Migraine Update

Hope for migraneurs? Doc Gumshoe takes another look

By Michael Jorrin, "Doc Gumshoe", August 6, 2018

When I last took a look at what was happening in the treatment of migraines, I took careful pains to elucidate the differences between migraines and a plain old bad headache – the fact that migraines affect only one side of the head, and a detailed disquisition on the symptoms that many migraineurs (that’s the term for people who are prone to migraines) experience in advance of the onset of the headache.   It turned out that what I was experiencing was an overdose of scruples. Judging from your comments, of which there were a good many, the denizens of Planet Gumshoe are not confusing migraines with other garden-variety headaches. Nobody responded with an “Aha! So that’s what’s been making my life miserable!”

I will once again, but more briefly, summarize the characteristics of migraines with and without aura and also go over such matters as risk factors and triggers.   The main focus of this piece will, however, be managing migraines – which, of course, is what you really want to know.

There is one problem area that I will need to deal with.   Let me state it briefly: the actual pathophysiology of migraines is poorly understood.   If the goal of studying migraines is to arrive at treatment modalities that are consistently effective, this is far from a tiny problem.   Effective treatments for many ailments have certainly been discovered by trial and error. For example, a tincture made from willow bark will ease pain and lower a fever, but who knows how many tinctures were tried before that particular one was identified.   (As I’ve recounted several times before, that’s how aspirin came to be – salis, the Latin name for the willow, was the source of acetyl salicylic acid, aka aspirin).

But more often the treatment arises out of an understanding of the disease itself – what’s going on in our bodies that is making us have that undesirable response.   We understand infections; the treatment is to kill or disable those pathogens that are causing the infection. We understand the malfunctions that lead to heart disease, and we have reasonably effective means of countering these malfunctions.   We understand cancers, and even though we cannot always reliably stop those rapidly multiplying cancer cells, we do have the means of waging wars against them, and these wars sometimes result in outright victory, or at least a truce.

So it is with a great many human diseases and ailments.   The treatment takes direct aim at the cause. Unfortunately, this is not so with migraines.   The essential root cause of migraines is still somewhat mysterious. I will quote two sentences from two papers about the pathophysiology of migraine.   The first is the very last line from a paper entitled “Migraine: Multiple Processes, Complex Pathophysiology.” (Burstein R et al. J Neuroscience  2015;3 5:6619-6629)

“Given the enormous burden to society, there is an urgent imperative to focus on better understanding the neurobiology of the disease to enable the discovery of novel treatment approaches.”

What the authors of that paper are saying is that, despite a great deal of meticulous research into the possible causes of this disorder, they are quite far from having it nailed down.

The second sentence is the very first line from a paper by Peter J. Goadsby, who recently chaired the meeting of the American Headache Society.   The paper’s title is “Pathophysiology of Migraine.” (Goadsby PJ. Ann Indian Acad Neurol  2012;15(Suppl1):S1-S22)

“Migraine is likely to be a brain disorder involving altered regulation and control of afferents, with a particular focus on the cranium.”

I call your attention to the word “likely.”   Goadsby, despite his eminence, is reluctant to assert any explanation with certainty.   (“Afferent” in that sentence refers to signals travelling to any of various brain centers rather than away from those centers.)   Goadsby is saying that the cause of migraine is more likely to be a brain disorder than a disorder of the vascular system, which was the explanation that had held sway for quite a number of years.   That previous explanation was that the migraine headache was caused by the dilation of blood vessels around the periphery of the brain. The idea was that these dilated blood vessels would press on the sensory nerve endings, which would naturally result in a headache.   This theory, the “vascular hypothesis” is supported by the greater prevalence of migraines in women; estrogen makes blood vessels more flexible, which makes them more likely to dilate and press on nerve endings.

But the vascular hypothesis fails to account for the observation that migraines are almost always on one side of the head only; why would the vasodilation phenomenon be unilateral?   Also, brain imaging studies have shown that during the headache phase of the migraine, blood flow is not increased, which would be the case if the cause of the headache were vasodilation.       

An alternative theory, which has more recently gained currency, is the sterile inflammatory response hypothesis.   (A sterile inflammatory response, as the name suggests, is an inflammatory response to a non-infectious trigger.)  This suggests that the migraine symptoms result from the release of plasma, which can press on the trigeminal nerve fibers, resulting in pain.    

Several substances have been identified as possibly or likely to be involved in the pathway that leads to the characteristic headache pain.   These include calcitonin gene-related peptide (CGRP) and another peptide labeled substance P, which conveys pain information. Research into forms of treatment that block these neurotransmitters has demonstrated some effectiveness in preventing migraines. .

The most successful theory, from a purely pragmatic perspective, is that migraine is a syndrome characterized by low levels of serotonin in the plasma.   Serotonin (5-hydroxytryptamine, or 5-HT) has a number of physiologic effects, including the ability to suppress pain and to contribute to normal sleep. The evidence is as follows: first, during the headache phase of a migraine episode, the main metabolite of 5-HT is found in increased amounts in the urine (meaning that it is being broken down more quickly); second, during the onset of the migraine attack, 5-HT levels fall by as much as 40%; third, agents that deplete amines including 5-HT can trigger a migraine attack; and, fourth, intravenous 5-HT can abort migraine attacks.   However, we need to note, intravenous 5-HT has a number of adverse effects, such as rapid vasoconstriction and increases in blood pressure, which make it unacceptable for clinical use.

Serotonin acts through a number of receptors, classified as 5-HT1 through 5-HT7.   The 5-HT1 subclass includes those most likely to be involved in pathophysiology of migraine, especially 5-HT1B and 5-HT1D.   Most of the current generation of migraine medications  – i.e., the triptans, which we’ll say a bit more about later – are activators of those serotonin receptors.   They are both potent constrictors of blood vessels in the brain, and, perhaps more important, inhibitors of the sterile inflammatory response.

Another chain of reactions that is linked to migraines involves glutamate release.   A mutation which is common in about half of persons who are migraine sufferers involves the calcium channel gene.   The calcium channel transports calcium ions from the plasma into cells throughout the body. This particular mutation results in increased release of glutamate.   Perhaps not coincidentally, a similar mutation also resulting in higher circulating levels of glutamate, is linked with epilepsy and seizures. This may have some bearing on the widely reported heightened sensitivity to monosodium glutamate (MSG) reported by some individuals who experience migraines.

What all this comes down to, however, is that the root cause or causes of migraines have not been precisely identified.   It’s clear that something is impacting the nociceptors (the nerves that detect any possible damage and transmit a warning signal in the form of pain) in the brains of migraineurs, whether it’s the dilation of the blood vessels in their immediate proximity, or an inflammatory reaction in the brain tissue triggered by an ionic reaction, or a deficiency in circulating serotonin, or an excess of glutamate, or a number of other reactions.   These possible pathologies continue to be investigated, and more effective treatment modalities for migraine will – we hope! – emerge.

How common is migraine and what are the risk factors?

Migraine is a lot more common than most people would guess.   Globally, the estimate is that 14.7% of the population experience migraines – that’s about a billion of us here on Planet Earth .   In the US, 18% of women, 6% of men, and 10% of children have migraines from time to time – a total of 39 million.

As you see, migraines affect women at three times the rate than they affect men.   The reason for this may be hormonal; women have greater levels of estrogen in their circulation than do men, and estrogen affects a number of physiologic characteristics; in particular, estrogen facilitates the dilation of arteries.   Female migraineurs commonly report a significant drop in the frequency of their headaches after menopause, when estrogen levels diminish. Among children, boys tend to experience more migraines than girls, but the prevalence strongly tilts towards girls as they reach puberty.   The peak ages for migraine are in the 30s, after which migraine frequency tend to decline.

A key risk factor for migraines is family history, which certainly points to genetic factors rather than external causes.   However, migraineurs report a considerable number of triggers that they strongly believe bring on their own migraine episodes.   Here is a list, courtesy of the National Headache Foundation, part of NIH.

Foods & beverages

  • Ripened cheeses (such as cheddar, Emmenthaler, Stilton, Brie, and    Camembert)
  • Chocolate
  • Marinated, pickled, or fermented food
  • Foods that contain nitrites or nitrates (bacon, hot dogs) or MSG (soy sauce, meat tenderizers, seasoned salt)
  • Sour cream
  • Nuts, peanut butter
  • Sourdough bread
  • Broad beans, lima beans, fava beans, snow peas
  • Figs, raisins, papayas, avocados, red plums
  • Citrus fruits
  • Excessive amounts (more than 2 cups total) of caffeinated beverages such as tea, coffee, or cola
  • Alcohol (including red wine and beer)

Menstruation

For many women, the menstrual cycle is a major trigger. Attacks usually occur a few days before or during their period or, for some women, at ovulation. A drop in estrogen is believed to be the culprit. As women near menopause, fluctuating estrogen levels may also trigger an increase in migraines.

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Environment

Strong perfume is an immediate trigger for some, making common spaces (offices, churches) a challenge, and the beauty counters in big department stores a particular hell. For others, it can be flickering lights—even a movie screen in a darkened theater or sunshine flashing through trees on a road as they’re driving.

Stress

The most common migraine trigger is stress. Migraine sufferers are thought to be highly responsive emotionally. Anxiety, worry, shock, and sadness can all release certain brain chemicals that lead to a migraine headache. (Ironically, the sense of release after a stressful period can also lead to migraines, which could be the cause of weekend headaches.)

The list is far, far from complete; in fact, I would question whether a complete list is possible, since migraine triggers vary enormously among individual migraineurs.   For every migraineur who is apparently exquisitely sensitive to chocolate, there will be another one who can feast on chocolate with impunity; for every migraineur to whom a glass of red wine is forbidden, there will be another who can drink red wine with no ill effects, but is laid low by a cup of coffee.   

As we look over the list of potential food triggers, it’s worth thinking about what’s in some of those foods that makes them risky for some migraineurs.   To the list of ripened cheeses (which could go on and on and on, of course), we should add preserved and smoked meats, which also contain purines.   Chocolate and coffee (and tea also) contain related methylxanthines; caffeine is a methylxanthine, but not all methylxanthines are the same; thus the migraineur who shuns chocolate may be able to drink coffee and vice versa.

And to the environmental factors, we should add the prevalence of exceedingly bright piercing lights that we see everywhere these days – bicycles with pinpoint flashing headlamps that burn little holes in the retina, flashing lights on every kind of vehicle, whether responding to an emergency or racing to the corner deli for a cup of java, the flashing lights on the deli itself, flickering LEDs and compact fluorescents.   These may pose threats not only to migraineurs, but to persons who are susceptible to seizure disorders.

… but might migraineurs be a bid muddled about these triggers?

Data were presented at the 2018 meeting of the American Headache Society that cast doubt on the relationship between these triggers and migraine episodes.   A study enrolled 774 migraineurs who tracked their migraine headaches and also their food consumption. Of these, just over half (53.7%) suspected that chocolate was a trigger for migraines.   Most (27%) characterized chocolate as a mild trigger, 14.6% thought it was a moderate trigger, and 12% thought it was a strong trigger. But when these participants entered their actual migraine experience, using a web-enabled smartphone app, chocolate was found to be associated with an increased risk for migraine in only 10 people, which amounted to 1.7% of the 606 study subjects with enough data for analysis.   For the huge majority, 95.7%, no association at all was noted. Similar results were found for nitrates and MSG.

Speaking from my habitually skeptical position, I hesitate to characterize those data as “evidence” one way or the other.   A woman I know well who formerly had fairly frequent migraines pointed out that she had identified both chocolate and red wine as strong triggers and consequently avoided both.   If she had been recording her migraine episodes after having eliminated both of those, there would have been zero association with either trigger. That does not mean that chocolate and red wine would not have been triggers.   With due respect to the investigators who presented that data to the American Headache Society, in the opinion of Doc Gumshoe, it’s not worth much.

Participants at the AHS meeting were divided on the issue of avoiding triggers, with some experts saying that migraineurs should shun all triggers like the plague, and others opining that, on the contrary, they should go ahead and consume those triggers and “learn to cope.”   The above-mentioned Peter Goadsby had his own take on the matter. I will quote what he said:

“What we’re learning by studying the premonitory phase that occurs in the days or hours before the attack, when the patient will feel tired or get a bit moody or crave sweet or savory things, is that the brain has actually started to have the attack.   Chocolate is an excellent example. When the brain drives you to take some chocolate and a day and a half later you get migraine, the association is absolutely correct, but the causality is different — the mechanism has already started.

What we’re learning from the diary work is that while you can recommend general regularity, an individual needs to ask themselves whether what they’re calling a trigger is actually the beginning of their attack. That releases them from the punishment of worrying about the trigger and gives them information about what is about to happen.    Obviously, if you feel you’re in the premonitory phase that is not a night to go out, to stay up late, to find your favorite alcohol. It’s a night to be careful, to look after yourself, to prepare for the next day. This understanding is going to empower patients to get better control.”

I’m not sure that Dr Goadsby is asserting that those changes in the brain in the premonitory (or as it is sometimes termed “prodromal”) phase are specifically what drive people to eat chocolate or drink red wine.   Migraineurs as well as non-migraineurs can be smitten by chocolate or red wine or Camembert cravings at any time for any reason or no reason, and these do indeed originate in brain activity. The difference is that the migraineurs, looking for some kind of source for their misery, may blame whatever it was that they consumed before the headache descended on them.   It’s a natural assumption, and it might or might not be correct.

Despite the positions cited above, I am not at all prepared to dismiss the idea that triggers do have something to do with migraine symptoms.   I definitely agree with Goadsby that migraine is “likely” to originate in a brain disorder, but that certainly does not eliminate the possibility that there are external stimuli at work.   I would definitely not concur with the view that migraineurs should go ahead and consume the triggers and “learn to cope.” For some migraineurs, coping consists of taking to their beds in a darkened room and waiting for the episode to pass.   Avoiding the trigger in the first place is probably a better tactic.

What about those premonitory / prodromal symptoms?

Many migraineurs can feel the migraine coming on.   Sometimes, but not always, migraineurs can head off the migraine by taking action.   Sometimes simple activities can prevent the onset of the full-fledged migraine – vigorous exercise, a hot or cold shower, sex (yes, sex!), a bite of food.   And sometimes taking a prescription anti-migraine medication before the migraine hits can stave off the worst of it.   

A headache is not considered to be a migraine unless it is accompanied by other clinical symptoms, the most usual of which is nausea, sometimes with vomiting.   Migraineurs are also extremely sensitive to light and sound, frequently taking refuge in dark, quiet rooms. In some cases, odors which are not usually thought to be unpleasant are intolerable to the migraineur.   And they may experience blurry vision, stuffy nostrils, diarrhea, stomach cramps, pallor, flushing, or localized swelling of the face, hot or cold sensations, sweating, stiff neck, tenderness of the scalp, and a range of mental symptoms including anxiety, depression, irritability, and impairment of concentration.

Visual auras, experienced by a minority of migraineurs, were depicted by the 12th century mystic and musician Hildegard von Bingen, who experienced them as visions while sick in bed in a darkened room.   She drew pictures of her visions that are recognized