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?

Overcoming MS with diet.

This morning, I found a truly inspiring TedTalk from a woman diagnosed with multiple sclerosis, an autoimmune neurodegenerative disease not completely unlike narcolepsy. Like narcolepsy, which is neurodegenerative and believed to be autoimmune, multiple sclerosis presents as a life-long disability, from which there is “no known cure,” and medications are prescribed only for symptom management.

This life-long disability was not an option for Dr. Wahls, and, like so many of us who receive dissatisfying prognoses and aid from conventional medicine, turned to PubMed to begin searching for her own answer.

What Dr. Wahls found was not only symptom management but reversal of her multiple sclerosis through diet-modification, excluding gluten and grains, and consuming a paleo/hunter-gatherer diet rich in leafy vegetables. Here “cure” came in just 4 short months.

You can find more about Dr. Terry Wahls at her website. Thank you Dr. Wahls for being a outspoken doctor, patient, and advocate of healthy eating for autoimmune disease!

 

 

 

Top Ten Reasons I Will Never (Not) Be Paleo

10.  I feel incredible.  I’m confident that 90% of people would feel 100 times, if not more, better consuming a “paleo”-type diet. I don’t like confining myself to the “gluten-free” or “paleo” movements, but I am both gluten-free and “paleo.” The longer I go without eating processed foods or sugared-alternatives, the more I can feel how food actually affects my body. Whenever I “cheat,” and eat a high glycemic-index meal, I crash and feel like crap for the next day. I don’t like feeling like crap. So I keep eating paleo.

9.  Freedom from food. Sugar is addictive. Bread is addictive. Prior to going gluten free, I noticed NOTHING I ate didn’t have some kind of wheat (or at least food starch) in it. In fact, most times, something starchy was the center of the meal. That’s the American way, right? “Here, honey have a roll.” My sugar addiction began when I was young, craving sweets and cakes, anything I could get my hands on. I’m sure I had it worse than some, but maybe not. As I became older, my sugar addiction spiraled out of control, and I had no idea it was even happening. I had learned in school to stay away from candy, but that grains and bread were the bottom of the food pyramid. I was SUPPOSED to be eating >300 carbs per day! When I moved out on my own, I couldn’t keep chips, candy, sugar, ice cream, or even alchol (it’s just another source of sugar for me) in my house for fear I would overeat… and that’s when I started thinking maybe it was the sugar.

Like most “dieting” women I know, I counted calories and fat (like I was instructed to by the bread-on-the-bottom-food-pyramid-nutritionists) like a mad woman. I took my weight 3 times a day. I obsessed over my clothes-size, how I felt in them, and was self-consious to eat in front of people. I would restrict my eating to point of refractory bingeing. Even if I only skipped lunch, I was trying to devour everything in site come dinner. This was before I found gluten free / paleo.

On gluten free / paleo, I no longer obsess over the calories and sugar I am putting into my body. I have complete freedom from the obsession of food. I eat when I am hungry. I don’t eat when I am not. I don’t worry about the nutritional content of what I’m eating most of the time, because my diet is inherently filled with nutrient-dense foods. Simple as that.

8. No more naps. Mid-afternoon crashes are the worst. On paleo, I don’t get them any more. I remember as a highschooler, coming home and sleeping for 2-3 hours every day. I was so fatigued. I have had a nap twice in the past year. Adding it up, that’s more than 730 hours of gained productivity, which is desperately needed as a hard-working graduate student.

7.  “I’m regular.” I don’t want to delve into the realm of too much information, but prior to Paleo I was incredibly irregular. Irregular cycles, irregular digestion, irregular sleeping habits, irregular moods. More than that, I had never been regular. Many of my earliest memories of childhood were surrounded by GI problems, mood problems, and sleeping problems… but how was I supposed to know they weren’t normal? No one ever really told me how often I was supposed to be going to the bathroom. Anyway, you name it, on a low-fat, high-fiber diet, mine wasn’t normal. By body’s internal clock was just all warped. On paleo, I’m like a machine. Everything is all “regular,” a feeling I haven’t had in my entire life until now.

p.s. – I hardly ever eat fiber.

6. Better cholesterol. I get made a lot of fun of where I work because I love to eat pork rinds. Lots of them. I will eat a bag for lunch without blinking. They are such a common and frequent part of my diet, that it seldom occurs to me that it’s weird, until someone comments that I am so unhealthy for eating them (ironically, I am the skinniest person at my work).  I eat a very high cholesterol diet. I eat red meat once or every other day. I eat about 3 eggs a day. I eat pork rinds to my hearts content (insert pun), and snack on nuts. Sounds like I should have the worlds worst heart, right? Wrong.

I began having my cholesterol monitored after a blood test revealed high LDL and low HDL cholesterol, and high triglycerides.  This was a bit scary for me, having a family history of heart disease.  My abnormal cholesterol test came at 20, while I was doing a low fat, grain-based diet, and running a mile a day.

Since going “paleo,” my LDL is normal and my triglycerides are down. I still haven’t been able to raise my HDL, despite maintaining very frequent cardio exercise (>5/miles of running per day), but I think this may just be true genetics at play.

5. I’m thinner and more tone.  I have never not felt fat. Even when I was thin and severely calorie-restricting, I always felt fat on a grain-based diet. In addition, as I entered late adolescence/early adulthood, I actually started becoming fat, peaking at 150 (quite large for my small 5’3 frame) while in college. I became fat because I was eating the recommended diet of low-fat, whole grain. In addition to becoming fat, I also became sick. On paleo I maintain a healthy and fit 115 no matter how much I exercise or how many bags of pork rinds I eat.

4. I’m happy. All the time. This seems like a weird statement, but, I’m always happy. Literally. I remember struggling with depression as young as Kindergarten. My grandmother told me in my teenage years, when I battled daily with manic depression and fatigue, “sometimes as a child you just looked so sad.” It broke my heart to realize that my family had noticed my sadness at such a young age. On a low-fat, whole-grain diet I cried, screamed, had emotional outbursts, resented, and surfed the lowest-of-lows and highest-of-highs. On paleo, I’m simply happy. That’s it.

3. No more pain. As a young girl, I remember my mother struggling with chronic headaches and backpain. I never knew her agony until I was about 17 years old, when I began having chronic headaches and migranes with auras.  I had also had joint pain (primarily knee and back) for most of my life (the doctor’s decided I had “growing pains,” which is code for, “it’s all in your head.”) I dealt with the chronic headache and low-grade aches and pains by taking 800mg of ibuprofen every day. For years. After going gluten free, my chronic pains and headaches subsided, but the auras persisted. When I went fully paleo, the frequency of auras (without pain) reduced from once or twice a day to once every two months or so. They still happen randomly every once in a while, but not nearly with the frequency they used to, and their usually triggered by taking a hot shower. I now take Advil once a month for cramps, but some months I don’t need it at all.

2. Paleo (nearly) cured my narcolepsy. I first became gluten free about a year after I was diagnosed with narcolepsy, and became full paleo about a year after that. Before deciding to become gluten free, I realized I was getting tired after eating, and if I went all day without eating, I was less tired. I went searching and found a truly incredible blog called The Zombie Research Institute. A woman whose brain clearly worked like mine did, who cured her narcolepsy with gluten free? It sounded ridiculous, but I was desperate for anything to work. I tried it. Very strict. And it worked. Gluten free combated narcoleptic attacks and hypnogogic hallucinations, but I feel my most awake and alert by excluding all refined sugars and grains and adhering to a paleo diet.

1. Paleo saved my lifeThis might seem like an inflammatory statement (another pun), but it’s not a joke. I believe going gluten free (and later paleo) literally saved my life.  Throughout my childhood, adolescence, and young-adult years I was only sick and sad. There were many many days where I was quite sure that I wouldn’t make it past 40. I had physically struggled for so long, that I didn’t want to make it past 40. I couldn’t bear the thought of living another 20 years in tiredness and pain.  Now, I am exited to age in health and grace; and, actually look forward to tomorrow.

In addition to posting these reasons that I “do paleo,” the new fat-diet of the day, quite proudly, I would also like to take a moment to respond directly to some of the “points” raised in the original post “Top 10 Reasons I’m Not Paleo” by Cheeseslave.

1. To first answer Cheeseslave’s question:

But honestly, if you’ve been eating paleo for any length of time, don’t you miss grilled cheese sandwiches? Quesadillas? Pizza?

 

Sure. Yes. I miss pizza, pudding, ice cream, M&M’s, and especially peanut butter. I miss sugar the way a 3-pack-a-day smoker misses a cigarette. There is a twinge of pain everytime I see someone eating a doughnut in part because I hate wheat, but also in part because I WANT THAT DAMN DOUGHNUT.

That said, I miss the narcolepsy less than I miss the doughnut.

2. In response to:

Is the modern epidemic of “gluten intolerance” really caused by eating wheat? Or is it possible that something else is causing gluten intolerance?

There is a theory that antibiotic drugs cause an imbalance of gut flora and cause prevent the digestive tract from secreting enzymes that enable us to break down complex proteins such as gluten. Sounds a lot more plausible than the idea that wheat suddenly started causing gluten intolerance out of nowhere.

In the first place, the alternative theory isn’t bad. I agree that something other than gluten could be causing gluten intolerance. Genetics, a changing gut microbiome, antibiotics, sugar, birth control. Alternative theories are fine and dandy, but gluten is a very good candidate, as the protein has been demonstrated to be inflammatory and barrier-compromising to the intestinal tract all on it’s own. It also stimulates antigen presenting cells to be “preactivated” among “normal” healthy individuals without celiac disease or gluten sensitivity. Here’s another one demonstrating positive benefits of gluten-removal from IBS patients who did not have clinical celiac diseaseBut a different cause for gluten intolerance, doesn’t justify continuing to eat it. It would still be a gluten intolerance; wheat’s fault, or not. 

In the second place, gluten isn’t the only thing found in wheat. Wheat germ agglutinin (WGA) is a lectin found in wheat and has been demonstrated to have antinutritive effects irrespective of gluten intolerance and celiac disease. Concentrations of WGA are higher in the seed and young shoots of wheat, to protect it from predation from fungus, insects, and animals. In fungus and insects WGA binds to the chitin. Chitin is found in the cell wall and intestinal system of fungi and insects, respectively.  In animals and in humans, it binds strongly to sialic acid on intestinal cells, where it is internalized, and can also agglutinate bacteria and red blood cells. Because it is stable at low pH (i.e. poorly digested) and resistant to gut proteases, it is gaining widespread attention and research to be utilized as a carrier for drug delivery.  Once inside epithelial cells of the digestive tract, it accumulates in lysosomes and resists degradation. It alters intestinal permeability, allowing for the passage of small molecules across the intestinal barrier. In addition, in sufficient concentrations, it stimulates proinflammatory cytokine release as well as affecting the activation of immune cells in the gut, and can cause pancreatic hypertrophy.  It should be mentioned here that lectins are not only found in wheat (but wheat has among the highest lectin concentrations and is the most prevalent plant lectin), and their entrance into the blood stream and implications on systemic health has yet to be widely investigated. For another good review, go here.  How is that for “antimicrobial” theory?

I struggle with anger towards my mom for not figuring out that I was tired after I ate.  Because of food, I was sick and sad for most of my life. If only my mother had known or realized that food could affect how you feel SO MUCH, I know she would have changed my diet at a young age and not let me have dessert at all (or, made a nice paleo alternative).

In contrast, I know I will be the most-hated parent on the block when my child realizes that Oreos exist. But, to me, if I were to allow my child to indulge in sugar, I might as well put vodka in their bottle, and a joint in their hand. Sugar is a drug. It works the same on the brain. And I’m sure little Johnny will sneak away to Billy’s house to eat ice cream on the weekends. But I refuse to allow my children to become addicted to sugar and food in the same way that I was. And they sure as heck won’t be sad, sick, or worse for the pie that I put on their plate. 

 

 

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.

 

Hashimoto’s disease, lichen planus, and lupus

While many autoimmune diseases are known to be associated with one another (take celiac disease and type I diabetes, for example), few reports exist in the literature documenting what is termed “Multiple Autoimmune Syndrome,” whereby an individual patient manifests three or more autoimmune diseases at the same time.  In fact, it is commonly asserted, though not conclusively shown (in my humble opinion), that multiple autoimmune syndrome is rare. 

I do not believe that this is accurate. In my limited experience, it seems to me that multiple autoimmunity is actually quite common, particularly in individuals with documented food sensitivities, such as celiac disease/gluten intolerance. When gluten, and other food, sensitivities exist, the gut becomes leaky and allows foodstuffs, bacteria, and other pathogens to pass the intestinal barrier, where they can be detected by the immune system.  While everyone likely harbors “self-reactive” immune cells, not everyone mounts an autoreactive immune response, like people with autoimmune disease do.  Pathogen (food, bacteria, or otherwise) encounter by the immune system in the gut delivers inflammatory signals, that may then lead to the activation and response of autoreactive immune cells.  In fact, current data suggests that all autoimmune diseases may begin in the gut.

Because of the supposed rarity of multiple autoimmune syndrome, my favorite articles are case studies of individuals with multiple autoimmunity. In the case reported here, a 24-year-old female presents with lichen planus (a suspected autoimmune disease), lupus (a known autoimmune disease), and hashimoto’s thyroiditis (also called autoimmune hypothyroidism), and to date, it is the first association of it’s kind.

 

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. 

Narcolepsy gene in a celiac patient.

As many of you know, autoimmune diseases are generally complex diseases, where people on a certain genetic background (i.e. those whore are “predisposed”) come into contact with environmental triggers and eventually develop autoimmune disease.

Particularly important for autoimmune diseases, the genetic predisposition seems to lie within a region of our genes called Human Leukocyte Antigen or HLA for short. Narcolepsy has one of the highest genetic (HLA) associations, with more than 90% of individuals with narcolepsy possessing the MHC clas II gene HLA DQB1*0602.  

Celiac disease is also shown to be associated with certain HLA genes, in particular with MHC class II HLA-DQ2.  In this recent study, a patient with confirmed celiac disease was demonstrated to have the narcolepsy gene DQB1*0602.