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SPECIAL SOMNUSNOOZE ALERT!!

URGENT: Let’s Get #BeyondSleepy campaign matching donations for the next 24 hours to raise funds now for research and awareness of hypersomnia.

For the next 24 hours all donations to our giving season campaign will be matched, up to $5000!

The Pillows and PJ’s challenge has taken off, and we are more than halfway toward our goal of raising $20,000 by December 31st!

Supporters from as far away at the Netherlands and New Zealand have donated and contributed photos, then challenged friends and family to do the same. Check out our Facebook page to see the gallery of fun and creative photos, like these of Board Members Cat Rye and Diane Powell:

diane-pjscat-pjs

 

 

 

 

 

 

 

 

DON’T WAIT, PLEASE DONATE NOW WHILE WE HAVE AN OFFER TO MATCH YOUR GIVING (you don’t need to take a PJ photo to donate!). DONATIONS can be made here: http://www.hypersomniafoundation.org/2016givingseason/

To see all the PJ photos, check us out here: https://www.facebook.com/Hypersomniafoundation/
Thank you, as always, for your wonderful support of the Hypersomnia Foundation and our campaign to get #BeyondSleepy! Campaign continues through December 31st.

Posted in: Awareness, BeyondSleepy, 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 gamma-aminobutyric 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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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.

Posted in: Conference, News, Research, SomnusNooze

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Introducing New Board Members

The Board of Directors of the Hypersomnia Foundation is pleased to introduce Diane Powell and to announce the appointment of two new members of the Scientific Advisory Board, Prof. Nicholas Franks and Dr. James Krueger. As members of the Scientific Advisory Board, Prof. Franks and Dr. Krueger will be assisting the Board of Directors in developing a grant application and review process, as well as in setting a research agenda and reviewing requests for use of data from the Hypersomnia Foundation’s registry. 

Diane Powell, LCSW

Diane is a founding member of Maverick Collective, a women’s philanthropy group working with Diane Powell at SRK Headshot DayPopulation Services International, Inc., to benefit women and girls in developing countries. Diane is sponsoring a pilot project in southern Senegal to reduce maternal mortality and improve child nutrition.

As a Licensed Clinical Social Worker, Diane has used her skills to provide psychotherapy for clients struggling with anxiety, depression, bipolar illness and many other mental health diagnoses. Her previous community projects include leading a task force on alcohol abuse among expat teens in Singapore and founding a bereavement support group for young widows and widowers in Florida. Through a program of the Episcopal Church, Diane helped lead the launch of community projects in Guatemala among Mayan populations devastated by years of civil war. 

Diane is president and co-founder of The Robertson Powell Foundation, which supports research and innovation in the field of health.

In 2014, an alert physician named Karel Kooper at the University of Southern California’s Health Center referred Diane’s daughter for an evaluation at the Tower Sleep Center at Cedars Sinai Hospital in Los Angeles. The daytime sleepiness that she had been struggling with since age 14 was diagnosed by Dr. Roy Artal as hypersomnia. Since then, Diane and her husband, Andrew, discovered the Hypersomnia Foundation and are proud to support its work and the research of Dr. David Rye.

Professor Nicholas Franks, FRSB, FRCA, FMedSci, FRS

Franks photo for Hypersomnia FoundationAs Professor of Biophysics & Anaesthetics at London’s Imperial College, Prof. Nicholas Franks has sought to understand how general anesthetic agents work at the molecular, cellular, and, most recently, neuronal network levels. Almost 40 years ago, he asked the question, “Where do general anaesthetics act?” in the journal Nature and has been pursuing the answer through funded studies in his laboratory since that time. Along the way, he has expanded his research to better understand the relationships among anesthesia, consciousness, and sleep and has also asked, and answered, the question, “Do sedatives engage natural sleep pathways?” Among the many discoveries that he has made throughout his long and storied career, Prof. Franks recently identified the exact binding location of propofol to the GABA-A receptor.

In 2007, Prof. Franks was elected Fellow of the Royal College of Anaesthetists and, in 2011, Fellow of the Royal Society. He has been awarded the Ebert Prize of the American Pharmaceutical Association, the Gold Medal of the Royal College of Anaesthetists, and the Excellence in Research Award from the American Society of Anesthesiologists.

 James M. Krueger, PhD

Dr. Krueger is Regents Professor of Neuroscience in the Elson S. Floyd College of Medicine at Washington State University. Early in his career as a postdoctoral fellow, Dr. Krueger worked with Krueger4167Dr. John Pappenheimer to isolate, purify, and characterize Factor S and subsequently published their seminal work in The Proceedings of the National Academy in 1978. Today he is recognized as a worldwide expert on sleep in his own right.

Among Dr. Krueger’s numerous awards are election to the Washington State Academy of Sciences and recipient of the Doctorem Medicinae Honoris Causa from the University of Szeged, the Distinguished Scientist Award from the Sleep Research Society, and the Senator Jacob Javits Award in the Neurosciences from the National Institutes of Health.

Dr. Krueger’s research has been continuously funded by the National Institutes of Health for over 28 years; it is focused on the biochemical regulation of sleep, molecular mechanisms responsible for the effects of infectious diseases and inflammation on sleep, sleep function, and brain organization of the initiation of sleep.

Dr. Krueger’s 350 peer-reviewed publications cover the gamut from sleep function to sleep and cytokines, and physiological markers of localized sleep. His latest research documents his theoretical predictions that sleep originates in small neural networks, discoveries that open the door to a deeper appreciation of the genetic, molecular, and electrical aspects of sleep disorders.

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ADHD Symptoms in Children with Narcolepsy

Background
Compared with adults with narcolepsy, children with narcolepsy often have higher levels of excessive daytime sleepiness (EDS), are more likely to have cataplexy without a trigger, and are more likely to have a secondary form of narcolepsy. The EDS and disturbed night-time sleep of narcolepsy may lead to reduced quality of life and lower academic performance because of the associated obesity, depression, and attention-deficit/hyperactivity disorder (ADHD) that often accompany narcolepsy. ADHD has two main types of symptoms–inattention (such as trouble paying attention or organizing tasks or Sleepy childbeing easily distracted) and hyperactivity-impulsivity (such as fidgeting or trouble staying seated or waiting for a turn). Other research has shown that adults with narcolepsy have ADHD at a higher rate than the typical adult population, but no one has studied this in children.

Who were the participants and what did they do?
All children with narcolepsy who were seen at one of the national narcolepsy centers in France over a four-year period were invited to participate in this study. Children with narcolepsy (86 with cataplexy [NwC] and 22 without [Nw/oC]) and children without narcolepsy  (67 control subjects) were recruited. With the help of their parents if necessary, these children completed several questionnaires, including the Pediatric Daytime Sleepiness Scale, Chalder Fatigue Scale, the ADHD Rating Scale, and the Children’s Depression Inventory.

Who were the researchers and what did they do?
The researchers were physicians from the four national narcolepsy centers in France. They examined each of the participants, calculated the subjects’ body mass index (weight divided by height, in meters squared), and prescribed treatment for narcolepsy for those subjects who had narcolepsy. They did not specifically treat the symptoms of ADHD, although many of the wake-promoting treatments for narcolepsy are also used for ADHD. They reviewed the patients’ responses to the questionnaires.

What were the results of the study?
sleepy teenThe children ranged in age from 6.5 to 17.9 years. The children with Nw/oC were, on average, younger that those in the other two groups. Slightly more than half of the children with narcolepsy were overweight, as compared with 10% of the control subjects. About 20% of patients with narcolepsy were obese, compared with 4% of the control subjects. Of the control subjects, 5% to 6% had clinically significant ADHD symptoms, as did 30% of patients with NwoC and 15% of patient with NwC. Those with higher levels of ADHD symptoms had higher rates of depression and decreased quality of life.

With regard to medications, 73% of children with Nw/oC were receiving treatment (> 90% with stimulants, none with sodium oxybate) and 67% of children with NwC were receiving treatment (>90% with stimulants, 14% with sodium oxybate). “Moreover, in contrast to narcolepsy symptoms, for which some benefit of therapy was observed, ADHD symptoms appeared to be largely unresponsive to psychostimulant therapy. It remains unclear, therefore, whether psychostimulant therapy is effective for ADHD symptoms in pediatric narcolepsy and whether hypersomnias and ADHD may or may not share a common underlying pathophysiology.”

Lecendreux M, Lavault S, Lopez R, Inocente CO, Konofal E, Cortese S, Franco P, Arnulf I, Dauvilliers Y. Attention-deficit/hyperactivity disorder (ADHD) symptoms in pediatric narcolepsy: a cross-sectional study. Sleep 2015;38(8):1285-95.

Reviewed by Dr. Isabelle Arnulf.

Posted in: narcolepsy, Research

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Raising Awareness of the Underpinnings of Hypersomnia

Awareness of disease means different things to different people. One’s awareness takes origin in experiences and goals, both personal and professional. Diversity in awareness therefore comprises our community of people who have hypersomnia, their significant others, healthcare professionals, and research scientists. People who have hypersomnia need to become more self-aware of their symptoms; significant others, employers, and educators, more accepting of the limitations of the person with hypersomnia; and health care providers, more vigilant as to how hypersomnolence negatively impacts their patients’ health. Clinician scientists are becoming increasingly aware of unconventional treatments for hypersomnolence and are soon to launch clinical trials of even more novel medications. For the research scientist working at a laboratory bench, what form does awareness take? Their efforts are critical to leveraging the collective awareness of all of the stakeholders in hypersomnia if the diagnosis and treatment of hypersomnia are to be realized.

In this spirit, we would like to share where we find ourselves with the basic science of idiopathic hypersomnia (IH) and where this science might be headed in the immediate future. Although for many years IH has not attracted a considerable amount of attention from basic scientists, recent discoveries have yielded two successful grant applications funded by the National Institutes for Neurological Diseases & Stroke—a division of the National Institutes of Health (NIH), and, in turn, the Department of Health and Human Services. The most recent, and substantial (nearly $3 million spread over 4 years), is pending an award after regulatory approval to a team lead by Dr. David Rye at Emory University. (For further information, see SomnuSnooze June 16, 2015.) The funded work follows upon their findings published in 2012 in Science – Translational Medicine,1 in which they described their research regarding 14 people who had no sleep problems (i.e., control subjects) and 32 people who had idiopathic hypersomnia (IH) or Type 2 narcolepsy or were long sleepers with otherwise normal results on Multiple Sleep Latency Tests. The Emory researchers discovered a bioactive substance in the cerebrospinal fluid (CSF) of two thirds of the people with hypersomnia regardless of their formal diagnosis. This substance boosted the natural ability of the neurotransmitter gamma-aminobutyric acid (GABA) to dampen or inhibit the nervous system. The substance was not found in the CSF of any of the control subjects. Moreover, vigilance was improved in seven of seven subjects who exhibited this excess enhancement of GABA’s actions at the “A” subtype of GABA receptors (i.e., GABAAR) and who received the GABA antagonist flumazenil. Because researchers have not yet identified the exact constituent within the CSF of people with hypersomnia that enhances GABAAR function, some researchers and patients have come to affectionately refer to this substance simply as “sleepy juice.” Yet, there is much to be done to ultimately prove causality and thereby hasten the pace of progress in the realms of diagnosis and treatment.

GABA receptor

GABA receptor

In the late 20th century, Robert Koch, a German physician, who later received the 1905 Nobel Prize in Medicine, set forward four conditions that must be met to establish a microorganism as the causative agent of disease: (1) the microorganism must be found in all cases of the disease, (2) it must be isolated from the host, (3) it must reproduce the original disease when introduced into an unsuspecting host, and (4) it must be found or retrieved from the experimental host that is so infected. The Rye team has satisfied most of these points in demonstrating that (1) the GABA-ergic bioactivity (that is, the activity of the “sleepy juice”) is greater in people with hypersomnia than in control subjects,1 (2) the “sleepy juice” is likely a peptide with a fairly modest size (500-3,000 Daltons),1 (3) the amount of sleep time increases in rats in whom this component of CSF is infused into the central nervous system (unpublished data), and (4) antagonists of the GABAAR, such as flumazenil, have been shown to normalize vigilance in people with hypersomnia.1 Nonetheless, the magnitude of GABAAR enhancement by individual patients’ CSF samples in Rye’s initial study did not correlate with any measure of hypersomnolence, including flumazenil-related improvements in vigilance.

To “nail down” Koch’s postulates and thereby establish cause and effect (causality), Rye’s team will be performing new experiments. These experiments will compare GABAAR enhancement in people with IH and Type 2 narcolepsy with control subjects, people with Kleine-Levin syndrome, and people with obstructive sleep apnea in the hope of identifying a protein “fingerprint” that distinguishes the groups from one another. They will also look more closely at the CSF to see how and where the “sleepy juice” acts at submicroscopic levels by studying genetically engineered GABA receptors cloned into cell lines and, separately, mice bred to have genetically altered or missing GABA receptors.

The Rye team is at the doorstep of a major research project that seeks to identify the “sleepy juice” and how and why it works to promote hypersomnolence. The biological pathways responsible for its synthesis, accumulation, and degradation should then more rapidly identify themselves. This knowledge will breed awareness among basic researchers who are otherwise focused on how and why we sleep as opposed to treating disease. In turn, new knowledge will emerge, thereby identifying new means to diagnose hypersomnolence and a plethora of additional avenues for non-medicinal and medicinal means to improve the symptoms of hypersomnolence – even, ultimately, a cure.

1. Rye DB, Bliwise DL, Parker K, et al. Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Sci Transl Med 2012;4(161):161ra151.

Posted in: idiopathic hypersomna, Research

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Antibiotic May Decrease EDS in GABA-related Hypersomnia

clariA study of clarithromycin in the treatment of GABA-related hypersomnia indicates that this drug may be effective in some patients with idiopathic hypersomnia (IH), narcolepsy without cataplexy, and subjective hypersomnia.

Background

The US Food and Drug Administration (FDA) has not approved any drugs for the treatment of IH. Therefore, current treatments are all prescribed off label, meaning that the FDA has approved the drug for some other purpose but not for IH.

As reported in 2012, researchers at Emory University discovered that the cerebrospinal fluid of many of their patients with central disorders of hypersomnolence contained an unknown substance that, when tested in the laboratory, enhances the action of GABA (gamma-aminobutyric acid, the main inhibitory neurotransmitter) in a way similar to that of benzodiazepines or sleeping pills, such as Valium or Ambien. The researchers termed this a “somnogen” and the resulting disorder, “GABA-related hypersomnia.”

The researchers then tested a treatment to counteract these sleep-enhancing effects in seven patients who had been diagnosed with GABA-related hypersomnia (two with IH, two with narcolepsy without cataplexy, and three who had “habitually long sleep”). The researchers gave all of these patients a GABAA-receptor negative allosteric modulator, flumazenil, intravenously. The patients both reported being less sleepy and improved their reaction times on the Psychomotor Vigilance Task (PVT).

In subsequent papers, the Emory researchers reported that clarithromycin, a macrolide antibiotic that is typically used to treat skin and respiratory system infections, also decreased daytime sleepiness in people with GABA-related hypersomnia.

What kind of research study was this new study?

This was a 5-week, double-blind, placebo-controlled, crossover study.

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

All of the participants had IH, narcolepsy without cataplexy, or habitually long sleep times. They took either clarithromycin, 500 mg, or placebo at breakfast and at lunch for two weeks. They then took no drug for one week, followed by the opposite drug that they took in the first part of the study—either clarithromycin or placebo—for another two weeks. They came to the Emory research clinic at the same time on the same day of the week for these five weeks, where they completed several questionnaires and performed two PVTs during each visit.

Who were the researchers and what did they do?

Dr. Trotti and her colleagues at Emory University in Atlanta, GA, selected the participants, reviewed the questionnaires, and analyzed the data from the PVTs.

What were the results of the study?

Fifteen women and five men took part in this study. There was no difference in mean reaction time on the PVT at week two between people’s scores when they were taking clarithromycin versus when they were taking placebo. However, significant differences were found on the results of the questionnaires. When taking clarithromycin, the participants had an average four-point lower score on the Epworth Sleepiness Scale, improved scores on the Functional Outcomes of Sleep Questionnaire, and increase in the energy subscale of the SF-36.

Those in the clarithromycin group were more likely to report an altered sense of taste or smell. Otherwise, no differences were found in side effects. These changes are similar to or better than improvements typically seen with modafinil for the treatment of excessive daytime sleepiness associated with narcolepsy or shift work disorder.

What were the authors’ conclusions?

“Clearly, the long term use of an antibiotic must be justified by clinical benefit that exceeds these potential risks, as we have elaborated elsewhere. . . This preliminary study suggests that there is a subjective treatment benefit from clarithromycin for idiopathic hypersomnia, narcolepsy without cataplexy, and subjective hypersomnia, consistent with the benefit previously reported in clinical practice. . .  “[C]larithromycin might be considered, especially in cases that are otherwise treatment-refractory.”

Trotti LM, Saini P, Bliwise DL, Freeman AA, Jenkins A, Rye DB. Clarithromycin in GABA-related hypersomnolence: a randomized, crossover trial. Ann Neurol 2015. doi: 10.1002/ana.24459. [Epub ahead of print]

Posted in: idiopathic hypersomna, Kleine-Levin syndrome, narcolepsy, Research, Uncategorized

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