Hypersomnia Foundation

Interview with David Rye

1. How many people suffer hypersomnia? Is this different from narcolepsy?

YES these disorders are different from narcolepsy as narcolepsy is traditionally defined.  The term narcolepsy literally translates as something like “sleep seizures”—e.g., epiLEPSY—in fact, when narcolepsy was first described in the 1870s-1880s—-it was thought to potentially be a seizure or a disorder of epilepsy.  Ironically, this sort of narcolepsy is classified under the broad heading of primary hypersomnia (or “too much sleep”) – even though these ‘genuine’ narcoleptics do not sleep more time over 24 hours than do normal people.  Sleep is generally refreshing – and wake is interrupted by brief “attacks” of sleep that last 10-15 minutes or so–and these naps are generally refreshing.  The patients that we describe in our paper are not these.  Rather, they have long, deep, unrefreshing night-time and naptime sleep.  Some say that they do not take a nap—-”I take a coma”.  They typically resort to elaborate means to get themselves to wake-up – for example, multiple alarm clocks – some that fly, some that walk and that need to be physically “caught” in order to turn them off.  They DO sleep more over 24 hours than the normal person – we’re talking on average nearly 11 hours.  Unfortunately, some of them are given the label “narcolepsy” due to convention of sleep medicine experts – which is unfortunate because they are not at all like the narcoleptics I describe above.  True narcolepsy is also caused by a loss of the neuropeptide hypocretin which these other patients have normal amounts of.

Because of these confusions and an absence of a gold standard test for these non-narcoleptic hypersomnia patients (and the use of many different labels/names that have been applied to them) – a true prevalence has not been determined.  Classic texts state that the disorder is rare.  We would disagree – although our paper does not really speak to commonality – we show 32 patients – not hard to find them – over the same time frame in our clinic we saw only 9-10 “genuine narcoleptics”.  We have some data suggesting that the prevalence is at least 1 in 800 – which is more common than the hypcoretin deficient narcolepsy which is described above (e.g., 1 in 2000).

 2. How would you describe the symptoms of hypersomnia and how long do they last?

See above a bit about the characteristics of these patient’s sleepiness.  Even though they sleep long periods, they wake up with difficulties – often with a sort of “sleep drunkenness” – and are sort of in a constant state of slumber.  The disorder begins at a young age (19.4 years in our paper sample) – and is generally chronic – quoted ranges of spontaneous resolution of remission of symptoms by others and in our experience is 10-15%.  So, a lifelong disorder in most.  In our paper I believe the most sleep per week reported by one patient was 94 hours (routinely).  The symptoms can also wax and wane – so folks can have good weeks/months and worse weeks/months.  Some women report that symptoms intensify just before and early in their menses.

 3. Can you describe cerebrospinal fluid?

Cerebrospinal fluid is a clear fluid that “bathes” the brain and spinal cord.  Humans have about 150mls of this fluid and it recycles at a very high rate – e.g., about 1/2 ml /per minute.

 4. What is the magnitude of the chemicals effect on GABA receptors (in other words, how does it compare to the GABA receptors of a normal person)?

If one takes a sleepy patients spinal fluid (i.e., a hypersomnia patient) – by itself it does nothing to a GABAA receptor in a dish – and that is because there is very little GABA in the spinal fluid.  However, if one takes this spinal fluid together with a high concentration of added GABA – there is an accentuated or enhanced level of response to the GABA (when compared to spinal fluid collected from non-sleepy control patients).  One can reverse this effect with the drug flumazenil in the dish assay that we use.  This indicates the presence of a positive allosteric modulator – i.e., a substance that binds to the GABAA receptor which changes its biohysical properties so that it now becomes MORE sensitive to GABA when it sees GABA.  Thus, the enhancement of GABA’s effects.

 5. Any guesses as to what the substance that causes the GABA receptors to be hyperactive could be, and what is your reasoning?

We report that the above enhancement can be reversed 90% by flumazenil which is thought to be solely a traditional antagonist at the GABAA receptor and FDA approved for reversal of benzodiazepine overdosage – (e.g., prolonged sedation when given or overdosing with valium (e.g., diazepam), versed (e.g., midazolam) -or say . ambien (e.g., zolpidem).  Also, we can get rid of nearly 100% of the activity if we treat spinal fluid with trypsin -which is an enzyme that “eats up” -inactivates proteins/peptides.  So, we think the molecule acts like a benzodiazepine near to, but not exactly at the benzidiazepine binding site on gABAA receptors—-and is a small peptide.

 6. What is the current treatment for people suffering from hypersomnia?

There are no approved treatments.  Doctors typically prescribe:  amphetamine derivatives (meth-amphetamine, dex-amphetamin)—e.g., Adderall,; or methylphenidate (Ritalin) or modafinil (Provigil)—someties gamma-hydroxybutyrate -(Xyrem)—-there is little data to support their usage.

 7. Why is this sleep disorder so under-studied?

Scientists are drawn to dramatic things – and genuiine narcolepsy – with sudden attacks of sleep and cataplexy is certainly dramatic.  Even though folks recognized this other group of people who sleep too much at roughly the same time in medical history—-many other things have been associated with – but not necessarily proven to “cause” hypersomnia = for example:  depression, chronic fatigue syndrome, being “lazy”, or having a medical disorder like anemia, or iron deficiency or low-thryoid…..thus, absent a very well defined symptom or biological marker unique to a subgroup of these patients—–they sort of get lost……..they, as mentioned are said to be “rare” – but we strongly believe that this is not so…..we see many more of these patients than genuine narcolepsy.

8. Is there anything else you would like to share.

YES—-This knowledge begets new avenues to properly diagnosing this large, unmet clinical need and providing more rational and effective treatments that is driven by knowledge of the biology—not simply empiric treatments—-driven by little knowledge and that do not work too well in these patients and can have significant side effects otherwise.

Posted in: Research

Leave a Comment: (3) →

3 Comments

  1. Shep Greenberg January 20, 2013

    Thank you for your research into IH. I finally feel like there is some hope out there for those of us afflicted to have normal lives again.

    reply
  2. Jennifer January 21, 2013

    My 9 year old daughter suffers from idiopathic hypersomnia she has tried several stimulants but they made her OCD worse so she is now trying dextroanphetamine we have to up her dosage but it seems like it is starting not to work again. My daughter only weighs 56 lbs so she is little for her age. She also takes meds for her OCD. Are they working on anything that will help kids? Are there any treatments you are aware of for kids?

    reply
  3. sleepydoc April 2, 2014

    Why can’t Roche, Jazz, Cephalon, Novartis and other pharmaceuticals with big stakes in the “sleep disorder business” just save us from narcolepsy, primary and other hypersomnias!

    The main problem is GABA receptor dysfunction (inappropriate endogenous production and/or irregular, unpredictable receptor stimulation etc).

    We have potent, reliable GABA agonists (for both A and B receptors). Flumazenil is a potent GABA receptor antagonist, which can be “re-engineered” for a long acting oral, sublingual or other non injectable administration.

    I’m 99.9 % certain, that taking GABA receptor agonists at bedtime and long acting GABA antagonist on waking up, should provide effective control in 99.9 % of hypersomnias.

    Daily 2 hour, full body workouts (stretch, tone, cardio) and supplements like L Tyrosine and Glutamate, required for endogenous dopamine production, should add flavour and spice to above standard narcocataplectic regimen.

    The massive funds spent on hypocretin, CSF or brain somnogen and other purely academic research, may be used to subsidise the drug costs.

    Let’s manage the patient, not the pathophysiology.

    reply

Leave a Comment