Charles Matthews M.D.
Director, the North Carolina Comprehensive Headache Clinic
Raleigh, N.C.
Last Revised 5-14-10
What's really going on in headache?
Dr. Charles Matthews is a neurologist who specializes in headache. He is the director of the North Carolina Comprehensive Headache Clinic. Since 1993, the Headache Clinic has had over 30,00 outpatient visits for the evaluation and treatment of patients with headache. An interview with Dr. Matthews follows.
Dr. Matthews, you've pointed out before that many people have headaches, and they go to their eye doctors, ENT doctors, neurologists, psychiatrists, their GYN doctors, they have MRI scans, and sometimes they still have headaches. In many cases they have other multiple illnesses, such as weight gain, fatigue, depression, and sleep disturbance. And basically, I'd like to ask you what you think is causing these problems? What's really going on in headache?
I'm going to surprise you by actually answering the question, "What's really going on headache?".
But first I should say that we have to be careful about generalizations. They're often misleading for people with headache. One of the most common mistakes with headache is that the headache sufferer is misjudged by those around them, because almost everyone has had a little headache from time to time. Since most people function perfectly well with their occasional headaches, they make the mistaken generalization that the headache they are suffering from is the same kind that you are suffering from. Their reasoning goes, "Since I could keep going when I had a headache, and you can't, then you must be weaker than I am". Or, they are a spouse, and the spouse thinks that you don't like them because you can't do something fun or take care of the children or something like that. Or, you have to go to the ER to control pain and vomiting, and the ER doctor treats you like you are some kind of moral failure. Not all spouses and doctors are like that, and when they think like that they aren't being terrible people, they're just generalizing inaccurately. They don't understand that the headache they had is not the same type of headache you have.
And so it's very important that you don't make the same mistake for yourself. In recent years there has been a push to call all headaches migraine, as there are some medications that work well to prevent migraine. But increasingly patients come to see us, at the end of their ability to tolerate life, and they have been diagnosed with migraine, when they have another type of headache that doesn't respond to migraine medication at all. If you go to our website, you can click through to our member associations, the National Headache Foundation, and the American Council on Headache Education, and there are many educational articles on those sites. But basically, when you are having trouble with headaches and first measures with your family physician or neurologist aren't working, you should be seen at a headache clinic as the next step. It will save you a lot of trouble.
Now, let's assume that we are talking about migraine, which is common. That is, even if your headaches are unusual, most likely you have terrible migraines, and so with the caveat that you shouldn't assume that this is about you, let's talk about the common problem of migraine that's difficult to treat, and where the patient is getting sicker with a lot of other things such as fatigue, weight gain, and irritable bowel syndrome. As you asked, "What's really going on here?".
It turns out that migraine isn't just a brain illness. Although the brain is involved, we now know that multiple organ systems are also involved, both during the headache phase, and between attacks of headache. For example, we know that the whole inflammatory and clotting cascade in the blood is involved in migraine; serotonin, for example, is a neurotransmitter that's involved in platelet aggregation and clotting. During a migraine, there are changes in the tendency of the blood to clot. The cardiac system is involved too. Some patients with migraine have a condition called Prinzmetal's Angina, where the heart vessels go into spasm similar to those in the brain; they can be said to have "migraine of the heart". The autonomic system is involved, as blood pressure fluctuates during a headache, often going higher but sometimes lower such that patients with headache may also faint or feel weak when they stand.
The endocrine system is involved as well. We have a female ratio of about 7 to 1 in the clinic, and about half of the males we see don't have migraine, so migraine is really a disease of women in almost all cases. More interestingly, the condition tends to occur after a young woman begins to have periods, often (but not always) worsens during her menses, and may go away altogether during the last two trimesters of pregnancy, and after menopause. So migraine certainly involves the reproductive hormones. But other endocrine problems are common as well, such as problems with glucose regulation (insulin), with hunger cravings, hypoglycemia, weight gain, and associated problems with stress hormones like cortisol. There is a developing field, psychoneuroimmunology, that looks at the interactions of psyche on the brain, which translates to changes in the pituitary and the autonomic system, that goes on to effect changes in the output of glands- and these loops go the other way, changes in the glands affect the brain, and feed back to the pituitary.
Migraine also affects the gut; some patients have only "abdominal migraine", where they have the vomiting of migraine without the headache. And patients with migraine are very likely to have irritable bowel syndrome (IBS).
To sum up: migraine affects the whole body, it affects the whole person, and it even affects those around you. You get weight gain, you get fatigue, you get insomnia, you get irritable, your periods become irregular or heavy, you have a risk of blood clots, you get depressed, you have problems with IBS. Every specialist has a different interpretation, a different orientation.
Q-Is it a problem of how to consider wholeness in the patient?
That's a good way to understand it. Consider the problem of wholeness for a moment. When you have all these parts that are misfunctioning together, what could possibly coordinate all these activities? If the body is an orchestra, is there an evil conductor?
We have a clue about this from basic research in neurology. Physiology measurements of the brain during actual migraine attacks demonstrated that there is a slowly spreading wave of cortical depression, called the Spreading Cortical Depression of Leao. What happens during a migraine attack is that a part of the brain "browns out", stops metabolizing glucose, and this brown-out spreads slowly across the cortex.
As the brownout slowly spreads across the brain, surrounding areas become involved. In some cases, patients can tract this spread across their brain by observing the march of symptoms through their body parts controlled by affected areas of the brain, for example when you have numbness on one side of the face that slowly spreads to the arm on that side.
I have to point out that the Leao brownout phenomena is one of the most interesting phenomena in medicine. Why is it so interesting? Because it is a precise picture of something we don't understand in medicine well; it's a picture of wholeness in the brain. The situation reminds me of Gallileo looking through his telescope and considering the possibility that the earth moves. It's easy to see through the telescope; it's easy to take a picture of the Leao brownout, and all the neurologists know about it. It's harder to believe it because there isn't any reductionistic explanation at all. In scientific terms, we have to think about this in terms of equilibrium processes between parts of the body. of which there is much more to say than we can discuss today. I infer that this brownout occurs throughout all systems of the body, but the Leao phenomena is known best because that's what we can take a picture of. That's where the light is, so to speak.
The brownout ties together all the features of migraine in the following way. Briefly, Le Chatelier's principle states that, in any complex system at equilibrium, the entire system reacts to maintain equilibrium. In a word, nerves stabilize nerves. That means when the brownout occurs in the brain, all the surrounding areas of the brain, and the nerves coming from the brain, become overactive, in a response to the brownout. And this overreactivity leads to sensitization of the trigeminal nerve to the face, causing pounding in the temples; to sensitive optic nerves which make you intolerant of light, to sensitive auditory nerves which make you sensitive to noise. (It's more complicated than this, so apologies my neurology colleagues reading this, but I am struggling to express the big picture here).
So, in my view the brownout ties together all the features of migraine. The astonishing thing about the Spreading Depression of Leao, the brownout, is that it can't be explained as a problem in any particular place. It's not just a problem with a particular blood vessel, because it slowly marches across different blood vessel territories.
What about the usual suspect- is the brownout caused by a problem "in my genes"? Do certain genes explain a tendency to brownouts? Many research scientists think so. There is a great deal of pharmaceutical money pouring into research on the genetics of migraine, and many biotech companies are vying for these funds and writing grant justifications about the promises of genetics. We know that migraine runs in families, and we even have candidates for precise gene location in certain subtypes of migraine that have frequent stroke-like manifestations, a condition called Familial Hemiplegic Migraine. So, the genetic researchers are hoping that when we find all these genes, that will be the final answer to the question, "What's really going on in migraine?".
The problem I have with accepting the genetic explanation as the final answer is, first, it's a research paradigm, not an experimental finding. But more fundamentally, there is a reason to expect that this paradigm is limited, and that there is only a loose connection between the way an organism looks and acts, and the simple kits we are made of.
There is a fundamental biological reason why the connection between the components of the kit are not directly tied to the activities of the organism as a whole. It's the same reason we are not made simply like can-openers; we adapt, we learn, we interact. In fact, there are three systems in biologically that fundamentally use the "kit" approach of simple components combining to form systems that adapt and learn; the genetic system which produces the protein kit, the immune system that produces immune responses to a kit of small spatial features of antigens, and a few simple types of neurons that form a kit to build complex behavior. And in all of these systems, the simple kit is only loosely tied to the what the kit can ultimately do.
The complexity of the gene interactions somewhat protects against a single error that would cause fatality. In complex adaptive gene system interactions, a system that survives over time would be expected to adapt to single genetic errors. So, the advantage of loosening the connection between genes and behavior is that you can adapt, including adaptation to any particular genetic error. So there is an evolutionary pressure to make the expressions of these kits complex, rather than direct.
Complexity researchers call these "kits" complex adaptive systems.
If this is true, we should expect that genetic research will do wonderful things for rare diseases, but not common ones. It should be a rare event that a simple gene error leads to a simple behavioral expression. Genetic diseases that are good targets for gene research are those that cause degenerative problems in children such as when they are born missing a particular metabolic ability for a relatively simple pathway, such as in the copper storage diseases. These illnesses cause a tragic downhill course and death in children, and we have every reason to hope for dramatic progress here from genetic research. But in those diseases of adulthood, such as migraine, and for really the broad class of illnesses that make up most of medicine, such as heart disease and cancer, the genetic connections are necessarily looser, to allow us to protect against damage to the kit, and to be able to learn and adapt in these systems.
But I don't find the genetic answer really answers the question. It doesn't tell us how all these genes, in separate cells, all get together to produce all these manifestations of a migraine attact at the same time. It doesn't answer the issue of wholeness. How are these things tied together? What makes the Leao brownout march together, and not just scatter? What holds the phenomena of headache together?
Here's where I am going to answer your question, what's really going on in migraine? What causes the brownout? Here's my best answer: the brownout is a metabolic problem. The coordination into a brownout is a metabolic event caused by interactions among carbohydrate and protein metabolism affected by diet, energy budgeting through exercise and the sleep-wake cycle, hormonal effects of metabolism (especially the reproductive hormones and the stress hormones adrenalin and cortisol), and the release of a hormonal and blood-borne cascade of inflammatory factors. And, genetic variability likely has some role to play in susceptibility to brownouts and where they might occur. In other words, functional disorders like migraine, IBS, mood disorders, fatigue, can be thought of in terms of where brownouts occur.
In a brownout, the body is selecting a particularly active metabolic area to shut down and conserve energy. The brain is the most metabolically active organ in the body, and a natural choice for temporary partial shutdown under energy budgetary constraints. If the brownout persists for too long, the body will respond by attempting to maintain homeostasis (equlibrium among parts) through Le Chatelier's principle,and all systems become down regulated in response. The patient with chronic headache then becomes fatigued, their metabolism slows, and they become progessively less able to stay active and participate in life. Much of the basic science was done by such researchers as Hans Selye, who studied the stress response. There are many others.
Q- So, what causes the metabolic problem that causes the brownout?
A- Here's my list. 1) Genetics play only a partial role in susceptibility to brownouts, and also probably to where the brownouts occur. 2) Environmental endocrine mimicry- substances in the environment that look like hormones to the body. Environmental influences on hormones are probably extremely important; the average age where young girls begin having periods is now 11, and it used to be 16 or so. 3) Interactions between sleep, and exercise habits, and lack of rest, producing chronic metabolic stress. 4) A diet of food products designed to be metabolically unusable to optimize shelf life. Processed foods metabolize poorly on the grocery shelves, and continue to manifest that problem after we ingest them, causing disruption of the substrates of energy metabolism, carbohydrates and fats. Disordered fats in intensively farmed meats, trans fats, and processed carbohydrates and grains, are likely common problems. It's not likely we have evolutionarily adapted to these dietary changes yet. 5) Deficiencies of magnesium and other trace minerals, and vitamins including the fat soluble vitamins A, D, E, and K2, are lacking in intensively farmed food, and sometimes determination of these levels and correction of deficiencies can be very helpful.
At the end of the day, in my view, it's mostly environment, and a little bit genes.
Here's just one example of how fascinating and important environmental effects on headache can be. We discovered here several years ago that vitamin D deficiency was even more severe in the headache population than it is in the general population. (Everybody knows these days that vitamin D deficiency is rampant in the general population; it's even worse in patients with headache). Vitamin D is made in the skin from cholesterol under the influence of sunlight, and is used by the body to dampen the immune reaction to skin damage by UV rays, and also to cause the injured cells to be cleared out and to grow new ones, a process called apoptosis that is involved in preventing cancer. But vitamin D also is absorbed and works all over the body to prevent other areas of autoimmunity and reduce cancer risk. It turns out that many patients with chronic headache not only have a deficiency of vitamin D, which predisposes them to inflammation of the trigeminal nerve that produces head pain, but they also often (about 30% in our clinic) have an abnormal laboratory test for Hashimoto's thyroiditis, an autoimmune disease of the thyroid gland. In turns out that the many patients with Hashimoto's thyroiditis have yet another condition called celiac disease, or at least some markers for having problems with the gliadin protein found in wheat.
Well, wheat looks a lot like the thyroid to the immune system, and for some people the immune system attacks the thyroid when you eat wheat. (The term for this cross-reaction is "molecular mimicry"). Now it's known that there are genetic differences in the vitamin D receptors in people with Hashimoto's thyroiditis, such that even though their vitamin D levels are low, they actually need higher levels of vitamin D than the general population to regulate autoimmunity after injury.
I wish we had more time o talk about the interactions between sugar and other carbohydrate addictions, food cravings, dysglycemia, hypoglycemia, type 2 diabetes, weight gain here, and how swinging insulin levels leads to mood disturbances, diabetes, heart disease, and headache. But at least some of these metabolic disturbances are almost universal in patients with chronic migraine.
A- First, we examine the patient, listen carefully to their story, and think about the whole person. When cases are severe, we often use pharmaceutical agents aggressively to induce a remission of chronic headaches. Long term, our goal is to get people off medication and onto a self-directed wellness program.
When we talk about wellness, we really focus on what has been effective for other people with headache; it's impractical to just say be healthy and exercise and change your life, especially when people are so sick. People need practical advice that's going to actually work for them.
