DR. GOADSBY: I’m Peter Goadsby from the University of California San Francisco (UCSF), where I direct the headache program. I have with me in the discussion today Rami Burstein, Andrew Charles, and Jean Schoenen. I’ll let them introduce themselves.
DR. BURSTEIN: I am Rami Burstein. I am the academic director of the Headache Center at Beth Israel Deaconess Medical Center; Vice Chairman of Research in the Department of Anesthesia and Critical Care; and Professor of Anesthesia and Neuroscience at Harvard Medical School.
DR. CHARLES: I am Andrew Charles. I am a professor in the Department of Neurology at the UCLA School of Medicine and Director of the Headache Research and Treatment Program here.
DR. SCHOENEN: I’m Jean Schoenen. I’m a neurologist and professor at the University of Liege in Belgium and Director of the Headache Research Unit at the University hospital.
DR. GOADSBY: We are talking about the pathophysiology of headache progression, and in order to so, we should define at the start what we mean by “headache progression” so we’re all starting from the same point. Dr. Charles, when we talk about headache progression, what does it make you think about?
DR. CHARLES: It makes me think about a patient who has episodic migraine that occurs infrequently, let’s say once a month or once every other month, who at some point in the course of their life begins having headaches much more frequently, let’s say 2 or 3 or 4 times per week. Accompanying that, there may be a change in the quality of the headache, where it becomes somewhat less classic for episodic migraine and has fewer of the typical features that we consider associated with migraines.
DR. GOADSBY: That’s very helpful. What we’re really talking about and what we’re going to narrow ourselves down to is talking about the pathophysiology of migraine progression because we wouldn’t be able to cover all of the types of headaches. Dr. Schoenen, what is your comment on headache progression?
DR. SCHOENEN: I agree with what Dr. Charles said, although, clinically, I think that this disorder is quite heterogeneous between patients. Any migraineur has experienced, at some time in his life, progression of the disorder, where it becomes more frequent and then drops back again to its former frequency, but there seems to be a small population of patients in whom the disorder sometimes progress and then tips over into chronic migraine. That’s not the case for all migraineurs who progress, and many patients progress for some time and then do not progress up to what we call chronic migraines. So that may be something we have to consider from the pathophysiological point of view: What differs between those who progress to chronic migraine from those who do not?
DR. GOADSBY: Yes, you make a good point. Dr. Burstein?
DR. BURSTEIN: Maybe another aspect of the progression of headache is defined by treatment. When younger patients get a migraine, they go to sleep. When they wake up, their migraine is gone. They then progress to a point where they are unable to sleep off the migraine. They combine sleep with over-the-counter drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) in order to abort the migraine. As the disease progresses, they need something stronger than sleep and NSAIDs. As the disease continues to progress and they develop symptoms such as depression, anxiety, and fatigue, they benefit less from sleep and NSAIDs and seek alternative therapies, such as triptans.
Eventually, some aspects of the progression make them more and more resistant to conventional treatment and clearly define a pathophysiological or pathological change that makes it more difficult for them to become pain-free or respond to medication.
DR. GOADSBY: I think the other aspect of this, which is not often stated but may be incredibly informative if we understood it, is the basis for the regression of this progression. It seems that the population estimates for chronic migraine are stable, and that there’s clearly a group of people for whom the frequency of headaches can increase each year. There must be, clearly, a group of people in equal size who go from having more headache to less headache, and I wish I thought that was because we treated them properly, but I don’t think that’s the case on a population basis.
The resolution is almost as interesting as the induction. When we talk about progression, we’re talking about addition of burden, whether in terms of frequency, change in the type of headache, or, as Dr. Burstein just said, treatment. The other aspect of progression that’s discussed is whether there’s any progression of a consequent nature: Progression to acquisition of brain changes and, what have been, I think, erroneously been called brain lesions, progression in cognitive function. Dr. Schoenen, do you have a view about any of those things?
DR. SCHOENEN: I do not really believe that the majority of migraine patients accumulate brain lesions over their lifetime, even when they progress. Most patients who progress and experience chronic migraines have migraines without aura, very few or no white-matter lesions, and very little or no increased risk for stroke.1 Brain lesions on magnetic resonance imaging (MRI) were mainly reported in migraine-with-aura patients, and predominantly in females. The nature of these lesions is not known. In some studies, their prevalence was somewhat correlated with attack frequency, but the majority of subjects in the general population who suffer from migraine with aura experience low frequency of attacks. So, I do not believe that migraine without aura causes lesions in the brain, but I do believe that migraine without aura impairs, to some extent, cognitive performance, but that’s not related to the frequency of attacks, but likely due to the abnormal information processing that can be recorded in the brain of migraineurs between attacks.
DR. GOADSBY: Yes, exactly. Dr. Charles?
DR. CHARLES: The other imaging modalities that have shown changes are morphometric studies with MRI and functional MRI scans that show chronic changes in brain structure and function, particularly in areas related to pain processing, in patients with migraine. That is, I believe, something that may be occurring in patients who have progression of migraine, that there’s a plasticity of the brain that results in these structural and functional changes over time. I think that’s an area of great interest in terms of trying to understand how to reverse that process of progression.
DR. SCHOENEN: I agree completely with that. The problem is that many of these changes do not seem to be very specific to migraine. They are merely a consequence of the recurring head pain and also found in other pain disorders. Very few are specific to migraine. When patients develop chronic migraine, central sensitization occurs, and plastic changes appear in brain areas involved in pain processing and control. These areas are not specific to migraine. Taken together, I think brain changes seen in episodic migraine interictally are, for most cases, causally related to the disorder. In chronic migraine, these migraine-specific changes become overwhelmed by other brain modifications related to chronic pain, which have therapeutic implications.
DR. CHARLES: Yes, I agree.
DR. BURSTEIN: I think the biggest question that keeps coming up from all the imaging studies that show differences between migraine and non-migraine patients or migraine patients that progress and migraine patients that do not progress is what comes first: the changes that we see, which are responsible for the patient’s symptoms in the migraine, or the progression of the headache, which is causing the brain changes. For this, at least now, we don’t have a clear answer, although I think that most believe that progression of the migraine results in progressive changes and the beginning of brain malfunction. But the answer is not clear, and this belief somewhat conflicts with the concept of genetics, because if migraine patients do have genetic defects, you expect all changes to be there all along.
DR. GOADSBY: We currently have no clear data on what happens to migraineurs’ brains over time. Various changes in structure have been reported, but we do not know what happens, for example, if the migraine is controlled, do the brain changes revert? First, we must consider whether brain changes over time are linked with anything related to the headache. For example, if there’s high headache frequency or severity and then resolution, did changes occur? There don’t seem to be any long-term consequences of migraines. All the work done studying French people over the age of 70 on a population basis points to no untoward effect of a migraine on cognitive status,2 as do the data from the Women’s Health Study.3 Prospective examination of cognitive functions in that cohort identified absolutely no cognitive death attributable to migraine status. Whatever is happening in the brain can’t be all bad, since it doesn’t seem to have palpable consequences. I find that reassuring for patients.