TRANSCRIPT

Molly O’Brien: Hello and welcome to Spotlight on Migraine by the Association of Migraine Disorders. I’m your host Molly O’Brien. Let me ask you a question. When you have a migraine attack, do you typically feel the headache pain on one side of your head? Well, as it turns out, which side of your head you feel that headache could mean something. Today we’re going to talk about the differences between left and right migraine. To help us learn more about this fascinating topic, I’d like to introduce our guest, Dr. Adam Sprouse Blum. Dr. Blum is an assistant professor of neurological sciences at the University of Vermont. His current research centers on understanding migraine pathophysiology through both human and animal studies. Dr. Sprouse Blum, thanks so much for joining us today. 

Adam Sprouse Blum, MD: Happy to be here. 

O’Brien: A couple years ago, you started looking back at what science actually knew about migraine attacks and where that headache pain occurred. Fascinating – I’d never even thought that it would matter before. So really excited to have you today. You’ve published a few papers in the past few years. So, let’s dive into what you have learned. Before we do that, can you just explain to us what it means to have left-sided migraine versus right-sided migraine? What does that even mean? 

Sprouse Blum: Well the first thing to know about this concept of left and right migraine is it’s a bit of a misnomer. Because, you know, in most people’s mind, they think migraine equals severe headache. But in reality, all of the symptoms of migraine are just as much migraine so sensitivities to light, to noise, to smell, nausea, brain fog, cognitive impairment. And so all of those symptoms are just as much migraine. But for the purpose of what we’re talking about today, we did use the headache side as kind of the different…to group people into people that experience typically left-sided headache and people that experience typically right-sided headache.

O’Brien: Let’s dive into the right side first. For those people out there who experience headache pain on the right side of their head, what do we know? What did you learn from your research?

Sprouse Blum: So we did this review of existing literature. So what have people published on people with right migraine and left migraine. And so we…in a standardized way and we work with the medical librarians, and we pulled more than 5,000 papers that met our initial sort of poll of trying to find these papers. But, at the end of the day, we ended up with just 26 studies out of more than 5,000 that met our criteria and talked about people that we felt had either left or right migraine. And so for people with right migraine, and these studies were across, you know, different groups of people doing the studies using different testing modalities and instruments and questionnaires and such. 

But people with right migraine were more likely to have depression, perform worse on certain types of cognitive testing, have impairments in a certain type of memory called visual spatial memory, more likely to have asymmetry in their pupils, changes in what’s called the autonomic or the fight or flight nervous system, changes in blood flow in certain arteries of the head, and changes on EEG so electricity, you know, electrical activity in the head. So people with right migraine, those were kind of the findings that were sort of grouped with people that experienced right migraine. 

O’Brien: So what do we know about left-sided migraine?

Sprouse Blum: So from that same review that we did, findings in people that had left migraine, left migraine was associated with more depression. Remember, right migraine in another study was associated with (4:16). So you have separate studies showing conflicting results there. Left migraine was associated with worse anxiety, bipolar disorder, and PTSD, other changes in that autonomic nervous system. As well, science accumulates over time. You need multiple studies showing similar things, and you got to weigh the…check the weight of the evidence. You know, looking at everything together, what do we see? And so my take home from doing that review wasn’t about these specific findings. It was more that there appear to be differences between these headache lateralities across multiple domains using multiple instruments and that caused me to want to, you know, go deeper with this.

O’Brien: There could be some differences here. That was kind of the takeaway message. Do you know why that might be, why we might have these differences? 

Sprouse Blum: So the study that we’re working on, the manuscript for right now, is we were trying to get at that. You know, are there brain regions, for example, that are active in people experiencing an attack which is on the left or the right in terms of the headache? And we did actually find differences, you know, using functional MRI. So taking pictures of activity in the brain, we actually brought really nice people who are having an attack with just left-sided or just right-sided headache into the MRI Research Center here.

O’Brien: That’s brave of them. 

Sprouse Blum: I know, and it was actually before…and they actually withheld taking their acute pain relievers until after the MRI. So it wasn’t a fun study to participate in. But yeah, the long and short of it is that we do see some brain regions that light up specific to either left- or right-sided headache. And you know, we’re going to have to dig deeper to, you know, understand what that means. So is the physiology…the pathophysiology of migraine even a little bit different maybe in these two lateralities? 

O’Brien: Do we know anything about the differences, possibly the symptoms, or what people experience when you compared the two groups?

Sprouse Blum: We had the question of whether the attacks themselves differed. And so, I work at the University of Vermont Headache Clinic, and we pulled 20 years of our patients diagnosed with migraine. And so we had more than 5,000 people that had been seen through our clinic diagnosed with migraine. And then each patient that is seen in our clinic completes an intake questionnaire. And there was two questions on that intake questionnaire that we used to group people into left or right migraine, and one of them was, you had to draw on a three view of the face where your symptoms typically occur. And so we got people that only drew marks on one side of the head and face. And then there was a second question about whether you have symptoms that are just typically on one side. 

And so, out of more than 5000 people, we were really stringent to find people that seemed to exclusively have headache on one side, because we didn’t want…you know, think about it. While 50% of people have headache which can be worse on one side during attacks, that’s not the most common form of migraine. I mean, we didn’t talk about it, but the word migraine is actually derived from the Greek hemicrania. So, you know, people knew from millennia ago that there’s something about migraine, the headache of migraine, that is one sided. And like I said, about half of people have headache worse on one side, but that’s not the common form. So a lot of people have right-sided headache, 25% of the time, left-sided headache 25%, 50% of the time affecting both sides. Or maybe it starts on one side and then becomes bilateral, you know. 

And so how do you group? So in our study, we were trying to differentiate, say, does a left and a right migraine attack differ? We were looking for people who, pretty exclusively, just had attacks where headache was just on one side. And sorry, I’m going long-winded, but the take home when we looked at the two groups is there was really almost no difference. But there is a little excitement. So there was no difference in light sensitivity, no difference in noise sensitivity, no difference in nausea, no difference in the presence of aura so a lot of these symptoms. But you know what there was a difference in? There was a difference in the number of days with headache and the number of severe headache days. And we’re not talking a really small difference. People with left migraine had more than 25% more severe headache days per month than people with right migraine. 

O’Brien: Wow, that’s wild.

Sprouse Blum: Yeah, it’s unexpected.

O’Brien: And you account for a lot of factors. You said you’re pretty stringent. So, I’m just trying to think, do we know why that is yet? Do we know why people who have left migraine have more headache days or is that still to come?

Sprouse Blum: Let me clarify one little thing. So we did actually look at most severe pain score on a scale of 0 to 10 and typical pain score on a scale from 0 to 10. So those specific factors didn’t differ statistically significantly between left and right migraine. 

O’Brien: Okay. 

Sprouse Blum: However, severe headaches days did differ – left migraine having more severe headache days than right migraine. We did notice even though none of these findings were statistically significant, that all of the measures that we looked at there was 1, 2, 3, 4, 6 additional measures, including headaches causing a change in plans, most severe typical pain score, attack duration lasting more than a day, and two measures of headache, migraine-related disability. In all of those cases, even though they were not significantly different, all of them favored left migraine as having a more severe sort of type. And so my impression is that left migraine may have a more severe, you know type. But we were only able to detect that statistically in the number of severe headache days and a number of total days. 

But in response to your question about, you know, sort of, why this exists, you know, we don’t know is the short answer. But there are…we also don’t know if this finding is specific to left versus right migraine versus left- versus right-sided pain more generally. So for example, you know the left hand is more sensitive to painful stimuli in studies than the right hand. And also, after stroke, shoulder pain is more likely to be chronic when it occurs on the left. And chronic neck and low back pain was associated with worse quality of life in men when it occurred on the left. So there’s not a lot of other data points that we can pull from. But from the data that we do have, there might be something there as to pain occurring on the left, whether it be specific to migraine or not, having kind of a worse experience than occurring on the right.

O’Brien: Really interesting. Okay, let’s talk a little bit about treatment. Do we know if people with left or right migraine respond to any treatments differently, or if treatments might be more effective for people who have migraine on either side?

Sprouse Blum: So this is a question that I would really like to know the answer to as well. So we don’t know the answer to that question. We do know that there’s been several studies showing about five different medications where they found that people that had unilateral headache compared to bilateral – both sides of the headache – where unilateral was more responsive to treatment than bilateral headache across multiple medications. But then they didn’t further look at within unilateral headache, did left versus right, for example, respond differently to treatment.

O’Brien: Okay, that makes sense. So now that we kind of have a better understanding of all this – and you’ve done a great job putting things into context – what does that mean for people out there? If there’s folks out there who have right migraine, what does that mean to them? And what does it mean to providers? And what does it mean to researchers, I suppose? I feel like down the line there’s a lot more that we can learn from this. 

Sprouse Blum: Two areas are important from this research. One of them is that we shouldn’t assume that migraine with headache occurring on the left is the same, is just a mirror to migraine with headache occurring on the right. And so when we perform studies in people with migraine, we should think about the side of headache. This is also relevant for medication studies, for example. When people are treating attacks, it’s probably useful to add to the questions that they’re being asked, where on the head they’re experiencing the pain. Because it would be really interesting if we, in the future, found that, for example, one headache laterality was more responsive to either, you know, a class of treatment or a specific treatment. 

The other thing that’s, I think, going forward going to be interesting would be whether the pathophysiology – so the underlying things that are happening in the brain and other parts of the body in the nervous system – differ by headache collaterality, and whether these findings actually are more part of a more general pain processing of, you know, think that people are familiar with language processing being on the left. 

But, you know, the brain, even though if you were to look at the two hemispheres, would look pretty similar, there’s actually a built in asymmetry intentionally. It’s more efficient to kind of have, you know, there’s a lot of duplication. But having kind of one process primarily occurring on one side allows you to be more efficient than have kind of dual parallel processing. So, yeah, we don’t know if this is going to become kind of a more left/right pain thing, or if it’s specific to left/right migraine. So, you know, to be determined.

O’Brien: To be determined. Do you think it could be valuable for patients out there if they’re meeting with a neurologist or healthcare provider – whomever it is – do you think it’s important to mention, hey, I have primarily pain on my right side or pain on my left side? Do you think that can be valuable in the future to help a patient out?

Sprouse Blum: Yeah, I’d say not yet, because, you know, we don’t know yet if the treatment might be…it’d be nice to have kind of tailored treatment to one headache laterality, if that ends up becoming a thing. But right now, we don’t know it to be a thing. And I think it’s more of a personal knowing that it’d be interesting for people, I guess, to start thinking about whether their attacks that occur on the left versus the right differ for themselves. Recognizing that there may be some underlying basis for those differences that they’re experiencing.

O’Brien: You’ve also recently published one additional study that looked at white matter hyperintensities in people with migraine and the relationship on which side of the head their migraine pain was. What have you learned? Have you found anything? What do we know so far?

Sprouse Blum: And so that study that we did where we pulled, you know, thousands of people diagnosed with migraine from the headache clinic here, we realized that a lot of those people had undergone MRI at some point in the past. And so, it got me thinking, you know, it’s long been known people with migraine have these white matter hyperintensities, these kind of white spots that if you look at them on the brain, they’re not that…I don’t want to cause any alarm, so they’re not thought to cause any symptoms in migraine. In fact, they can be helpful in making a diagnosis of migraine if you have a young person that doesn’t have sort of the other causes of those white matter hyperintensities, things like high blood pressure, diabetes, or smoking. And you know, a young person that has those often has migraine. 

And so, I got to thinking, you know, we have this kind of subset of people that pretty strictly has migraine with headache just on one side or the other. Maybe we should look at their MRIs and see if the location of those white matter differed on their imaging. And so about half of the people we had had an MRI in their records. And then when we compared, what we found was surprising to us. We found that people with left migraine had more than 50% more of those white matter hyperintensities, and it wasn’t sort of left headache, left location of those hyperintensities or the opposite side. People with left migraine had more than 50% more of those hyperintensities on both sides in both hemispheres than people with right migraine. And that, again, was surprising to us. We don’t know what it means. I know obviously, the next question is, what does it mean? 

So, like I already said, white matter hyperintensities in migraine have not been associated with any symptoms. And so, in more common forms of white matter hyperintensities, such as due to high blood pressure and diabetes and smoking cigarettes, they are associated with dementia and stroke. But cognitive impairment has been looked at as it relates to these white matter hyperintensities in migraines, and that association has not been established as of yet, and not as much is known about stroke as it relates to white matter hyperintensities in migraines. So while we see this difference, I would say it’s more scientifically interesting at this point. We have no correlation with anything dangerous or anything else. But I guess it does provide further evidence that there appears to be some underlying physiologic/pathophysiologic difference between migraine with typically left. 

And again, the other thing I should re-mention is that, you know, this subgroup of patients that we studied, it’s not patients…people might be thinking for themselves, you know, oh I get right-sided, or I get left-sided attacks sometimes. This was, you know, less than…this is like 5% of our group where it was really headache almost exclusively occurring just on one side of the head, and that’s not a very common subset of people with migraine. And so, you know, we studied that subset because we wanted it to be pretty clean in terms of looking for these differences with the concern that if you had, you know, half the time on one half, that it would kind of dilute any differences we might see. And so our findings, while interesting, they don’t apply to most people that experience migraine. So, yeah, at this point, I’d say it’s more scientifically interesting than clinically relevant. 

O’Brien: It seems like there are differences. So who knows? Maybe down the road, people will get a…maybe there’ll be two different types of migraine before we even have all those subsets, or maybe there’ll be additional ones. It’s really interesting. 

Sprouse Blum: Absolutely. 

O’Brien: Dr. Sprouse Blum, thanks so much for joining us today and sharing all of your knowledge. 

Sprouse Blum: This was fun. I hope it was helpful. 

O’Brien: Yeah. Well thank you so much for joining us today. I learned a ton, it’s super fascinating topic, and hope we have a lot more to hear from you in the future about this and other research you’re working on. 

Sprouse Blum: See you later.

O’Brien: This podcast is made possible by supporters like you. If you enjoy our content and would like to hear more, you can make a tax-deductible donation today at migrainedisorders.org.  That wraps up Spotlight on Migraine. I’m Molly O’Brien. We’ll see you next time.

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