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Jordan Gaines
Neuroscience
Pennsylvania State University USA

A blog on biology, psychology, cognition, learning, memory, aging, and everything in between. Explaining recent discoveries in neuroscience, translated to language we can all understand!

My posts are presented as opinion and commentary and do not represent the views of LabSpaces Productions, LLC, my employer, or my educational institution.

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Thursday, June 7, 2012

Check out this short video of "Rusty the Narcoleptic Dog." I was first introduced to Rusty in a video presented to my high school psychology class. As expected in a classroom full of teenagers, we erupted into a fit of laughter when the happy-go-lucky dachshund suddenly collapsed into a deep sleep.

Gallup polls reveal that 56% of Americans complain that daytime drowsiness is a problem in their lives, the majority of which is caused by sleep deprivation. A controlled, objective scientific study once revealed that 34% of participants were considered "dangerously sleepy," even when they didn't complain about daytime sleepiness.

America is a sleepy country—but narcolepsy takes it to a whole new level. Imagine feelings of exhaustion at all times, accompanied by inappropriate sleep attacks. Sure, falling asleep on the job is embarrassing and unprofessional, but also imagine the danger of a narcoleptic attack while driving. What is narcolepsy, and what causes this mysterious disorder?


What is narcolepsy?
Narcolepsy is a curious disorder characterized by excessive sleepiness. The sleep attacks are particularly strange; typically, it takes us at least an hour of sleep to reach the REM (rapid eye movement) stage—the period during which we dream and our muscles are essentially paralyzed. In narcoleptics, however, they're locked into REM in as quickly as five minutes. Additionally, when experiencing a strong emotion, some fall into a state of cataplexy, or a sudden muscular weakness. This can result in something as benign as facial drooping to as dramatic as a total collapse.

Narcolepsy is a sleep disorder, not caused by psychological problems or mental illness. Occurring more often in men, there is a wide variation in diagnosis between countries. In Japan, as many as 1 in 600 people are diagnosed; Israel comes in at just 1 in 500,000. The rate for the United States is 1 in 2,000.


A genetic link
People with narcolepsy are more likely to have a relative who also has the disorder, suggesting that the disorder is genetic.

Indeed, a correlation has been identified between narcoleptic individuals and variations of the human leukocyte antigen (HLA) gene. Certain variations in this gene appear to increase the risk for an autoimmune response against particular neurons in the brain.

The affected neurons are responsible for producing a protein called hypocretin (A.K.A. orexin), which controls eating and sleeping patterns. Narcoleptic individuals with the HLA gene mutant have reduced hypocretin, suggesting its possible role in disrupted sleep.

In 2004, Australian researchers found that mice injected with antibodies from narcoleptic humans developed narcolepsy-like symptoms, another link suggesting that it may be autoimmune.



Narcolepsy and...flu?
Anyone who has contracted the flu or some other virus can relate to the inexorable tug of sleepiness and—many times, most likely—fell asleep at the drop of a hat.

Even when I got my flu shot back in October, I was exhausted. I slept 10 hours that night. Woke up, made pancakes, ate them in bed, then putthe plate on the floor and promptly fell back asleep. I spent the remainder of the day studying for an upcoming exam and nodding off every few minutes.

Is this all more than simply your sick body's way of forcing you to rest?

Currently, researchers are investigating a link between the swine flu (H1N1) vaccine Pandemrix (GlaxoSmithKline) and an increased prevalence of narcolepsy in Irish, Swedish, and Finnish children post-vaccination. This particular vaccine is unique because it is "double-boosted." Thirty-seven new cases of narcolepsy were documented in Finland, in comparison to the annual average of three.

Last August, a study published in Nature Reviews Neurology described how the number of narcolepsy cases in China tripled after the 2009 swine flu pandemic, a country where only 6% of the population received flu shots.

In retrospect, the narcolepsy/immune system link may have been unknowingly established for awhile. Interestingly, in the years following the 1918 flu pandemic, doctors had described a seasonal sleepiness they termed "encephalitis lethargica."


The future of narcolepsy
Current treatments range from stimulants (meth-/amphetamines) to long naps, but is there a hopeful future for individuals suffering from this potentially dangerous disorder?

A study published by Harvard researchers in 2004 found that transplants may function as long-term, non-pharmacological therapeutic—in rats so far, anyway.

In this study, rat hypocretin-containing cells from the hypothalamus (a brain region largely responsible for endocrine function) were grafted to the pontine reticular formation (involved in arousal and awakening). The grafts appeared successful, compared to tissue taken from cerebellar cells, which do not contain hypocretin.

In the meantime, individuals suffering from narcolepsy learn the best ways to cope. Perhaps the most famous narcoleptic in history, Winston Churchill, evidently made the most of it, offering some words of wisdom: "You must sleep sometime between lunch and dinner... Take off your clothes and get into bed... You get two days in one. Well, at least one-and-a-half."

Photo courtesy Narcoleptics.net, Wikipedia, Sleepy G's, and Sunlight Uplands. Video courtesy crusheddiamonds (YouTube). 

Arias-Carrión O, Murillo-Rodriguez E, Xu M, Blanco-Centurion C, Drucker-Colín R, & Shiromani PJ (2004). Transplantation of hypocretin neurons into the pontine reticular formation: preliminary results. Sleep, 27 (8), 1465-70 PMID: 15683135

Wood, H (2011). "In brief." Nature Reviews Neurology, 7 (10), 537.

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Moshe Turner

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Thanks for he article on Narcolepsy.  I have a few comments.

 

You write: “Imagine feelings of exhaustion at all times…..”.   Now please hear me, this is NOT nitpicking or semantics; it is a very important point.  Narcoleptics do not have this experience of exhaustion.  Narcoleptics (or PWN [persons with narcolepsy] as the boards have it) make a very clear distinction between feeling sleepy and feeling tired.  To a PWN, tired means weary in a physical way as in you have no energy, while sleepy means, well, sleepy.  The better way to say what you meant would be,  “Imagine feeling half-awake and groggy all the time…”

 

Narcolepsy has long been listed as a sleep disorder but this is a holdover from its earliest days when its cause was unknown.  Beginning with the discovery of the neuropeptite orexin, also called hypocretin, and the recognition that the sleepiness of narcolepsy is simply the most visible physical symptom of low or absent orexin levels in the brain, it became clear that narcolepsy is a disorder of the endocrine system that develops out of an autoimmune attack on the relatively few brain cells that produce orexin.  Orexin has been called the “conductor of the endocrine symphony” as it directly or indirectly regulates a great many neurochemicals including GABA, acetylcholine, leptin, and the monoamine neurotransmitters dopamine, serotonin, norepinephrine, histamine and epinephrine, among others. We find that blood pressure, breathing, body temperature, intestinal motility, olafactory sensation, weight regulation and of course the sleep/wake cycle are some of but not all of the physical processes upon which orexin acts and which are affected in PWN.

 

I read a news report recently that one of the diagnostic guides has proposed moving narcolepsy into the category of an endocrine disorder.  Further research on this is strongly advised, but in the interim I think it would be best not to continue to refer to narcolepsy as a sleep disorder.

 

Cataplexy, the sudden loss of muscle tone in response to an emotional stimulus, is found in 3 out of 5 narcoleptics.  Samples of central spinal fluid taken from narcoleptics with cataplexy show no evidence of orexin being present, while samples from “ordinary” narcoleptics showed orexin in varying, but low, amounts.  In short, PWN having cataplexy have no orexin, while PWN w/o cataplexy don’t ever have quite enough, i.e. not all their orexin-producing cells have been destroyed, giving rise to the “good brain day / bad brain day” pattern found among that group.

 

In my understanding to say narcolepsy is a genetically transmitted disorder is not entirely correct.  What would be more correct to say is that in the case of a person having the gene mutation you cited (and there is a test for the marker for that) there is a stronger likelihood that an “ordinary” illness such as the flu, or another immune system stressor such as an infected wound or a very high fever can trigger an autoimmune response which can destroy orexin neurones, which would result in the person becoming narcoleptic.  To say it this way makes it clear that even someone with a propensity toward such an autoimmune response can escape becoming narcoleptic if his immune system never has any reason to get all excited, so to speak.

 

The above explains why so many children in the Scandinavian countries developed narcolepsy after being innoculated with the GSK vaccine, and why the Chinese have noted an increase in narcolepsy after each flu season. Your article was not at all clear in explaining this.

 

You stated that the treatments for narcolepsy range from stimulants to long naps.  I hope you will forgive me for saying, but this is simply unforgivably bad journalism reflecting a paucity of research.  In fact, the latest research you cited is eight years old, a lifetime in the fast-moving area of neurology research.  I would suggest many more and longer visits to pubmedcentral.gov.

 

Narcolepsy is treated with medicines ranging through certain antidepressants, central nervous system stimulants such as methamphetamine, non-CNS stimulants such as modifinil (Provigil), and sleep-enhancing drugs such as Zyrem, the infamous “date-rape drug” which is so powerful and fast acting that one needs a license to take it, and which must be taken while already in bed.

 

The cure for narcolepsy, or rather the pharmaceutical treatment for the complete elimination of symptoms, is to give a person orexin.  Simple, right?  Actually, it only sort of is.  For some years after the isolation of orexin, it was thought impossible to get orexin past the blood-brain barrier. However, in a landmark study conducted at Wake Forest University in 2007 improbably entitled “Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effect of Sleep Deprivation on Cognitive Performance in Non-Human Primates”, it was shown that orexin administered via nasal spray did in fact pass the blood brain barrier and was more efficacious at improving cognitive function than orexin that was intravenously administered.  Importantly, this study was done for DARPA, which would explain (in my opinion) why no more has been heard on this subject.

 

My doctor says that there are not enough narcoleptics in the world for Big Pharma to be interested in improving our lives.  Rather, they are much more interested in the over 3 billion dollars a year market for drugs that are orexin antagonists, i.e. block the orexin receptors, thus getting the worlds insomniacs to sleep without the risk of a drug hangover in the morning.  That may be so, but while I am in no way a conspiracy theorist of any kind, try writing about why this information has mysteriously vanished off the medical community’s radar and I guarantee you will get a call or a visit from DARPA.

 

Interestingly there was a study done in Germanyin called “Olfactory Dysfunction in Patients with Narcolepsy with Cataplexy is Restored by Intranasal Orexin A Administration”.  In this study orexin was given to human narcoleptics. Even the dosing information was included.  The results?  Yes, if you give a narcoleptic orexin it will improve his sense of smell.  (Duh.) Unbelievably, there is no mention made of whether or not these people reported any improvements in their other cognitive faculties or in their lives generally!  Now why do you suppose that was?

 

My doctor also told me that it is ILLEGAL in theUnited Statesto give a human being orexin.

Hmmmn.

 

I neglected to mention that I am a 56 year old PWN w/o cataplexy.  My life has been destroyed several times over by this horrific, insidious, evil disorder.  I really need this medicine. Why is it illegal to do human research with it in theUS?

 

So how bold are you?  Why not write an expose on how tens of thousands of people in this country, hundreds of thousands worldwide, are being deprived of a virtually life-saving medicine and get it published in a big media outlet.  And see if you get a visit from some big guys with shades arriving in a dark sedan.

 

  


Jordan Gaines
Pennsylvania State University
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Hi Moshe,

Thanks for your insights and corrections. You certainly taught me a great deal in your comment. 

I apologize for skipping over the treatments—I didn't really intend to go into great detail about treatment, but I did want to bring up the orexin neuron study. You're right, 2004 was certainly a long time ago in the big world of research, but the fact that it was a landmark finding set the stage for the Wake Forest and Germany studies. You finished the story for me with the unfortunate ending of orexin being illegal in the U.S.

In my online research, it seems DARPA got some backlash in the media for the Wake Forest study when people advertised Orexin-A as the "miracle drug" you could take to make you feel awake even when you didn't get a full night's sleep. There are cynical articles about truckers and college students who would abuse it. It's rather infuriating to read given that the people who DO need it are not considered.

Big Pharma seems to be all about the money and target audiences—I think of it as putting out a pilot TV episode and scrapping it when it doesn't receive enough viewers despite people that enjoyed what they saw.

I thank you again for your information and planting an idea in my head for further investigation.

Tina

Guest Comment

This is interesting

 

Sisu

Guest Comment

Actually, I expect that there will be a huge boom in the study of various treatments, not because narcolepsy is a hot subject, but because finding ways to treat it may also find ways to make fat people thin.

 

http://www.ncbi.nlm.nih.gov/pubmed/21982708

 

Although it may seem irrelevant, brown fat is the new "skinny drug" that they're discovering. And it takes orexin to make it work- which means that orexin boosters may be developed for the purpose of turning on brown fat for metabolism enhancement. In the long run, the billion-dollar war on obesity may benefit PWN the most.

 

 

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