcoleptics showed a 70% reduction in receptors.
I have Type 1 Narcolepsy myself and I noticed it is a very diverse heterogeneous group. I can’t find two who are the same, even if they have undetectable levels in their CSF. I suppose each brain adapts differently based on other genetic factors, how quickly the loss occurs, etc.
As for sodium oxybate, this is no wonder drug. I’ve used it myself and the delta sleep it produces is not the same as natural stage 3. It was carefully studied in two groups of non-narcoleptics and they found it did not alter homeostatic N3 drive after an afternoon Xyrem nap vs. a drug-free nap. Makes sense — stage 3 does not naturally come about by bombarding GABA-B. It seems to be rebound effect mostly. Not worth it unless you have refractory drop cataplexy.
Thanks for those comments. Unfortunately the Emory work hasn’t really progressed and others haven’t been able to get the same results with flumazenil so it’s not clear what its role is at the moment.
I like this article but also agree with Michelle regarding the DSM 5 & ICSD-3. It’s strange that the birthplace of IH and the US have different definitions of the disorder. The AASM is updating their definition of IH this year and I hope that the situation will be fixed by basing everything on research. Monosymptomatic never meant short sleep. What I do know is that when we did the update of CRDs this year with the AASM there was an emphasis on what the research corroborated. It’s going to be an interesting change- one I hope will also happen with disorders of hypersomnia and eventually help to influence the DSM 6 & ICSD-4.
For some hypersomnia patients, their symptoms are due to a psychological illness, but for the majority of patients the depression comes after the hypersomnia symptoms and is due to their current situation. It’s fine with me if the DSM 5 wants to include certain forms of hypersomnia but IH, Kleine-Levin syndrome, narcolepsy T1 & T2 and hypersomnias that are due to things like neurological disorders don’t belong in the DSM because they’re not psychological disorders. PWNs have won several battles over this so that narcolepsy was changed to a neurological disorder. I can only hope the same will happen with IH and KLS.
Thanks for those helpful comments Kasha. I agree that DSM 5 and ICSD-3 don’t have it right with regards to hypersomnias. I do like the cluster analysis Michelle refers to as I think that fits a bit better with my clinical experience, but don’t think it is perfect either.
Hi, just wondering if there is any research currently happening around the genetic links for narcolepsy? Myself and my 2 adult daughters have all been diagnosed with this.