This is the first part (and working draft) of my mini-series titled:
My Theory of Cluster Headache
The following is a discussion and not a definitive statement. Like any good finding resulting from the scientific method, the conclusions must be open to challenge with attempts to replicate the underlying methods to see if same or similar results can be obtained. If it cannot be duplicated with similar results consistent with the theory, the theory is dismissed.
This theory, more appropriately, the scenario of events leading up to a cluster headache (CH), a.k.a., CH pathogenesis, holds as it’s fundamental premise, that CH is a genetotrophic disease/disorder. A genetotrophic disease/disorder is caused by genetically determined nutritional needs not being met by the individual and which result in a disease/medical disorder... in this case, the cluster headache syndrome. (Also applies to other TACs and Migraines)
Readers also need to buy into the concept of genetic expression as well as autocrine and paracrine signaling as the fundamental mechanisms of action by which the anti-inflammatory regimen with vitamin D3, Omega-3 fish oil and the vitamin D3 cofactors prevent CH.
For readers new to this topic/thread, nearly all the data discussed in this paper come from several hundred CHers posting here at CH.com who have started the anti-inflammatory regimen since December of 2010. More specific data comes from participants in the online survey of 187 CHers taking the anti-inflammatory regimen as of 15 April 2016. (It is still online... Take it if you haven't already done so.)
The rest come from my research and old fashion Navy fighter pilot logic... that includes among other things... "If it's not broken... Don't screw with it", Occam's razor - that essentially states... "When looking for an explanation for an occurrence, the simpler one is usually better", and my long time favorite from Admiral of the Fleet of the Soviet Union Sergey Georgiyevich Gorshkov, a.k.a., "The Father of the modern Soviet Navy." After viewing a new weapon system claimed to be better than the existing system... he remarked, "'Better' is the enemy of 'Good Enough'"
To date, more than 80% of CHers taking the anti-inflammatory regimen have experienced a significant reduction in the frequency, severity and duration of their CH. 54% of these CHers have experienced a lasting CH pain free response as long as they remain on this regimen.
The basic mechanism of action by which vitamin D3 prevents CH involves the genetically active metabolite of vitamin D3, 1,25(OH)2D3 triggering target genes to express autocrine and paracrine signaling agents to down-regulate or suppress the production of CGRP and likely other neuroinflammatory agents from neurons in the trigeminal ganglia.
Genetic expression involves:
• Replication
• Differentiation
• Up- or Down-Regulation of Genetic Products
• Apoptosis – (Programmed Cell Death – what we hope is happening to cancer cells)
The simple explanation of genetic expression as it applies to vitamin D3 preventing CH involves the genetically active metabolite of vitamin D3, 1,25(OH)2D3, attaching to a vitamin D receptor (VDR) where it unlocks the cell’s genetic library of instructions so the cell can execute them.
One of the instructions is to create a peptide that signals the cell to down-regulate CGRP production (autocrine signaling) and other near by cells to do the same (paracrine signaling).
The following slides provide a notional illustration of this process that starts with a molecule of the vitamin D3 metabolite 1,25(OH)2D3, attaching to a target gene segment VDR, messenger Ribose Nucleic Acid (mRNA) genesis, genetic transcription and translation leading to the production of autocrine and paracrine signaling agents.
The first slide illustrates a molecule of 1,25(OH)2D3 that has combined with a molecule of vitamin A (retinoic acid) to form a dimer (a two molecule chain) and both have attached to their respective receptors (RXR and VDR) at a vitamin D receptor element (VDRE) on a target gene sequence located on a spiral DNA helix.
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This next graphic illustrates how a set of genetic instructions are replicated and transcribed from a target gene sequence on the DNA helix onto a messenger RNA (mRNA) sequence.
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The final graphic illustrates an mRNA segment with genetic instructions transcribed from the parent gene segment, passing out of the cell nucleus into the cytoplasm where it is taken up by a ribosome. Ribosomes are the cell’s pharmaceutical factories. They take in the mRNA genetic instructions then build peptides (proteins) according to the instructions from amino acids in the cytoplasm.
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These new peptides serve as autocrine and paracrine agents that signal the cell and surrounding cells with instructions, in our case neurons within the trigeminal ganglia to down-regulate or inhibit CGRP production as one of the likely mechanisms of action.
With that as a premise, let’s set the stage with a vitamin D3 deficiency/insufficiency. Results from the survey of 187 CHers taking the anti-inflammatory regimen to prevent their CH indicate CHers with active CH have a mean baseline 25(OH)D serum concentration of 22.8 ng/mL with a range of 4 to 47 ng/mL before starting this regimen. The following normal distribution curve illustrates the mean baseline 25(OH)D serum concentration before start of regimen.
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At this point in the scenario of events leading to CH, we have the cluster headache canon loaded with black powder and it only needs a spark to fire.
This is where antigens, allergens, trauma, surgery, other comorbid conditions and mast cells come into play. Mast cells are a type of white blood cell that’s part of our immune system. They’re found in tissues throughout the body primarily in mucus membranes lining breathing passages and the GI tract, but they are also found around capillaries throughout the body and brain. It’s these strategic locations that provide mast cells with the opportunity to defend the body against invading pathogens, allergens and other inflammatory agents.
Mast cells are loaded with “granules” filled with all kinds of things our immune system uses to combat pathogens and allergens as illustrated in the following electron microscope image. As I spent many years in the military, I liken mast cells to an IED/Cluster Bomb spring loaded to the pissed off position…
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All it takes is an insult from a pathogen, allergen or byproducts of inflammation and mast cells can either selectively release the contents of these granules or explode (degranulate) rapidly as the cellular biologists call it, releasing a boatload of nature’s pharmaceutical products… in most cases, designed to keep us healthy… However, if the mast cell degranulation is widespread and occurs too rapidly, anaphylactic shock can occur.
In our case as CHers, mast cell degranulation releases a flood of histamine and that results in a humongous CH triggering mechanism… The following graphic illustrates the products of mast cell degranulation. Note that histamine is released in a matter of seconds and that leukotrienes and prostaglandins are released in a matter of minutes from start of degranulation.
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As a result of this mast cell degranulation, histamine, leucotrienes and prostaglandins are released. In turn, histamine, leucotrienes and prostaglandins trigger neurons throughout the brain and in particular, the trigeminal ganglia to release calcitonin gene-related peptide (CGRP) and Substance P (SP). Both trigger neurogenic inflammation and CGRP is directly associated with the terrible pain, a.k.a., nociception in neurology speak of CH and migraine headache (MH). It gets worse…
The CGRP released in this process in turn triggers mast cells to release more histamine, leucotrienes and prosteglandins resulting in a bi-directional or circular chain reaction that continues until the reactants are consumed… at which point the CH attack ends… for now…
I am quite confident that the histamine and prostaglandins released as a result of an allergic reaction are responsible for many CHers being refractory to nearly all means of intervention, i.e., oxygen therapy not effective or less effective at best and traditional CH preventatives like verapamil either don’t work or their preventative effect is minimal. It’s also very likely this flood of histamine and prostaglandins are responsible for busting to become ineffective.
Hopefully, we’re all on the same page at this point…
Regarding the question about the histamine – CGRP circular chain reaction taking place in an absence of allergens... My first reaction… No such thing, or at least, it’s highly improbable. The more likely scenario is this chain reaction initiates with an allergen insult. After that, the histamine – CGRP circular chain reaction is capable of continuing on its own without further insult by an allergen until running out of one or more of the reactants and the CH ends. While this appears to be the primary mechanism of action, there’s reason to suspect there are other mechanisms in play… I’ll get to that a little later.
The simple fact remains there are thousands of potential allergens around us all the time, day and night, no matter the season. There is a question of how much of a particular allergen it takes to trigger the histamine – CGRP circular chain reaction. I don’t know the answer, but logic and the law of mass action would suggest the triggering mechanisms are always present and at some point, a threshold will be reached where mast cells start degranulating.
Before we go any further, it’s important to understand the law of mass action so the rest of my discussion will make sense.
The law of mass action deals with the relationship between a drug, a nutrient like vitamin D3, or an allergen and a receptor (a molecular socket) located on a cell membrane, the cell nucleus or somewhere on a specific gene sequence on a DNA helix.
The law of mass action dictates that:
• The combination of drug (also called ligand) and receptor depends on the concentrations of each
• The amount of drug-receptor complex formed determines the magnitude of the response
• A minimum number of drug-receptor complexes must be formed for a response to be initiated (threshold)
• As drug concentration increases, the number of drug-receptor complexes increases and drug effect increases
A point will be reached at which all receptors are bound to drug, and therefore no further drug-receptor complexes can be formed and the response does not increase any further (saturation).
In the case of an allergen and mast cell interaction, immunoglobulin E antibodies (IgE), part of the body's immune system, bind to an allergen and then this complex attaches to a receptor on mast cells triggering degranulation.
Circadian and Circannual rhythmicity can be factors in CH pathogenesis due to the central role played by the hypothalamus in our autonomic nervous system. During circadian and circannual rhythmicity we experience an ebb and flow of hormones and peptides as we transition through day and night, wakefulness and sleep, moon cycles and seasons with long and short days eliciting more or less cutaneous vitamin D3.
Sleep is the only time our brains can go offline for house cleaning… I’ve little doubt the chemicals flushed from our brain during this house cleaning are capable of triggering mast cells to degranulate if the conditions are right… and in accordance with the laws of mass action. That said, circadian and circannual rhythmicity are only one possible explanation for variations in CH cycles. Seasonal blooms of allergens can just as easily explain the increased frequency of CH cycles during Spring and Fall seasons.
Even living in a hypoallergenic bubble is no guarantee we can be free of allergens. We have Dermatophagoides pteronyssinus a.k.a. the common house dust mite.
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These little beasties live in your bedding, carpets and just about anywhere in fabrics touched by humans as their diet is mainly flakes of skin our bodies shed all the time.
Over the course of 10 years, your mattress can easily double in weight because of the accumulation of dust mite debris (let's be real here: dead dust mites and dust mite poo), your dead skin cells, etc.
Before you burn your mattress or buy a new one, buy a hypoallergenic mattress cover and wash all the bedding and pillows in 140° F water. Unfortunately, no matter what you do, you can’t get rid of dust mites completely… Fortunately, for most of us, our immune systems adapt to the allergic nature of dust mites and their droppings… as long as the concentrations don’t get too high…
That said, this is another example where the law of mass action applies. By that I mean if there’s a major bloom of dust mites, the allergic effect will increase to the point where mast cells will start degranulating and release histamine. If our vitamin D3 status is low, i.e., a 25(OH)D less than 40 ng/mL and mast cells start degranulating… we’ll experience the circular histamine – CGRP chain reaction and Bang!... we’ll get hit with a cluster headache.
Then there’s the dynamic duo of Demodex folliculorum and Demodex brevis, both frequently referred to as eyelash mites.
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Studies indicate a prevalence as high as 41% among people over 18 years of age who carry these little beasties… Even if they didn’t, the family dog, cat or any furry pet likely carries a close genetic relative. Whatever the case, they’re potential allergens.
Even with the best hygiene and super effective house cleaning that kept us completely free of these beasties, we still have hundreds of different colonies of biota numbering in the trillions, living in the GI tract, nasal passages and lungs called the microbiome. Most of these colonies are beneficial... but some are not, particularly if they leave the GI tract and enter another part of the body. Yeast and E. coli infections are classic examples. While infections like these are technically not associated with an allergic reaction, they do result in inflammation and the release of neuroinflammatory peptides that could easily trigger mast cells to degranulate.
Prostaglandin E(2) (PGE(2)), could easily be the case here as PGE(2) has been found capable of triggering the release of CGRP from trigeminal neurons. This poses a problem for CHers as first-generation antihistamines are ineffective in blocking prostaglandin receptors. Fortunately, the Omega-3 fatty acids, are the best treatment in the event prostaglandins are playing a major role in CH pathogenesis.
Then there are mold spores… The drip pan under your frost-free refrigerator, the air handler in your central heating and air conditioning system, window mounted air conditioners, shower curtains and even your washing machine are all potential breeding grounds for mold.
Viral and bacterial infections can also cause problems for CHers. For starters, they trigger an immune system response that consumes serum vitamin D3, 25(OH)D and the essential enzymes needed to hydroxylate both to the genetically active vitamin D3 metabolite 1,25(OH)2D3 that helps us prevent CH. If the scale of the infection is such that mast cells are triggered to degranulate… Bang! We get hit.
Finally, there’s a whole host of metals and chemicals, some industrial and some produced from things we eat or drink… Aldehydes and ketones produced during the process of metabolizing alcohol and certain vegetable oils are capable of triggering mast cells to degranulate…
The microbiome... colonies of symbiotic/friendly bacteria a.k.a., "biota" living in the GI tract can also become corrupt with "bad" unfriendly biota or decimated by antibiotics or other chemicals causing a bloom of potential allergens... If this is the case, probiotics are indicated.
In addition there are a number of studies linking migraine and cluster headache to higher and lower concentrations of metals.
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So where does that leave us? The simple answer is to maintain a healthy immune system. This is one of, if not
the major beneficial side effect of taking the anti-inflammatory regimen to prevent our CH.
The final questions on the relationship between mast cell degranulation and circadian rhythmicity and why the cycles appear in 12 to 24 hours cycles bring to mind a few basic principles of biochemistry… Most biochemical reactions associated with human physiology take place at a sweet spot temperature. For humans, that’s 98.6° F. These biochemical reactions also work best within a pH range of 7.35 to 7.45, not surprisingly, that’s the normal pH range of human serum. Remember the Andromeda Strain?
Let’s take the increase in the frequency of CH during sleep as an example. During sleep, most body functions slow. Blood pressure, heartbeat and respiration rates all drop and are as low as they ever get during sleep. While we inhale sufficient oxygen to stay alive, the partial pressure of arterial O2 (PaO2) drops significantly below normal. The reduced lung ventilation during sleep also allows the partial pressure of arterial CO2 (PaCO2) to rise and arterial pH to drop. This sets the stage for a perfect storm for CHers.
To be continued...
While you're waiting, please take the time to watch the fascinating documentary titled: Battlefield Cell from the Curiosity Series on the Discovery Channel:
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This video will put you in the same frame of mind that's kept me well outside the box of conventional thinking regarding cluster headache.
Take care,
V/R, Batch
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