Lectures on the cluster headache

Foreword

The aim of this paper is to present a working hypothesis which seeks to explain the phenomenon of CR in every sense, with the sole idea of establishing mechanisms to combat this disease. The greater or lesser success of these methods can be applied directly to determine the reliability of the assumptions.
As the author of this hypothesis is not anywhere near the knowledge or minimum qualifications required for membership of a document of this nature, it should be interpreted merely as a fun “pseudo-scientific document" and all events in the discharge must be considered under this perspective.

The facts and statements that are incorporated in this document are the result of years of careful reading of studies of many kinds. There is no documentation of the sources of such information or its reliability, have just been collected over the years in memory of the author, so absolutely no valid documents. However I urge the reader to accept without more generously in a first reading to get an overview of the working hypothesis, which is what matters, leaving for a second phase, the questioning of the information contained herein.

While seemingly existing documentation on the cluster headache is very extensive, in fact most of it is recurring. Known and classified the disease for decades, most reports are nothing but collections or synthesis of other existing reports. Most of the information in this text comes from psychiatric studies, particularly relating to anxiety, depression or stress, general studies on migraine with fibromyalgia syndrome or Dawn, and even issues such pilgrims as breeding animals or the study of their migration.

Mechanism of the crisis

Before we can hypothesize about the cause of the CR, we must discuss the mechanism by which the characteristic "crisis" or "attacks" of pain occur.

In general, there is a growing consensus that crises are essentially in the inflammation of the trigeminal nerve due to pressure of the cerebral arteries dilated on the nerve. The inflamed nerve contribute to the flow of blood, through the walls of an artery, with a substance called CGRP peptide (calcitonin gen-related peptide), and this peptide and other activate platelets and mast cells, producing a discharge of serotonin and histamine, vasodilator, which would maintain the status of vasodilatation of the artery with consequent compression of the nerve, thus creating a feedback system during the crisis.
There are many other theories, including the question of whether it is before, the chicken or the egg, that is, if the nerve is inflamed for other reasons who initiates vasodilation, or whether, by contrast, is really the first vasodilatation phenomenon and inflammation resulting from it. Raised here because by accepting the first hypothesis that this  may be the real mechanism of the crisis, and we began to build the global scenario. We will also accept, as we shall see below, which need not have such a disquisition of the chicken and the egg, the two concepts are not mutually exclusive.

Also we accept the idea as a second hypothesis, as expressed by the creators of sumatriptan, that vasodilatation is caused by the momentary lack of adequate levels of serotonin, which would be responsible for acting on 5HT1D receptors in the walls of the cerebral arteries, responsible for vasoconstriction. Sumatriptan was in fact designed as a selective agonist of serotonin, that means, serving as it, specifically acting on these receptors to produce vasoconstriction, which should have been produced by at least absent or inadequate serotonin.

Because of the CR

Either way, it is clear that the trigeminal nerve becomes inflamed in many circumstances in CR patients and not in a healthy individual. One might imagine that the neurochemical systems that regulate vasoconstriction and / or vasodilation of the cranial arteries operate incorrectly in CR patients, or, in other words, the CR patients suffering from excessive vasodilatation and that this would be the cause of the problem.

However, it is public knowledge that a patient may suffer a CR of a sudden crisis, or even start a cycle, by a direct action on the trigeminal nerve or its branches. Examples include oral infections, extractions mouth parts, the mere application of a pre-anesthesia tronculares manipulation, otitis and even trauma. If a direct action on the trigeminal nerve can cause a crisis immediately, without any intervention by neurochemical processes, we must conclude that the trigeminal nerve is damaged in some way.

Strengthens our hypothesis the sidedness of the event. If the processes were strictly neurochemical it would be difficult to explain that it only affects one side, and always the same. However, the consideration of physiological sensitivity of the nerve can explain this fact with absolute ease. We do not have the two sides never equal, there will always be a trigeminal more sensitive than the other and it will be the first to be inflamed.

The determination of whether damage is due to friction with the bone structure, damage or sensitivity of the neurons themselves, or any other cause, is outside of this dissertation. It would therefore be the primary cause of CR in this scenario: a particular sensitivity of the trigeminal nerve.

A sensitive trigeminal would ease to ignite at a vasodilatation bit severe, and even normal, in any case depending on the degree of sensitivity of the nerve and the intensity of the vasodilation. These two parameters are those that determine the method and level of suffering of each individual disease: being the sensitivity different for each individual, and although it may also theorized about the possibility of a sensitivity fall, it’s a stable parameter. By contrast, serotonin levels necessary to achieve a vasoconstriction that does not lead to inflammation are much more variable, and therefore, patients in CR are fully exposed and directly dependent on the levels of this neurotransmitter.

The facts explained on the basis of the hypothesis

We’ll begin to use our hypotheses to explain each of the facts relating to the CR.

One-Sided

From the hypothesis we can now easily explain why the disease manifests itself on one side, usually in the same, why the existence of changed hand and their rarity, and even the obvious that persons subject to unilateral surgery begin to suffer the crisis on the other side.

As we have said in passing, and will discuss later, when an inflammation of one of the two trigeminal begins, there is a release of serotonin from platelets. The released serotonin, which will finally end the crisis by vasoconstriction, reverses from the first moment the drop in the level and prevents the other nerve to be affected. This explains in a simple way the one-sidedness of the CR, although in theory there could be some cases, very unlikely, in which inflammation began almost exactly at the same time on both sides, then it would result in a bilateral crisis.

Neither holds any mystery in this scenario the fact of changing the side of the crisis. Some people may have similar sensitivity to both nerves and could ignite one or other without distinction, although it would not be normal. This group is small because it is a coincidence as the two eyes have the same height, just like seeing or hearing same level from both sides, or have both hands identical.

We explain that even within this already small group of people with similar sensitivity on both sides, as is normal that once a cycle on one side, stay there, and just because he has already undergone trigeminal daily sessions compression and inflammation is more sensitive and more likely to be the first to catch fire again.

People who receives stimulation by surgical techniques, or other padding to help one of the trigeminal to avoid inflammation, are just protecting the weaker of the two, this which started the crisis and thus protected the other. As serotonin levels drop to the level required by the other trigeminal, and without the surgered trigeminal intervention, the crisis will just change the side. We theorize that, since this is less sensitive than the other trigeminal surgery, the crisis may be less important.

Circadian rhythm

The explanation for the circadian rhythm is very simple, and that serotonin levels in the body follow a daily rhythm, marked by changes in daylight by the body directly on the retina (even without light, the day exists for the body but not 24 hours, just some 25 ½, this why “Circadian” in latin, “Circa die”, near a day). The level is highest at noon, and descends slowly as the day goes on. As we approach the darkness, we begin to transform the serotonin into melatonin, and its  levels descends steeply into the night, reaching minimum at mid-dark. After that is replenished very slowly and rises again rapidly from the time we woke up and brought to light the eye, reaching back to maximum (midday) and back to start.

This explains why the most common and practically unavoidable, are crisis at night, especially during sleep. However, if our levels are really inadequate, in the morning, we can also suffer a crisis.

The hypothesis can make predictions about the multiple crises. As already mentioned, while suffering a crisis the platelets release serotonin, which acts sooner or later to produce adequate vasoconstriction and abort the process. After the crisis, the platelet re-capture the serotonin they had released, and when it comes back to the previous level, another crisis will begin.

Exacerbated this process by the reduction of serotonin throughout the day, we could theorize that anyone who suffers a crisis in the first hours of maximum levels, at the zenith of the day, must suffer more crises, because the standards of the rest of the day will always be lower . The elapsed time between two crisis is given by the time it takes platelets to re-capture that released serotonin and reduced to the extent that decreases serotonin in the body. Thus, the time between crisis should decrease as the day progresses, and minimum during the night.

Those who have high average levels, will face only a crisis everyday, in the middle of the night, preferably during sleep. Who has the crisis relatively quickly, well before bedtime, would run greater risk of repeating during sleep. Also it is expected that the time of serotonin reuptake by platelets is proportional to the time of release, that is, the duration of the crisis, so longer crisis should be more spaced in time, and shorter, more together in time.

These considerations are made with the circadian rhythm of serotonin as the only consideration, but not so far from it. Later we will see many other factors that affect serotonin levels and thus the behavior of the disease.

Rhythm circanual

Something that was already known, but it was not scientifically proven, is that the rate of serotonin varies with the seasons. The publication in September 2008 of some studies conducted in Toronto between 1999 and 2003 to a sample of 88 individuals has shown for the first time, no doubt, that the potential binding of serotonin transport are higher in autumn and winter than in spring and summer. Greater potential for the transport union, increased reuptake, less free serotonin available for neuronal transmission.
However, the study shows two things. The first serotonin levels are markedly lower in autumn and winter than in spring and summer. The second, more exciting, there is an inverse correlation between total hours of daylight and time of the sunset with these levels.

So with this, it is easy to predict that arriving the fall and moving  to lower levels of serotonin, some patients begin to experience difficulty, and as the winter comes, the other. Since February, the levels are restored gradually.

Again, there’s other factors involved here that can cause cycles in summer and prevent cycles in winter, but it is already obvious now that a great factor is that the fall / winter, or rather the hours of daylight and sunset hours are a increased factor for the start of the crisis.

Says study (conducted in the northern hemisphere, in Toronto) that in the southern hemisphere should occur equally in respect of the seasons, but with a rotation of six months of the calendar. He also said that he had found a small influence of moisture and age, and virtually none of the temperature.

Episodic and chronic

With our hypothesis in hand, it's easy to settle between people and people with episodic CR CR chronic. The episodic people are those whose serotonin levels are usually sufficient, but a circumstance in which an arrival time to drop these levels begin to engage in crisis and have insufficient levels until the end of the causes why the period of decline, forming the "cycles". The period is par season, but it can also come from other factors such as stress.

The chronically ill are simply those whose levels of serotonin are inadequate throughout the year. It seems valid to be considered that these patients would have more chance of remission in spring and summer and, with medium levels so low, they should be much more likely to suffer multiple crises, especially in autumn and winter. As a corollary, it follows that those who suffer from multiple daily crises, are proving insufficient levels, so it would in turn be more likely to become chronic with others who have more levels, for example, the people who have just a one night crisis.

In any case, given this scenario, there are no chronic or episodic, crisis is always suffered when serotonin levels are insufficient and will forward when eleven. The status of each one is always the circumstance of the moment, so that expressions such as "move to chronic" or "chronic", lack of the meaning they have in other areas of medicine, where the essential is the future remain. Here, a so-called chronic could stop their attacks from one day to another if it can raise its levels of serotonin.

Abortion: Oxygen and triptans

The only two known abortifacients, leaving aside various drugs, the triptans and oxygen. In neither case is known with certainty of their action, although it is accepted that in both cases it’s due to produce significant vasoconstriction, which would always end a crisis that is not excessive vasodilatation

As a crisis begins with a low level of serotonin, and that this level is not replenished by any means, only to be expected after the use of one or the other is that after a while and dismissed its impact, the crisis is restarted and even more strongly, as for the beneficial effects of the vasoconstrictor serotonin levels continued to decline.

There are two possibilities for this happening. The first is that in the time it takes to abort the crisis, it has freed enough to replenish serotonin levels and thus do not fall into a new crisis. This is more possible in patients of a single crisis that in the multiple, because this brief on first can allow replacement levels enough to not incur in another crises until the next day, making it possible more than a partial replacement of vasoconstriction over time are sufficient to avoid a reply. The latter, however, still suffering from the crisis not entirely replenished enough to prevent the next, so that the suffering resulting from the partial replacement of a crisis aborted early, can hardly avoid the effects following cessation of abortion.

Another possibility is that the use of an abortion is performed at night so that when the effect ceases, the levels of serotonin are replenished by its daily cycle.

Conclusions

Seems not to have found a cure here. If the problem is caused by a nerve, say, faulty, we are very far from being able to fix it with the knowledge of medicine today. So put this hypothesis to be adopted in one or more of the following measures:

1) Improving the status and situation of the nerve.
2) Increased levels of serotonin
3) Preventing falls in serotonin

Will be in another document in which I will enumerate and explore the means by which these objectives could be achieved, but we can not ignore the undisputed fact that serotonin levels in the body are good (except dysfunction), however by a good reason that currently only the body knows. Artificial lift will always disrupt our delicate neurohormonal balance, with unpredictable consequences.

There is also the added difficulty of homeostasis, the actual and expected reaction of the body who will try sooner or later to regain its previous situation.

It should, however, take a first step, without risk, and would be beneficial, measures to ensure that the body produces all that want to produce serotonin, ie, to avoid any gaps that are hindering the normal process the body. Not expected here, trying to cover deficits, homeostasis.

Interesting - will have to digest it over time. I can see that lots of thought has gone into it, and it seems to be a good starting point for discussion.

The one thing that doesn't fit entirely is the "reduce its (serotonin's) transformation to melatonin" ... first, we know that melatonin can be a good treatment. Second, we know that most clusterheads have low levels of melatonin.  Third (and this is personal, but might apply to some others), I pretty much always get hit in summer - when days are longest and my exposure to light is greatest.

Also, I would add an imbalance of excitatory/inhibitory neurotransmitters to the picture.  Gaba and taurine make nerves less likely to fire, while glutamate/nmda make nerves more likely to fire, and an imbalance here makes the trigeminal less stable in CH in my understanding.

You mention T-Hydroxylase as something that changes tryptophan/serotonin levels. What about other enzymes that do the same? Drinking alcohol greatly increases liver tryptophan pyrrolase activity (which breaks down tryptophan), and alcohol is the most identified trigger.  Also, there is tryptophan 2,3-dioxygenase and Indoleamine 2,3-dioxygenase.

Along with lowering the levels of tryptophan and serotonin, these enzymes also create new chemicals (kynurenine and its related compounds like kynurenic acid and 3-hydroxykynurenine). These kynurenines may have their own role in promoting CH. For instance, the wikipedia page says that kynurenine is associated with tics, and I tend to get twitches (maybe tics?) before and during a cycle. Coincidence, maybe, but twitches and tics can be a sign that the nerve fires too much.

Some people have reported benefits from 5-htp to increase tryptophan/serotonin, but others get hit harder when taking 5-htp. This could be from an increase in kynurenines that result from taking 5-htp alone, when the body is set to produce kynurenine.

Random association that floats to mind: Indoleamine 2,3-dioxygenase can be inhibited by propolis (bee glue) - this might be a potential therapy, although if there is pollen in the propolis (unpurified), it could cause allergies.

This abstract was written in a style that is a little difficult ... but possibly useful info when decoded.

Quote:

I think we should talk a little about the metabolism of tryptophan to clarify the situation. Tryptophan can be mainly degraded at intestine, liver and brain in several "ways":

1) Way of serotonin and melatonin. Tryptophan is oxidized by the enzyme Tryptophan hydroxylase-(T-hydroxylase) to form 5-Hydroxytryptophan (5HTP), which is decarboxyled by decarboxylase to 5-hydroxytryptamine (5HT or serotonin). Finally, serotonin may be degraded by MAO to 5-hydroxy-Indalate (5HIAA) or transformed by action of hydroxy-indole-methyltransferase to melatonin.

2) Way of kynurenina. Tryptophan is oxidized by the T-2 ,3-dioxygenase (also called T-dioxygenase or T-pirrolasa) or Indolamine 2.3-dioxigenasa to produce different products for all with the kynurenina.

3) Way of indoles. It is produced by the action of bacteria in the gut.

4) Production of B3 (niacin, nicotinic acid). Used 50 mg. tryptophan to produce 1 mg. B3. The need of tryptophan daily minimum stipulated by 175-250 mg. The Western diet provides 600-1200 mg .. The daily requirement of B3 is set to about 16 mg. To produce this amount would be spent 800 mg. tryptophan, almost all of ingestion.

Its going to take a bit of time to study this.  An impressive amount of research, sir.  Thank you.

PFDAN y'all
kathy

But I disagree with your recommendation #6, "Reduce its (serotonin's)  transformation into melatonin."  Melatonin is low in clusters, and should be raised.  If serotonin is brought up to normal levels, I don't think anything should be done to prevent it from being turned into melatonin.

The difference we have is the departure point. You part from that melatonin is necessary, that is low and that it is necessary to raise it. I part from that what is low is the serotonin and that's why melatonin is low, and that no matter it'is low. This would in principle affect only to sleep and immune system in the long run; there is no direct relationship with the CH.

And you can avoid serotonin becoming melatonin, naturally, giving melatonin externally. As you take it, the body reduces its endogenous production, reducing the consumption of serotonin. One might also play with light during the day and night, but should be considered if the impact of this measure would be relevant. I have a testimony of someone whose "siestas" always started a crisis, but now he's doing "siesta" with the light on, an he no longer suffers this crisis.

But here is a point to reach an agreement. I say that melatonin is not involved in the CH, its reduction is only a reflection of decreased levels of serotonin. It has no more importance and no other role here.

It would be great to try to explain the mechanism by which drugs we are prescribed

It's a good idea to start thinking about. I had some ideas, if you have time (and I), we can do it in the future.

I agree - it both reduces serotonin, AND it increases kynurenines, which themselves may be bad for cluster headaches

As with melatonin, we disagree on the same type of question, I do not think that is a factor kynurenina of CH. I think that their levels are a consequence of, and show, what's happening at the level of the metabolism of tryptophan. However, at this point at least we agree on avoiding the formation of kynurenina.

Yes, 5-htp is one step away from serotonin, and most 5-htp gets converted. So in that sense, it may be a better thing for people with CH to take...

But the reports of some people getting worse with 5-htp indicates that it is not just low serotonin levels

This topic has me curious result ever since. The most logical thing is that 5-HTP feel good, but really are who actually not. There is however a logical reason for it, and that these people would have trouble running the phase transformation of 5-HTP to serotonin. Recipients in all this has much to say, but I do not miss the blame for this so directly.

The nicotinamide form of niacin has a direct effect in blocking the increase of the pyrrolase enzyme in the liver

Ok, did not know. Noted. In this case, the B3 should be doubly beneficial. Inhibits T-pirrolasa and not spent tryptophan in it's synthesis. The truth is that to me it has been always great.

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

When I have time i'll post a resume of the elements of recommendation #2 and actions to take over each one. This could be a good discussion with practical results.

Best regargs.

OK, I am starting to understand you views better, although some things I disagree with.


This would in principle affect only to sleep and immune system in the long run; there is no direct relationship with the CH.

I disagree here - I don't see any reason to limit the effects of melatonin to sleep and immune functions.  It seems to be involved in many other important functions, including neuroplasticity and neuroprotection.  Melatonin can also affect the PI3K pathway.

Melatonin itself affects the serotonin receptors.  See the article "Melatonin potentiates 5-HT(1A) receptor activation in rat hypothalamus and results in hypothermia." (pubmed ID 12121481). This article also states that the effects of melatonin can be blocked by stimulating the 5-ht2 receptors ... this supports my idea that it is not only the amount of serotonin (which I agree is usually too low), but also the number, type and functioning of the different types of receptors.  Triptans and other drugs stimulate the 5-ht1 receptors and turn off clusters (at least in short run), while blocking the 5-ht2 receptors (kudzu, olanzapine, ergotamine, psilocybin, etc) can also turn the pain down or off.

And you can avoid serotonin becoming melatonin, naturally, giving melatonin externally. As you take it, the body reduces its endogenous production, reducing the consumption of serotonin.

When melatonin first became popular in the US (early 1990s), I remember reading an article that said taking extra amounts of it (exogenous) did not cause the body to make less - ie, addiction and withdraw were not seen as likely.  Not sure if that is true or not ... will check. While abrubtly stopping exogenous corticosteroids, morphine, testosterone, etc leads to an obvious deficiency, this has never been noted with melatonin to the best of my knowledge.   


In other news, I dusted off a program I wrote a while back to search the medical research - it is now looking for connections between things like IDO/pyrrolase and a few thousand herbs and foods. Will check the results of that tomorrow.

Ok - a few other possible therapies.

At least 2 probiotic bacteria (Bifidobacterium adolescentis and Bifidobacterium longum) reduce tryptophan pyrrolase activity in the gut.

Shiitake mushroom stimulates Bifidobacteria breve and Lactobacillus brevis, and leads to reduced levels of tryptophanase in the gut. PMID: 18982487

Curcumin (turmeric) decreases conversion of serotonin to 5-HIAA (MAO inhibitor?) Curcumin also has beneficial effects on the balance of 5-ht1 and 5-ht2 receptors (stimulates -1 and inhibits -2). For a variety of other reasons, curcumin seems like a potential good treatment. Am working on a longer write-up of curcumin, but will throw it out here.

"Excessive doses of retinol (vitamin A) reduces liver t-pyrrolase ... not sure how toxic these 'excessive' levels are.  PMID 17942093.

Will keep sifting through the list to see what else might be significant. 

That remains to be seen. If something seems to have the right effects in lab studies and it works dramatically enough to make an immediate difference (as did Kudzu), then it may become part of the arsenal against CH.  If something takes longer to kick in and/or only leads to a modest reduction, it may be difficult to pick up on.... someone tries it, and it maybe sorta improved things, but a cycle could have been winding down etc etc.

But I think that there are things out there waiting to be discovered (by anyone) that can reduce CH pain. Having a model or understanding of the disease lets us search for safe and effective treatments. If a serotonin deficiency is a main cause of clusters (as was asserted above), there is much that can be done in response to that.

monty wrote on Feb 18^th, 2009 at 3:52pm:


That aspect of CH has been looked at and many treatments have been based on that but so far the results are mixed. CH is a very complex condition and simply raising serotonin level or maintaining serotonin level has not given us the answer.

The serotonin relevant to CH is the intracranial one, which is only a very tiny amount compared to the serotonin in the rest of the body, especially in the digestive system. There is a very strict control of the amount of serotonin in the brain, regulated by the hypothalamus. External factors that affect the overall serotonin level in the body does not have much direct effect on that in the brain.

I totally agree that it is important to search for influential and causative factors in order to come up with possible treatment plans. However, one needs to be able to evaluate the practical implication of each hypothesis. One can never get  funding for a proper study or lab experiment unless practical applications can be demonstrated.

So far, the hypothesis discussed failed to address one of the most peculiar and important aspect of CH : the clockwork timing of the hits and the seasonal feature of the cycle. Is there any way you can reconcile the above hypothesis to this aspect of CH ?

On another point, although the level of cerebral serotonin is relatively stable, and so is the level of melatonin, there is a significant variant present between day and night and even during the awake or asleep state, both levels ebb and flow according to the circadian rhythm. Again this is regulated by the hypothalamus. How do you propose to correct the level of serotonin with regards to this constant variant ?

Please understand that I am criticizing anything or anyone. It is important to discuss and challenge hypothesises so that we can come closer to proving it or disproving it, and in the process, understand the condition better.

Thank you Gonzalo for starting the discussion, I am looking forwards to hearing your views.