NHS,
Good question... and fascinating topic that I allow myself to indulge in on occasion... and this is one of them.
I've several ideas, but none that would rise to the level of a hypothesis. You've already brought up some excellent candidates. I'm also in complete agreement that a healthy and happy gut plays a role in CH prevention.
Without time to compose my thoughts properly on paper and sleep on them, the following will likely be a stream of consciousness... with holes and fragments... so please bear with me...
(Editor's Note - I've tidied up most of the dangling participles and disconnected thoughts after a pleasant combat nap.)
I start with the age old question of genes or environment... With respect to CH, I think there's sufficient evidence to make a case for causality based on a combination of both genes and environment.
The following quote by Motulsky A.,
Nutrition and genetic susceptibility to common diseases. Am J Clin Nutrition, kind of sums it all up... at least for me...
"Dr. Williams coined the term "genetotrophic disease" to describe diseases which resulted from genetically determined nutritional metabolic needs not being met by the individual and which result in poor gene expression. Motulsky has recently argued that many of the common degenerative diseases are the result of the imbalance nutritional intake with genetically determined needs for good health."
With that as a preamble, my base level causal factor lies in the morphology of the trigeminal ganglia and surrounding vascular structures.
When the arterial structures in and around the trigeminal ganglia are so arranged as to impinge or chafe any part of the ganglia, externally or within during vasodilation, there's a cascade effect of pain emanating from within the vascular structures and the transmission media, (the trigeminal ganglia and the three trigeminal nerves).
Natural asymmetry occurring during embryo phase of development could easily account for the one-sided nature of the CH disorder.
Although the vascular theory of CH pathogenesis has taken a back seat to the neurogenic theory, (I spent two days discussing this very topic with Dr. Arne May, MD, at his UKE facilities, University of Hamburg Medical School in 2009). Even he says vasodilation still plays a role, but downstream from the neurogenic initiation.
In as much as I've a dated degree in chemistry circa 1966 with requisite courses in biochem, instrumental analysis and physics, I look at the cluster headache syndrome much like the fire triangle made up of heat, fuel and oxygen. If you set the stage with any two of these components in place, the third component becomes a trigger and we have fire... or in our case with the CH disorder, we get hit.
Accordingly, if the trigeminal ganglia's vascular structures are not arranged properly, we have one corner of the fire triangle, hence we're predisposed or susceptible to CH.
The really fascinating chemistry takes place at the genetic level. They didn't start the $3 Billion dollar human genome project until 1990, and didn't declare it complete until 2003 when they had sequenced and mapped out most of human genome...
BTW, I used to walk by a display of the hardware and stacks of notebooks used to sequence the human genome at NIH at least once a month for over 5 years... I was a study participant in three back-to-back clinical trials for an eye condition at the National Eye Institute, NIH...
Since 2003, there have been tens of thousands of papers and studies involving the genetic underpinnings of nearly every degenerative disorder known to man.
There is no question in my mind that the success of the anti-inflammatory regimen with vitamin D3 as a CH preventative represents an "out of the box" new insight into the pathogenesis of CH... It just needs to be reverse engineered to look at causality.
I'm also firmly convinced that the mechanism of action for this regimen lies with the autocrine/paracrine signaling role vitamin D3 plays at the genetic level triggering genetic expression.
This is where a 1,25(OH)2D3 molecule combines with one of the retinoid molecules (vitamin A) to form a dimer bridge that then attaches one end to a vitamin D receptor (VDR) and the other to a Retinoid X Receptor (RXR) in a vitamin D response element (VDRE) on a candidate gene.
When this happens, and Dr. Robert Heaney explains it best by saying, "vitamin D3 unlocks the cells genetic library of instructions and the cell starts executing them" i.e., genetic expression.
During genetic expression, the cell starts performing one or more of the following activities: it replicates, differentiates, starts producing or inhibiting the production of peptides and other active chemicals that signal or control other biological processes elsewhere throughout the body, or the cell dies.
There's a mind blowing (pardon the pun) study titled,
Distribution of the Vitamin D receptor and 1 α-hydroxylase in human brain, Eyles et al, published in the Journal of Chemical Neuroanatomy in 2005. This study found VDR and 1α-OHase, the enzyme that's needed to hydroxylate 25(OH)D to 1,25(OH)2D3, throughout most of the brain tissue.
However, it's significant to note, they were found in the highest concentrations in the trigeminal ganglia and hypothalamus. (Ι'm confident Dr. Arne May would love this finding... Now we're talking the neurogenic head waters of CH pathogenesis.).
If we follow this confluence of findings and add in calcitonin gene-related peptide (CGRP), which several studies have found is produced in the trigeminal ganglia and elevated in the bloodstream during the pain phase of CH and migraine... we have a possible trigger.
Adding one more factoid (and assumption), that vitamin D3 has been shown to down regulate/suppress the production of CGRP, (quite possibly through genetic expression), we have a viable candidate mechanism of action for vitamin D3's capacity to prevent CH.
I say possible candidate, as a 2010 study identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D3... Sooo... there are thousands of other candidates for genetic expression made possible by vitamin D3... and any one or more of them could easily play a role in a mechanism of action inhibiting CH pathogenesis...
That said, I'll stick with the CGRP gambit for now as there is corroborating evidence provided by none other than the good Dr. Peter Goadsby and Dr. David Dodick. These two neurologist have tag teamed on a pair of phase 2 RCTs involving the use of two monoclonal antibodies, ALD403 (Alder BioPharmaceuticals Inc) and LY2951742 (Eli Lilly and Company), both with an appetite for CGRP... to prevent migraine headaches...
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Given there is sufficient overlap in the pathophysiology of CH and migraine and that CGRP is a common component in both headache disorders, it's not unreasonable to expect these two MABs will eventually find their way into the treatment of CH... at an average cost of $5000/week...
Unfortunately, all biologics/MABs carry a long list of side effects that range in order from nasty to down-right onerous including: compromised immune system, life threatening infections like tuberculosis and pneumonia, fungal infections and a growing list of cancers. Watch the TV ads for Humira (Adalimumab) and you'll get an even longer list of adverse side effects.
Having taken one of the MABs, daclizumab, (a potent immunosuppressant used following kidney transplants to prevent rejection), during one of the clinical trials at NIH... experiencing squamous cell carcinoma and eosinophilic meningitis within two months after starting it... I'll stick with the anti-inflammatory regimen with 10,000 IU/day vitamin D3 and the cofactors at ~ 40 cents/day to prevent my CH...
As a side note... it's entirely possible that serum vitamin D3 enters the target nerve cells where it is hydroxylated into 25(OH)D and on to 1,25(OH)2D3 so as to initiate genetic expression rather than waiting for vitamin D3 to be hydroxylated first to 25(OH)D, then entering the target nerve cell. This might appear to be a minor difference in the overall process, but it speaks to the initial speed of response.
In looking at the favorable response time data after start of regimen from the online survey of CH'ers taking the anti-inflammatory regimen to prevent their CH, the shape of this response curve matches the absorption of vitamin D3 into the blood stream...
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As you can see the serum concentration of 25(OH)D doesn't reach a maximum concentration until the 5th to 6th day after dose.
Moving on... Your comment on the human microbiome, the friendly colonies of flora and fauna living in the human GI tract from mouth to tail pipe, playing a role in the pathogenesis of CH has just as much merit as anything I've suggested.
When you consider the human microbiome represents several orders of magnitude greater biodiversity than the human genome, and many of these wee beasties (Leeuwenhoek), respond to vitamin D3, the number of possible CH causal factors are huge...
Moreover, as most (70%) of the immune system lies within a 4 inch radius of the GI tract, it's entirely possible that CH could easily fall among the other 80 degenerative conditions that ride under the heading of autoimmune disorders...
That throws the paradigm that cluster headache is a neurological disorder that should be treated only by a neurologist, into a cocked hat...
Clearly, neurologists specializing in headache disorders are better trained to diagnose CH... That said, until the anti-inflammatory regimen becomes part of the standards of care recommended treatments for CH... I'm not sure that training equates to effective treatment.
Moreover, CH'ers might be better served by seeing an endocrinologist, immunologist or practicing nutritionist after being diagnosed for CH by a neurologist...
So there you have the latest thoughts on the pathogenesis of CH currently rattling around my 70 year old brain...
Take care,
V/R, Batch