Retraction of Paper “Confirming” Narcolepsy as an Autoimmune Disease

Today is a disappointing day in the narcolepsy community.The scientific
manuscript reported to have “confirmed” narcolepsy as an autoimmune disease has been formally retracted.

The retraction notice states, “The researchers report that they have been unable to reproduce the paper’s key findings.” (source www.retractionwatch.com)

m.stm.sciencemag.org

Source: m.stm.sciencemag.org

The paper, entitled  “CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy,” and published by Science Translational Medicine in December 2013, caused more than media ripple.  Submitted by co-senior authors Mellins and Mignot and collaborators, the original article was highlighted in more than 100 news and press releases, and received featured articles and posts on major news sites including Nature News, Scientific AmericanThe Huffington PostMedical News Today, National Geographic, Psychology Today — it even made waves in The New Reddit Journal of Science

The article has been cited 4 times since it’s publication in Dec. 2013, according to PubMedCentral.

At the time of publication, the paper was reported to demonstrate immune cross-reactivity between a flu antigen and the orexin protein — so-called molecular mimicry. In layman’s terms, if an immune response was generated recognizing flu antigen (such as during natural infection or in a vaccine), that immune response could also target neurons in the brain expressing orexin. Specifically reported was (1) characterization of narcolepsy-specific auto-immune CD4+ T cells, (2) their corresponding epitopes, and (3) evidence of a mimicry-based mechanism potentially explaining the association between narcolepsy and influenza infection.

Orexin is a hormone critical for maintaining wakefulness. Loss of orexin-producing neurons is believed to be the primary cause of symptoms in many individuals with narcolepsy. You can learn more about narcolepsy here.

These results were poised to explain the increases in narcolepsy following Pandemrix vaccinations in Europe during the 2009 H1N1 influenza pandemic.  Earlier studies suggested that the adjuvant used in the Pandemrix vaccine, AS03 (which was not approved for use in the United States) may have been to blame.

The findings of the paper in question caused a stir because for many years studies have failed to demonstrate orexin immunoreactivity or a cell-specific immune response to orexin producing neurons, despite the fact that narcolepsy contains other “autoimmune signatures” including a high (90%) association with a specific HLA genotype (HLA-DQB1*0602), and a strong association with the T-cell receptor alpha locus, among others.

A quote from the Nature News article summarizes the general sentiment well:

“Thomas Scammell, a neurologist at Harvard Medical School in Boston, Massachusetts, says that the results are welcome after “years of modest disappointment”, marked by many failures to find antibodies made by a person’s body against their own hypocretin. “It’s one of the biggest things to happen in the narcolepsy field for some time.”

 

Co-senior author of the study Mellins is quoted:

“Up till now, the idea that narcolepsy was an autoimmune disorder was a very compelling hypothesis, but this is the first direct evidence of autoimmunity. I think these cells are a smoking gun,”

 

With many basic science manuscripts which make significant discoveries, the excitement is often confined to the scientific community. What is different about this paper is that the enthusiasm bubbled over into patient circles and prominent outreach organizations. Narcolepsy has been long suspected to be of immune origin, and the fact that this theory hasn’t been yet confirmed has meant the often stimatized patient population continues to struggle with being incorrectly diagnosed with mental and behavioral disorders, often up to 15 years before receiving a correct diagnosis. One of the important advancements that might have been made from the discoveries of this paper was the development of a new diagnostic test for narcolepsy, which could improve diagnosis and time-to-diagnosis for patients.

Interestingly, a letter written by inventors of Pandemrix was submitted in February 2014 stating that  “CD4+ T cell cross reactivity” was part of a “research plan.(update 9-9/30/14: the letter has since been retracted). The research plan, authored by GlaxoSmithKline researchers is entitled “Narcolepsy and A(H1N1)pdm09 vaccination: Shaping the research on the obeserved signal” was published in December 2013.  In it, they listed key areas of research needed to fill the information gap about how the Pandemrix AS03-adjuvanted influenza vaccine could have caused increases in narcolepsy:

Therefore, the following key areas of research can be identified, (1) characterization of hypothetical narcolepsy-specific auto-immune CD4+ T cells, (2) mapping epitopes of such T cells, and (3) evaluating potential mechanisms that would enable such cells to gain access to the hypothalamus. Addressing these questions could further our understanding of the potential links between narcolepsy and A(H1N1)pdm09 vaccination and/or infection. Of particular interest is that any evidence of a mimicry-based mechanism could also explain the association between narcolepsy and A(H1N1)pdm09 influenza infection.

 

As a reminder, the reported findings of the now retracted “CD4+ T cell cross reactivity…” paper were: (1) characterization of narcolepsy-specific auto-immune CD4+ T cells, (2) their corresponding epitopes, and (3) evidence of a mimicry-based mechanism potentially explaining the association between narcolepsy and influenza infection.

A timeline of events is shown below:

retraction timeline crop

It should be noted that the publications of GlaxoSmithKline researchers did not reportedly contribute to the rectraction of “CD4+ T cell Autoimmunity…”

According to RetractionWatch.com, Mignot has said regarding the retraction:

Mignot tells us:

We were just continuing our work based on the finding, trying to establish it as a diagnostic test, but could not replicate it.  No other work is affected, and in fact the DQ binding studies of that article are perfectly fine.  Only the [Enzyme-Linked ImmunoSpot (ELISPOT)] results are in question.

The retraction notice first appeared on the mobile site of Science Translational Medicine on July 23, 2014, but linked to a “Content Not Found” page. The “Retraction” section was missing from the non-mobile version of the website, and no reply was received when the Editors of STM were contacted to clarify whether the article had been retracted or not.

In spite of this disappointing turn of events, the community is hopeful that we will continue to move forward in our pursuit of understanding the molecular mechanisms of narcolepsy and that these developments will lead to improved diagnostic tools and treatments.

References:

A. K. De la Herrán-Arita, B. R. Kornum, J. Mahlios, W. Jiang, L. Lin, T. Hou, C. Macaubas, M. Einen, G. Plazzi, C. Crowe, E. W. Newell, M. M. Davis, E. D. Mellins, E. Mignot, CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci. Transl. Med. 5216ra176 (2013).

M. Brandt. “Narcolepsy is an Autoimmune Disorder, Researcher Says.”  Stanford Medicine News Center. (2009.)

K. Conger. “H1N1-triggered narcolepsy may stem from ‘molecular mimicry,’ study finds.” Standford Medicine News Center. (2013)

E. Yong. “Narcolepsy confirmed as autoimmune disease.” Nature News. (2013).

S. Harris. Notes on NarcolepsyPsychology Today. (2012).

J. Hallmayer et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nature Genetics. 41, 708 – 711 (2009)

The First Documented Case of Narcolepsy – Is the flu to blame?

Narcolepsy, as a documented disorder, first appeared in medical literature in 1880. Dr. Jean Baptiste Edouard Gélineau published an account of a 38 year old man with a two-year history of narcolepsy. The man experienced up to 200 sleep attacks a day, and also had cataplexy. Interestingly, Dr. Gélineau also describes the patient as having a “nervous, volatile temperament” and “histrionic personality” – an endearment many of u220px-Jean_Baptiste_Edouard_Gélineaus with narcolepsy can probably relate to. The patient also reports having conceived his child “in a moment when the illness came over him.” Cataplexy at orgasm is a phenomenon that has been largely discussed in PWN forums, and has been recently described in medical literature.

Narcolepsy has also been recently linked to influenza. Outbreaks of narcolepsy occurred after the 2009 Swine Flu pandemic and was apparently precipitated by the adjuvant used in the Pandemrix vaccines. However, it has been determined that there is potentially some molecular mimicry occurring between orexin proteins and specific proteins found in influenza itself and the influenza vaccines, confirming that type I narcolepsy is of autoimmune origin It begs the question, could this first case of narcolepsy have also been precipitated by influenza?

In Dr. Gélineau’s description, the abrupt onset of this particular case led to the suggestion of a potential head trauma in precipitating the disease. This phenomenon is still described today. In this particular report, the patient had been punched in the head and also had a log fall on his head about three years prior; it was determined that these probably did not contribute to his disease in the initial report, though.

What if it was actually precipitated by influenza? The 38 year old man described in the report was first seen by Dr. Gélineau in 1879.  Five years prior, he had “suffered acute rheumatism in the joints and Herpes tonsurans at the same time.” 

Rhuematism is an inflammatory inflammatory disease that occurs following a Streptococcus pyogenes infection. Importantly, patients with recent onset narcolepsy have demonstrated in increase in anti-streptococcal antibodies. Additionally, influenza infection boosts subsequent Strep pyogenes infection and invasion. For a more detailed perspective on this, check out one of Heidi L.’s most recent posts, H1N1 Flu Virus may cause Narcolepsy via Secondary Infection.

Interestingly, the patient’s symptom appearance is sandwiched between two influenza pandemics (the 1847-1851 pandemic and the 1889-1893 pandemic). Capture

If the patient had a childhood bout of influenza (a likely event, particularly during the pandemic), this might just have been the original trigger of his narcolepsy. To be sure, many people are now discussing respiratory events as predisposing factors in their own narcolepsy. Just check out how many times sinusitis is listed on this thread. Below is a timeline of documented events for that first patient.

influenza pandemic

So, could the influenza virus and Strep infection have a played a role in the first case of narcolepsy? Maybe, but maybe not. Share your opinions below!

 

Anti-Narcoleptic Vitamin Regimen

BIG FAT DISCLAIMER: I am not a medical doctor. The following is not advice or medical recommendation. Please see the official disclaimer here.

 

I have been off of conventional narcolepsy treatments for 3 years, and gluten free for 4 years. Over time, I have found a host of vitamins and non-prescription nutritional supplements that have greatly increased my wakefulness and helped with other aspects of daily functioning. Please note that this is my personal log. What they are, and how I think they are helping are below.

L-tyrosine :

I began taking L-tyrosine about a year ago following a blog post concerning “Narcolepsy, dopmine and tyrosine“. I started the tyrosine regimen (between six and nine grams a day, broken up into two doses [1 at breakfast, 1 at lunch]) following reading a paper in the Lancet that reported total remission of daytime sleep attacks and cataplexy after six months of treatment. The military has also used L-tyrosine in sleep-deprived pilots to improve performance during long flights. Another report which included more rigorous controls noted that only 3 of 10 patients noted a positive effect, and so L-tyrosine could not be considered therapeutically relevant. Personally, I noticed that at the 9 gm dose I experienced a great deal of anxiety – particularly in the evenings. However, lowering the dose to 3-5 gm per day and them in the morning and early afternoon gives me the benefits of wakefulness during work hours without increased evening anxiety. A summary of how I think it’s working is below:

L-carnitine: I take 1000 mg of L-carnitine per day (500 mg in the morning, 500 mg at night). Carnitine is is an important essential nutrient, and has been demonstrated to be therapeutic for individuals with narcolepsy. Click here for my long blog post on L-carnitine and narcolpesy.

In short, individuals with narcolepsy have very low levels of serum acylcarnitine. Reduced acylcarnitine means impaired fatty acid oxidation, disturbed sleep, and impaired orexin cell functioning.

Oral supplementation of L-carnitine restores β-oxidation (fatty acid oxidation) and mitochondrial ATP generation from fatty acids.

Carnitine also has marked effects on proper intestinal development and function and reduces intestinal inflammation.   Carnitine is also necessary for proper immune functioning and promotes regulatory cell function (think: anti-autoimmune). Carnitine supplementation can also improve obesity, glucose tolerance and energy expenditure

 

 

Wordless Wednesday: WEGO Health Activist Writer’s Month Challenge Day3

I painted this last year for a dear friend of mine who also has narcolepsy.

A few of my favorite things about the piece:

1) Black areas of the brain “dotted out” to demonstrate the areas of neurodegeneration seen in narcolepsy.
2) Hand and eyeball to demonstrate the visual hypnagogic hallucinations which are a specific feature of narcolepsy.
3) wave-like motions and sound waves above the reclining spine and brain reminiscent of the wave-like physical and auditory experiences in individuals experiencing hypnagogic hallucinations
4) Lilluptutian hallucinations (the little black men), a not-uncommon feature of hypnagogic hallucinations.. It is also significant that the dreams (i.e. little black men) invade the surrounding space and reside on the area where the chest would be of the person. A “Witch sitting on the chest” is also a common feature of hypnagogic hallucinations and sleep paralysis events.
5) A symbol for science in the upper right hand corner, as a reminder that our scientific efforts can shed light, hope and relief, on all neurodegenerative disorders, among them narcolepsy.
6) White speckles resembling migraine-related auras. These are seen in vascular and neurodegenerative dementia, in epilepsy, neurotoxicities, multiple sclerosis, among others, and may also be seen in narcolepsy on occasion.
 Here’s a close up of the piece. I’m a huge fan of 3D-ness.

 

Narcolepsy, dopamine and tyrosine.

Recently, I have been intrigued by the link between dopamine and narcolepsy.  About a year ago, I had a blood test done for neurotransmitters, which indicated that I had normal serotonin, but low circulating dopamine. Nutritionally, this would indicate a deficiency in intake of L-tyrosine, or maybe a defect in the conversion to dopamine, or some other mechanism of dopamine release in the brain.

I didn’t really appreciate the bloodwork, until I realized there were signs of dopamine deficiency in family members on my mother’s side. My maternal grandfather has long suffered with restless legs syndrome, which can be caused by dopamine deficiency (and, also iron deficiency, which is important for dopamine storage and neurotransmission in the brain). Prior to going gluten free, I often struggled with restless legs, and still cannot take anti-histamines without feeling like my legs are going to dance off my body (anti-histamines are known to aggravate RLS).

I also am a runner, and thrive off of the runner’s high that I get. Running stimulates the release of beta-endorphins, which disinhibit dopamine transmission. In otherwords, running increases dopamine levels in the brain.

In addition, my mother, sister, and I have all struggled with attention deficit disorder (ADD), which has been demonstrated to be connected to low dopamine transmission.

Though not well currently reviewed in the literature, dopamine and narcolepsy appear to have a close association with one another. Orexins act on dopaminergic nuclei, which express orexin receptors, indicating that orexin influences dopamine neurotransmission. In rats, infusion of orexin increases dopamine in the brain. Additionally, increases in orexin (and correspondingly dopamine) increased the time the rats spent awake. For narcoleptics, a deficiency in orexin neurons and orexigenic neurotransmission could cause a secondary dopaminergic neuron transmission deficiency. (i.e. – if orexin isn’t released, dopamine isn’t released).

From a therapeutic perspective, dopamine agonists have long been used to treat cataplexy and excessive daytime sleepiness associated with narcolepsy.  Amphetamines (such as Ritalin) have long been used to reduce daytime sleepiness associated with narcolepsy, and amphetamines have been shown to increase levels of dopamine in the brain. In addition to the traditional stimulants, a more recently adopted wakefull-ness promoting drug, Modafinil, has also been shown to increase dopamine (and histamine) release, potentially by inhibiting the reuptake of dopamine.

In addition to conventional medicinal treatments, administration of the amino acid L-tyrosine, which is a precursor to dopamine, has been shown to positively affect symptom management in narcolepsy.  Patients were administered 100 mg/kg/day (which is about 6 grams of L-tyrosine for the average person) for 6 months, and were reported to have complete remission of symptoms.  Another study found that quantities of about 9 grams/day provided some wakefulness promoting effects, but it was not deemed a suitable alternative for use alone.  There are limited reports of the use of L-tyrosine in scientific literature, however, and no studies have been published on it’s use recently.

Another compelling  piece of the dopamine/narcolepsy connection comes from another neurodegenerative disorder, Parkinson’s disease (PD), whereby individuals lose dopamine-producing neurons in the brain. In fact, PD shares many features with narcolepsy including REM disorder and hallucinations as well as daytime sleep attacks. Indeed, it has been demonstrated that orexin-producing neurons are also lost in individuals with Parkinson’s disease, and narcolepsy has recently been implicated as a potential risk factor for PD, although it is unclear if this is an intrinsic risk factor, or if the treatments associated with  narcolepsy (i.e. long-term amphetamine use) contribute to the deterioration of dopaminergic neurons and development of PD.

Due to the compelling literature evidence that dopamine and narcolepsy are interconnected, I recently began a regimen of 6 grams of L-tyrosine a day. I have had great results so far, and have noticed a significant reduction in daytime sleepiness and  total time spent at night sleeping. I suspect that the effect will gradually wear off (I have been taking L-tyrosine for about 4weeks now), and I am interesting in speaking with others using L-tyrosine for it’s wakefulness-promoting uses; so, anyone out there?

Narcolepsy on National Geographic

This week, narcolepsy will be in the limelight on the National Geographic program Taboo: Strange Behavior.  The show will air on the National Geographic channel on June 24, 2012 from 10:00 – 11:00 pm EST.  This episode follows the life of one narcoleptic man, Dee Daud, who has a severe form of narcolepsy with cataplexy. A preview of the episode can be found here

Dee Daud featured on Taboo: Strange Behavior

Narcolepsy may present with or without cataplexy.  Cataplexy is a loss of muscle tone (without loss of consciousness) often in response to emotional triggers. Not all narcolepsy presents with cataplexy as does Dee’s, and not all cases of narcolepsy are as severe as Dee’s.  Nonetheless, I am excited about it being featured on a prime time TV show.

Taboo’s self-declared mission is to “journey beyond your comfort zone to explore behaviors and lifestyles that are acceptable in some cultures but forbidden, illegal or reviled in others.” In this season, topics such as “murderabilia,” extreme tattooing and scarification, polyamory, and “furry culture” are presented alongside individuals living with Tourette’s syndrome, autism, and narcolepsy.  The concept of presenting rare medical diseases alongside other “taboo” behaviors (as if narcolepsy is a culturally taboo lifestyle choice) seems to me to belittle, dramaticize, and promote further sterotypification of individuals living with disabilities.  That said, I am excited to watch the program, and am confident that Dee and the program itself will help to promote awareness of narcolepsy and cataplexy; and, awareness of any kind can’t be bad.

After the program, I will be posting a more detailed recap of the show and how it may help or hurt the public view of narcoleptic individuals or narcolepsy in general, and I would love to hear your thoughts on the concept behind featuring narcolepsy on a program such as Taboo: Strange Behaviors.

——-UPDATE——–

After watching Taboo: Strange Behaviors I am pleasantly surprised.  National Geographic presented Dee’s story along with Paul Stevenson (a man with Tourette’s and an accomplished Tourette’s advocate.), Bethany Scheiderman (a young girl with Trichotillomania), and autistic friends Larry Bissonnette (who is also an accomplished artist) and Tracy, who are advocates for individuals with autism, recently creating a documentary for autism awareness called My Classic Life.

Overall, the program was moving, inspiring, and very well done. At the end, the program even raised the question of whether it was individuals with disabilities whose behaviors were taboo, or if rather the reaction by society is what should be deemed taboo.

Many thanks to National Geographic and Dee Daud for raising awareness about narcolepsy (and other disabilities)!

3 Day Fast Experiment

In a previous post, Starving Yourself Awake, I wrote on the eating = asleep phenomenon (i.e. postprandial somnolence) experienced by many people, including those with narcolepsy.

In conducting research for the article, I discovered several key links between orexin activity (orexin expression and orexin receptor expression) and fasting.  A few of the important connections are summarized below:

1) Orexins stimulate arousal and wakefulness.

2) Orexins are found in the hypothalamus as well as the gut, and are up regulated during starvation/fasting, and inhibited during feeding (particularly in response to glucose).

3) Women with anorexia have been demonstrated to have higher levels of circulating orexin, while narcoleptics (with cataplexy) have little to no orexin in their CSF.

In addition to the specific effects of fasting on orexin and orexin receptor expression in the brain, fasting has been demonstrated to be effective in management of other autoimmune diseases, including MS, rheumatoid arthritis, and lupus (SLE). To my knowledge, no one has yet scientifically demonstrated this effect in narcoleptic patients. 

In light of these findings, I am conducting a 3 day fast to determine it’s effects on wakefulness and energy levels. The last time I ate was 9:00 PM 6/17/2012, and I slept 7 hours last night with no memorable sleep disturbances or hypnogogic hallucinations. I will post daily with reports on energy levels and wakefulness, and hope to provide anecdotal evidence to support (or refute) the use of fasting in narcolepsy.
——–UPDATE – 38 hours———

I have now been fasting for 38 hours. So far so good.

I do not have any remarkable changes in mood or energy level, as of yet. Last night I was less sleepy than I normally am upon laying down, but I didn’t have any trouble falling asleep. Only have had 2 short (less than 5 minute) periods of hunger (complete with tummy grumblings), but otherwise have not felt hungry.

I am hoping to see changes in energy levels and beginning about the 48/60 hour mark. My goal is to do a complete 3 day (72 hour) fast, but would be happy to make it to 48 hours. More updates tomorrow!

—–Update 48 hours——

Because I didn’t see any remarkable changes in energy level or alertness, I broke my fast at 48 hours.

I promptly went to sleep, and have been sleepy since breaking my fast.

That said, becomming sleepy after eating doesn’t really account for the fact that I didn’t feel dramatically more awake on the fast, as I had expected. Now, I did have coffee during the fast – maybe that was what kept me from feeling any better than I did?

Most people who fast for autoimmune therapies do a water only fast, and also may fast for up to two weeks! Especially because I was so dramatically tired after breaking my fast, I would like to reattempt the fast, this time for longer and to do a complete water fast.

I also think that a ketogenic diet (i.e. a diet from only fat and protein) may be more beneficial to narcolepsy than by fasting alone. 

In the first place, the benefits of fasting arise from your body’s ability to use fat and protein stores for fuel; carbohydrate metabolism (other than those arising from gluconeogeneis) are not utilized. Secondly, it was recently demonstrated that a diet of amino acids activates orexin producing neurons, and that the excitatory effect of dietary amino acids outweighed the inhibitory effect of glucose.

The best dietary “prescription” to be then would seem to be a gluten-free (benefits covered in other posts), low-carbohydrate ketogenic diet, coupled with bouts of intermittent fasting.

Anyone out there with fasting experience and narcolepsy? Or other low-carbers? What about for the treatment of other autoimmune diseases?

 

Starving yourself awake

One day when I was in college, about my second year, I suddenly realized I felt awake. At the time, I had just been diagnosed with narcolepsy, and hadn’t yet discovered gluten free, so to feel actually awake was mind-blowing. After a few days of thinking about it, I realized I was feeling awake because I wasn’t eating. Not only that, but I found several other people talking about not being able to eat without going to sleep, too.  Apparently it was a common experience for some of us.

There is a good blog article documenting this, as well as comments from many other sufferers at N is for Narcolepsy.  While the author describes the opposite of what I previously stated (eating = asleep vs. no eating = awake), the concept is exactly the same.  There’s something about eating that makes many of us tired. Maybe it has to do with glycemic control, carbohydrate content, insulin spikes, and maybe it is a food intolerance, but the it is clear that the orexin/hypocrein system plays a role in controlling postprandial somnolence.

All of this brings me to these four articles:

  1. Sleepiness after glucose in Narcolepsy,
  2. Widespread Distribution of Orexin in Rat Brain and Its Regulation upon Fasting
  3. Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting, and
  4. Plasma levels of leptin and orexin A in the restrictive type of anorexia nervosa.

In the first paper, Sleepiness after glucose in narcolepsy, the authors investigated the anecdotal claim (such as those from N is for Narcolepsy shown above), that narcoleptic patients were more tired after ingesting glucose. In this study, they gave 12 narcoleptics (and 12 controls) an additional 50g of glucose in a punch just before allowing them to take a nap.  Overall, they found that narcoleptic patients who ingested glucose had increased sleepiness and decreased wake duration. Additionally, 11 of 12 demonstrated increased REM. This also corroborates the effect of low-carbohydrate diets on sleepiness in narcolepsy demonstrated by Husain et al. covered elsewhere on Autoimmune Patient.com. So, in response to N is for Narcolepsy, I would say that there is good evidence that eating (especially sugar and carbohydrates) makes us narcos sleepy. 

I’m not going to review the second paper, but allow it to serve as a segway to the third paper (Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting). In it, the authors examined expression of the orexin 1 and orexin 2 receptor subtypes (OX1R and OX2R; i.e.  receptors for orexin) in the brain. They looked at where the receptors were, and if they were upregulated in different areas of the brain in response to fasting. It should be noted here that OX1R has a moderate specificity for Orexin A, and OX2R can respond probably equally well to both Orexin A and B. Overall, the found that the different receptors had different distribution patterns, but they had some overlapping areas in their expression as well.  I’ve uploaded a graphic below summarizing where the receptors were found and in which areas of the brain.

The importance of differential expression of orexin receptors in different structures of the brain suggests that they play novel roles in multiple circuits, each of which do different things.

For example, expression of these receptors in the lateral hypothalamic and dosomedial hypothalamic regions implicates orexin involvement in feeding behavior, circadian activity, and body-weight regulation.  

Expression in the hippocampal regions suggest orexins are also involved in regulating the monoaminergic systems (for example, histamines, dopamine, serotonin, melatonin, norepinephrine, epinephine and others).  These systems are of obvious importance, particularly because this is the only region of the brain which produces histamine. Histamine has been shown to be critical for wakefulness, and ablation of histamine in the CNS results in hypersomnolence, sleep fragmentation, and increased REM. Additionally, low levels of histamine are found in the CSF of narcoleptics, and is also reduced in animal models.

Additionally, expression of these receptors in the amygdala implicates partial orexin-regulation of memory, attention and emotion. 

In addition to the receptors, orexin itself has also been shown to be upregulated during fasting (and, interestingly, also by insulin-induced hypoglycemia).  

In another interesting study that investigated circulating orexinA levels in recovering anorexic women, found that as anorexic women who began a recovery program and gained weight (as shown by an increase in BMI and leptin levels), their circulating levels of orexin decreased significantly at every time point during the course study.

So what does this all mean? In the first place, it means that the sleepiness exhibited by narcoleptics after eating is real. For some, this may mean that not eating all day, in order to maintain wakefulness.  While certainly this doesn’t seem optimally healthy, it may be a legitimate alternative method to controlling daytime sleepiness for some, particularly in younger patients who may still have functioning hypocretin neurons that have not yet been destroyed by autoimmune attack.  In the second place, it means that dietary restriction can modulate expression of orexin/hypocretin and their receptors in the brain (and speculatively in the gut and pancreas as well).

While it is certain that more literature on the gut/brain axis and the role of the enteric nervous system in narcolepsy is sure to come, it is an exciting time to theorize major players of the disease that may extend beyond the hypothalamus, which may also pave the way for novel treatments or palliative care.

 

 

Trouble with Tribbles?

Currently, the theory that narcolepsy is of a neurodegenerative autoimmune cause is the most widely supported among narcolepsy researchers, but the data to support this theory has been somewhat lacking (admittedly in part because there are simply fewer studies on narcolepsy than other autoimmune diseases).

In the first case, narcolepsy has a high HLA association, which is seen with other autoimmune diseases. In fact, narcoleptics with cataplexy have a 90% chance of being a carrier of the gene HLA DQB1*0602, an association among the highest of all autoimmune diseases.

Secondly, there is a reduction of hypocretin (a.k.a. orexin) producing neurons in the hypothalamus of narcoleptic patients, which leads to a reduction of hypocretin in the cerebrospinal fluid (CSF).  While it is still possible that the neurons are there and just not producing hypocretin, current data suggests there is a total loss of the neurons according to some imaging data via Mignot et al, which is covered in a separate post. In spite of this lack of hypocretin, no antibody to neurons or hypocretin have been found in narcoleptic patients.

So, if narcolepsy is indeed autoimmune and neurodegenerative, where is the proof?

Back in 2010, a paper came out in the Journal of Clinical Investigation suggesting that there was an association with narcolepsy and antibodies to a protein called Trib2 (tribbles homolog 2).  This work was redone by Mignot et al. and also replicated by a Japanese group, demonstrating that the antibodies seen in the study were found in multiple populations, including those of different ethnic origin. While tribbles is made by many cells in the brain, hypocretin-producting neurons make larger amounts of it, and it is theorized that these neurons could be preferentially attacked by the immune system.

In short, they found that 25% of individuals with the so-called narcolepsy gene (HLA DQB1*0602) with cataplexy had antibodies to Trib2, while antibodies to Trib2 were rare in individuals without cataplexy or controls. In addition, anti-trib2 antibody positivity correlated with disease progression, with antibody being higher in those individuals who were more recently diagnosed.

While the findings themselves are not disputable, it does beg the question of where the antibodies are coming from in the first place. Antibodies do not arise de novo to do the body harm, but rather are products of a sustained encounter by the body with antigen under the context of inflammation.  Antibodies are products of adaptive immunity; that is, B cells which have been activated through their B cell receptor in an antigen-specific manner, and have had the antigen presented to them by an antigen presenting cell. So the fact that antibodies against Trib2 are found does not necessarily mean that Trib2 is the primary target of the immune response, although it could be.  In reality, antibodies to Trib2 in narcoleptic patients could arise by several mechanisms, and may be secondary to neuronal cell death.  To me, this seems the most plausible explanation, as Trib2 is normally found intracellularly, and it is widely expressed in the brain.

In the first place, it is clear that an individual (probably) must be genetically susceptible to developing narcolepsy at some point in their lives. These individuals generally harbor the HLA DQB1*0602 gene, or a TCRalpha chain polymorphism.  On this background of genetic predisposition, environmental factors begin to play a role, as they do in other autoimmune diseases.  Whatever the inciting factor may be, the role of Trib2 antibodies is not clear, despite their association in narcoleptic patients. It is entirely possible that already damaged neurons are engulfed by the innate immune systems phagocytic cells, and their contents presented to adaptive immune systems B cells and T cells, which then coordinate to produce antibody to multiple components of the damaged neurons, one target of which may be Trib2.

While the finding of a self-protein or “autoantigen” response in narcolepsy is compelling, and serves an important piece in bolstering the autoimmune theory of disease progression in narcolepsy, it is by no means necessarily the causative agent or end of the story, particularly for individuals who do not have cataplexy or the classical HLA DQB1*0602 gene.  In this way, although an autoantibody has been found in some patients, a Trib2 antibody response is clearly not necessary or sufficient to cause narcolepsy in all cases.

In future studies, it will be interesting to determine if other autoantibodies will be found, or if there are multiple self-targets that may give rise to narcolepsy symptoms.

 

New Neurons in Your Narco Brain

 

When I first was diagnosed with narcolepsy, I was devastated. I had put together the story that was being told about my brain: probably autoimmune, neurodegenerative, and sorry but you will be this way for the rest of your life.  The assumption that there is a neurodegenerative loss of hypocretin/orexin-secreting cells of the hypothalamus in narcoleptic brains is probably not totally inaccurate.  Throughout the course of my research, however, I became convinced that an underlying food intolerance could mediate the autoimmune process;  if I cut out the food I was intolerant to, I could turn off that process and cool my brain down. And it worked. A month after going gluten free, my symptoms of narcolepsy disappeared.

Even though I was excited to not be tired anymore, I was concerned about this supposed neurodegeneration that was happening in my brain. Even as a scientist, I was taught all throughout school that once you lost a neuron, that was it. Game over. No new neurons for you. However, at the time, there were a few studies coming out demonstrating how aerobic exercise could promote neurogenesis.  So — I started running. As I run, I like to image the little dendrites of the hypocretin-secreting neurons I do have left reaching out and making new connections, restoring my narco brain to something not handicapped by some mysterious autoimmune process.

The plan was (and still is) simple: 1) stop all future neurodegeneration by turning off the autoimmune and inflammatory processes (this was made possible by going gluten free), and 2) promote new neuronal growth by exercising every day.

All of that was fine and dandy, but as a rational person, I needed some proof. What if the current view was right? There was always a crippling fear in the back of my mind that I was wrong. That somehow, someway, the narcolepsy was going to win.

I lived with this fear, until I read this paper: Adult Neurogenesis in the Hypothalamus. And there it was. I could stop the inflammation with a gluten free diet, and make new neurons in areas that I thought may have been completely ablated. The realization that we all in fact have the potential to make these new neurons is nothing but relief.

It means, without a doubt, that once you turn off the inflammation, you can turn your brain back on.