Hypersomnia Foundation

Hypocretin Level as a Biomarker in KLS

Background: Kleine-Levin syndrome (KLS) is a rare disorder in which affected people experience episodes at least once per year during which they sleep for at least 11 hours out of every day (but often for days at a time), eat excessively (megaphagia), have abnormal thinking and behavior, and hypersexuality. Between episodes, their alertness, behavior, and thinking are normal.

Both the International Classification of Sleep Disorders and the Diagnostic and Statistical Manual of Mental Disorders include criteria to diagnose KLS, but there are no biomarkers—no substances in the body that can be measured—that can help doctors in making the diagnosis of KLS. Some scientists who study KLS think that KLS is caused by something in the immune system that makes the part of the brain called the hypothalamus not work properly. Nerve cells (neurons) in the hypothalamus produce two neurotransmitters, hypocretin and histamine, that are involved in regulating alertness, feeding, and neuroendocrine and autonomic function.

Who Were the Researchers?
Dr. Yves Dauvilliers and his colleagues in Montpellier, France, have a large sleep clinic in which they specialize in the treatment of various forms of hypersomnia.

Who Were the Research Subjects?
This research was performed on two males aged 13 and 16 years with typical symptoms of KLS.

What Did The Researchers Do?
The researchers performed lumbar punctures and removed cerebrospinal fluid (CSF) in the subjects during the KLS episodes and when the subjects were not having symptoms. In the laboratory, they measured levels of histamine, hypocretin, and a major metabolite (a substance that is the result of the breakdown) of histamine, called tele-methylhistamine (t-MHA) in the CSF samples.

What Were the Results of the Study?
When tested between KLS episodes, both subjects had normal levels of hypocretinhistamine, and t-MHA. However, when tested during the KLS episode, the hypocretin level of the subject with more severe symptoms decreased to a level typically found in people with Type 1 narcolepsy. The other patient’s hypocretin level decreased by 42% from his level obtained between the KLS episodes, but it did not fall below normal levels. The histamine level of the subject with more severe KLS symptoms dropped twofold when he was having symptoms, as compared with when he was not. The other subject did not have a change in histamine levels when his levels during and between episodes were compared. Neither had a change in t-MHA levels.

What Did The Authors of the Paper Conclude?
“Evidence of reversible changes in CSF hypothalamic biomarkers in a typical patient with KLS reinforces the hypothesis that KLS episodes may be caused in some patients by recurrent functional alterations of the hypothalamus. Further longitudinal studies including a larger number of patients are needed to more accurately determine the diagnostic value of measuring CSF hypocretin-1 in KLS patients during acute periods and to assess relationships between abnormal behavior, potential dysautonomia, functional neuroimaging, and CSF hypothalamic biomarkers in and out of symptomatic episodes.”

What Does This Mean for People With KLS?
The results of this study indicate that hypocretin levels in the CSF appeared to correlate with KLS episodes in these two patients and may, therefore, serve as a biomarker of KLS. However, additional larger studies are needed to support this finding.

Lopez R, Barateau L, Chenini S, Dauvilliers Y. Preliminary results on CSF biomarkers for hypothalamic dysfunction in Kleine–Levin syndrome. Sleep Med2014; Oct 22. Epub ahead of print.

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Does modafinil improve sleepiness in people with IH without long sleep time?

In Europe, modafinil used to be available as a treatment for the excessive daytime sleepiness (EDS) associated with idiopathic hypersomnia (IH). However, in 2010, the European Medicines Agency (EMA, the equivalent of the Food and Drug Administration [FDA] in the United States) changed the labeling, and the drug is now approved for use only in narcolepsy. Amphetamines are available in Europe for the treatment of excessive daytime sleepiness (EDS), but are not labeled for treatment of sleepiness associated with IH in any European country.

Who were the researchers?
Mayer and the other researchers were from three different research institutes in Germany.

What was the purpose of the study?
The primary aims of this study were to assess changes in sleepiness using theEpworth Sleepiness Scale (ESS) and the Maintenance of Wakefulness Test (MWT). The secondary aims were to measure changes in the Clinical Global Impression (CGI) rating scale (item: severity of illness), laboratory tests, and vital signs and to measure the number and type of adverse events, number of unintended daytime naps, and responder rates (defined as ESS scores ≤10 at final visit on medication).

What was the study design?
This was a double-blind, randomized, placebo-controlled study.  Patients in the active medication group received modafinil, 100 mg in the morning and 100 mg at lunch.

Who took part in the study?
Thirty-three patients with IH without long sleep who were older than 18 years, had IH for more than 2 years, had an onset of IH symptoms between the ages of 10 and 30 years, had a Beck Depression Inventory score of less than 16, and had more than 110 pg mL-1 of hypocretin-1 in cerebrospinal fluid (if this measurement was performed) originally agreed to take part in the study. One subject did not complete the study and one was ruled ineligible, leaving 31 patients who completed the study (17 received modafinil and 14 received placebo).

What did the research subjects do?
The research subjects stopped taking their usual medicines for at least one week and then completed the ESS during the baseline visit (V2), day 8 (V3), day 14 (V4), and day 21 (V5). They also completed the MWT during visits V2, V3, and V5, and kept a sleep-wake diary throughout the study. In the morning and at noon, they took either placebo or 100 mg of modafinil for three weeks and then no medication for one week.

What did the researchers do?
At V2, V3, V4, and V5, the researchers completed the CGI. At the end of the study, they calculated the difference between baseline values and end-of-treatment values for the sleep latency on the MWT, the ESS scores, and the CGI scores for each patient.

What were the results?
Compared with placebo, modafinil reduced daytime sleepiness significantly, as measured by the ESS (modafinil: > 5 points vs placebo: 1.8 points). The sleep latency according to the MWT did not improve significantly in the modafinil or placebo groups (the difference between sleep latency on V2 and V5). The results of laboratory tests and vital signs did not change throughout the study and did not differ between the modafinil and placebo groups. The CGI severity-of-illness score changed significantly more in the modafinil group from baseline to V5 than in the placebo group. According to the data from the sleep-wake diaries, performance and exhaustion improved significantly at weeks 2 and 3 in the subjects who received modafinil, with no changes in these scores in subjects who received placebo, and the number of reported naps and duration of daytime sleepiness decreased significantly.  Subjects in the modafinil group and placebo group were equally likely to experience at least one side effect, but headaches and gastrointestinal distress were more commonly experienced by subjects taking modafinil.

Mayer G, Benes H, Young P, Bitterlich M, Rodenbeck A. Modafinil in the treatment of idiopathic hypersomnia without long sleep time-a randomized, double-blind, placebo-controlled study. J Sleep Res. 2014 Sep 5. doi: 10.1111/jsr.12201. [Epub ahead of print] PubMed PMID: 25196321.

This study was funded by Cephalon GmbH, Germany, the maker of modafinil.

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Submission to the FDA’s Regarding Hypersomnias

On September 24, 2013, the US Food and Drug Administration (FDA) held a public meeting to solicit information on the impact of narcolepsy on affected individuals’ daily lives and the effect of currently available medication on their disease symptoms. A summary of that meeting, “The Voice of the Patient Report—Narcolepsy,” is available on the FDA’s web site.  After the meeting, the FDA asked for additional input as part of its Patient-Focused Drug Development Initiative. This initiative is designed to ensure that the FDA pays proper attention to developing drugs for conditions that affect Americans. On behalf of the Hypersomnia Foundation, Drs. David Rye and Lynn-Marie Trotti from Emory University submitted the following letter to the FDA highlighting the need for additional attention to, and clear unmet needs among patients with, hypersomnia but not classic Type 1 narcolepsy.

RE:  FDA  DOCKET# –  2013-N-0815

We are clinician scientists board certified both in Sleep Medicine and Neurology with a combined 30 years of clinical experience that includes a particular focus on narcolepsy and related disorders collectively referred to as the “central hypersomnias”.  We are well published in the area and regularly participate in the annual patient conferences of the Narcolepsy Network.  We join with our patients in thanking you for your effort to reach out for input regarding the disease state(s) and especially the unmet needs of the patients who we treat. Having viewed the webcast of the recent September 24th public meeting on narcolepsy patient-focused drug development, we would like to add our voice to those of others.

Excessive daytime sleepiness remains common and the socioeconomic burden to the individual, family, and society is large.  Unfortunately, while routine sleep laboratory testing for genuine narcolepsy with cataplexy is sensitive, it is becoming clear that it is highly nonspecific.  The electrodiagnostic criteria for narcolepsy, for example, are satisfied by 2.5-4.0% of the general population 1,2, and even higher proportions of patients with comorbid sleep apnea, Parkinson’s disease, and end-stage renal disease.  Narcolepsy with cataplexy is caused by loss of the wake-promoting excitatory peptide hypocretin and manifests as discontinuous wake and sleep, abrupt transitions from wake to sleep, restorative naps, and the overt expression/experience of dream sleep phenomena such as cataplexy. What it is not associated with is hypersomnia – i.e., a condition characterized by abnormally long or frequent periods, or abnormal depth, of sleep.  Narcolepsy with cataplexy affects 1 in 2,000-4,000 individuals, and is the prototypical sleep disorder which medical students and physicians are first introduced to, and how they learn sleep biology.  There is therefore a deep rooted propensity to approach and treat any complaint of sleepiness as a loss-of function problem.  Conventional psychostimulants, newer wake promoting agents, and drugs in development to treat the excessive daytime sleepiness ofnarcolepsy” are purposefully targeted to restore wake by way of enhancing neural pathways downstream from hypocretin.   In summary, a perfect storm is brewing for the overdiagnosis of “narcolepsy” and a real potential for the over prescribing of medications for its treatment.

With this background, we were not at all surprised to hear a number of presumed “narcolepsy” patients (and others at your April patient conference on Chronic Fatigue Syndrome) speak about the unmet clinical need that hypersomnia represents.  Despite feeling physically awake, we have heard innumerable stories of persistent cognitive problems and “brain fog” from hypersomnic patients prescribed conventional psychostimulants or wake promoting agents. Compelled by clinical intuition that these patients were not suffering from any loss in function (and finally brave enough to challenge a conventional wisdom that had even influenced our personal practice preferences for at least a decade), our team has recently shown, that a majority of patients suffering from hypersomnia do so because of an apparent gain in function in inhibitory GABAA receptor signaling due to a peptidergic somnogen3.  In this instance sleep is long, continuous, and unrefreshing, and followed by a transitional state of impaired consciousness termed “sleep drunkenness”.   Such a prolonged state of stupor that follows upon sleep has never been operationalized and its neural substrates remain ill-defined.  Thus, diagnostic means to differentiate the symptom of hypersomnia as part of, or distinct from, diagnoses such as narcolepsy without cataplexy, idiopathic hypersomnia, long sleeper syndrome, and depression and even chronic fatigue syndrome, and rational and effective treatments, have not been forthcoming.  The benzodiazepine antagonist flumazenil, which has little-to-no wake promoting actions in non-sleepy controls, reverses GABA enhancement in vitro, and normalized vigilance in seven of seven hypersomnic patients 3. Our serendipitous discovery that the macrolide antibiotic clarithromycin is also an antagonist at GABAA receptors, provided a rationale for its successful use in the central hypersomnias, where sustained improvements in vigilance were observed with off-label use 4, as well as in a double-blind, placebo-controlled, cross-over trial in 20 patients 5.

In summary, our experience in evaluating and treating nearly 500 patients with central hypersomnia would suggest that there is a well-defined group of genuine, hypocretin deficient, non-hypersomnic patients with narcolepsy who generally do quite well with the existing approved treatments.  The same can not be said of hypersomnics.   The prevalence remains ill-defined, but we are confident that it is greater than “rare” as stated in review articles and texts (we estimate a prevalence of at least ~ 1:800).  And, hypersomnia can be extraordinarily disabling.  In one-third of patients with hypersomnia, the magnitude of enhancement of GABA’s sleep-inducing effects is equivalent to: a) 5 mg of Versed®; b) a blood alcohol content of 0.10; and c) the psychomotor slowing that emerges after 30 hours of continuous wakefulness3.  We feel for these patients.  They are not simply “seized by sleep” as the narcoleptic with cataplexy, they are literally and figuratively consumed and transformed by it.  Many whom we have evaluated and treated are refractory to conventional wake promoting agents or experience intolerable side effects.  Strategies aimed at inhibiting sleep as opposed to promoting wake would appear more rational in that they would be targeted closer to the underlying pathophysiology.  In our hands such an approach to treatment continues to demonstrate remarkable and truly life altering results.

We hope that our perspective better informs the FDA in their future assessments of treatments being developed for narcolepsy versus hypersomnia.  Our ultimate desire is a more efficient means to diagnosis so that more rational and effective treatments can be instituted sooner, more knowledgeable about the risk-benefit ratios and cost.


1.   Singh, M., Drake, C. L. & Roth, T. (2006). The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 29, 890-5.

2.  Mignot, E., Lin, L., Finn, L., Lopes, C., Pluff, K., Sundstrom, M. L. & Young, T. (2006). Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults.[see comment]. Brain 129, 1609-23.

3.   Rye, D. B., Bliwise, D. L., Parker, K., Trotti, L. M., Saini, P., Fairley, J., Freeman, A., Garcia, P. S., Owens, M. J., Ritchie, J. C. & Jenkins, A. (2012). Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Science Translational Medicine 4, 161ra151.

4.   Trotti, L., Stout, A., Saini, P., Freeman, A., Jenkins, A., Garcia, P. & Rye, D. (2012).  Clarithromycin reduces sleepiness and improves vigilance in patients with central nervous system hypersomnias. Sleep 35, A278.

5.   Trotti, L., Saini, S., Freeman, A., Bliwise, D., Jenkins, A., Garcia, P. & Rye, D. (2013). Clarithromycin for the treatment of hypersomnia: A randomized, double-blind, placebo-controlled, crossover trial. Sleep 36, A248.

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The Long and Sleepy Road: A Parent’s Perspective



It’s been a long and interesting road. Growing up in the Dakotas, Trevor was an athletic, outgoing, energetic boy. He played soccer and hockey, enjoyed hanging out with his buddies, and was a great student. In retrospect, we noticed a few strange things about his sleep habits. He could fall asleep at a moment’s notice, even in a loud crowd of children’s roughhousing and a noisy television. Many times we had difficulty waking him. Even so, Trevor was a relatively normal, active boy.

At 9, Trevor started showing the beginnings of something not normal. We starting having trouble getting him to hockey practice—something he loved to do. After spending a day in school, he would be so exhausted that he would nap—for hours. If we could get him to practice, when he would return home, he would immediately go to sleep. We wrote this off as growing pains—he had a major growth spurt over a few months’ time.

In middle school, his sleepiness started to be more noticeable. Once, after playing hockey out of town, he asked to go to the car and take a nap while we stayed to watch the other team play. Two hours later, when the other game was done, we went to the car and found Trevor asleep with the doors locked. He had the keys. We couldn’t wake him. Finally, after getting the assistance of three of the coaches, we were able to rock the car enough to awaken him. Something was not right. We talked to our doctor who shrugged it off, even though sleep disorders run in the family.

His sister became very concerned and suggested that Trevor have a sleep study before he started high school. Our doctors refused to do a sleep study prior to Trevor turning 15 years old. In November, when he turned 15, we found a pulmonologist/sleep specialist locally to complete a sleep study. We took Trevor to the sleep lab, where he completed both an overnight study and a daytime Multiple Sleep Latency Test (MSLT). The overnight test showed no abnormalities; however, the MSLT was a different story. Trevor fell asleep almost immediately and was in rapid eye movement (REM) sleep in less than four minutes. Based upon these results, the pulmonologist diagnosed Trevor with severe hypersomnia/narcolepsy without cataplexy. His prescribed treatment included morning and afternoon stimulants (amphetamine and dextroamphetamine—Adderall). We thought, “At last, some relief.”

Trevor joined his regular hockey team about a month after the diagnosis. The stimulants negatively impacted his endurance and breathing. We worked with the pulmonologist to adjust the medications to provide some relief. In January, Trevor’s world came crashing down. He suffered two concussions over a period of one week. He was now also seeing an orthopedic concussion specialist to help him recover. He compared Trevor’s baseline impact test to a current test—Trevor’s results showed significant impairment. Both doctors discussed his recovery path, and they decided that we should take Trevor to a neurologist for treatment.

Nearly a year later, Trevor was cleared from the concussion but was still struggling with his sleep and memory. The neurologist didn’t like Adderall for Trevor’s treatment and prescribed modafinil instead. This was a disaster—Trevor did not respond at all to modafinil. He spent much of the summer in bed, extremely tired and lethargic. Eventually, Trevor requested to switch back to Adderall. At this point, the neurologist became frustrated with Trevor and us. He ordered an MRI—normal; he ordered two separate depression tests—normal. As a family, we felt this doctor was not helping Trevor. We went back to the concussion specialist after an issue Trevor had early in the next hockey season. The concussion doctor ordered neuropsychological testing to measure Trevor’s brain activity and processing capabilities. Through this testing, we discovered some significant deficits in Trevor’s memory and cognitive ability. The concussion specialist suggested that we find another sleep disorder doctor.

After searching the area, making hours of phone calls, gaining approval from the insurance company and asking numerous questions, we found a doctor in Omaha, NE, who thought that he could help. Once we arrived, it became very apparent that this clinic, and this doctor in particular, had no experience with severe cases. Once again, the search continued. We took Trevor to a clinic in the Midwest, where he was accepted for treatment by a nationally known pediatric sleep disorder specialist. The doctor ordered several tests, including a tilt-table test, blood work, and an actigraph. We returned home with an appointment one month later to get the results of the actigraph. Ultimately, the doctor diagnosed Trevor with circadian rhythm disorder in addition to his previous hypersomnia/narcolepsy diagnosis. Trevor was prescribed light-box treatment along with melatonin to assist with his sleep. After this diagnosis, Trevor was sent to a neurologist within this same institution because of the previous concussion to determine if there were any residual effects. This doctor ordered an electroencephalogram (a test that measures brain waves), which came back normal. We asked for a second opinion from another doctor at the same clinic, who prescribed sodium oxybate and removed melatonin from the prescription. Trevor had a bad reaction to sodium oxybate, and we removed it from his treatment. This institution gave up on Trevor, and we gave up on them. Back to square one.

After attempting to work with another local sleep specialist, we were grasping for answers. We contacted Narcolepsy Network, who informed us of two doctors that we should attempt to see. They highly recommended that Trevor get an appointment with Dr. David Rye in Atlanta, GA—they felt that he could help. We contacted Dr. Rye’s office, and they asked that we forward all information and documentation collected during his treatments. Dr. Rye accepted our request and scheduled an appointment with Trevor for a Friday afternoon. We made the 22-hour drive to Atlanta. Dr. Rye evaluated the documentation and then spent a couple of hours visiting with Trevor and our family. He had each of us complete the “reaction box” test. He diagnosed Trevor with idiopathic hypersomniaIH. At last, some hope.As a family, we have spent countless hours helping Trevor understand his diagnosis. Since the diagnosis, Trevor has graduated from high school. He was able to hold a part-time summer job, working in production with a local sports team. His daily struggles with sleepiness continue, but Trevor is learning his limits and is taking control of his medicine. Although he had to give up playing hockey, he has become one of the best young hockey referees in the state, allowing him to give something back to the sport that he loves. Trevor plans to attend college sometime in the near future—we are working to find a way for him to have a chance to succeed. Even as we are trying to find a way for Trevor to have successful treatment now, he looks forward to advances in treatment for IH—that one day he can return to a more normal existence.

Randy and Nancy Preston – South Dakota

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2015 Hypersomnia Conference Registration is Now Open!

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The 2015 Hypersomnia Conference Registration is now open.  Won’t you join us at this special event?

The 2015 Hypersomnia Foundation (HSF) conference to be held Friday July 17, 2015 – Saturday July 18, 2015 at the Emory Conference Center Hotel

1615 Clifton Road, NE

Atlanta, Georgia 30329

HSF is dedicated to educating, advocating, and resourcing so that people with Hypersomnia can live optimal and fulfilling lives.  The goal for this conference is to play a key role in helping people with Hypersomnia, their supporters, medical professionals, and scientists in the field increase their understanding of Hypersomnia.  The Conference provides the opportunity to learn about the latest in Hypersomnia research and treatments and offers a forum for discussion among professionals concerned with Hypersomnia.

For more information about the conference and to register to attend this special event, click here.

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The Hypersomnia Foundation’s 501 (c)(3) status has been approved!

We are so excited?! We have great news, and we want you to be the first to know. The Hypersomnia Foundation received a letter from the Internal Revenue Service stating that we have met all of the requirements to be a charitable organization. That’s right. The IRS has officially APPROVED the Hypersomnia Foundation’s 501(c)(3) status!  

Not only are we exempt from paying federal income tax, but contributions made to the Hypersomnia Foundation by individuals and corporations are deductible under Code section 170. You will want to check with your tax advisor, but, basically, this means that any donations made to the Hypersomnia Foundation on or after January 21, 2014, are tax deductible to the extent allowed by law.

See our recent Newsletter for more details

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The Hypersomnia Foundation has submitted our 501(c)(3)!

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Read our latest Newsletter by clicking on this link.



Topics included in this Newsletter include:

  • Our 501(c)(3) has been submitted
  • 2015 Hypersomnia Conference Announcement
  • The Hypersomnia Foundation’s current initiatives
  • Our social media links
  • 2014 Hypersomnia Conference DVD Order Form

Want to make sure you our next Newsletter comes to your inbox?  Subscribe to our Newsletter here.

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2014 Hypersomnia Conference DVD Set is Now Available to Order!

DVD Case 3D Front Cover


Click HERE to order your 2014 Hypersomnia Conference DVD today!

On March 8, 2014, the first Hypersomnia Conference was held in Atlanta, Georgia.  Featured guest speakers included;

David Rye, MD, PhD, Professor of Neurology at Emory University
Lynn Marie Trotti, MD, MSc, Assistant Professor of Neurology
Andrew Jenkins, PhD, Associate Professor of Anesthesiology
Lloyd Johnson, Living with Hypersomnia Founder

This DVD was created for you by an all volunteer staff and includes a 3 disc set in a limited edition DVD case. The 3 disc set includes all 10 sessions from the 2014 Hypersomnia Conference. If you were able to attend the conference, this is a great way to experience it all over again. If you were not able to attend the conference, this is a great way to hear cutting edge information pertaining to underlying causes of and treatments for Hypersomnia.

DVD cost is $35.00 (per DVD set) plus $5.00 shipping in the US and $15.00 shipping outside of the US. Increased shipping charges may apply for those ordering multiple DVD’s.  100% of the proceeds from the DVD sales will go to the Hypersomnia Foundation.

After completing this form, you may expect an invoice to be emailed to you. This invoice will include your shipping charges. Once the invoice is paid (via PayPal or credit card), you will be placed in line for shipping.  Please allow 2 weeks for delivery.   There are a limited number of DVD sets available so be sure to support the Hypersomnia Foundation by ordering your copy today!

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