State of the Hypothesis- Meta Edit

 Update:
This document has been superseded by a more current version.

------------------------------------------------

After seven years of dietary restriction and infection awareness, it has become obvious there are a number of things that need to be added to my original Narcolepsy hypothesis. I have been hinting at most of this on my blog, but it needs to be made explicit.
  1. Recurring infection seems to be a ubiquitous and lifelong experience.
  2. Dietary dysfunction involves more than just gluten and sugar. There are other food sensitivities and immune reactions in the digestive tract.
  3. The microbiome is central. It is the intersection between diet and microbes.
  4. I have done a lot more thinking about the hallucinations and have some ideas about that.
All of this new stuff assumes you have read my narcolepsy website, and are familiar with the basic symptoms of narcolepsy and functions of orexin. I don't have the energy or motivation to repeat all that.


INTRODUCTION


Despite the fact that doctors don't seem to know the slightest bit about it-
Orexin is a fundamental molecule to human existence.
It regulates energy usage. In the brain. In peripheral tissues and organs like muscles and the liver. It is intimately involved in the immune response. And digestion. Orexin helps control the Gut-Brain axis. The sympathetic vs parasympathetic nervous systems. It is crucial to consciousness and anything involving movement.

It switches parts of your body on or off. It's that basic.

Narcolepsy is not a sleep problem. It an energy management problem. Sleeping a lot is only one manifestation of overall low energy levels. So is gaining weight. And mood problems.

It is also not a mystery anymore.
Although most sources claim that narcolepsy is a rare condition of unknown cause, I believe the existing information can explain most of the symptoms and that knowledge can be used to reverse engineer and prevent the proximate and ultimate causes of our misery.


MECHANISMS

Narcolepsy is caused by the depletion of the neurotransmitter orexin in the body and the brain.

There seems to be two primary things that lower orexin levels naturally.
Diet- The orexin system is a basic regulator of digestion and metabolism.
Orexin cells sense glucose in blood and alter their output based on that information. When blood sugar rises, orexin cells produce less orexin. That's why people get sleepy after eating.

Infection- in addition, orexin is critically involved in the immune response.
When there is bacteria in the bloodstream, orexin production is drastically curtailed. This shifts metabolic resources to fighting the infection. That's why people get tired when they are sick.

Narcolepsy seems to be a combination of both of them.... infections that cause or interact with digestion problems.
The combination of these factors create an array of effects. The resulting symptoms range from low level to acute, vary dependent on the pathogen and location of the infection, what you eat, what the climate is, and whether you are male or female.



INFECTION

The evidence is accumulating that numerous respiratory and oral infections can trigger narcolepsy.
I believe this occurs in two different ways.

  • Chronic infection and the accompanying immune response contributes to inflammatory mechanisms of orexin depletion. Low level infection alters intestinal function.
  • Acute systemic infection curtails orexin production directly and drastically.

STREP

It is my belief that Narcolepsy is a rheumatic disease. Specifically, it's an immune complication to certain strep infections, similar to arthritis and rheumatic heart disease.

The post infection complications of strep infections have historically been an enormous public health concern. Rheumatic fever, scarlet fever, rheumatoid arthritis, kidney nephritis- all were common illnesses. Before antibiotics, there were entire hospitals of people just recovering from the post infection complications. They had to rest for weeks or months until they healed from kidney or heart disease.

Those commonly recognized streptococcal autoimmune disorders are triggered by Strep pyogenes. This is the species which causes "strep throat" .
Although antibodies to S. pyogenes are commonly found in narcoleptics- and associated with the sudden onset of symptoms- I get the feeling Strep pneumonia is a more persistent trigger. It is less annoying and people do not treat it as aggressively. I also believe that instead of attacking the joints or heart valves, the immune reaction affects the digestive system.

There is reason to believe there is a whole group of strep bacteria that colonize narcoleptics and trigger symptoms. Strep is a recurring infection. The bacteria share some basic molecules with humans so we never get complete immunity, and usually have a residual population in us somewhere.  Different strains of the same species are common. Families tend to share strains- acquaintances tend to infect us with novel strains.  Narcoleptics just tend to be more prone to them for some reason.
These are the ones I encounter most often in your reports and mine.

S. pyogenes, also known as group A Streptococcus (GAS),
This is the causative agent in a wide range of group A streptococcal infections. These infections may be noninvasive or invasive. The noninvasive infections tend to be more common and less severe. The most common of these infections include streptococcal pharyngitis (strep throat) and impetigo. Scarlet fever is also a noninvasive infection, but has not been as common in recent years.
The invasive infections caused by group A streptococci tend to be more severe and less common. This occurs when the bacterium is able to infect areas where it is not usually found, such as the blood and the organs. The diseases that may be caused include streptococcal toxic shock syndrome, necrotizing fasciitis, pneumonia, and bacteremia.

S. agalactiae, or Group B Strep-
This species causes pneumonia and meningitis in infants and the elderly, with occasional systemic bacteremia. They can also colonize the intestines and the female reproductive tract, increasing the risk for premature rupture of membranes during pregnancy, and transmission of the organism to the infants.

S. pneumoniae (sometimes called Pneumococcus)
Despite the name, the organism causes many types of pneumococcal infections other than pneumonia. These invasive diseases include bronchitis, rhinitis, acute sinusitis, otitis media, conjunctivitis, meningitis, bacteremia, sepsis, osteomyelitis, septic arthritis, endocarditis, peritonitis, pericarditis, cellulitis, and brain abscess.
More than 90 different serotypes are known.

S. Mutans
Commonly found in the human oral cavity and is a significant contributor to tooth decay.

(via Wikipedia with slight editing)


The association between these illnesses and your symptoms is obscured and difficult to recognize because-
  • These are common illnesses. They are sort of "expected" parts of life.
  • Different species colonize in different areas of the body.  And they tend to cycle.  You think of them as independent events.
  • Other infections or conditions that affect or mimic the immune response.
I am still not sure what immune trigger these particular strep variants have in common that might cause narcolepsy. The traditional and newer classifications do not seem to be based on molecular similarities. The genetic data show they share a common ancestor. They do share some heat shock proteins. I am now leaning towards the streptococcal cell walls, which contain a known pyogenic superantigen (molecule that causes ulceration). That would probably explain a lot.

I go over all this in more detail later.


INFLUENZA

The other major infectious illness associated with narcolepsy is H1N1 flu. Although no direct causation has been proven, an increased incidence of narcolepsy after the 2009 pandemic has been documented. That this result occurred after both vaccination and natural infection provides strong evidence this is a real and specific effect. The 1918 influenza epidemic was also a strain of H1N1 and had a similar occurrence of a post-infection sleeping sickness called Encephalitis Lethargica.

My preferred explanation is that H1N1 flu facilitates a secondary strep infection. It alters the immune system which facilitates the strep infections that then trigger the autoimmune complications of narcolepsy. There are many studies showing that infection with the flu virus lowers immunity to strep pneumonia and that it is the most common complication. I have covered most of that here...

H1N1 also affects the digestive system in addition to the lungs. Ulcerative lesions in the intestines were much more common in H1N1 infected animals than from other flu strains.
This may be due to some kind of molecular mimicry with orexin nerve fibers in the intestine, but that hypothesis has not been verified.

Even if these ulcerations in the intestines do not directly bind to and disable orexin cells, they probably facilitate another common reaction to infection...


SEPSIS
(This is a really big piece of the puzzle that I have been missing...)

When there is bacteria in the bloodstream, there is an immediate cascade of neurological and hormonal and immune effects and orexin is a key factor.

When animals are inoculated with microbes into their tissues, abdomens or bloodstreams, orexin production is rapidly curtailed. It seems to happen with anything they've tried.

Orexin production is rapidly reduced to about one-sixth of normal.
You also become insulin resistant almost immediately. That's why you don't feel like eating.
Anorexia is a symptom of acute infection. Bacteremia. Sepsis.
That applies to most animals and has been documented since the beginning of civilization.

You shouldn't be eating because the energy ordinarily used for digestion is needed to fight off the infection. Your whole metabolism shifts to accomplish that. Tries to knock you out so you don't interfere.

Pharmaceuticals have changed all that. Interfere is exactly what we do.
They dull the pain, shrink the inflammation, shut down your immune system, give you energy and keep you going even though you are actually still sick...they address the symptoms and create chronic illness.
And then we are given the advice to eat "healthy" high glycemic meals to increase our energy...

Vitamin D deficiency and orexin deficiency both tip the immune system to chronic response.
This is the hallmark attribute- these infections can be invasive or commensural, acute or chronic. And one leads to the other. and vice versa.

But The Really Interesting Thing about bacteremia- it has so many causes.
Including inadvertent ones.
It can be caused by traumatic injury, or acute ulcerative infections, or a chronic infection that progresses to abscess. In addition, bacteria are spread into the tissues and circulation by dentistry or the surgical procedures used to repair injuries or excise fetid infections.

Read that again. It is crucial to understanding our predicament.

Not only is trauma or infection or neglect able to cause this acute systemic response- many of the treatments actually trigger and compound the pathology.

That puts a whole new perspective on tonsillectomy, now doesn't it.

-------------------------------------

Here's another perspective we need to consider.
Over time, infection activates the hypothalamopituitary axis- it increases the production of stress hormones.

If you survive the septic infection-
Epinephrine goes up in chronic infection. So does cortisol.   And dopamine.
This reduces some of the insulin production, and lessens fatigue.

Chronic infection causes increased stress response. If it isn't too severe, we use that to our advantage while we're awake.
Unfortunately, while infected we tend not to sleep too well. Fractured light sleep with raging REM. Nightmares. We never turn off completely.
Just to be explicit- the technical term for that is slow-wave sleep deprivation.

And it causes panic attacks. Twitchiness. Surely contributes to cataplexy.


ANTIBIOTICS
Although I am convinced that bacterial infection is a primary cause of Narcolepsy, I do not believe that antibiotics should be a primary treatment option, except for in the case of sepsis.  After my latest round of illness I am now convinced that the liberal use of antibiotics to control these underlying infections actually contributes significantly to Narcolepsy pathology.
I think there are a number of ways:
  • The commonly accepted mechanism is that the antibiotics kill off most, but not all of the infection, leaving a population of naturally resistant bacteria that, although not clinically detected, remains viable.  This is how the current strains of antibiotic resistant bacteria were created. I believe they also trigger autoimmune reactions.
  • There is a new study showing that antibiotics may actually create altered proteins that the body identifies as 'foreign" and then attacks them.
  • They also drastically alter the composition of the microbiome. Broad spectrum antibiotics wipe out whole classes of bacteria in the digestive tract.

The use of antibiotics has been associated with subsequent long term complications.
  • Other pathogenic infections. Killing off a bunch of microbes seems to allow others to flourish.
  • Increased food allergies. like wheat. and nuts. both of which can cause ulcerative lesions.

Since both infections and food allergies also affect the orexin system- this solution is a big part of the problem.

-------------------------------------


Theoretically- it looks like any pathogen that will create an ulcer and sepsis and morph into a chronic infection will predictably curtail orexin production and possibly result in narcoleptic symptoms.
I really wonder about Staph aureus... it also has a superantigen, and it's everywhere.  Always.
Herpes lesions probably also contribute to this effect.

However, for historical and epidemiological reasons, I am still going with the various Strep species as the "most likely to be causing the problem".


-------------------------------------

DIETARY

I still think the nap attacks and excessive sleepiness and cataplexy work pretty much the way I outlined in the original hypothesis. They are the result of metabolic dysfunction- glucose overdose exacerbated by immune activity in the digestive tract.


GLUCOSE / CARBS
As I expalined on my website, orexin cells are glucose sensitive.
As blood sugar increases, orexin production decreases.
As blood sugar decreases, orexin production increases.
If you have low orexin levels, you cannot tolerate as much glucose before you fall asleep.

And lowering glucose levels increases orexin function.
More specifically-
Orexin expression is upregulated by fasting and insulin-induced hypoglycemia.

Read that again. It explains a lot.

There are two "ingestive behaviors" that increase orexin levels- fasting and bingeing.

(They probably didn't test alcohol induced hypoglycemia... )

Unfortunately all of those are unsustainable.
Intermittent fasting has been shown to increase insulin resistance over the long term.
And bingeing increases it over the short term.
An overall long term restriction diet seems to work better.


GLUTEN/FOOD ALLERGY

I am changing up this portion a bit. I now think there are more intestinal problems than just a specific gluten antibody response. A number of not-mutually-exclusive possibilities.

I think food allergies add to the effect of the glucose by impairing the intestines where the orexin neurons terminate.
  • The HLA evidence suggests it is likely that we do produce antibodies to gluten, and I think they may preferentially bind to orexin neurons somehow. That's my original hypothesis.
  • It's undeniable however, that most of us report multiple food sensitivities in addition to wheat.  Dairy. soy. grains. nightshades...
  • That cannot be ignored.

Although it's not required, I really want to find a specific interaction between strep infection and food sensitivity.
For example- If the strep antigen is a sugar molecule on the cell wall- that may explain why there seems to be an immune response to a wide variety of carbohydrate based foods.

It could be antibiotics instead though. Antibiotics and infections usually occur together and confound each other's effects, now don't they...
Antibiotic use has been associated with subsequent celiac disease.

Alternatively,
A strep infection could upset the balance of the intestinal microbiome. more on this later.

I also think a biofilm explanation might work.
IgG antibodies have two binding sites. They can bind to more than one thing. If there are a lot of them they attach to each other as well as other molecules and create a cross-linked matrix.
So let's say we make IgG antibodies to gluten, and IgG antibodies to strep, this could combine with the mucous membrane and create an "impermeable" biofilm.
Just clog everything up.

It might also be the opposite- all the ulcerative activity just compromises the integrity of the intestines. I have been reminded that "leaky gut" fits in here- it causes endotoxin and bacteria in the bloodstream, just at low enough levels not to be considered sepsis. Wheat allergy is strongly associated with leaky gut, so it may just be that. Wheat may just facilitate bacteremia.

Or any combination of the above.  That's most likely.

Update-  ooh there it is!
Strep pneumonia in the lungs causes intestinal dysfunction in mice.
Although relatively few bacteria gained access to the blood stream, the pneumonia was accompanied by increased intestinal epithelial barrier permeability.

I don't know if it causes food sensitivity or just amplifies it, but either way it explains a lot.

-------------------------------------

On a slight tangent-

The areas that seem to promote these chronic infections are also affected by low orexin levels.
The intestines definitely have reduced functionality, and bacterial overgrowth is a known effect.
Olfactory bulb function is reduced, and strep pneumonia forms low level colonies in the nose and sinuses.
Lung function is reduced and strep pneumonia also likes to live there. I think this is probably a common cause of asthma.

Maybe impaired orexin function due to sugar facilitates less immune response- and allows the infection to colonize and directly disable the orexin cells via retrograde action from the peripheral tissues...
...and that makes me wonder if certain orexin cells in the brain control certain organs... or if it's more general.


-------------------------------------

Theoretically, once again-
It could just be a general infectious response.
Combined with any intestinal compromise.

And strep and gluten are just the most likely to occur and interact and cause lifelong complications.


---------------------------------------


EFFECTS
So, now we have low orexin levels, what happens?

Things start getting complicated here. I am having a hard time trying to figure out how to present the network of interactions....

I can go forwards with biochemistry...

Low orexin levels are associated with:

LOWER EPINEPHRINE
This seems to result in mitochondrial dysfunction which causes the brown fat cells to deteriorate.
It also results in less energy in skeletal muscles.
This gives us less overall energy. Really, truly, it does.
But you are probably more familiar with the shame-laden term "lazy".   Possibly.   Definitely.


INCREASED INSULIN RESISTANCE
This makes us fat.
On my Zombie website I think I got this mechanism backwards.   It seems orexin may alter insulin resistance instead of production.  Increased insulin resistance stimulates increased production of insulin though, so it works out pretty much the same.  Increased insulin production also raises resistance, so it's a positive feedback loop.

Estrogen amplifies the production of insulin so this explains why 75% of narcoleptics are women. and why we are fatter than the men.

High insulin levels also amplify the effect of GABA. So if you have high insulin levels you will be extra sensitive to it's effects. And GABA suppresses the central nervous system. Puts you right to sleep. It definitely contributes to central apnea, daytime sleepiness, and negative affect.

HIGHER HISTAMINE
There is a remarkable increase in these cells in narcoleptic brains.
Histamine regulates fever.   This may be an artifact of chronic infection.


----------------------------

Or, I can go backwards from symptoms...

Sleep attacks- a combination of rising blood sugar and allergic response lowers orexin levels after a meal.

Cataplexy- a sudden spike in blood sugar due to stress causes orexin levels to crash.

EDS- cumulative antibody, inflammation and insulin responses eventually suppress the nervous system perpetually.

Obesity- less brown fat, more insulin resistance and production.

Depression- GABA sensitivity, less dopamine stimulation, constant multiple neuralgias

Memory- memory in childhood is actually improved due to post everything naps. Sleep helps you remember. The short term memory seems to fade rapidly right around the tipping point of type two diabetes, though.


Either way, the effects combine to ultimately make you sick and fat and tired and cranky.

 ------------------------------------


ALSO EXPECTED BEHAVIOR

This really needs to be made explicit-
If we restrict our diets-  cut out the carbs and allergens and lower our insulin burden we will feel better.
We will.
However, it has also become evident that if you do that- remove the suppressive influences without also addressing any infections - it's very predictable that you may experience increased stress hormones.   Especially if you continue using stimulant drugs.   If it progresses to anorexia and bacteremia, you will become manic.

It feels really good, it really does.   It's really too good though.   Real life really isn't that great.  You really don't need to change the world.  You really don't need to run a marathon.  You really don't need to clean your electric outlets.  You really need to check for infections and injuries and calm your nerves.   You really do not want to get worse and crash and burn.

Hypergraphia seems to be our most common manifestation.  If you write to me and use a lot of exclamation points, I will probably assume you are in this phase of the cycle.



-------------------------------------


DRUGS
 
The basic knowledge of the functions of orexin also allows us to understand the action of the drugs we use to treat our condition.
Most of the pharmaceutical drugs for narcolepsy improve sleep propensity by altering glucose metabolism. They are fundamentally weight loss medications. In a few different ways, they alter insulin production or insulin resistance, and stabilize blood glucose levels. I have a paper about that here...
Since writing that, I have realized they probably also increase production of epinephrine, and reverse the brown fat deterioration. But I haven't looked them all up individually yet.

It seems our drug seeking behavior is more effective than our food seeking. The food we like to eat usually makes the symptoms worse. The drugs we spontaneously choose actually do seem to have positive effects. They pretty much do the same thing as the commercial drugs.
Nicotine increases orexin production in the brain, improves glucose control, down regulates GABA sensitivity.
Caffeine- increases orexin production, improves glucose control.
Nicotine and caffeine are also antibacterial.
Opiates-  seem to improve lung function
Sudafed- increases epinephrine


VACCINES

I do not know enough about them to determine the theoretical or practical efficacy of vaccines to alleviate our autoimmune problems. But I do have enough experience with the H1N1 vaccine to be wary.

Vaccines work really well for certain microbes in certain situations. The historically successful vaccines target fairly simple pathogens. Highly mutable strains are not usually so successful.
  • The flu virus assembles from known subunits which change often to avoid detection. Every time it switches, slightly different surface proteins trick the immune system into thinking it's a new infection. That's why flu vaccines have multiple strains and always change every year.
  • Strep is similar as there are rapidly mutating versions of all the species.

There just may be a natural limit to the efficacy of that approach.
It may also be exactly the wrong strategy for an immune disorder.

I am VERY concerned that initiating an immune response to these pathogens may actually cause the problem.
It may stimulate the production of the autoimmune antibodies you want to avoid.
  • Flu vaccine may trigger the post flu immune suppression, causing any number of other effects.
  • Pneumococcal vaccine may introduce cell wall antigen into our systems and trigger a septic event.

(see Pandemrix. Antigen cocktail with Pyrogen chaser. Hmmmmm...)



MICROBIOME

I really should know more about this than I do.  I read a lot of medical history. I am stuck in the past.  This is surely the direction where our future lies.

The jillions of bacteria our digestive system contribute to our metabolisms. They not only help us digest by breaking down food molecules, they produce some nutrients we can't. They also assist and modulate the immune system. And facilitate some healing processes.

If things are working properly, the different microbes coexist and combine with the mucous coating to form a biofilm that acts as a mediator between the intestines and the food.
And it seems all the narcolepsy related triggers somehow alter that balance. Go figure.

  • Diet.  There are different microbes that gain dominance if you eat mostly carbs, or protein or fat.  If you change your diet the microbiome can shift drastically in less than a day.
  • Antibiotics definitely alter the microbiome, lessening microbial diversity in the intestine. this has been correlated with a number of disease states, including obesity.
  •  Food allergies have been documented to alter the microbiome.
  • An infection can establish a population in the intestines and directly disturb the ecosystem.
  • Or it triggers an immune response that selectively skews the population.

It doesn't even have to be an intestinal infection-
Tuberculosis lung infection causes changes in the diversity of gut bacteria in mice
I'm telling ya, this microbiome stuff is the future. I would be real surprised if someone were not already trying to insert an orexin gene into some gut microbe in some lab somewhere...



OTHER
Other things I should think about more, but haven't yet-

Sunshine and circadian stuff-
This is also a primary input for orexin production.   We make less orexin in the dark.
The evidence shows this is probably to conserve energy in the winter.
It's also got something to do with cold and brown fat though.
Since moving from Seattle to Arizona, I am kind of doing inherent experiments with this.  More light, but no cold.  I think it might be a wash, metabolically.

Oxytocin- it's crucial in intestinal and wound healing. also learning and memory. crosses over with orexin a lot.

maoA- "The Warrior Gene"
I think this is probably a major modifier of symptoms.
It increases the stress response so I would expect it to contribute to anxiety symptoms in males.
On the other hand, I think it may actually alleviate some of the depressive symptoms in females.

Thyroid- this is real important but Christina knows a lot about it so I just ask her when I have questions. Lots of associated thyroid dysfunctions with N.  Certain antibodies have been shown to bind to the both the thyroid and orexin cells.
It's part of the HPA axis and stress response.  Hyper vs hypothyroid is also surely a major modifier of symptoms with sex differentiated effects.


-------------------------------------

For the record- I don't believe that complete destruction of the orexin cells is necessary to exhibit narcoleptic symptoms.
And I do believe that Orexin cells may possibly regenerate naturally if the degenerative influences are removed.


-------------------------------------

And to be specific, the dietary techniques are prophylactic treatments.   They alleviate our symptoms, but do not technically put us in remission.
Nonetheless, it's the best we got right now.

-------------------------------------


The Grand Irony

Hyperinsulinemia is beneficial if you are injured or truly starving.
Thus our ancestors survived.
Thus we all exist.



-------------------------------------


DISCUSSION

Okay, now that I've got all that technical stuff out of the way, I'd like to Carry On for a while...

This is the reason I don't think flu is a major trigger- we don't complain about flu. I don't ever remember having it. And our symptoms don't seem to be that seasonal.
We do report a lot of bacterial infections though. And our onset and progression seems to be more related to those events. Here is a list of the things I hear about all the time. I've collated them together, most people don't have all of them, but you all report some of them.


A walk through the life of a common narcoleptic.

The parade of infection.

Gestation and Birth.
Strep B - I think this may be the "gateway" infection that primes the body for all future encounters with similar microbes.

Infancy
Teething - oral bacteria, meet bloodstream. nom nom nom. surely a trigger for febrile seizures.
Ear infection problems- facilitated by smaller mandibles, facial hypotonia, oral inflammation, sleeping after eating.

Elementary school
Strep pyogenes thrives in classrooms. mutans and pneumonia too. they survive pervasively on surfaces and the strains are constantly changing.
I think the reason strep throat triggers the onset of narcolepsy- it's the most ulcerative strain. It causes major tissue damage and fever.

If strep throat is a recurring problem, then the normal reservoirs, tonsils and adenoids are removed and some other site gains dominance.

I think one of the most common reservoirs is the periodontal spaces. I believe teething and tooth loss and secondary eruption all allow the bacteria into the tooth sockets and infiltration of the facial nerves.
primary symptom- tooth grinding.
cause- Apical periodontitis.

A propensity for sleeping after eating facilitates bacterial growth in the mouth.
Inflammation of the tissues promotes crevices and impairs salivary drainage, especially behind the molars.
The hypotonia of the airways leads to snoring and apnea.
Periodontal bacteria contribute to sinus and lung infections. they break loose, are inhaled into sinuses and lungs. where they proliferate and then are exhaled back into the mouth and nose.

Adolescence-
I believe orthodontia greatly contributes to chronic oral infection. The appliances tear up the oral tissues, and the traction damages the bony structure.
Gum recission is documented to increase after braces.

Teenagers also tend to exchange their oropharyngeal cooties. Cavities and runny noses are contagious, you know.

College seems to be a time of behavior change.   Poorer diets and dental care.   Less sleep. All which promote infection.

Adulthood-
Crowded and impacted wisdom teeth are probably the number one cause of symptoms in young adults.  They often rot even before eruption, and even if not, they crush the surrounding tissues and promote infection.
The symptoms are usually ignored until no longer possible.  And then there is some pretty traumatic surgery.

Sexual activity. Novel strains are acquired from romantic partners. for example, urinary tract infections.

Travel in general messes with your immune system and introduces novel pathogens.

Then for the ladies- during pregnancy- insulin production and immune activity is increased. Not to mention a propensity for Strep B to flare up. and a chronic lack of sleep.
Which brings us to birth again...all kinds of hormones and invasive procedures going on.
And... then those kids bring home more strep strains when they go to kindergarten.

and Middle Age is delightful.
All our dental work counts for nothing.  Teeth start crumbling and falling out.  Implants, dentures, it's all bad.
All our tubes and ducts get crusty.  Urinary tract problems become chronic.
And doctors like to cut on us a lot.


-------------------------

I think there is also an external epidermal version of this scenario.... people who get recurrent and chronic skin infections.
Rashes in childhood, chronic acne, dermatitis, excema, psoriasis, hair loss, slow wound healing, etc. Parallel to the oropharyngeal ailments, the constant skin lesions and abrasions cause lifelong immune activity. (This may actually be a staph variant of the pathology, but I have no data to support that guess.)

---------------------------------

The reason it gets cumulatively worse is because of the glucose problems.
We eat lots of carbs and we never recover properly from the infections.
(We crave them and we are told to, so go figure.)

Sugar promotes infections.
Dental bacteria for sure.
Also predictable- urinary tract infections. Kidneys excrete excess glucose and bacteria take advantage of that.


-------------------------------------


Periodontal Disease-
I know I obsess and nag on this subject, but all the triggers and effects of orexin depletion point to periodontal disease as a common cause and practically inevitable outcome of narcolepsy.

  • Sleeping after eating facilitates bacterial colonization of the mouth.
  • Low orexin levels curtail osteoblast production. Your bone production is lower than normal.
  • Strep bacteria alter calcium metabolism. They get in cells and rapidly pump out calcium. This causes plaque on your teeth, in your arteries, while depleting your bones and teeth.
  • We tend to have smaller jaws from reduced human growth hormone production. that causes poor saliva drainage.
  • Strep bacteria also deposit calcium in your salivary ducts clogging them up, Low saliva allows more bacteria to grow and more calcium to accumulate.
  • Stimulants reduce saliva production further.
  • This fundamentally alters carbohydrate digestion as amylase is in saliva.

And don't forget, periodontal lesions and abscesses are the Number One Cause of bacteremia and sepsis...

-------------------------------------


When I first started writing about narcolepsy, I noticed how people were vehemently opposed to the idea of giving up carbs. It really bugged me at first. And then I realized it's a symptom. We're not idiots. We don't want to be sick. We really do crave carbs.
Since advocating dental care, I have noticed the same thing about periodontal disease. Everyone dismisses it. That makes a certain amount of sense, but still, I can't ignore all of you.   That's your doctor's job.
More importantly, I think I am pretty smart and I have all kinds of dental problems.
And then I realized, it must also be a symptom.

So once again, here's a Wicked Twist-

Small Fiber Neuropathy seems to be a completely unrecognized symptom of our illness.

The sensory nerves are made up of two kinds of fibers. Large and small.
As you would guess, the small fibers sense specific areas and the large ones are more general.
If your small fibers are damaged, you cannot feel pinpoint sorts of pain in the epithelium. Things like punctures and cuts.

Anyhow, here's a list of a few things that contribute to the atrophy of the small fibers in your mouth-

salt
nicotine
toothpaste
tooth whitening products
mint, menthol
calcium buildup
gluten
alcohol
acid
dehydration
stimulant drugs

And Sugar. This is Number One. The more I think about this, the more I realize that the peripheral neuropathy diabetics get in the feet and fingers.... that's way late in the glycemic party. The nerves in your mouth and guts stop working way before that. That's why we don't realize we have food allergies. We just don't feel the damage. That's why we get obese or diabetes, the neuropathy starts in the digestive tract.

Lack of feeling is well documented in diabetics. I also have Doctor's Notes that are a hundred years old explaining that most people with dental abscesses feel NO PAIN.
My mouth doesn't hurt until I have exposed some tooth pulp to air.
My neck and shoulders do, though.

This is so fundamental. We are not stupid. We are not crazy. The pathology masks the perception of the pathology.
Our sensory input is totally messed up. We are not aware of our own chronic illness. It just doesn't ever even occur to us. Everyone expects a toothache or stomachache to hurt...


And just for some bonus irony-
The insensitivity probably occurs first where the most immune activity is.
It isn't uniform. We do have some sensation in healthier spots. But we can't feel the bad spots.
And the more infected we are, the less able we are to feel pain in general.


Now, let's twist a little further...

HALLUCINATIONS

I believe trigeminal neuralgia from oral infection also causes the visual and auditory phenomena, depending on the site of the neuralgia. The trigeminal nerve is the major sensory nerve of the face. It innervates all around the main sensory organs up there.

The primary symptom of trigeminal neuralgia is described as sharp intense pain.
I would like to dispute that. I think the primary symptom of trigeminal neuralgia is actually loss of sensation. The pain doesn't come until much later.

Although the small fibers are damaged, the underlying large fibers are usually still functioning. These evoke a more diffuse and aching sort of pain. That's why we have headaches a lot.
The infectious and immune activity also creates spontaneous nerve activity.

So this is the result:
Sensory paralysis- we can't feel real input
Spontaneous nerve activity- we experience erroneous input

This is how I think most of the hallucinations are generated. Your nerve is "pinched" or "poisoned" or "asleep" but you don't feel the pain, you experience the associated sensation- vision or hearing or odors or whatever.
  • If the neuralgia is in your ophthalmic branch, your eyelids don't hurt (they will probably droop), but you will experience visual phenomena.
  • If it's in your mandible or mastoid process, not only do you lose hearing function, you also generate false auditory signals. You won't have an earache but you will have tinnitus or auditory hallucinations.
  • If it's in your sinuses, you will be prone to puffy eyes, droopy cheeks and uncontrolled weeping. I actually think that spontaneous crying often results in chronic rhinitis. And I think runny noses are a major cause of depression. I think crying actually causes depression.

This is how Botox works for depression and migraines, they paralyze the nerves around the nose and eyes.

I think a lot of the other phenomena are similar, but are triggered by other nerves somehow.
Especially the one where you feel like there's something holding your chest down. That must be a vagus/cardiac thing.

Crawling sensations must be peripheral neuropathy of the skin.


The obvious corollary to all this also needs to be made explicit-
We do have symptoms of our infections.  It's just not what we think.
If you are having visual or auditory hallucinations-
Or are lying on the floor crying your eyes out-
Or spend your nights lucid dreaming-
Or have the sudden urge to write your life story-
You probably have an oral or nasal abscess you can't feel.


----------------------------


YO SLEEP MEDICINE INDUSTRY. RESEARCH THIS STUFF.

Please use the known knowns to modify your clinical practice methods and research goals.
There are a lot of promising avenues here. Appropriate tools and interventions already exist.

Your diagnostics are worthless. The PSG and MSLT are a complete waste of time and money.  All they do is validate your ability to measure highly variable symptoms without controlling for obvious and documented triggers.

This is what you need to test for:

Hyperinsulinemia, or Insulin Resistance. Something. Sheesh.
This should be the first order of business for anyone presenting with rapid or uncontrollable weight gain, depression, excessive fatigue or dementia.

Infection. An array of strep and flu and herpes antibodies is probably a good start.
Acute symptoms like hallucinations, major depression, cataplexy, and Klein Levin warrant a sensitive test for bacteremia.

Food allergies- you can't ignore this any more. We all have them. The tests are easy and widely available. What the hell.

And most definitely- Instead of pushing CPAP and mouth guards that breed bacteria, you should be monitoring and preventing periodontal infection and oral neuropathy.


And here's some obvious treatment possibilities that need research:

All the metabolic ones- shown to improve glucose control.
Metformin- really, I shouldn't even have to say this.
Epinephrine- activates brown fat
Exercise- improves glycemic control, lowers insulin resistance
Cold therapy- also shown to activate brown fat.

And we could really use some appropriate diet protocols.
We all need to be told to lower our carbohydrate intake and eat more protein. It just doesn't get any more basic than that.

But we also need a more comprehensive list of things to avoid. The food reactions are complicated.
Since we have so many carb problems, I am thinking it may be something like FODMAPS. (although I have only read about it briefly, I noticed that I already avoid most things on their list due to ulcerative reactions.)
Or one of the autoimmune diets. Terry Wahls' protocol. Or the Paleo version etc.
We need some real data on that please.

Microbiome stuff-
Oh, the possibilities are endless.
We surely have an unbalanced constellation of microbes in common. I hope somebody is cataloging it.
We can probably treat a lot of our infections with probiotics, or other commensurals.
Fecal transplants have shown some positive effects for autoimmune disorders.
I would not be surprised to learn there are bacteria that can produce orexin.


Infection/immune control-
We need something besides antibiotics and steroids. Like Right Now.
Aspirin and the Cox2 inhibitors show some beneficial properties and have been associated with alleviating symptoms of rheumatic disease since um... always.
Vitamin D3. Should be on the checklist when the doctor first talks to us.
Olive oil-  Oleic acid suppresses strep bacteria.  It is safe for use on the skin and in the ears, nose, mouth and nether regions.
Maybe ketamine or statins. They have preliminarily been shown effective for bacteremia.
I am quite sure there are traditional or herbal remedies that would be highly effective, I just don't know what they are.

Pregnancy Care.
We are extra vulnerable to the predictable immune and metabolic effects of pregnancy and that needs to be addressed.
Infections and commensural microbes and antibodies are transmitted at birth.
There is also reason to believe that the prenatal effects include autism related disorders in our offspring.

Dental care.
We need some appropriate, evidence-based preventative care advice.  
Brush and Floss does not count.
We need some ideas how to control our oropharyngeal microbes without burning the whole place down.
Some dentists who understand that we need gentle care, not more invasive surgery.  Who realize that periodontal probing with pointy sticks actually causes bacteremia.  That would be real nice to find...
And some more research into the calcium dysfunctions, please.

Marijuana
There is reason to believe that medical marijuana would have significant positive effects on narcolepsy.
It seems clear that narcoleptics really do have a tendency to alcoholism. And it really looks like marijuana is the most appropriate social substitute for alcohol. Especially for alcoholics-
It lowers insulin resistance and stabilizes blood sugar, it lowers dopamine response, and it heals mucous membranes in the alimentary tract. Not to mention it alleviates depression.
Orexin and CBD receptors interact. Marijuana probably actually mimics orexin in some ways.
THC also seems to stimulate the olfactory and glossopharyngeal nerves. It increases their function. You smell and taste things better. I hypothesize it may do something similar in the lungs.

--------------------------


CONCLUSION

I think I have covered almost everything I had intended.

The assortment of strep infections.
The variety of food triggers
The other contributing factors.
All combining to create an individual constellation and progression in each of us.

This is why the overall syndrome has been so hard to detect.

Sepsis explains the sudden onset or worsening of symptoms.
Chronic infection and dietary dysfunction explains the persistence and cumulative effects.
Estrogen effects on insulin function explain the sex distribution.
And why girls have more of the metabolic effects.
In boys, I think it's more infectious. You guys have higher stress and less pain.  More injuries.

Gluten and sugar cause depressive/sleep symptoms.
Infection seems to cause the hyper symptoms- anxiety, nightmares, obsession.
We seem to navigate between the highs and lows and approximate a sort of normalcy.

We instinctively choose adaptive behaviors.
As our orexin levels drop we adopt behaviors that compensate for our deficiencies.
Alter our diet
Compulsive exercise
Stress avoidance behaviors
Self medication
Self injury
And those things really do help a lot, until they just don't anymore.

Unfortunately-
The illnesses which actually trigger our problems seem insignificant and unrelated to our really debilitating symptoms.
So we tend to ignore them.
If you live in Seattle, you expect your nose to run all the time
If you have braces, you expect your mouth to be ragged and inflamed
And nobody ever suspects that acne might be making them seriously ill...

 That's why this all needs to be made explicit.


  -------------------------------------


This outline covers evidence and reality based mechanisms that can explain the spectrum and distribution of symptoms seen among narcoleptics. It also has a few suggestions on how that information could be used to improve the quality of our lives. Please do not mistake this for a philosophical exercise.


Why This Matters

If you take a recurring infection model of orexin depletion
And overlay a lifetime of cumulative digestive dysfunction
And then you add in an occasional injury or surgery or invasive systemic infection...

...You get something that looks suspiciously similar to our constellations of symptoms:  Our neurological rollercoaster ride through the freakin valley of the damned.


Sepsis is a predictable outcome of these processes.
Sepsis explains the sudden onset of acute symptoms.
Especially suicidality.

Low orexin levels cause depression. Sometimes perpetual debilitating melancholia. But it's really not the worst feeling in the world. Most of the time we usually don't actively consider suicide. It's a lot of effort, and we're too tired. So we just lie in bed and get sicker.

On the other hand, the eventual resulting bacteremia,  causes an immediate spike in cortisol and other stress hormones, while further lowering orexin levels. Not only are we miserable, we start to panic. And that's when things get really bad. We get self-destructive.
And we suddenly have the motivation and energy to follow through...

That's absolutely terrifying.
That's what I call a nightmare.

But it's no longer a mystery.


---------------------------------

Thanks for reading my rambling.

-----------------------------------

This document was first posted August 13, 2014
but I am probably still tweaking on it.

BIBLIOGRAPHY

Strep
Hypothalamic orexins/hypocretins as regulators of breathing
http://www.ncbi.nlm.nih.gov/pubmed/18828950

Narcolepsy and Streptococcal Infections
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786037/

Relationship between Kleine-Levin syndrome and upper respiratory infection in Taiwan.
http://www.ncbi.nlm.nih.gov/pubmed/22215926

Flu
Flu Virus Wipes Out Immune System's First Responders to Establish Infection
http://wi.mit.edu/news/archive/2013/flu-virus-wipes-out-immune-system-s-first-responders-establish-infection

Virulence differences of closely related pandemic 2009 H1N1 isolates correlate with increased inflammatory responses in ferrets
http://www.sciencedirect.com/science/article/pii/S0042682211004971

The 2009 Pandemic H1N1 and Triple-Reassortant Swine H1N1 Influenza Viruses Replicate Efficiently but Elicit an Attenuated Inflammatory Response in Polarized Human Bronchial Epithelial Cells
http://jvi.asm.org/content/85/2/686.full

Gastric Complications For Patients with H1N1 (Swine Flu)
http://www.nleducation.co.uk/resources/abstracts/gastric-complications-for-patients-with-h1n1-swine-flu/

Intestinal ischemia secondary to H1N1 influenza.
http://www.ncbi.nlm.nih.gov/pubmed/22273335


Sepsis

Orexinergic Activity Modulates Altered Vital Signs and Pituitary Hormone Secretion in Experimental Sepsis.
http://www.ncbi.nlm.nih.gov/pubmed/24105451
Orexinergic activity decreased six-fold following cecal ligation and puncture. This change was associated with decreases in arousal, temperature, and heart and respiratory rates. Levels of selected pituitary hormones increased 24 hours post-cecal ligation and puncture but were significantly lower than baseline at 48 hours. Injection of orexin-A increased vital signs to baseline levels. Hormone levels were unaffected at 25 hours but increased to supranormal levels at 49 hours.
CONCLUSIONS::
Sepsis-induced changes in activity, vital signs, and pituitary hormones are modulated by the orexinergic system. This finding implicates central nervous system dysfunction in the pathogenesis of sepsis, suggesting further study of neurological dysfunction to identify novel approaches to management.

Inflammation-induced lethargy is mediated by suppression of orexin neuron activity
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155688/

Hyperinsulinemia compensates for infection-induced impairment in net hepatic glucose uptake during TPN.
http://www.ncbi.nlm.nih.gov/pubmed/10913021

Hyperinsulinemia induced by canine distemper virus infection of mice and its correlation with the appearance of obesity
http://www.sciencedirect.com/science/article/pii/0305049188901939

Free cortisol in sepsis and septic shock.
http://www.ncbi.nlm.nih.gov/pubmed/18499615

Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia.
http://www.ncbi.nlm.nih.gov/pubmed/11882496

Hyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans.
http://www.ncbi.nlm.nih.gov/pubmed/11466585



Glucose/Carbs

Insulin acts on the hypothalamic glucose-facilitated neurons to induce hyperglycemia and hyperinsulinemia in the rat
http://link.springer.com/article/10.1007%2FBF01929887

Intermittent fasting induces hypothalamic modifications resulting in low feeding efficiency, low body mass and overeating.
http://www.ncbi.nlm.nih.gov/pubmed/24797627

An orexin hotspot in ventral pallidum amplifies hedonic 'liking' for sweetness.
http://www.ncbi.nlm.nih.gov/pubmed/23463152

Orexin neurons as conditional glucosensors: paradoxical regulation of sugar sensing by intracellular fuels
http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2011.217000/full


Gluten/ Food allergy

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy.
http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003270

An Autoantibody in Narcolepsy Disrupts Colonic Migrating Motor Complexes
http://www.jneurosci.org/content/28/49/13303.long

Antibiotic exposure and the development of coeliac disease: a nationwide case–control study
http://www.biomedcentral.com/1471-230X/13/109


Epinephrine


Brown Fat
Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system.
http://www.ncbi.nlm.nih.gov/pubmed/19945404

Insulin

Insulin in the Brain
http://www.hbo.com/alzheimers/science-insulin-in-the-brain.html

Insulin Increases Sensitivity to GABA
http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2006/319/tw36

GABA

Opposing effects of activation of central GABAA and GABAB receptors on brown fat thermogenesis in the rat.
http://www.ncbi.nlm.nih.gov/pubmed/2843778
The results indicate that activation of central GABAB receptors stimulates the activity and hence metabolic rate of brown adipose tissue. However, activation of the GABAA receptors opposes the effects of GABAB stimulation on the thermogenesis of brown fat.




Drugs
Nicotine upregulates orexin production in the brain:
http://endo.endojournals.org/content/141/10/3623.short

Caffeine upregulates cFos production in hypocretin-containing neurons.
http://www.ncbi.nlm.nih.gov/pubmed/14521986

Neurochemical effects of nicotine on glutamate and GABA mechanisms in the rat brain.
http://www.ncbi.nlm.nih.gov/pubmed/1675543

Treatment of narcolepsy with codeine.
http://www.ncbi.nlm.nih.gov/pubmed/3518019


Antibiotics

Can antibiotics cause autoimmunity?
http://www.sciencedaily.com/releases/2014/03/140331153520.htm

Microbiome

When good gut bacteria get sick
http://www.sciencedaily.com/releases/2014/07/140711153331.htm

TB lung infection causes changes in the diversity of gut bacteria in mice
http://www.hopkinsmedicine.org/news/media/releases/tb_lung_infection_causes_changes_in_the_diversity_of_gut_bacteria_in_mice


Thyroid

Stimulation of orexin/hypocretin neurones by thyrotropin-releasing hormone
http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2008.167940/pdf

Effect of levothyroxine on prolonged nocturnal sleep time and excessive daytime somnolence in patients with idiopathic hypersomnia
http://www.ncbi.nlm.nih.gov/pubmed/21570346

Disturbed hypothalamic-pituitary axis in idiopathic recurring hypersomnia syndrome.
http://www.ncbi.nlm.nih.gov/pubmed/1963255

Histamine

Hypothalamic neuronal histamine modulates febrile response but not anorexia induced by lipopolysaccharide.
http://www.ncbi.nlm.nih.gov/pubmed/15855300