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Research is Critical and Ongoing

YOU COUNT!

Time to update CoRDS information!

Please make time to log into the CoRDS online portal and keep all of your information up to date. Not only is it important to keep your information up to date in case researchers would like CoRDS to contact you, but it also helps potential researchers monitor the progression of rare diseases and rare disorders.

Every bit of information you can share, and keep updated, helps the rare community move one step toward solving the puzzle both now and in the future.

Visit http://www.sanfordresearch.org/cords/ and click “Update Your Registry” on the left side of the page.

Read the full annual update reminder here: CoRDS Annual Update Reminder

Posted in: CoRDS Registry, Research, SomnusNooze

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Let Sleep Researchers Know What’s Important to YOU

HF urges the entire hypersomnia community, including people with IH, people with narcolepsy, all supporters and healthcare professionals, to take a short survey prepared by Project Sleep in partnership with the University of Arizona “to capture perspectives of the narcolepsy and hypersomnia community.”

Julie Flygare of Project Sleep notes, “…we hope it will be useful to help illustrate to the sleep researchers what PATIENTS’ research priorities are and how they may differ from their preconceived notions of what’s important – and hopefully spark some new collaborations between patient leaders and organizations and researchers.”

After we posted the link on our HF Facebook page, followers weighed in on the survey, commenting that it takes only about ten minutes to complete. Note that the deadline for completing the survey is May 17th.

To read more, and to take the survey:

http://project-sleep.com/narcolepsy-research-survey/

Posted in: narcolepsy, Research

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Rare Disease Day: Research Brings Hope – My CoRDS Experience

Research Brings Hope – My CoRDS Experience

On February 28, 2017, the Hypersomnia Foundation (HF) joins with all those participating in Rare Disease Day supporting the slogan, “Research Brings Hope to People Living with a Rare Disease.”

On Rare Disease Day, through social media and our SomnusNooze newsletter, the HF once again encourages the entire hypersomnia community, including anyone with a central disorder of hypersomnolence (idiopathic hypersomnia, narcolepsy type 1, narcolepsy type 2, and Kleine-Levin syndrome), to help us get #BeyondSleepy by registering and completing the CoRDS registries. This is also a perfect opportunity for those who have already completed the registry to consider reviewing and updating their information if needed.

“When the CoRDS Hypersomnia Foundation patient registry debuted last year, I was incredibly excited about the opportunity to personally contribute to primary hypersomnia research. As a person with Idiopathic Hypersomnia, my energy, especially my cognitive energy, is extremely limited. This can make tasks like filling out a registry database quite difficult. However, it’s exactly the severity of my symptoms and the lack of effective treatments for and knowledge about the primary hypersomnias that make this registry so necessary.

Thankfully, the registry is set up so that you can easily complete it in small pieces, taking breaks whenever you need. You can even skip questions and come back to them later (just make sure you note the question number). Check out more helpful tips and FAQ at http://www.hypersomniafoundation.org/registry/.

I strongly encourage every single person with Narcolepsy, KLS, and Idiopathic Hypersomnia to push through their brain fog/sleepiness/exhaustion and prioritize contributing to this critically important database. Together we can dramatically increase knowledge of and treatment options for these devastating illnesses.”

Michelle E.

CoRDS is a centralized international patient registry for all rare diseases and has partnered with the NIH’s GRDR (Global Rare Disease Registry) program: https://ncats.nih.gov/grdr/partners.

For researchers to make advances in understanding and treatment of hypersomnia disorders, they need data. By completing the registry questionnaire, you are making a very valuable contribution to this cause. Learn more about the registry and how to sign up here:
http://www.hypersomniafoundation.org/registry/

People who have completed the registry also have this to say about their experience:

“In preparation for completing the Hypersomnia registry survey with CoRDS, I gathered as many of my medical history documents as possible. I reviewed these documents thoroughly, so that I knew what information I had and where it could be found before beginning the survey. I found this to be incredibly helpful. The survey is a bit lengthy, so being organized and understanding my personal data beforehand allowed me to complete the questions without becoming overwhelmed. Participating in this registry is an easy and effective way for all of us to contribute valuable information for the advancement of research on Hypersomnia.”
Amy H.

“I signed up with CoRDS and did the hypersomnia registry because I knew it was important to get my information out there for the doctors and researchers who are working on finding a treatment for this horrible disease. It only took a few minutes to register, but the survey itself took quite a bit of concentration that is difficult for someone with IH. I filled it out in little bits and whenever I felt I had enough energy I would go back to fill out a few more questions. I hope that my info will help in some way. If it does, then the time and energy was worth it!”
Dustin H.

If you have any questions, difficulties, or concerns while completing the CoRDS registries, please feel free to contact them at cords@sanfordhealth.org or call 877-658-9192.

If you have completed the CoRDS registries and want to share your experiences and advice with others, you can send them to us at: http://www.hypersomniafoundation.org/understanding-hypersomnia/share-your-journey/.

Posted in: Awareness, CoRDS Registry, Research

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Flumazenil for the Treatment of Refractory Hypersomnolence

Background

In 2012, researchers from Emory University published a paper on their finding of a substance that increases the effectiveness of GABA in people with central disorders of hypersomnolence, particularly idiopathic hypersomnia. In that paper, they discussed their findings in seven patients who were treated with flumazenil. In 2014, Kelty et al published a case report on the use of flumazenil given intravenously to a single patient for 96 hours and then implanted under the skin. The current paper from the group of Emory researchers includes information from additional patients who were treated with a compounded version of flumazenil.

What kind of a study was this?

This was a retrospective study, meaning that the researchers did not set out ahead of time to perform a research study with predetermined goals and questions. Instead, two neurologists prescribed the medication, flumazenil, as part of their routine practice to all appropriate patients who came to their clinic. Then, at a later date, they formulated their questions.

Who were the patients and what did they do?

One hundred fifty-three patients (92 women) were prescribed flumazenil by the physicians at Emory.
sleepy
Their average age was 35.5 years. All of the patients completed the Epworth Sleepiness Scale (ESS) before starting treatment with flumazenil, and some patients completed a second ESS after starting treatments.

Who were the researchers and what did they do?

Dr. Trotti and her colleagues at Emory University reviewed the charts of their patients with hypersomnolence for whom they had prescribed flumazenil. They also reviewed the patients’ electronic correspondence and pharmacy records.

What were the results of the study?

Ninety-six of the 153 (63%) patients reported that they were less sleepy after taking flumazenil. On the other hand, 19 people reported that they were more sleepy after taking flumazenil. Among these 19 patients, nine continued taking flumazenil because the increased sleepiness was only temporarily worse right away after taking the medication or the sleepiness improved after the flumazenil dose was changed.

Before starting treatment, the average ESS score was 15.1, even among those who were taking wake-promoting agents. After starting treatment with flumazenil, the average ESS score dropped to 10.3 among the 40 people who reported improved sleepiness and who completed a second ESS.

awakeOf the 96 patients who reported that their sleepiness improved in response to treatment with flumazenil, 59 continued to take the drug long term (average, 7.8 months at follow-up). Interestingly, 72% of women reported a positive response to the drug, whereas only 48% of men had a positive response. Similarly, people who reported having sleep inertia (difficulty waking up, including grogginess or disorientation immediately upon awakening) were more likely to respond to flumazenil, as compared with those without sleep inertia (72% vs 42%).

Seventy-nine participants (52%) reported experiencing an adverse event (the most common being dizziness, anxiety, and headache), with 17 people stopping the medicine because of adverse events. Two patients had serious adverse events, and another had changes in liver function tests that resolved after stopping the drug.

What were the researchers’ conclusions?

According to the authors of this study, “In summary, our clinical experience in a large group of patients with treatment-refractory hypersomnolence demonstrates meaningful and sustained clinical response in a substantial fraction of patients. Important questions remain about optimal formulation, dosing, long-term safety, and effectiveness. Prospective, controlled studies, ideally with measurement of plasma or cerebrospinal fluid flumazenil levels, are clearly needed. However, our experience suggests the possibility of clinical use of flumazenil in carefully selected, severely affected patients lacking other treatment options.”

Trotti LM, Saini P, Koola C, LaBarbera V, Bliwise DL, Rye DB.  Flumazenil for the treatment of refractory hypersomnolence. J Clin Sleep Med 2016;ePub ahead of print.

Posted in: Flumazenil, Hypersomnia, idiopathic hypersomna, Research

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Hypersomnia Research-Where We Are And Where We Are Headed

During the presentation by David Rye, MD, PhD titled “What are the latest developments in research on idiopathic hypersomnia?” at the Beyond Sleepy in the Mile-High City Hypersomnia Conference, he pointed out that, while on the one hand without a known biological biomarker there is a large unmet clinical need for people with idiopathic hypersomnia, on the other hand a growing awareness garnering increasing interest and recognition within the medical community is gaining momentum.

Following is an abbreviated summary of his talk prepared by Dr. Michelle Emrich.  As Dr. Rye had mentioned this is not an all-inclusive list but specific highlights of recent development in research, collaboration, and treatments of idiopathic hypersomnia:

  • In the fall of 2016 The Emory University sleep research team and collaborators anticipate applying for a newly announced FDA orphan products natural history grant that has the possibility to yield $400,000/yr of additional financial support for up to 5 years.
  • Nearly half of chronic fatigue syndrome patients meet MSLT criteria for IH. Data not yet published. Population based control MSLTs (n=1019) summarized courtesy of E. Mignot vs. CFS (n=46) from Wichita, KS (Reeves WC, et al BMC Neurol (2006); 6:41).
  • Studies of non-sleepy controls indicate that nearly ¼ (22%) are asleep by 8 minutes, which demonstrates that MSLT based criteria of ≤ 8 minutes put forward by the International Classification of Sleep Disorders (ICSD) is poor at discriminating IH from controls (i.e., it is a “poor” test in lacking specificity).
  • 71% of IH with long sleep have MSLT > 8 min (i.e. considered to be normal), showing that MSLT based criteria also have poor sensitivity for rendering a diagnosis of IH (C Vernet and I Arnulf, Sleep (2009)).
  • A “cluster analysis” (i.e., unbiased probing for the degree of commonality ofsymptoms) by Sonka, Susta and Billiard suggests that IH and Narcolepsy Type 2 (NT-2) share more similarities than differences. (Narcolepsy with and without cataplexy, idiopathic Hypersomnia with and without long sleep time: a cluster analysis.  Sleep Medicine 16(2):225-31).
  • Dr. David Plante (U. Wisconsin) is continuing his work looking at hypersomnia in affective disorders (e.g., depression and bipolar disease). Sleep propensity in psychiatric hypersomnolence: a systematic review and meta-analysis of MSLT findings.  Sleep Medicine Reviews – in press (2016).
  • Dr. Plante has a five-year K23 training grant from the National Institutes of Health (NIH). Research
    • Aim #1: to probe for deficits in slow wave electroencephalogram (EEG) activity in depression with hypersomnolence as standard sleep variables demonstrate increased sleep duration with normal efficiency in major depressive disorder (MDD) with comorbid hypersomnolence.
    • Aim #2: increased EEG slowing during wakefulness. Global reductions in pre/post sleep waking theta frequency band in MDD without hypersomnolence (relative to controls and hypersomnolent group).
    • Aim #3: Investigate slow wave induction as a treatment strategy. Subject recruitment is planned for Fall 2016.
  • Dr. Plante has also been successful in getting a strategic research award from the American Sleep Medicine Foundation (ASMF) to test the usefulness of a multidimensional assessment in improving the evaluation and treatment of hypersomnolence. Questions he’ll be looking at with this research award:
  1. Do novel objective hypersomnolence measures incorporated into routine MSLT workflows capture aspects of hypersomnolence not quantified by current standards?
  2. Is the Hypersomnia Severity Index a valid subjective measure in patients referred for evaluation of suspected CNS disorders of hypersomnolence? This is a new index he’s developed.
  3. Do novel objective measures of sleepiness and the Hypersomnia Severity Index faithfully capture improvement with treatment?
  • Dr. Lynn Marie Trotti (Emory University) also has been awarded a K23 training grant from the NIH relevant to IH and hypersomnia.
    • Aim 1: Define functional neuroimaging signatures of pathological sleepiness of different etiologies (IH vs. Narcolepsy Type 1 during WAKE). She anticipates unique signatures by disease state diagnosis in FDG-PET regional hypo- metabolism. She hypothesizes that in the resting state functional magnetic resonance imaging (fMRI) will reveal increased connectivity within what has been termed the brain’s “default mode network” (DMN) whereas portions of this brain circuit will deactivate when subjects perform a simple cognitive task (N-back). Diffusion Tensor Imaging (DTI) – decreased fractional anisotropy will also be explored. Aim 2: Brain circuits underlying the symptoms of sleep drunkenness in IH will be explored with similar imaging modalities.
  • Dr. Andy Jenkins’ (Emory University Depts. of Anesthesia and Pharmacology) research continues to move forward. Midazolam and other drugs in the benzodiazepine class exert their sedative actions via gamma-amino-butyric acid (GABA) by binding between the alpha and gamma subunits of the GABA-A receptor. Dr Jenkins and his team are attempting to decipher precisely the presumptive somnogen that contributes to hypersomnia in many IH and NT2 patients that is acting on the GABA-A receptor. They are methodically exploring the % change in small, GABA-mediated current results after making single amino acid substitutions on the alpha2 subunit of the GABA-A receptor. So far they have successfully identified how small changes dramatically influence how well GABA does its job.
  • Is somnogen bioactivity specific to IH or might it be a biomarker for other origins of hypersomnia/hypersomnolence?  The large NIH R01 grant awarded to Emory University and Dr. Rye supports studying this by comparing IH & NT2 and their spinal fluids with clinical features and spinal fluids collected from sleepy and non-sleepy sleep apnea patients, and non-sleepy controls. They are also anticipating assessing Kleine-Levin-Syndrome (KLS) patients both when in and out of their episodes of hypersomnia.

In order to help discover/define the biological pathways in which the somnogen calls “home” as well as, ultimately, the very nature/structure/chemical identity of the somnogen itself, the Emory University sleep research team is collaborating with:

  1. Dr. Nicholas Seyfried – Assistant Professor in the Emory Dept. of Biochemistry is the lead investigator applying proteomic methods to spinal fluid samples.
  2. Dr. Art Edison – A University of Georgia (U) Georgia Research Alliance scholar is the lead investigator applying metabolomics methods to spinal fluid samples.
  3. Dr. Mark Bouzyk – Founder and Chief Scientific Officer of AKESOgen – is studying genetics
  4. Dr. Gary Bassell – Chairman of Emory’s Dept. of Cell Biology – is especially interested in studying myotonic dystrophy patients (in whom hypersomnia is a prominent symptom). RNA splicing abnormalities in myotonic dystrophy cause problems with proteins derived from RNA. The GABA 2γ receptor subunit in myotonic dystrophy because of this altered splicing yields a receptor more sensitive to the effects of the sedating benzodiazepine midazolam (see above).

Genetics/Molecular Biology– Daly DD and Yoss RE A family with narcolepsy (Mayo Clinic Proceedings (1959) 34:313-319). Dr Rye spoke about this during this conference as well as at the 2015 Hypersomnia Foundation Conference.   Four generations of this family were identified. Narcolepsy Type 1 is now known not to be as heritable as the sleepiness described in this family. Only 3 of 13 (16) of these family members exhibited cataplexy. So hypersomnia/hypersomnolence, not Narcolepsy Type 1, appears to be what’s being inherited in this family. Dr Rye also showed several smaller family trees collected at Emory, in which IH, Narcolepsy Type 2, and long sleepers cluster together in families.

Toward genetic research Dr. Rye/Emory has collected $187,500 in donation commitments to begin studies of the genetic components underlying IH and related disorders.  The overall goal is to raise $250,000 to fund these preliminary studies, and using this data to position themselves to apply for larger streams of NIH or foundation funding. They are in the process of collating samples and deciding how to best assign diagnoses given the diagnostic challenges alluded to above (e.g,  IH vs. Narcolepsy Type 2 vs. long sleepers).  The team is also discussing internally and with external collaborators what best first strategies to employ (Genome Wide Association Studies (GWAS) vs. whole exome sequencing [which would be feasible and possibly more fruitful with larger families inclusive of affected and unaffected individuals]).
Most comparable GWAS studies require  ~ 1000 samples. The Emory sleep program has 825 plasma samples, 783+ DNA samples, 473 CSF samples. Including DNA samples collected since November 2015 waiting cataloging into their larger biorepository.
Also, 11 patients with repeat CSF samples have been collected under different clinical conditions, which should be very useful for determining what features are unique to wellness vs. hypersomnia by way of proteomic and metabolomics comparisons.
Very recently skin biopsies h=are being collected to derive fibroblasts from which they are then able to morph into immature brain cells to study more intensively, and in a repeated manner.

Clinical Trials & Treatments:  Pentylenetetrazol (PTZ; aka BTD-001). This is an anti-GABA-A receptor study drug with mechanism action similar to that of clarithromycin.  It is being further developed/studied by Balance Therapeutics for the treatment of cognition and memory deficits in Down’s Syndrome as well as hypersomnia/hypersomnolence in IH and Narcolepsy Type 2.  Interestingly, PTZ is still available as one ingredient (viz., cardiazol) of a cough syrup available in Italy. This is the ongoing clinical trial with the acronym of ARISE. Www.arisestudies.com is the first industry sponsored clinical trial of any treatment seeking FDA approval for treatment of IH. This trial is testing the efficacy of Pentylenetetrazol (PTZ) in a rigorous, controlled, crossover, and blinded design.  ARISE is actively enrolling patients at > 20 centers including Emory University (see the website for participating centers). This drug has a long and substantial safety record (i.e,. Phase 1 requirement of safety in humans has already been established). A small, unblinded Phase IIa study – 5 subjects (3 IH and 2 Narcolepsy Type 2) each with hypersomnia responsive to clarithromycin and/or flumazenil demonstrated very promising results. So much so that the much larger Phase IIb study is moving forward necessitating recruitment of 120 subjects (60 each with IH and Narcolepsy Type 2).

Emory’s open label experience with flumazenil continues to be promising and publication of their “open-label” experience in an initial 153 treated patients is forthcoming. The paper was accepted June 27, 2016 publication in the Journal of Clinical Sleep Medicine. Beyond this experience which is limited to those patients seen and treated by Drs. Rye or Trotti prior to January 1, 2015, it is estimated that nearly 300 patients with hypersomnia resistant to traditional treatments with wake promoting drugs have been empirically treated with flumazenil through Emory’s outpatient sleep clinic alone.  Many additional physicians outside of Emory are increasingly prescribing flumazenil to their patients.

Much has transpired since the 1950’s when Dr. Bedrich Roth coined the term “idiopathic hypersomnia” and progress will continue as we work together and tease out understanding of the causes of idiopathic hypersomnia.

Posted in: BeyondSleepy, Conference, Education, Hypersomnia, Research, SomnusNooze

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Act Today and Let Your Voice Be Heard

Very recently, the Hypersomnia Foundation became aware of an opportunity to help shape the future of sleep research. The National Institutes of Health, the primary source of funding for medical research in the United States, has issued a Request for Information, which you can view at: https://grants.nih.gov/grants/guide/notice-files/NOT-HL-16-312.html.

The final date to submit your comments has been extended to today, May 16, 2016.Screen Shot 2016-05-16 at 12.41.44 PM

Last week, we sent an email to everyone in our database to encourage you to make your voices heard. We are urging you again to act today. Please share your hypersomnia story with the people who determine medical research priorities and allocate funds.

  • Tell them why the currently available diagnostic tools and lack of awareness about hypersomnia led to a lengthy delay in your diagnosis.
  • Tell them why research into the cause of and effective treatments for hypersomnia are so desperately needed.
  • Tell them why we need a cure as soon as possible because hypersomnia is limiting your ability to achieve your dreams, complete your education, or even provide financially for your family.

Please join your voice with ours as we fight to secure the place of hypersomnia at the top of the nation’s sleep research agenda. The Hypersomnia Foundation Board of Directors has submitted the following response, and we encourage you to send your comments and suggestions to the NIH, as you deem appropriate, at rfi-sleepplan2016@collaboration.nhlbi.nih.gov.


 

Hypersomnia Foundation Response
to the National Institutes of Health’s Request for Information:

For nearly a century, the study of sleep and its function(s) in health and disease has been principally focused within approaches that center on not enough sleep. Although excessive daytime sleepiness (EDS), cognitive dissonance, and other symptoms not surprisingly result from sleep deprivation, central disorders of hypersomnolence (CDH; e.g., idiopathic hypersomnia, Kleine-Levin syndrome,
narcolepsy type 1 [NT1], and narcolepsy type 2 [NT2]) in humans (in which EDS is often accompanied by extremes of sleep length) emerge spontaneously. Studying patients with CDH has already proven to be fertile ground for investigation, as evidenced by the discovery that loss of brain hypocretin causes narcolepsy with
cataplexy (i.e., NT1). Yet, for the other CDH, there remains a large unmet clinical need, with further research and development prime for discovery and the potential for extraordinary translational opportunities.

Symptoms of CDH can be disabling, and because, for example in NT1, they also begin in adolescence or young adulthood, are chronic, sometimes progressive, go undiagnosed or misdiagnosed for decades, and respond variably to medications.
Despite advances around NT1, the knowledge gained has not translated smoothly to
the clinical realm. Diagnoses of CDH inclusive of NT1 since 1975 have relied upon a
forty-year-old test (viz., the Multiple Sleep Latency Test [MSLT]) that is cost, time,
and labor intensive and that was born of practical necessity and subsequently
tweaked to specifically identify NT1. In 2006, two preeminent sleep researchers concluded that the MSLT yields “a large number of false-positives” and that an increased daytime propensity to REM-sleep—traditionally accepted to be the sole domain of NT1—does “not appear to have any specific pathognomonic significance.” Yet, in 2016, the MSLT remains the gold standard that drives diagnoses and all that it implies. For clinician scientists, this means, for example, how clinical trials are designed and studies of heritability are conducted. Even more so, for patients, this has enormous implications for prognosis, treatment choice, access to medication(s), and accommodations/disability status.

There are currently no FDA-approved treatments for the CDH—medication choice being limited to those for narcolepsy. Since the 1930s, conventional
psychostimulants such as ephedrine have been used to treat NT1. The majority of the current pharmacological armamentarium and drug development are similarly designed and focused upon promoting wakefulness by enhancing brain monoamines. Drugs more directly designed to replace hypocretin continue in development 16 years after the discovery of hypocretin. An alternative construct in approaching the biology and treatment of CDH has recently been proposed that appears to hold great promise for many patients. People with CDH without NT1 (i.e., hypocretin being intact) do not appear to suffer from any “loss of function” per se but, rather, a gain of function in sleep-promoting brain circuits. Thus, pharmacologic agents that antagonize the sleep-promoting and consciousness-dampening neurotransmitter gammaaminobutyric acid (GABA), such as flumazenil, clarithromycin, and pentylenetetrazol, have either been demonstrated to be effective or are in clinical trials for CDH patients in whom traditional wake-promoting agents have not been helpful.

We advocate for initiatives to fund discovery research that translates to improve the human condition of people with CDH in whom sleep is prolonged and ostensibly persists into “wake.” Enhanced recognition and improved treatments call for greater understanding of not only the clinical spectrum of CDH and the natural history of these disorders, but also mechanistic understanding of their biological underpinnings. Diagnostic tools that are highly discriminative and designed to capture more than just EDS and an increased daytime propensity to REM sleep are an absolute necessity. CDH remain diagnoses of exclusion such that greater understanding of potential mimics—which themselves would enhance mechanistic understanding of sleep—and biomarker discovery are also high priorities. As there are numerous stakeholders in such endeavors, as evidenced in the summary provided above, the absolute need to encourage greater dialogue and collaboration among patients, patient advocacy groups, professional organizations representing sleep physicians, funding agencies, and industry cannot be understated. With increasing dissemination of knowledge through many means, not the least of which includes social media, patient consumers with CDH-like symptoms have become increasingly knowledgeable. They are acutely aware that CDH outside the realm of NT1 is not well served by current medical knowledge or practice in this realm. Accepting the status quo risks alienating the public and medical consumer.

We would, therefore, propose including a sleep neurobiologist on the NHLBI Sleep
Disorders Research Advisory Board and developing mechanisms for solicitation of
program projects and set-aside funds specifically to research hypersomnia, with requests for proposals to prioritize filling unmet clinical needs in the following areas:

R37 Javits Neuroscience Investigator Award
NIH EUREKA grants
R13 funding to support conferences
T32 grants for postdoctoral study
RFAs and more specifically RFPs
SBRI funding for better diagnostic tools

Because the breadth of scientific inquiry or line of investigation needs incredible resources and sustainability, we would advocate for funding initiatives with set-aside monies at all levels of training, including predoctoral, doctoral, postdoctoral, junior investigator, and senior investigators, and we envision promoting set-aside monies for all the Career Development K Awards for investigators with projects relevant to CDH.


 

SN-Image

Learn about the latest hypersomnia research on June 12th at the Hypersomnia Foundation’s regional conference, Beyond Sleepy in the Mile High City. Scientists will share findings from their recently completed clinical trials and other ongoing studies, lead us on a journey through the drug discovery and approval process, and help us to cope with the daily struggles of hypersomnia. You will also learn how your future participation in the registry can help to solve the puzzle of hypersomnia.

Tickets are running out so order your $25 ticket online to join us in person in Denver or wait until June 1 to sign up for a live Internet stream of the conference, brought to you free of charge through the generous support of Balance Therapeutics, Inc., and Flamel Technologies, SA.

 

 

 

Posted in: Action, Awareness, Education, Hypersomnia, idiopathic hypersomna, Kleine-Levin syndrome, narcolepsy, News, Research, SomnusNooze

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Sleep-Wake Disturbance Following a Traumatic Brain Injury

Background

According to the Centers for Disease Control and Prevention (CDC), more than 2 million people in the United States suffer a traumatic brain injury (TBI) every year. Most people with a TBI will also experience a sleep-wake disturbance (a real or perceived change in night-time sleep with resulting daytime impairment, SWD).

Over the past 10 years, a group of scientists in Switzerland has been focusing their research on SWD after TBI. In 2015, Dr. Imbach and his colleagues published their results of a study in which they examined the sleep of 60 patients 6 months after the patients had experienced a TBI. They found that the presence of bleeding in the brain at the time of injury was the greatest risk factor for developing a SWD. A new study followed those same patients for another 12 months (18 months total), and we report the results of that study here.

Who were the participants in the study and what did they do?

brain_xray158w210hThe 60 participants in this study were selected from among 140 adults who had experienced a first-ever TBI. They each underwent a computerized tomographic (CT) scan within 4 hours after the TBI and detailed assessment with standard clinical metrics (e.g., the Glasgow Coma Scale, which is a rough measure of the severity of the brain injury). The participants were matched with 42 people who did not have a TBI but who were of similar age, sex, and sleepiness (control group). Eleven people in the control group dropped out of the study, leaving 31 with complete data from all testing.

The average age of participants was 33 in the TBI group and 36 in the control group. Eleven participants in each group were men.

All participants wore an actigraph for two weeks on two separate occasions: for those with a TBI, six months after having the TBI and then again 18 months after the TBI. (An actigraph, which looks like an oversized watch, is typically worn on the nondominant wrist [that is, if you are right-handed, you would wear it on your left wrist]. It contains an accelerometer and records movements. Once the testing period is complete, the data are downloaded from the device and analyzed off line.)

Participants also reported their subjective perceptions of sleepiness and daytime fatigue by way of Epworth Sleepiness (ESS) and Fatigue Severity (FSS) Scales at these same intervals.

Who were the researchers and what did they do?

Dr. Lukas Imbach and his colleagues in Zurich and Bern, Switzerland, conducted a number of objective measures of sleep in all of the participants in both groups. In the TBI group, this testing took place six months after the TBI and, again, 18 months later.

They performed overnight sleep tests (polysomnography), commencing at 23:00 and terminating at 07:00, before then assessing for participants’ increased propensity to daytime sleepiness by way of daytime nap studies (i.e., the Multiple Sleep Latency Test or MSLT). They compared the findings from the actigraphs, polysomnograms, and MSLTs and the FSS and ESS scores between the two groups, and among the TBI patients at two different time points following their head injuries.

What were the results of the study?

When measured over 24 hours with actigraphy, night-time sleep, but not daytime sleep, was longer in the TBI group (8.1 hours) as compared with the control group (7.1 hours).

Delta power, sleep fragmentation, and distribution of sleep stages on the polysomnogram were normal in the TBI group. Sleep latencies on the MSLT were shorter in the TBI group (an average of 7 minutes) as compared with the control group (11 minutes). Based on the MSLTs (objective measure), excessive daytime sleepiness (EDS) was present in 67% of people with a TBI and 19% of control subjects. These levels of EDS remained fairly constant in the TBI group when comparing results at six and 18 months after the injury.

When comparing the objective and subjective measures of EDS (that is, MSLT vs ESS and FSS), the researchers identified a mismatch, “indicating persistent misperception of sleep-wake disturbance” in the group with TBI.

The presence of bleeding in the brain with the TBI and more severe TBI (lower Glasgow Coma Scale scores) predicted objective metrics of increased sleep quantities at night only during the major sleep period and EDS at 6 months after the TBI. Although findings at 18 months following the TBI emphasize the chronic nature of the negative impact of TBI upon SWD, the 6-month association between bleeding in the brain with the TBI and initial clinical severity of the injury was inexplicably no longer evident at 18 months following TBI.

What were the authors’ conclusions?

“We now provide long-term, prospective, controlled, and electrophysiologic evidence that sleepiness and [increased sleep need] remain a significant problem not only in the first months after TBI, but also in the long run.”

Imbach LL, Buechele F, Balko PO, Li T, Maric A, Stover JF, Bassetti CL, Mica L, Werth E, Baumann C. Sleep-wake disorders persist 18 months after traumatic brain injury but remain underrecognized. Neurology. 2016 ePub ahead of print.

An accompanying editorial to this paper concludes that, “Imbach et al. make a compelling case that posttraumatic sleep-wake disorders may represent a silent epidemic. With epidemiologic studies showing rising rates of TBI in civilian and military populations over the last decade, and with Imbach et al. now showing that the majority of patients with TBI have objective evidence of sleep-wake disturbance, the authors of future clinical guidelines will need to consider the emerging evidence supporting sleep studies in the care of patients with TBI.”

Edlow BL, Lammers GJ. Bringing posttraumatic sleep-wake disorders out of the dark. Neurology. 2016 ePub ahead of print.

Editor’s comments

It is important to realize that, although the MSLT results showed a shortened sleep latency in the participants with TBI, as compared with those without TBI, actigraphy identified no differences between the two groups with regard to amount of time spent sleeping during the daytime.

Note also that the overnight sleep studies were terminated at 0700, resulting in a maximum potential sleep time at night of 8 hours. Thus, while 67% of participants with TBI had a mean sleep latency of less than 8 minutes on the MSLT and would therefore meet International Classification of Sleep Disorders-3rd edition (ICSD-3) criteria for idiopathic hypersomnia, how many may have qualified for a diagnosis based on an overall sleep length exceeding 11 hours is not clear based on how the testing was conducted. It remains to be determined whether TBI, no matter how severe initially, might contribute to hypersomnia otherwise presumed to be “idiopathic,” and, if eventually deemed to meet ICSD-3 criteria for idiopathic hypersomnia, what the implications might be for prognosis and treatment.

This article was written by a volunteer medical writer and reviewed by David Rye, MD, PhD.

 

Posted in: BeyondSleepy, Hypersomnia, idiopathic hypersomna, Research, SomnusNooze

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Calcium-dependent Pathway Helps to Regulate Sleep Duration

Background

How do our brains control when we go to sleep and when we wake up? Previous studies have tried to answer this question, but, despite years of research, our understanding of this process is incomplete. Therefore, the goal of this study was to identify the elusive mechanisms underlying the control of sleep.

Who were the researchers and what did they do?

Dr. Ueda and colleagues at the University of Tokyo constructed a computer model (called computational modeling) of a neuron (a type of cell in the brain) during sleep to predict what pathway(s) might be responsible for sleep regulation. They then manipulated the proposed pathway in mice to test if the computer model was correct. Dr. Ueda and colleagues employed cutting-edge techniques to either remove the proposed pathway gene products from mice using genetic engineering (called knockout mice), or block the proposed pathway gene products using drugs (called pharmacologic inhibition). The authors then measured how these experimental manipulations of the proposed pathway in mice impacted sleep.

What were the results of the study?

This study revealed that the proposed pathway from the computational model does indeed control sleep duration in mice. Seven genes involved in the pathway emerged as having effects on sleep duration, out of a total 21 examined. The identified genes are involved in the regulation of a calcium-dependent pathway in neurons. Interestingly, changes in this calcium-dependent pathway can increase or decrease sleep duration.

What are the authors’ conclusions?

The authors conclude that this calcium-dependent pathway helps to regulate sleep duration. Future research in this pathway may help uncover the “missing switch between sleep/wake cycles.” This crucial research will lead to a better understanding of normal sleep function, in addition to associated sleep and psychiatric disorders. 

 

Tatsuki F, Sunagawa GA, Shi S, et al. Involvement of Ca(2+)-dependent hyperpolarization in sleep duration in mammals. Neuron. 2016;90(1):70-85.

A video overview of this research is available from the authors at https://www.youtube.com/watch?v=W4NrSa1R4mU

 

 

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Learn about the latest hypersomnia research on June 12th at the Hypersomnia Foundation’s regional conference, Beyond Sleepy in the Mile High City. Scientists will share findings from their recently completed clinical trials and other ongoing studies, lead us on a journey through the drug discovery and approval process, and help us to cope with the daily struggles of hypersomnia. You will also learn how your future participation in the registry can help to solve the puzzle of hypersomnia.

Order your $25 ticket on line to join us in person in Denver or wait until June 1 to sign up for a live Internet stream of the conference, brought to you free of charge through the generous support of Balance Therapeutics, Inc., and Flamel Technologies, SA.

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What Does One SOREMP Mean?

Background

The primary feature of the two main central disorders of hypersomnolencenarcolepsy and idiopathic hypersomnia (IH)—is excessive daytime sleepiness, defined in the International Classification of Sleep Disorders, third edition, as “daily episodes of an irrepressible need to sleep or daytime lapses into sleep.” Overnight sleep testing (polysomnography) and a Multiple Sleep Latency Test (MSLT) are necessary to make the diagnosis of a central disorder of hypersomnolence. The differentiating feature between narcolepsy type 2 and IH is the number of sleep-onset REM (rapid eye movement) periods or SOREMPs. The diagnosis of narcolepsy type 2 requires the presence of two or more SOREMPs on the MSLT or one SOREMP on polysomnography and one on the MSLT. The diagnosis of IH can only be made if the person has one or no SOREMPs on polysomnography and MSLT combined. Because MSLT results often vary from day to day, several researchers have criticized the MSLT as being “insufficiently sensitive and specific to diagnose or rule out central hypersomnia.” Therefore, Bozluolcay et al sought to study the “utility of the number of SOREMPs in differentiating the central disorders of hypersomnolence.

Who were the researchers and what did they do?

Dr. Bozloulcay and his colleagues in Turkey examined the polysomnographic records of 101 patients with a central disorders of hypersomnolence, all of whom had a sleep-onset latency (time to fall asleep) on MSLT of 8 minutes or less. They divided the records into three groups: those with 2 or more SOREMPs (narcolepsy), 1 SOREMP (intermediate), or no SOREMPs (IH). They excluded records from any patients who had another sleep disorder or slept 10 hours or more per night.

PSG

What were the results of the study?

Of the 101 patients, 54 were diagnosed with narcolepsy, 26 were intermediate, and 23 were diagnosed with IH. Those in the IH and intermediate groups had a much longer time from symptom onset to diagnosis, as compared with the patients with narcolepsy (12.7 and 11.2 years vs 6.1 years). People in the narcolepsy and intermediate groups had shorter sleep latencies and REM latencies on both polysomnography and MSLT, as compared with people with IH. Of the people with narcolepsy, 56.6% woke directly from REM sleep, as did 50% of the patients in the intermediate group, and 34.2% of patients in the IH group. Twenty people with narcolepsy had a SOREMP on overnight polysomnography; none of those in the other two groups had this finding. Half of the people with narcolepsy had cataplexy, as did one in the intermediate group. None of the people with IH had cataplexy.

 What were the researchers conclusions?

In the complex and frequently misleading characterization of idiopathic hypersomnia, conventional MSLT data should be carefully considered together with newer approaches.

Our results demonstrated that the presence of one SOREMP in MSLT or PSG should carefully be questioned in the context of clinical symptomatology, and alternative diagnostic strategies are needed to more accurately and reliably characterize the non–hypocretin-deficient hypersomnias.

Source

Bozluolcay M, Nalbantoglu M, Benbir Senel G, Karadeniz D. What does one sleep-onset REM period—during either nocturnal polysomnography or Multiple Sleep Latency Test—mean in differential diagnosis of central hypersomnias? J Clin Neurophysiol. 2015;32(4):364-368.

This article was written by a volunteer medical writer and reviewed by Dr. Chad Ruoff. Note that this study did not include patients with IH who slept for 10 or more hours per night.

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Summary of Rationale Behind and Research Studies Into L-carnitine as a Treatment for Narcolepsy

Background

In this 2013 study published in PLoS One, the researchers Miyagawa et al hypothesized that L-carnitine supplementation might help improve narcolepsy symptoms by increasing β-fatty-acid oxidation.

Fatty acids are a major energy source for the human body. For them to be broken down and metabolized via oxidation and thereby provide vital cellular energy, they must first be transported into the mitochondria (the energy-producing centers in cells) via the carnitine transport system. Carnitine palmitoyltransferase I (CPTI) is the rate-limiting enzyme in this process. This enzyme helps to combine carnitine with a fatty acid to form fatty acyl carnitine, which can then enter the mitochondria through the mitochondria’s membrane.

If this carnitine transport is slowed for any reason, the ability of a cell (presumably, also including brain cells or neurons) to produce energy can be decreased, potentially leading a person to feel more fatigued. For example, if carnitine or CPTI enzyme levels are low, fatty-acid transport and oxidation to produce energy will also be slowed.

Several lines of prior research have implicated problems with carnitine in individuals with narcolepsy (and potentially other primary hypersomnias and even fatigue in general). For example, some people with narcolepsy may have reduced fatty acid oxidation and low levels of acylcarnitine.

Other studies have shown that mice who have a carnitine deficiency have narcolepsy-like symptoms, including disrupted REM sleep, reduced motor activity, and low orexin (also called hypocretin) levels. Orexin is the neuropeptide whose deficiency has been determined to cause narcolepsy with cataplexy (that is, narcolepsy type 1).

Finally, a SNP (single nucleotide polymorphism) has been found in the gene that encodes CPT1B and associates with both narcolepsy type 1 and decreased expression of the CPT1B enzyme itself. SNPs are the most common type of genetic variations within human DNA. They are DNA sequence variations occurring when a single nucleotide (C, G, A, or T) differs between members of paired chromosomes (one pair derived from each parent). In this case, the more C nucleotides (“risk alleles”) a person has at this narcolepsy-related SNP (from 0-2), the lower the production of the CPT1B enzyme. Less CPT1B enzyme leads in turn to slower fatty acid transport and breakdown to energy.

Given the above lines of evidence, Miyagawa et al hypothesized that carnitine supplementation might help improve symptoms of narcolepsy type 1 by increasing the transport of fatty acids into mitochondria for energy production.

 Methods

The study design was a randomized, double-blind, placebo-controlled cross-over trial. The researchers studied 30 people with narcolepsy with cataplexy, of which 28 completed the trial. Each person underwent two 8-week treatment periods, one with the placebo and one with L-carnitine (the order of which was randomly determined). Dosage was 2 capsules in the morning and 1 capsule in the evening. Capsules contained either 170 mg L-carnitine or placebo. Participants were monitored every 4 weeks, and they were allowed to continue their other usual medications.

“The primary outcome measure was the patients’ subjective assessment of their sleepiness using total time for dozing off during the daytime in their sleep logs.” Secondary outcome measures (meaning that they were not the main purpose of the study) included:

1. The number of occurrences of daytime dozing off

2. The number of episodes of sleep paralysis and cataplexy, according to sleep logs

3. Japanese version of the Epworth Sleepiness Scale

4. SF-36 (Medical Outcomes Study 36-Item Short-Form Health Survey): vitality and mental health subscales

5. Body mass index

 Results

Total time for dozing off during the daytime (the primary outcome) was significantly reduced in participants while ingesting L-carnitine, as compared with when ingesting the placebo. No significant differences were found in any of the secondary outcomes measured. No participants experienced side effects when ingesting L-carnitine.

About half the participants had at least 1 narcolepsy-associated risk allele in the gene encoding CPT1B. However, the number of risk alleles (for example, 0, 1, or 2) did not predict response in overall nap times between L-carnitine and placebo. In layman’s terms, the presence of the higher-risk allelic variant did not seem to affect whether or not L-carnitine supplementation improved sleepiness.

Overall, the participants in this study had relatively low levels of acylcarnitine in their blood while taking placebo. After taking L-carnitine, their acylcarnitine levels improved significantly, as did their total and free carnitine levels.

 Discussion

These results support the hypothesis that taking L-carnitine supplements improves sleepiness or dozing in people with narcolepsy type 1. These improvements occurred regardless of whether or not people had a baseline carnitine deficiency.

Although this study was, in part, motivated by the finding of a gene association (SNP), the gene association did not predict efficacy of L-carnitine supplementation. L-carnitine supplementation showed efficacy in this modest-sized group of participants regardless of their CPT1B narcolepsy risk allele status. That being said, the study was not designed or “powered” to assess the effect of the gene on improvements with L-carnitine.

This study was also not powered (meaning that the number of participants was insufficient to show a statistical difference between the L-carnitine and placebo groups) for the secondary endpoints. Some of these secondary endpoints, in fact, did show some tendency towards improvement (see, #1, #3, and #4 above). Cataplexy and sleep paralysis improvements could not be well studied because patients were allowed to continue taking their regular medications during this study and subsequently had very low levels of cataplexy and sleep paralysis. This is sometimes referred to as a “floor effect.” That is, the absence of evidence (e.g., a desirable or suspected positive benefit to an intervention) is not necessarily evidence of absence. This is also referred to as Type II error (or a potential false-negative finding) because not enough observations were made or the choice of what to observe (e.g., cataplexy events) is so suppressed that any change in the number of events is artificially dampened (and thereby elude detection).

Participants in this study were found to have reduced triglyceride levels (though not significantly), indicating that carnitine absorption and use was likely normal in these people with narcolepsy type 1. It is possible that longer-term use of L-carnitine might improve body mass index and lipid profiles in people with narcolepsy. However, studies to assess these outcomes usually require 6 months to 4 years or more.

Further Reading

T Miyagawa, Kawamura H, Obuchi M, et al. Effects of oral L-carnitine administration in narcolepsy patients: a randomized, double-blind, cross-over and placebo-controlled trial. PloS One. 2013;8(1):e53707. The full text of this open-access article is available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547955/pdf/pone.0053707.pdf.

This article was written for the Hypersomnia Foundation by a volunteer medical writer.

 

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