Hypersomnia Foundation

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Meet the Doctor, Doctor Lecendreux

Meet Michel Lecendreux, MD, child psychiatrist, University Hospital, Robert-Debré, Paris, France, and newest member of the Hypersomnia Foundation’s Medical Advisory Board.

For those of you who watched the Livestream or attended the Denver Regional Conference in person, you may remember Dr. Lecendreux. He gave a fascinating presentation on what hypersomnia looks like in children and adolescents and told us that hypersomnia is often unrecognized and undiagnosed. He also shared some of his research findings, which indicate that many of these children and adolescents have emotional difficulties, have behavioral or cognitive problems (attention deficit hyperactivity disorder–ADHD–symptoms), have decreased academic performance, become loners, and avoid athletic activities.

Dr. Lecendreux is involved in pediatric sleep research, and he also cares for children and adolescents in the clinic. He is the head of the Pediatric Sleep Centre at Hospital Robert-Debré in Paris. His main fields of interests are sleep, alertness, narcolepsy, and ADHD.

Dr. Lecendreux is one of the directors of the French Reference Center for Pediatric Narcolepsy, Idiopathic Hypersomnias and Kleine-Levin Syndrome in the Department of Neurophysiology and is a member of numerous international sleep societies.

Dr. Lecendreux has written many journal articles, editorials, chapters and books in the area of pediatric narcolepsy, ADHD and sleep and is an editorial board member for the Journal of Attention Disorders. Together with his colleagues, he reported on the role of vigilance impairment in children ADHD and insisted on the role of iron deficiency in the pathophysiology of ADHD. Dr. Lecendreux is also involved in numerous activities, including teaching medicine and education and research on attention disorders at the Faculty of Medicine of Paris.

So now that you know all about Dr. Lecendreux, don’t forget to write into our Ask the Doctor column and ask him questions pertaining to children or adolescents and hypersomnia.

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Dr. Dale Edgar Joins the Hypersomnia Foundation SAB

The Hypersomnia Foundation invites you to join us in welcoming Dale M. Edgar, PhD, as the newest member of our Scientific Advisory Board. Dr. Edgar joins Drs. David Rye, Nicholas Frank, and James Krueger in crafting our research agenda, raising awareness about hypersomnia in the scientific community, and developing our mechanism for reviewing, scoring, and funding the best research on the understanding and treatment of hypersomnia from the brightest young scientists.
Dr. Dale Edgar is an experienced scientist, drug hunter, and entrepreneur, who recently retired as an executive leader at Eli Lilly and Company. He is also a renowned expert in sleep disorders research and development. Dr. Edgar recently cofounded Novion Pharmaceuticals, a start-up neuroscience biotechnology company focused on the discovery and development of novel treatments for sleep disorders, where he is senior vice president of research.

Dr. Edgar previously served as Chief Scientific Leader of Discovery Sleep Research at Eli Lilly and Company – a cross-functional preclinical and clinical R&D function focusing on innovative medicines for sleep disorders and sleep-related comorbidities in psychiatry, pain, neurodegenerative disease, and metabolic disease. Within a year of joining Lilly he was conferred the prestigious title of Lilly Distinguished Research Fellow — the highest honor bestowed upon a scientist at the company. Dr. Edgar’s global multidisciplinary teams—located in the United Kingdom, Singapore, and the United States—delivered numerous compounds from inception to human clinical trials. Later in his career, Dr. Edgar was promoted to Global Head of Science and Technology Partnerships, responsible for the strategy and oversight of consortia, public private partnerships, and academic affairs across the Lilly research enterprise. He served on numerous governance committees, led Lilly’s Post-Doctoral Scientist Training Program, founded the prestigious Lilly Innovation Fellowship Award program, and served as a senior science and technology advisor to the President of Lilly Research Laboratories.

Prior to joining Lilly, Dr. Edgar was Cofounder, Senior Vice President and the Chief Science & Technology Officer of Hypnion Inc—a spin-out of the science and technologies he developed at Stanford University. Dr. Edgar led Hypnion’s preclinical and clinical research teams responsible for the identification and validation of novel pharmacological treatments for insomnia and disorders of excessive sleepiness. Hypnion was acquired by Eli Lilly & Company in April 2007. Prior to founding Hypnion in 2000, Dr. Edgar was Associate Professor of Psychiatry & Behavioral Sciences and Director of the Sleep and Circadian Neurobiology Laboratory in the Sleep Disorders Research Center, Stanford University School of Medicine. During his 15 years at Stanford University, Dr. Edgar achieved international recognition as a leader in sleep and circadian neurobiology and sleep-wake pharmacology. He is well known for his mentorship and training of young scientists and his seminal contributions in sleep and circadian physiology, including the identification of wakefulness-promoting mechanisms controlled by the suprachiasmatic nucleus and opponent processes that modulate physiological sleepiness. Dr. Edgar is also the principal inventor of SCORE™, a family of computerized real-time sleep and physiological assessment technologies and integrated pharmacological database that have greatly accelerated the process of preclinical drug discovery and lead optimization. These technologies are being used to help transform drug discovery at Lilly.

Dr. Edgar is a member of the Harvard Medical School Division of Sleep Medicine Executive Council, the ASPIRE Advisory Committee at Vanderbilt University School of Medicine, and the NeuroNET Advisory Committee at UT Knoxville. He has previously served as an officer of the Sleep Research Society and on Editorial Boards of the journal Sleep and the Journal of Biological Rhythms. He has been the principal investigator of numerous NIH, DOD, and industry partnership grants focused on sleep and circadian neurobiology, pharmacology and phenotyping. He received his master’s degree in biology from San Jose State University while a NASA Graduate Research Fellow at the NASA-Ames Research Center and then received his doctorate in biology/physiology from the University of California. He received postdoctoral training at Stanford University under Prof. William C. Dement. Dr. Edgar has published extensively, has numerous patents in sleep-wake drug discovery, and continues to educate on sleep health awareness and its importance to health care, the economy, and national security.


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What’s New in the Diagnosis and Treatment of Hypersomnia in 2016?

Rather than writing our own article for this week’s edition of SomnusNooze, we are bringing you information from Dr. David Cunnington in Melbourne, Australia. Dr. Cunnington has agreed to share with us a recent post from his website (sleephub.com.au) that covers hypersomnia-related topics from the SLEEP2016 meeting in Denver. A podcast, which covers hypersomnia and other SLEEP2016-related topics, is available at sleephub.com.au/podcast (click on Sleep 2016 Update).

From Dr. Cunnington
In clinical practice it can be difficult accurately diagnosing people with hypersomnia and excessive sleepiness. Apart from narcolepsy with cataplexy, or type 1 narcolepsy, where there are distinct symptoms, and the possibility of testing orexin levels in cerebrospinal fluid, it can be hard to make an accurate diagnosis. Managing people with hypersomnia can also be difficult, as a substantial proportion of people are refractory to treatment with currently available wake-promoting medication.
Issues around diagnosing and treating hypersomnia were discussed at the recent Sleep2016 meeting in Denver, and I’ve tried to summarise some of the main issues that were covered.

Issues With Diagnosing Hypersomnia
The International Classification of Sleep Disorders 3rd Edition (ICSD-3), divides central disorders of hypersomnolence into narcolepsy type 1 (with cataplexy), narcolepsy type 2 (without cataplexy), idiopathic hypersomnia (IH) and then a range of other hypersomnias secondary to medical or psychiatric conditions or medications and the rare condition, Kleine-Levin syndrome.
The criteria for the diagnosis of IH listed in ICSD-3 are:

  • The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months.
  • Cataplexy is absent.
  • A Multiple Sleep Latency Test (MSLT) performed according to standard techniques shows fewer than two sleep-onset REM periods or no sleep-onset REM periods if the REM latency on the preceding polysomnogram was less than or equal to 15 minutes.
  • The presence of at least one of the following:
    • The MSLT shows a mean sleep latency (MSL) of ≤ 8 minutes.
    • Total 24-hour sleep time is ≥ 660 minutes (typically 12–14 hours) on 24-hour polysomnographic monitoring (performed after correction of chronic sleep deprivation) or by wrist actigraphy in association with a sleep log (averaged over at least seven days with unrestricted sleep).
  • Insufficient sleep syndrome is ruled out (if deemed necessary, by lack of improvement of sleepiness after an adequate trial of increased nocturnal time in bed (preferably confirmed by at least a week of wrist actigraphy).
  • The hypersomnolence and/or MSLT findings are not better explained by another sleep disorder, other medical or psychiatric disorder, or use of drugs or medications

Whilst people with narcolepsy type 1 can usually be differentiated from these criteria, narcolepsy type 2 and hypersomnia associated with medical or psychiatric disorders can often overlap significantly with these symptoms. In addition, I often see people with most, but not all, of these symptoms. What do they have? They clearly have a problem, as they have been severely impacted by their symptoms and sleepiness. How much sleep and sleepiness is normal? Some surveys suggest around 8% of people sleep for more than 9 hours per day, and 1.6% of people report sleepiness intruding on their waking activities. One of the tests we commonly use, the MSLT, whilst helpful, can be negative in people with all the other symptoms of IH. In one study, 71% of people with long sleep times and other symptoms of IH had a mean sleep latency of > 8 minutes. In addition, unpublished data from Emory University has shown that around 50% of people with chronic fatigue syndrome meet the MSLT criteria for IH. Other studies have shown that 25% of people with hypersomnia due to psychiatric conditions have an MSL of < 8 minutes.

There really wasn’t any clear consensus on how exactly to define hypersomnias and IH. Unfortunately there are not good biological markers, and trying to make a definite diagnosis based on symptoms is fraught with difficulty. So an approach put forward by the team from Emory and that seems to make sense is to try to exclude other factors that can add to sleepiness symptoms, such as depression and circadian rhythm disorders, as well as getting a number of objective measurements of sleepiness and it’s impact. They do this by performing the below tests and assessments:

Although the team at Emory were testing cerebrospinal fluid levels of GABA potentiation in everyone with hypersomnia at one point, they are not doing this routinely at the moment and have found that people with sleepiness due to other causes such as sleep apnea can also have GABA potentiation, meaning that what they had previously described as a “somnogen” may not be specific for IH, but may in fact be a mediator of sleepiness symptoms in a range of conditions.

Options For People Refractory To Available Treatments

With regard to treatment, we often find people with IH are refectory to treatment, and some groups report around 50% of people on modafinil not persisting with treatment because of a lack of efficacy, and only 30% to 60% of people on dexamphetamine continuing with treatment. Given this, other treatments to address symptoms of sleepiness symptoms are needed.

Clarithromycin – has been used by the team at Emory who published their research in Annals of Neurology in 2015. In that study, they treated 23 people with clarithromycin, and they reported the results on 20 cases using clarithromycin 500 mg twice daily. They did not show changes in reaction time but did show subjective measures of sleepiness were significantly improved. People did get gastrointestinal side effects and changes in taste, so it was not well blinded, so it is a little hard to know exactly how to interpret that, but, nonetheless, this may be a helpful agent.

Flumazenil – has also been used at Emory. At the meeting, they presented their experience with 153 patients they treated between 2013 and early 2015. They administered flumazenil as sublingual lozenges or transcutaneous lotion. Overall, 63% of people felt flumazenil had helped their sleepiness, dropping the mean Epworth Sleepiness Score in the group from 15 to 10.3, and 39% of people remained on treatment at the end of the observation period, which was an average of 7.8 months. Interestingly, one of the predictors of clinical response was the presence of significant sleep inertia, with 72% of those with sleep inertia getting a good response versus 42% of those without sleep inertia.

Sodium oxybate (Xyrem) – is another treatment that was discussed for sleep inertia, which can be one of the most difficult symptoms to manage in people I see with hypersomnias. Whilst Xyrem is most commonly used in treating narcolepsy, Isabelle Arnulf from Paris has treated a number of people with IH with sodium oxybate. Their results, published in Sleep Medicine in 2016, showed that it can reduce morning sleep inertia and probably had a greater effect on this than on overall sleepiness symptoms.

JZP-110 – is a compound being developed by Jazz Pharmaceuticals that has both dopaminergic and noradrenergic activity. In two small clinical trials with a total of 126 subjects, it has been shown to increase the MSL on a Maintenance of Wakefulness Test by 8.9 minutes. This may not sound like much, but, in comparison, in the sentinel modafinil studies, MSL increased by 2.3 minutes, and, for dexamphetamine, there is a 5.6-minute change. So, at this stage, results for JZP-110 look promising, and it appears to be significantly more effective than modafinil or dexamphetamine. Larger phase 3 trials, aiming to enroll more than 800 subjects with sleepiness started in mid 2015, and results are expected at the end of 2016.

Non-drug treatments – There is increasing acknowledgement that medications only partially address symptoms of sleepiness and that there is a role for psychological and behavioural treatments to reduce the impact of symptoms in people with hypersomnias and other conditions that cause sleepiness. For people with narcolepsy with cataplexy, napping has long been used as a strategy, but for people with IH, napping as a strategy often doesn’t work, as they can’t have short naps and have significant sleep inertia on waking from naps. Research on behavioural strategies to help manage symptoms of sleepiness is now being undertaken, and I had a chance to talk with Assistant Professor Jason Ong about it at the meeting in the following interview: Sleep Talk: Episode 8 – Sleep 2016 Update.

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