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Narcolepsy

Mechanism

This section is technical and boring.   Scroll down the next if you can't take it.

 

There are many things, infectious or genetic or otherwise which could cause orexin cell dysfunction.  For numerous theoretical reasons, and with many direct reports of remission, I am convinced that gluten induced immune activity is responsible for most cases of human narcolepsy.

 

The assumption that narcolepsy is an immune disorder is easy:

Narcolepsy is associated with the gene HLA DQB1-0602.  Very Strongly Correlated.  90% of patients with narcolepsy/cataplexy carry the gene.  

The HLA area of the genome codes for immune system molecules.  That gene specifies a portion of an antibody.

If you have a messed up antibody-  you have an immune disorder.  That's just a fact.

  • In this study, a stable structure for the DQB1*0602 antigen bound to an orexin molecule was determined.  This would permit the antigliadin antibody to attach to the structure and initiate destruction of the neurotransmitter itself. It is unknown however, if this process actually occurs in vivo.

Although this direct mechanism is appealing, I propose a less direct method of neural dysfunction caused by the  *0602 antibodies.

  • Many of the genes in the HLA-DQB1 region are highly associated with gluten intolerance- an allergy to wheat.   The locus is actually named CELIAC1.

  • The DQB1-0602 gene is specifically associated with NON-celiac gluten intolerance- documented symptoms are endocrine and neurological dysfunction.   I believe that is becaues these antibodies bind to neurons rather than epithelium.

The antigliadin study shows that IgG antigliadin molecules bind to the protein Synapsin I.

Synapsin 1 is crucial to neurotransmitter transport and release in neurons.   If you don't have functioning synapsin, your nerves can't release their chemicals.

  • Synapsin is found in the synaptic cleft, at the nerve terminal.   It is possible that the gluten antibodies bind to free synapsin, thereby making it unavailable for reuptake and use by the cell.

  • There are also processes which allow antibodies inside the cell, which would allow them to bind to Synapsin 1 in situ and block neurotransmitter release directly.

A number of factors contribute to the presentation of narcolepsy.

It seems different combinations of antibodies cause variation in the symptoms.

  • Narcoleptics are more likely to have two copies of DQB1*0602. Certain other combinations of HLA genes also predispose to narcolepsy.

  • DQB1*0602 association was highest in cases with orexin deficiency, most of which had narcolepsy-cataplexy. A weaker DQB1*0602  association was present in cases without cataplexy.

  • DQB1-0603 and 0604 are slightly different but also associated with narcolepsy.

Which is also supported by a very detailed study on the structures of antigen alleles in the DQB1 locus.  It  shows that minor differences in the coding sequences of the alleles produces differences in the antigen's ability to bind to target proteins.  Minor alterations in the amino acid sequence can create significant changes in the shape of binding pockets on the antigen.

 

This parallels the activity of the gluten antibodies.

  • The antigliadin binding study found that only certain subsets of antigliadin antibodies cross-react with synapsin I, and concluded that varying degrees of cross-reactivity to Synapsin I can be expected in different patients with gluten sensitivity

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Shorter Mechanism:

All the evidence points to diet as the most probable cause of narcolepsy.
ē Orexin neurons innervate the entire gastrointestinal tract and regulate metabolism.
ē Inflammatory diseases of the gastrointestinal tract have been shown to affect the function of orexin cells.
ē Autoimmune antibodies have been shown to affect the function of orexin cells.

 

Here's what happens-  after you eat gluten, your immune system sends out the antibodies.   They bind to the gluten in your intestine, but also to the nerve endings in your orexin cells, clogging them up.   You get sleepy and take a nap.

 

Heh.  If only it were that simple...

Metabolic obstruction by antigliadin explains the excessive sleepiness and orexin cell loss in narcolepsy but does not account for some of the signature symptoms.  Cataplexy is the sudden loss of muscle tone and onset of REM sleep which is triggered by stress. The mechanism described above suggests a delayed, more gradual onset of sleep associated with meals. I propose that cataplexy is a separate mechanism of orexin depletion caused by a spike in blood sugar in response to stress.

 

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Glucose Sensing


Orexin cells aren't ordinary.

All cells are sensitive to their own internal glucose levels and moderate their activity.

Unlike most brain cells, orexin neurons are sensitive to external glucose levels.

By altering the amount of orexin released-  they moderate the metabolic levels of cells other than themselves in response to serum glucose levels.

 

  • As blood sugar rises orexin cells lower their activity.

  • As blood sugar lowers they increase production of orexin.

  • There are four basic types of glucose sensors, each which senses a specific range of concentration, facilitating the very rapid and very precise sensing of changes in blood sugars.

  • This mechanism is sufficiently sensitive to encode variations in glucose levels reflecting those occurring between normal meals.

So every time you eat you alter your orexin system and everything it regulates.   Even if you don't have gluten antibodies killing the cells.   You can shut them down just by spiking your blood sugar.   That story the "experts" tell you about the Thanksgiving turkey making you sleepy-  they're wrong.  It's everything else- the glorious pile of carbohydrates:  potatoes, corn, stuffing, yams, cranberries and pie...

 

Sleep Attacks

Narcoleptic naps are just like real naps only more so.  The sugar and gluten gang up on your neurons and your orexin levels drop faster and go lower...


Figure 1. Nap Map


Nap Map

 

This is how I think a narcoleptic sleep attack progresses:


Your blood sugar level is low, and your orexin level is high so you're motivated to eat. If you're American, then it's pretty well assured that your meal includes carbs and gluten.

Your immune system starts to produce antibodies.

As the food is digested, your blood sugar starts to rise, so your orexin cells slow down.

Soon after that the gluten antibodies start clogging up the orexin cells.

At a certain point the orexin levels fall below threshold and you fall asleep.

Lowering of orexin levels stimulates the pancreas to release insulin.

Your orexin levels get really low, and your pancreas doesn't know part of it is caused by gluten instead of sugar, so dumps huge amounts of insulin into your bloodstream.

Blood sugars drop rapidly, and orexin levels begin to rise again.

And you wake up wanting more sugar. So you go eat a cookie.


 

(If you look at it carefully, it may be that part of the time we are sleeping because our orexin levels are low, other times because our blood sugar is low.  Our levels fluctuate wildly after a meal.)


Cataplexy


Stress Response

 

Cataplexy is highly associated with stress and panic. I believe the rapid rise in blood sugar triggered by the stress response is the factor which triggers such drastic symptoms.

  • During the stress response, the pancreas releases glucagon and stops releasing insulin. Glucagon causes the liver to convert stored glycogen into glucose and release it into the bloodstream.

Stress increases your serum glucose levels.  Rapidly.

Which shuts down your orexin cells. Rapidly.

Which shuts off your Locus Coerulus.   Rapidly.

 

Glucose sensitivity

I believe that one of the causes of cataplexy is atypical glucose sensitivity in orexin cells. I considered a number of alternatives as to how that could occur. Perhaps narcoleptics have extra sensitive mutant glucose sensors. Or an extra gene and therefore produce more of them. But then I realized the differential sensitivity of the cells would influence the pattern of neurodegeneration and spontaneously result in increased glucose sensitivity.

  • In addition to the four ranges of glucose sensing, orexin cells have two reactions to rising glucose. 30% of them shut down and stay inactive until glucose levels fall again. However, in the remaining 70% of orexin cells activity first falls but then, despite high glucose levels, they spontaneously resume firing.


Think about it: if antigliadin binds to synapsin in cells when they are actively transporting neurotransmitters, then those cells which shut down the fastest and stay off the longest in response to glucose will have the least damage from gluten. All the low and medium sensitive cells will clog up and die. Sooner or later the hypersensitive orexin neurons will be the only ones left.


If you have accumulated a lot of cell damage- not only will you have fewer cells to produce orexin, the ones you have will be, for practical puposes, binary. Even small amounts of glucose will turn them all off.


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If the patient's blood sugar is already raised, and he has an extra-sensitive set of orexin cells, and his liver starts dumping glycogen, it may be just the right combination for sudden onset of sleep.  Each additional source of glucose adds to the effect.

 

Figure 2. Additive effects on orexin cells.

  

 

So here's the wicked twist:  Narcolepsy increases the stress response. Low orexin in the locus coeruleus not only lowers your energy level but signals the vagus nerve to cause an increased startle response.


I believe this may cause a positive feedback loop- vagus nerve activity stimulates activity of the orexin cells which accelerates their uptake of the antibodies causing even quicker shutdown of the cells.

Itís also possible the rapid decrease in orexin triggers the stress response even further dumping even more glycogen.

Or something like that.

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And on a slight tangent- cataplexy often occurs during laughter.

  • Our human imaging data also show that cataplexy patients have elevated responses to humour in the left nucleus accumbens, a region known to be involved in humour processing and which has strong interconnections with the amygdala.    These results suggest that orexin physiologically modulates the processing of emotional inputs within the amygdala, and  the mechanisms of cataplexy involve a dysfunction of hypothalamic-amygdala interactions

I believe these results make more sense if you consider laughter as a modified version of the panic response instead of as an indication of happiness. The amygdala is one of the central processors of fear.

 


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This is also why alarm clocks donít wake you up: they induce narcolepsy as they startle you awake. Induce a nice surge of glycogen from your liver.

You arenít even conscious and youíre having a sleep attack.

Good Morning!

 

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Orexin Expression


  

This graph represents the orexin levels of a narcoleptic over a lifetime predicted by this model:


  

Figure 3. The sharp learning curve

 

  • Highly active orexin cells overproduce the neurotransmitter early in life.

  • Vigorous antibody activity creates wildly fluctuating levels during daily activity.

  • Cumulative neurodegeneration results in ever diminishing numbers of cells and overall orexin levels.

  • At a certain point levels begin to drop to the point affective symptoms become apparent, but are intermittent.

  • Eventually orexin levels drop to the point that daily functioning is chronically and severely impaired.


If you want to be specific, that was a narcoleptic male. Orexin levels in females also fluctuate with reproductive hormones, so it adds another level of variance.

 

Figure 4. The emotional roller-coaster

 

Look at that-  it predicts that some of you haven't killed all your cells yet...

 

 

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So- I hope I have at least made this much clear-   there are a number of overlapping factors that contribute to the symptoms of narcolepsy.  The combination you have determines your combination of symptoms.

  • Gluten antibody response- which combination of antibodies you produce and how much

  • Cumulative damage- how many orexin cells you have lost.

  • Primary insulin response -occurs before you eat. If you wait too long and allow your blood sugar get too low you will have dizziness and other symptoms before you eat.
    Secondary insulin response-occurs after you eat.  We produce too much and the result is hypoglycemia.  Women seem more susceptible to this than men.

  • Stress response.   This varies with age and infection status.   And men seem to have stronger responses than women.

  • Your diet.   Since orexin cells sense glucose, what you eat has the biggest effect of all.

 

And these factors change as the pathology accumulates.

For example, there's this interesting metabolic alteration that happens-

Glucose sensitivity amplifies over time.  But  insulin response wanes as you age. 

If you're lucky, they kind of cancel eachother out.

  

 

There are also a couple things that mimic cataplexy-  and we are susceptible to both of them.

  • Extreme hypogycemia causes syncope- loss of conciousness.

  • Hypotonia - loss of muscle tone- is a symptom of Sydenham's Chorea which is caused by a strep infection.

 

Those topics are covered later.

 

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Recommended Reading:

New Mechanism Explains Glucose Effect On Wakefulness

Why Sugar Makes Us Sleepy (And Protein Wakes Us Up)

Illness affects Orexin Cells

 

Special thanks to JL for insisting that glucose was involved and forcing me to reassess my paradigm. I was totally missing the big picture. He was so sure, he underwent a glucose tolerance test with real-time insulin monitoring. After ingesting the glucose, he had a complete cataplectic attack, and while he was out- his insulin jumped THREE TIMES normal levels. Thatís alarming.

(And his doctor told him he was imagining it too.)

 
 

 

  

 

 

 

 Big Fat Disclaimer:  The research on this website has not been peer reviewed in any way.   The conclusions presented are strictly the opinion of the author.  It is being self-published as a public service in consideration for sufferers and as a stimulus to the medical research community.  Information presented on this page may be freely distributed or copied. 

 

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