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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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Idiopathic Hypersomnia – A Turtle Going Uphill Through Molasses in January

Share the Journey Stories

Words escape me. I am a reader, a writer, and a highly educated woman with multiple degrees. Eloquence is high on my list of valued traits. Communication is one of my strengths, and something I’ve always been commended for. And yet, words escape me. I stutter, I stumble, I am tongue-tied. It’s like trying to grab water in your fist.

That is part of what it feels like to have brain fog, a symptom of multiple chronic illnesses, including my idiopathic hypersomnia. You can’t find the words you are looking for, even everyday words. But I am not stupid. I do not have a low vocabulary. I have a Bachelor of Arts in English; communicating in a clear and concise manner was something I was trained to do. But words escape me. Not just once in a while. All the time.

Brain fog is just one aspect of IH. It isn’t even the biggest aspect, nor the most important. However, it matters because how can you convey what it is like to have constant all-consuming fatigue if words escape you?

I would say that my fatigue is a “maelstrom,” or a “torrent” within and surrounding me, but the connotations of such descriptions bring up thoughts of fast and wild disasters. Fatigue is much more subtle and slow. It is not the quick death of a bullet to the brain. Fatigue is more like walking through thick, high mud. Like swimming through honey. Like drowning in an ocean. Like being in a bog, surrounded by impenetrable fog. Like a turtle going uphill through molasses in January. It is all of these things simultaneously. It is wearing a lead straitjacket while trying to escape drying cement. It is slow, and it eats you alive from the inside. It is the thick, heavy, slow, drained, helpless, hopeless feeling.

Imagine dealing with all of that, day in and day out. Now experience all of that while trying to be a competent part of society. Subtract caffeine. Add heart palpitations and a minimum nightly requirement of eleven hours of sleep. The hardest part of your day is waking up. The second hardest is getting out of bed. The third is staying awake. An eternal struggle. Stay awake. Be productive. Accomplish your tasks.

Imagine doing all your normal tasks (and they have to be done well and in a timely manner) when you haven’t slept in three days. Now imagine doing that every day. Can you? I can. Because that is what I do every day, because idiopathic hypersomnia means that I need a minimum of eleven hours of sleep in order to feel like I haven’t slept in two or three days. I cannot remember what it is like to feel refreshed, rejuvenated, and awake. It’s been years. I would, without hesitation, amputate an arm or a leg if that was the cure. Think about that.

Take all of that and tell me that fatigue isn’t debilitating. I dare you.

But you know what? No matter how many people read this, there are still going to be those that think fatigue isn’t debilitating. But life keeps going. So, just like that turtle, I will keep going, even if it is always uphill through molasses in January.

Caitlin Swinford
Germantown, MD

Posted in: Awareness, BeyondSleepy, Hypersomnia, idiopathic hypersomna, Journey, Share the Journey Stories, Social Media, SomnusNooze

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Sleep Disorders and Social Security– What You Need to Know

Social Security Disability Series: Part 2

Sleep Disorders and Social Security Disability – What You Need to Know

By Anjel Burgess, JD

Jennie has been fortunate enough to secure her short-term disability benefits. She has also hired an Attorney to assist her with the Social Security Disability application process. Although her family encouraged her to “file on her own instead of paying out of pocket to hire an attorney,” Jennie has learned throughSomnusNooze that Social Security Disability attorneys are not paid by a retainer, as many attorneys are. Rather, they work on a contingency basis, which means that Jennie does not have to pay out of pocket to get representation. For the attorney to get paid, two conditions must be met:

  1. The attorney must win Jennie’s case.
  2. Jennie must be entitled to past-due benefits (also known as back pay).

If both conditions are met, the Social Security Administration (SSA) will pay Jennie’s attorney 25% of Jennie’s back pay, up to a maximum of $6,000. Since obtaining the benefits is of the utmost importance to Jennie, she has decided that she can’t afford NOT to have an attorney. She has hired an attorney who will file an initial application for her and represent her through each step of the process.

Jennie’s attorney has explained to her that most people who receive Social Security Disability benefits have been through a three-step process and that it may take two years or more before she is approved (note that in some states, it is a 2-step process, as the Reconsideration step is eliminated). These steps include the following.

  1. Initial – Roughly 30% to 35% of applicants are approved at this level. Once SSA receives the initial application, they request medical records from Jennie’s providers. Once the SSA receives Jennie’s medical records, SSA will have its own physician or psychologist (or both a physician and psychologist) review the medical records to give their opinion as to what limitations they believe that Jennie has, as well as the impact of those limitations on her ability to work. This would also include a review of the opinion of Dr. Wonderful and any other of Jennie’s treating physicians. Oftentimes, SSA will decide that they need an outside opinion in making their decision. If this occurs, the SSA may require that Jennie be examined by an independent physician or psychologist (at SSA’s expense) who may not have an expertise in idiopathic hypersomnia. This independent professional then prepares a report that summarizes her or his observations and professional opinion. If the case is denied initially, Jennie can appeal.
  2.  Reconsideration – Roughly 7% to 10% of applicants are approved at this level. At the Reconsideration step, SSA obtains updated medical records and completes another internal review of Jennie’s file to see if any new evidence would result in a favorable outcome. It is possible that the SSA may send Jennie out for an independent examination at this stage as well. Again, if Jennie is denied, she can appeal.
  3. Hearing – Roughly 50% to 55% of the remaining applicants are approved at this level. This is the stage at which most people are awarded benefits, particularly after attending a hearing in front of an administrative law judge. The hearing is the opportunity for Jennie and her attorney to present the big picture to a judge. The big picture includes all medical records and testimony from Jennie herself. Jennie’s attorney will also have the opportunity to make oral and written arguments on Jennie’s behalf.

The common theme in each step of the process is medical records. Medical records are vital in a disability case because they can provide objective support for an individual’s complaints. For Jennie, her medical records tell the story of a very symptomatic individual who tried multiple medications but could only be productive for about 3 hours throughout the day. Her doctor ruled out many other conditions, and was able to confirm the diagnosis of idiopathic hypersomnia via a polysomnogram and Multiple Sleep Latency Test. Jennie’s medical records provide proof that she has idiopathic hypersomnia and authenticate her symptoms, which are reasonably due to idiopathic hypersomnia.

If you, too, are ready to file for Social Security Disability or have been denied at any step in the process, contact a qualified Social Security Disability Attorney to assist you with the process.

Anjel Burgess is a partner/attorney at the Law Firm of Burgess and Christensen located in Marietta, GA. She exclusively practices Social Security Disability Law for adults and children, as well as the ancillary areas of Guardianships and Special Needs Trusts. By doing so, she has been able to make a positive difference in the daily lives of people who need help the most. You may reach her at Anjel@DisabilityHelpLine.com or 770-422-8111. You can learn more about her services at www.DisabilityHelpLine.com

Have you joined the registry yet?
A patient registry is a collection that is established to collect standardized information about a group of patients who share a common condition or experience. In the case of the Hypersomnia Foundation Registry at CoRDS  (Coordination of Rare Diseases at Sanford), the people who participate have one of the central disorders of hypersomnolence: idiopathic hypersomnia, Kleine-Levin syndrome, or narcolepsy (type 1 or 2). Becoming part of the registry is easy and it could help solve the puzzle of hypersomnia! Simply go to http://www.sanfordresearch.org/cords/ and click on the ENROLL NOW button.

A patient registry is a collection that is established to collect standardized information about a group of patients who share a common condition or experience. In the case of the Hypersomnia Foundation Registry at CoRDS (Coordination of Rare Diseases at Sanford), the people who participate have one of the central disorders of hypersomnolence: idiopathic hypersomnia, Kleine-Levin syndrome, or narcolepsy (type 1 or 2). Becoming part of the registry is easy and it could help solve the puzzle of hypersomnia! Simply go to http://www.sanfordresearch.org/cords/ and click on the ENROLL NOW button.

 

Watch Beyond Sleepy in the Mile-High City

Denver6

Were you one of the more than 1250 people who joined us at Beyond Sleepy in the Mile-High City, the Hypersomnia Foundation’s Regional Conference, in person and online on June 12, 2016? If not, you can still watch the conference in its entirety by registering at http://www.hypersomniafoundation.org/2016-hypersomnia-regional-conference-register/. If you previously registered and missed any part of the program–or simply want to watch it again–please go to http://www.hypersomniafoundation.org/2016-hypersomnia-regional-conference-live/. The video will only be up for two more weeks!

 

Posted in: Action, Awareness, BeyondSleepy, Conference, CoRDS Registry, Education, Hypersomnia, idiopathic hypersomna, Kleine-Levin syndrome, narcolepsy, News, SomnusNooze, SSDI

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Solving the Puzzle of Hypersomnia One Piece at a Time

The Hypersomnia Foundation Board of Directors is thrilled to announce the launch of the Hypersomnia Foundation’s Registry at CoRDS (Coordination of Rare Diseases at Sanford). Whether you have idiopathic hypersomnia, Kleine-Levin syndrome or narcolepsy type 1 or 2, please enroll in the Registry today to help solve the puzzle of hypersomnia. Your information will help researchers comprehend the journey that people with hypersomnia travel in their search for a diagnosis and will answer many other questions, including the symptoms that you experience, which may help to distinguish among these disorders, and the treatments that have and have not worked for your symptoms. Registration is simple (the second figure below describes the process). Simply go to http://www.sanfordresearch.org/cords/ and click on the ENROLL NOW button. Your answers to the Registry questions will help researchers design better diagnostic tools and more effective treatments and, eventually, find a cure. CoRDS personnel are available to help you, if needed, during the registration process. They can be reached at cords@sanfordhealth.org or 1 (877) 658-9192.

 

What is a Registry? A patient registry is a collection that is established to collect standardized information about a group of patients who share a common condition or experience. In the case of the Hypersomnia Foundation Registry at CoRDS, the people who participate have one of the central disorders of hypersomnolence: idiopathic hypersomnia, Kleine-Levin syndrome, or narcolepsy (type 1 or 2).

What is a Registry?
A patient registry is a collection that is established to collect standardized information about a group of patients who share a common condition or experience. In the case of the Hypersomnia Foundation Registry at CoRDS, the people who participate have one of the central disorders of hypersomnolence: idiopathic hypersomnia, Kleine-Levin syndrome, or narcolepsy (type 1 or 2).

cords process

CoRDS Registration Process

 

Posted in: Action, Awareness, BeyondSleepy, CoRDS Registry, Education, Hypersomnia, idiopathic hypersomna, Kleine-Levin syndrome, narcolepsy, SomnusNooze

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NEWSFLASH!

With seating beyond planned capacity at the conference in Denver and to make the #BeyondSleepy conference more accessible, we will be streaming the entirety of the conference, including the question-and-answer portion. Thanks to a tech-savvy volunteer,Strike we will not only be livetweeting the conference from our Twitter account (@HypersomniaNews), but will also be able to accept your relevant questions. So tweet your questions using the hashtag #AskBeyondSleepy.

Please don’t wait until the last minute to register! Our website is a bit crotchety and slow, so if everyone tries registers at once immediately before the conference, you may miss part of the program!

We look forward to your participation in the conference!

Posted in: BeyondSleepy, Conference, Hypersomnia, idiopathic hypersomna, Kleine-Levin syndrome, narcolepsy, News, Social Media, SomnusNooze

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Five More Days!

Only five more days until the 2016 Hypersomnia Foundation Regional Conference!!!

Are you joining us in Denver or tuning into the live Internet broadcast? Either way, we understand that you might have a few last-minute questions, so we’ve put together a list of recently asked questions.

1. My schedule just changed, and I’ll be able to make it to Denver after all. Can I still buy a ticket?

Yes, you can, but we have only a few tickets left (At the time of publication, we had 4 tickets left). To purchase a ticket to attend Beyond Sleepy in the Mile-High City in person, please click on this link or purchase a ticket here http://2016hypersomniaconference.eventbrite.com/

2. I have purchased my ticket for Beyond Sleepy in the Mile-High City. I would like to get together with other people with hypersomnia. Where can I find them?

You’re in luck! We have created three separate opportunities to get together with other conference attendees. On Saturday evening, June 11, at 6 pm, we will gather in the Atrium Alcove on the fourth floor of the Embassy Suites Hotel, 1420 Stout Street. This informal gathering will include a cash bar, games, and camaraderie. On Saturday, we will be reserving tables so that we can all sit together for breakfast beginning at 7:30 am in the Embassy Suites Hotel (breakfast is not included). Head to the meeting room (Crestone) on the third floor of the Embassy Suites Hotel beginning at 10 am, where, once you have completed the sign-in process, you can just sit and chat or make plans with others gathered there to go out for lunch before the conference begins at noon.

3. What time will Beyond Sleepy in the Mile-High City get underway?

We will be starting promptly at noon, Mountain Daylight Time. People from around the world will be tuning in, so please calculate your viewing time based on GMT-6.

4. Will we have any food?

Well, this answer depends on how you are participating. We will be serving light refreshments at 2:00 pm at the Embassy Suites Hotel in Denver, underwritten in part by a grant from Pavilion Pharmacy. If you are watching via the Internet, you are on your own for snacks.

5. I am coming to the conference in Denver, but I know that I will have trouble remembering everything that the speakers are saying. Can I watch the Internet streaming later to refresh my memory?

YES!!! You can buy a ticket for the Denver conference and register on the Hypersomnia Foundation’s website to watch the streaming video. Once you have registered for the streaming video, you will be able to view the event as many times as you would like between June 13 and July 11, 2016. We are also working on creating a permanent link to the videos, but we don’t want to make any promises at this point.

6. I live in Australia. The Hypersomnia Foundation Conference, Beyond Sleepy in the Mile-High City, will be live at 4 am in my timezone. Are there any other options to watch?

YES!! Take a look at the response to the previous message.  Please complete the registration on the Hypersomnia Foundation’s website (http://www.hypersomniafoundation.org/register/) and you will be able to view Beyond Sleepy in the Mile-High City as many times as you would like between June 13, and July 11, 2016.

7. My sister would like to watch the Beyond Sleepy in the Mile-High City, but she is not on the Hypersomnia Foundation’s mailing list. Can she still watch the program?

YES!! She is more than welcome to join us. The purpose of this program is to educate anyone who would like to learn more about hypersomnia. From teachers and professors to employers, parents and friends, spouses, and children, doctors and pharmacists, the program will help people understand the full impact of hypersomnia on the lives of those affected. Registration is open to anyone with a streaming device and an Internet connection. Please widely share this link (http://www.hypersomniafoundation.org/register/) to the registration page and encourage as many people as possible to take part.

We hope this answered any questions you may have had and we look forward to your attendance at the conference! Please direct any additional questions you may have to conference@hypersomniafoundation.org

Posted in: Awareness, BeyondSleepy, Conference, Education, Hypersomnia, idiopathic hypersomna, Kleine-Levin syndrome, narcolepsy, 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.


 

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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.

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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Her

All I can say is my admiration for those that suffer with idiopathic hypersomnia (IH) is truly immense. I love an IH sufferer, and even though she fights every day just to participate and contribute, she still shares humor and kisses like smuggled chocolate drops in a dreary math’s lesson.

sleeping woman Some days you can see the drugs are in slow mo, and all you want to do is wrap your arms around her and pump her up with the normalcy of simply feeling awake. Every tomorrow brings fresh hope she will make it all the way to the end without a crippling migraine, or be slam dunked by a drooling sleep fest, stealing away her hard-earned achievements … Or worse still… a cruel and soul-destroying comment from an ignorant and narrow-minded baboon stewing in his ungrateful and wasted soup of well-being. Stupidly, he mistakes her for lazy, slow, or disconnected, having no idea that he has just had an encounter with a rare warrior—one who wins and conquers life one precious moment at a time in a world where whole years are abandoned and forgotten. She, so young, has learnt how to manage a bigger load, invisible to the untrained eye, with finite stamina, measuring routine activities carefully with brave grit and frowned-faced fortitude.

Yet, as I watch her slow drunkard-like stance, slowly mobilizing each muscle to reach vertical every morning, I no longer feel that dark despair and loss. I am now infused with hope, amused and bewildered by how love curled by pain for so long can march you back up a cranky forgiving road to welcome in our new norm. Two adult women, cradling acceptance and insistence, seesawing between the two, me and her, mother and daughter.

Anonymous Supporter

Posted in: Awareness, BeyondSleepy, Hypersomnia, idiopathic hypersomna, SomnusNooze, Uncategorized

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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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