This Podcast Will Kill You - Ep 126 Migraine: A Cacophony in Four Movements

Episode Date: October 3, 2023

“Throbbing, pulsating pain.” “Like a drill boring into your head.” “As though your head is gripped by a vise.” “Stabbing pain hammering through your brain.” There is no shortage of metaphors used to describe the horrific, incapacitating pain of migraines. But try as we might, can any of them truly convey what it feels like to be at the mercy of such pain? In many ways, migraines reveal our shortcomings: with language that fails to accurately describe pain, with empathy when we continue to dismiss migraines as “just really bad headaches”, with medicine as we struggle to find reliable treatments and preventatives, and with biology as we fail to understand the complete pathology of this condition. In this episode, we do our best to explore these shortcomings by deep diving into what we do know about the biology and history of migraines. Why do some people get migraines and others don’t? How do certain medications work? What the heck is going on with aura? Have migraines always been around? How have people dealt with them or perceived them historically? What’s on the horizon for migraines in the future? As always, we’ve got lots of questions and lots of answers for you, so tune in today! See omnystudio.com/listener for privacy information.

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Daisy Kent, and Jennifer Fessler. The reality of Greek life has been a mystery for those outside the sorority circles until now. Is it really a supportive sisterhood that's simply misunderstood, or is there something more scandalous happening on campuses across the country? Let's get dirty. Listen to Dirty Rush on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. My name is Kaylee. I've been getting migraines since I was a kid, but over the last eight years or so,

it's become a battle against chronic daily migraines. The singular worst pain I've ever felt in my life, I will never forget it. It was January 2019. at 3 a.m. during a blizzard, I woke up with a 10 out of 10 pain scale migraine, which is the kind where you worry that maybe this time it's actually something more serious like a stroke or a meningitis. It takes a lot to get me out of my bed to drive myself to the hospital during a snowstorm to get an IV shoved in my arm. Hopefully that gives some indication of how miserable these things are. They're not just headaches. For every day that I have actual migraine pain, pain. There's a period afterwards of what I call the migraine hangover where you're just completely

drained and foggy and the nausea can be horrific and I get really sensitive to smells, both as a trigger and in terms of getting phantom smells before a migraine hits, which is bizarre, it could be a totally debilitating thing and it could be really hard to feel like you're being taken seriously because it's invisible. It's incredible. incredibly frustrating to have to cancel plans or call off work because you have another migraine. But sometimes over-the-counters or even your prescription migraine medicine just still isn't enough to make you functional enough to go about your day. I'm Katie, and I have chronic migraine. Chronic is defined as 15 or more days a month with migraine symptoms. I average about 28 days a month.

I've had migraine pretty much my entire life. My mom also has migraine, so when I was five or six years old and started getting excruciating headaches, so bad I threw up, my parents knew what was going on. At the time, there weren't a lot of migraine drugs available, and especially not for young kids. So it was just over-the-counter painkillers, a caffeinated drink, and a nap. Over the years, I also started having abdominal migraine, like regular migraine, but the pain was mostly in my stomach. In high school, I occasionally had vestibular migraine, where the primary symptom is intentional. nausea and dizziness, without much head pain, and which could last for months at a time. I carried on having a few migraine episodes a month through college when I got sumatryptin,

an older abortive drug, which worked for a while. Still, about once a year, nothing would work, and I'd have to go to the ER for an IV cocktail. Then, in my mid-20s, the medication stopped working as well, the episodes became a lot more frequent until they were chronic, and they've been that way for about three years. In that time, I've tried most treatment options, some of which didn't work at all, and some of which had side effects I couldn't tolerate. Right now, I've landed on one anti-epileptic drug that helps. I get an IV infusion of monoclonal antibodies once every three months, and I take a pill nightly, and then another pill when I'm getting a migraine.

Even though they don't completely treat my migraine, these drugs are huge for my quality of life. But they're also really expensive, so I spend a lot of time on the phone with insurance. I also use a neurostimulation device and my trigeminal nerve to try to prevent and manage migraine. I have a hat made of ice packs to help with head pain. I see a therapist who specializes in chronic illness. I stay extremely well hydrated. I never leave home without sunglasses. And I try to be realistic when I'm feeling especially bad and take it easy,

which is sometimes easier said than done. The first sign that a migraine is brewing is that my eyes start mits behaving. I get my migraine solely on the right side of my head, and things just look brighter out of that eye. It feels like that eye is open wider than the other. even though it isn't. I'll have flashing lights and sometimes it's hard to find words. Sometimes I can avoid getting a full-on migraine if at that particular instant I take a CGRP inhibit or rescue medication, eat a candy bar, and drink a diet soda.

If not, the pain starts in the top back part of my head. There was a migraine commercial a long time ago that showed lightning bolts radiating out of a lot of a spot on the woman's head. And that's what it feels like. Lights, sound, smells, and heat become painful. My cheek feels like something is pressing inward. Sometimes, if it's bad enough, my jaw and teeth start hurting, and the pain begins to radiate down my back. At this point, pretty much all is lost, and I have to go lie down. Strangely, it helps to lie down on my right side and press the painful part into the pillow. It may be the cool pillow or the pressure, but if I can get to sleep, I'll generally be better the next day. My name is Darcy. I'm 28,

and I started having migraines when I was around 10 years old. I've been diagnosed with chronic migraines, but I also have atypical migraines occasionally. So when I was 19, I woke up one morning, and the right side of my face and my right arm felt a little tingly. The more I moved around, the worse the tingling got to the point where the right side of my body was just starting to feel numb. We let a couple hours pass, I think, and nothing was changing. So at this point, my parents were starting to feel pretty concerned because when you think about someone with symptoms of having one side of their body, be numb, you think about someone having a stroke. So we go to the hospital and one thing I'll never forget about this day is when we got there, they needed me to sign some sort of paperwork and

I couldn't do it. My hand was so numb that I couldn't hold a pen properly. They did all of the test that you would do for a stroke, all of which came back completely normal. After the test, a doctor came in and he asked me, do you have migraines? And I said, yes. And he said, I think what you're experiencing is in a typical migraine, which I had never heard of before. But he explained to me that they can come in all different shapes and sizes, but some of the more common types present as stroke symptoms. It took about two weeks for the numbness to completely fade away. but even now almost 10 years later, I still have a small spot above my right eye that just doesn't feel quite right. But that's my atypical migraine story. Definitely one of the

scarier days of my life, but I am grateful because I know what it feels like in case it happens again. Hi, my name is Catherine. I'm 35 years old and I've been having migraine since I was about 12. These progressed to having about 15 to 20 headache days per month. I had a lot of anxiety around my triggers such as flying in airplanes, weather changes, too much sun or heat, certain foods, and fluorescent lighting. I'm a veterinarian, so I went through a lot of schooling and school could sometimes be difficult since the migraines caused me a lot of pain and to lose concentration. I was taking over-the-counter pain medications almost every day, and I worried about long-term damage to my organs. I tried everything from diagnostics such as MRI, supplements, preventative medications, and glasses that would reduce the blue light from the fluorescent lighting.

And thankfully, this all changed about two years ago when my neurologist prescribed the new monoclonal antibodies, the CGRP inhibitors. I have the monthly injection for prevention and an oral abortive. And this has absolutely improved the quality of my life and reduce the severity and frequency of my migrants. Hi, my name is Chris. I'm a 26-year-old transgender man, and I've been dealing with migraines for most of my life. It all really started rolling when I was in middle school, so around 12 years old. And I started having weekly, if not multiple times a week, abouts of what I thought at the time. was food poisoning. My head would hurt like there was someone blowing up a balloon inside it, and there was just no space for anything to go. And the light would hurt my eyes. I would get

incredibly dizzy, nauseous, and I would have to excuse myself, go to the bathroom, throw up, and return to class, because that was really the only option I had. This kind of just continued for years and years. I never really had a chance to get things checked out until, God, now 14 years later. Now that I am an adult working in the health care system, I have decent insurance. So over the past 12 months, I have had two MRIs that showed absolutely nothing out of the ordinary. It's hard to stay hopeful in terms of treatment and possibilities, especially considering that we have no idea where this comes from. I almost was hoping that we would discover a freak brain tumor or something like that because that would mean a real answer. It's always an interesting concept to grapple with

knowing that this is something that is so incredibly common and we just have so few answers. as to why so many people deal with this. But it is something that I know there is a lot of research happening with. And despite having a very rocky history, I do remain hopeful overall. Thank you, everyone who shared your story with us. We really appreciate it. We really do. Yeah, thank you for taking the time to write to us

and to share your story with us and with everyone. It's, yeah, thank you. Hi, I'm Aaron Welsh. And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're talking migraine. Yeah. What a topic, Aaron. What a topic. I feel like I recently said something about, oh, this is the most requested topic. And I was wrong because it's got to be migraine, right? Yeah. I think it's definitely, it's up there. That's for sure. Yeah. And so I really sort of feel like this has been, A, a long time coming, but B, I still feel weirdly unprepared despite how much reading, I know that we've both done on this. Same. I like always feel unprepared. And then when it comes to brain stuff, I feel like an extra layer of unprepared. But today, it's still going to be a great episode, promise. Oh, yeah, for sure. And I feel like listeners of the podcast have gotten used to sitting with the

unknowability of certain things, aka great question, I don't know. I think that's one of my favorite parts about our podcast. Me too. Me too. Another favorite part of our podcast is guess what? Quarantini time. What's what? Absolutely is. So what are we drinking this week? this week we're drinking the hammerhead because migraines are debilitatingly painful and it feels like a hammer. In your head.

In your head. Yep. What's in the hammerhead? In the hammerhead is essentially like a boozy affigato. Yum. So good. It's got espresso, which you can do decaffeinated, if you would like. It's got ice cream naturally.

It's got bourbon. And it's got a little bit of amaretto. Yum. We'll post the full recipe for that quarantini as well as our non-alcoholic, Plissie Berita on our website, This Podcast Will Kill You.com. And on our social media channels, of course. Of course. On our website, this podcast will kill you.com, you can find all sorts of cool things.

You know, we've got transcripts. We've got links to merch, to bookshop.org affiliate account, to our Goodreads list, to Music by Bloodmobile, to our Patreon. You can find the sources for each and every one of our episodes. There's probably more stuff. How do we not have this down by now? Oh, I thought you did a phenomenal job. Thank you. Thank you.

I try. Well, with that, shall we get into the biology of migraine? Yes, please. All right. We'll take a quick break and get to it. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again. Blue Apron meals are designed by chefs and arrive with pre-portioned ingredients,

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It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit O'Keefscom. This Podcast and code this podcast at checkout. This season on Dear Chelsea with me, Chelsea Handler, we've got some incredible guests like Kumail Nanjiani. Let's start with your cat. How is she? She is not with us in.

Okay, great, great, great way to start. So this is a great beginning and hopefully you'll be able to, I don't know, maybe you will cry. Amanda Seifred. Life is so short. If you feel something like that, you have that fire in you for this experience. It's not for a guy. It's for the experience of being in love. And, like, it's bigger than a guy.

Elizabeth Olson. I love swimming naked so much. And I know you love taking pictures of yourself naked. Yes. I love to be naked. I just want to be in my brown underwear all the time. Ross Matthews. You know what kids always say to me?

Are you a boy or a girl? Oh, my God. That's so funny. I know. So I'm always like, hi. I try to butcher it up for kids, you know, so they're not confused. Yeah, but you're butching it up is basically like Doris Day. Right?

No. I turn into Be Arthur. Listen to these episodes of Dear Chelsea on the Iheart Radio app, Apple Podcasts, or wherever you get your podcasts. So what even is a migraine? That sounds like a great place to start. That's where we're going to start. I'm going to start with a quoted definition, which happens to be from a pretty old paper, but the definition holds. So we'll start there.

This is from a New England Journal of Medicine article from like 2002, which says, quote, migraine is a common, chronic, incapacitating, neurovascular disorder, characterized by attacks of severe headache, autonomic nervous system dysfunction, and in some patients an aura involving neurologic symptoms, unquote. biology section over. That's our definition. So that's the jargoned version. The way that I'm going to break down this biology section is to try and give you an idea of what migraine really is. And as much as we can know about what's happening during these migraine attacks.

So migraine attack can be divided into three to four main parts or kind of like sections. And then there's inter migraine intervals, like between migraines. So first we'll go over what these parts or what these phases of a migraine attack are, what they look like, what they feel like, which you heard a lot of in our firsthand accounts. And then we'll go over what we know so far about what's happening in our brain. during these attacks. But for warning, as will come as a surprise to no one listening to this episode, if you've ever listened to TPWKY before, there's a lot that we don't know. But there is some stuff that we do know, and so I'll try to get into some of the nitty-gritty

of that as well. So a migraine attack generally starts with a period of pro-dromal symptoms. This period is often called the pre-monitory symptoms period, which can start anywhere from two hours to two days prior to the actual headache that most of us associate with migraine. So these symptoms can range from anything like fatigue or yawning or impaired concentration. You could have neck pain or stiffness, water retention, nausea, photophobia, which is difficulty looking at light. You might have food cravings. It's a really long and kind of diverse list of symptoms that someone could have for up to two days, right, a day or two before the migraine attack itself. About 80% of people that get migraines have some kind of these prodromal symptoms. And then for about 30% of people with migraines, the next phase is an aura.

And a lot of people have probably heard of an aura. But an aura are these very bizarre, transient focal neurologic symptoms of various kinds. Most often, like 90% of the time, it's these visual symptoms. The most common one is called a scotoma or a scintillating scotoma. which sounds fancy but in fact is terrifying having had these episodes it starts as like a flickering spot a flickering kind of light spot either in one eye or in both eyes and then this spot can kind of grow or move or change and keep flickering and scotoma just means like a blind spot so wherever you see this flickering wave or curve of light you can't really see anything except

that light, but the vision around it usually remains the same. And this might expand or people can see different kinds of patterns like a crescent or a zigzag or different shapes. And then eventually it just stops. But an aura isn't only visual. That's one type of aura. People can also have like paresthesias, so like feeling tingling or prickling sensations, usually just in one part of the body. Or it could be like a numbness of the face or your arm. It could even be things like difficulties with expressive language, not being able to find your words or not being able to say words the way that you could just minutes prior. And even more rarely, an aura could be some kind of motor dysfunction, like all of a sudden not being able to use your hands or your legs. A lot of this might sound a lot like a stroke because some of these symptoms can really mimic that.

So this aura phase usually starts anywhere from five minutes to an hour prior to the onset of the headache. And it usually lasts under an hour and is followed pretty immediately by the headache part of migraine. That's the part that people think of when they think of migraine most often. So let's get to that. What is a migraine headache itself, aka how do we define a migraine headache versus any? any other kind of headache. So first, this is a headache that most often is unilateral. It's on one side of the head or it at least starts off on one side of the head and then it

might move to the rest of the head. It's usually described or characterized like a throbbing pain or like a pounding pain rather than a tension type pain. And in general, a migraine is classified as moderate to severe intense. intensity, like the pain is bad enough that you can't get out of bed. You feel like you need to just lay down. And that's also in part because the pain generally increases with activity, which essentially forces you to just lie down. So those four characteristics, unilateral, throbbing pain, moderate to severe intensity, and increasing with activity, based on the international

classification of headache disorders, which is like the criteria that are used to diagnose, migraine, a migraine has at least two of those four criteria. Okay. And on top of that, migraine has either nausea and vomiting and or photophobia or phonophobia. So like severe light or sound sensitivity. I know. Your face is like. It sounds, I mean, like, I know many people that have migraines, my mom, my grandma had

horrible migraines her whole life. And I think it's just when you lay out all of the things that you can experience, it's just horrific. It really is. And here's an even more horrific part, the duration. Yeah. By definition, a migraine is also a headache that's lasting between four and 72 hours. I'm going to say that. that again. This is a severe headache with nausea or photophobia, not being able to look at light, that increases with activity that's throbbing in your brain for four hours at a minimum or two hours if you're a kid. And it can last up to three days, meaning you go to bed with a headache and you wake up with this same headache.

And a migraine isn't even over when it's over, because the fourth phase of migraine is the post-dromal phase. And this can last again another one to two days after the headache subsides. This recovery phase can have increased in tiredness or somnolence. It can have difficulties in concentration. A migraine altogether is a phenomenon that, that affects the brain on a pretty large scale. And the full duration of a migraine attack can last up to seven days if you include the premonitory and the recovery symptoms as well as the headache itself.

I've heard it described as a symphony in four movements, but I feel like that's way, way too pleasant language to describe what's happening. I agree. It sounds like a symphony is like nice. This is a cacophony in form movements. Yeah. Yeah. Oh, my gosh. I know.

And that's kind of how. That's just how we define the migraine. So, of course, then knowing all of this, knowing how debilitating a migraine can be, how severe it can be, the question or questions are like, why does this happen? How does this happen? Who does this happen to? How can we stop this and never have this again? As promised, I do not have all those answers. But you have some of them. I sure do. So here is what we do know, or at least what the consensus so far is about what we think is going on in the brain with a migraine.

So what we know so far is that a migraine headache depends on the activation of a pathway in our brain called the trigeminovascular pain pathway. And it very likely involves a little peptide called CGRP or calcitonin gene-related peptide. This is a neuropeptide. We'll talk about it in a little bit more detail. But let's define some of these things, shall we? Yeah. So the trigeminal nerve, you may have heard of, this is cranial nerve number five. So this is one of our 12 cranial nerves that is responsible for all of the sensation to our face pretty much.

And also innervates muscles that are involved in chewing and biting. So this is a predominantly sensory nerve. It's mostly carrying information from the face to the brain and then from part of our brain stem into the cortex of our brain. and then there are some nerves that are also involved with muscles, and so are more efferent sending signals for muscle contraction, right? So this trigeminal nerve, mostly sensory, and like many nerves, most nerves, is very interrelated with vascular.

It forms like complexes of nerves and arteries and veins. And in the case of the trigeminal nerve, its projections, especially in our brain, are very strongly associated with the vasculature in our brain and our meninges. That's the covering of our brain and spinal cord, both the duramotor, which is the outer layer of our meninges, and the pia motor, which is the innermost layer of our meninges. So this trigeminal complex, as it's called, has these ascending nerve axons that project, into a whole bunch of brain regions in our brain stem, our hypothalamus, our thalmus, our cortex. All of these regions of our brain are involved in a whole bunch of stuff that we happen to see dysregulated during a migraine. These involve our response to pain and no seception.

So no seception is just the actual nerve signals of pain, like our nervous system getting those signals is the process called no-susception. Our no-siceptors are pain nerve fibers. There are a bunch of other neurons that are projecting to parts of our auditory, visual, and olfactory system, parts of our cortical brain, like regions that are involved with movement or even concentration, all of these different brain regions that happen to correspond to a lot of the non-pane symptoms of migraine as well as these no-susceptive or pain-related symptoms. So think things like photophobia, nausea, vomiting, difficulty focusing, all of that. So we know that the trigeminal vascular complex is activated and involved in this process of migraine and in kind of all of the phases of it.

But why? Erin. Have I ever answered a why question on this podcast, actually? I'm sure that you have, yes. I'm not going to right now. No. That's where I will get to the part where I go, I don't know. But let me tell you more about what we do know.

All right, all right. So we know that it's the trigeminalvascular complex that's activated. We also know that this specific peptide, CGRP, calcitonin gene-related peptide, is very involved in this process. This is a peptide that we see released by this trigeminovascular complex during migraines, and we now know that blockade of this peptide or its receptors by various medications is effective in many cases at stopping migraine. We think that CGRP acts predominantly in the Dura mater, so the outer layer of our meninges, and that what it does is modulate the trafficking of these netherp.

no-susceptive signals. What does that mean? It means that CGRP is involved in the sending and receiving of the pain signals that are involved in migraine. And it may also be involved in inflammation. And there's still some thought that inflammation is involved in the migraine process. So if you're blocking that or stopping that neuropeptide through whatever medication, then it's like, okay, it can't be the messenger that causes all the pain. and that also then leads to inflammation. Exactly. And so in terms, maybe this is jumping ahead a little bit,

but in terms of when you say stop a migraine, is that at what point can you stop a migraine? Is there like a threshold beyond which, like the point of no return, I guess? That's a really good question. In general, all the medicines that we use for migraine, especially for like acute migraine attacks, work best the earlier that they're given. And part of that is because once this process starts

rolling, and especially once the pain has really started to take hold, there's an additional process, we think, of like central sensitization. So there's a thought that, like, once the pain signals have started to be sent, now our brain is acting a little bit on overdrive in response to those signals and then yeah you're right that's a really hard ball to stop rolling essentially okay so it's like ah that all pathway like exactly i know it well and then you just speed down it and then pain goes up yeah and the variation in how long a migraine can last so like let's say that you don't stop the neuropeptide in time or you lived in a period before there were drugs that could do that or you don't have access to drugs, whatever, is the variability in how long that migraine will last is just

sort of like the half-life of the neuropeptide in your brain? I mean, maybe, no, yes. Who knows? Okay. Okay. The answer is that we have no idea because everything that I just told you is a lot of information. It's a level of understanding that we did not have, say, 15, 20 years ago.

No. But it's also not helpful at all when it comes to understanding the why or even how this trigeminovascular system is activated in people with migraine to begin with. We don't understand the initiation of migraine pain. We don't understand why it stops eventually, why it lasts for as long as it does, why it can be so different both between individuals as well as in one individual throughout their lifetime, there is so much that we don't know. It's really frustrating. It is. It is. And then there's aura.

Oh, gosh. ORA is very interesting. It happens in about 30% of people with migraine. So it's not the most common form of migraine, migraine with aura. and it can happen in absence of a migraine headache as well, but that's even more rare. And here, again, we know a little bit about the mechanisms, but so much remains unknown. ORA is thought to happen from a phenomenon called spreading depolarization or cortical spreading depression, depression depolarization. Same thing.

And so when we have an aura, the symptoms tend to start kind of small. And they grow or kind of propagate rather slowly, especially compared to another rapid depolarization phenomenon that we've talked about on this podcast, a seizure. Ah, okay. And so it's thought that what's happening during this time is that starting from some focal point in the brain, there's this membrane depolarization. And that's what happens whenever a nerve is firing, like a signal is firing. But this is happening like all in this one area and then propagating along the cortex of the brain. Like dominoes. Kind of, yeah.

And we have like MRI and PET scan studies that show additionally changes in blood flow, like hyperperfusion followed by hypoprofusion. So like more blood flow and then all of a sudden less blood flow in regions of the brain that are corresponding to the symptoms of aura. and there's evidence that this cortical spreading depression, this depolarization, can then trigger or activate the trigeminovascular system. But we still don't know what the susceptibility is for this cortical spreading depolarization or depression. And we also don't know why isn't then that only 30% of people have aura with their migraine, etc. Like there's there's like some oh this is involved and it activates the system and maybe that's

the pathway to then migraine pain. But what about when you don't have an aura? Because people with migraine with aura can also still have migraines without aura. So it's complicated. So I wrote down a few questions because I knew that I was going to forget them and I feel so overwhelmed by questions. I'm like brimming right now. Overflowing. I'll try. Okay. Why is the pain typically on one half of your head? Great question. So our cranial nerves are all paired, which means that you have two sets of them, and then you have two sets of those ganglia or the nerve bodies, and then two sets of those like ascending axons as well. So probably you're having activation of one of your trigeminovascular complexes like on one half of your brain at a time. Okay, but like why? That's my

best guess. Why? Erin, I just told you I don't know. Sorry, okay, okay. I'll try to stay away from the whys. Okay, another question I had was about the mechanism of aura as far as we understand. So you discussed how visual aura is the most common. Are the mechanisms the same for the other types of aura? Great question. Yes, it's thought that in general the mechanism of aura is this cortical spreading depression and what your symptoms are will depend on where that depolarization is happening in your brain. And we don't know how aura is or is not linked to migraine pain mechanistically.

We know from animal studies that the process of this cortical spreading depolarization can lead to activation of that trigeminalvascular complex. How exactly? We don't know, but we do see that correlation there. Okay. One last question. Okay. So you mentioned earlier when you were describing the various symptoms that can be associated during the migraine pain, like the headache part of migraine. And you commented on how similar they are to stroke. Why? How? Sorry, I said why. How? I don't have a lot of hows for you either, Erin. So that is a, it's kind of a can of worms question. And in part it's because it does get into associations that exist between migraine and other neurologic and psychiatric disorders, including stroke. I don't have a. easy, good answer for like why can migraine symptoms, especially aura symptoms, mimic a stroke,

but they can't. They also can mimic some forms of seizures or epilepsy. Yeah. So I want to go into a little bit more detail, not necessarily on this pathophysiology, but on like the big picture of migraine and migraine biology. Everything that I went over and the criteria that are, in the I-C-H-D-3. Those are all for migraine, like called classic migraine, and migraine with aura. There is also a distinction between what's called episodic migraine and so-called chronic migraine. But the term chronic migraine is confusing and like a crappy term because like most people who have migraines have them chronically. But what chronic migraine actually means is that people have a very high frequency of migraines.

Chronic migraine is classified as at least 15 headache days per month. Oh my God. Yeah, that's half of a month. And at least eight of these headaches meet criteria for migraine. Some of them can be non-migranist headaches. Up to 5% of people with migraine meet criteria for chronic migraine at some point in their like migraine lifestyle. span because migraines can also change over time.

But there are other types of migraine as well that I'm not going to really get into detail on, but I just want to mention that they exist because they're important. There's abdominal migraine, which is much more common in kids but can persist into adulthood. It's very similar in terms of all of the prodromal symptoms, but instead of headache pain, it's intense abdominal pain that lasts between two and 72 hours. And it has very similar non-pain symptoms, nausea, vomiting, photophobia, all of this. Huh. Yeah, I have a great paper if you want to read more details about it.

But there's a huge connection between the mind and the gut and there's associations between migraine headache and abdominal migraine. There's a lot there. Migraine is also in relatively large part genetic. About 40 to 60% of expression of migraine is from genetic factors. But that being said, this is nowhere close to like a one gene, one disease problem. There are 38 different loci so far that have been identified as increasing our susceptibility to migraines. But there are also a handful of monogenic migraine syndromes. these are a single gene mutation that also leads to migraine.

And these, while they're quite rare, have become really important in terms of studying and understanding migraine because we can identify the specific changes that happened as a result of this one genetic mutation. One of those that I just want to shout out is called familial hemiplegic migraine. and this is characterized by migraines. They're hereditary. And in addition to having all the features I just talked about of migraine and aura, they also cause a temporary hemiparesis, which means a one-sided muscle weakness really looks like a stroke.

Yeah. And there are four different subtypes of this particular monogenic migraine syndrome. And they're caused by mis-sense mutation in genes that are involved in neurotransmitter function, specifically in these voltage-gated ion channels. And I know that that's a lot of like biochem-y words. But the point is that it's these specific like ion channels that are responsible for passing information in our brain that are involved at least at this level of migraine.

So it gives us a lot of idea on potential targets for migraine treatment both for people with these gene disorders as well as migraines in general. That's really interesting. Yeah. So there's a lot of work on like mice model studies and things like that with these type of migraine disorders. But I'm not done. Okay. Can I ask a question before we go on? Yeah. Okay. So it was when you mentioned abdominal migraines. And I remembered I wanted to ask about like why the nausea. and vomiting and how, at least I read in some historical accounts, people felt better after vomiting,

and then everything was fine, which, like, I'm sure is not a universal truth. But is it just that, like, there are pathways that are connected? So, yes. In part it's because these trigeminovascular complex afferent nerves, the ones that are going from parts of our brain to other parts of our brain and carrying signals with them, are going to parts of our brain that might be involved with causing nausea, like involved with maybe our vestibular system or something. But it's also because the spinal trigeminal nucleus in our brainstem, in addition to receiving information from our trigeminal nerve, it also gets information from a bunch of other nerves, like our facial nerve, our glossophoringial nerve, and our vagus nerve, which is our main parasympathetic

nerve. And so whenever you have a mess up in our parasympathetic system, you can have a lot of very generalized symptoms. Right. Now, why would people feel better after they barf? I don't, I don't know. Okay. But yeah, that's, so it's, it's all complicated. It's all involved. But if all of that wasn't enough, as I kind of briefly mentioned when you brought up stroke, Aaron, there are also associations that are not well understood mechanistically, but definitely seem to exist epidemiologically, between migraine and a bunch of neurologic and psychiatric disorders. This includes epilepsy, it includes stroke, depression, anxiety, and probably more that I'm not mentioning. And one of the things that kept coming up in everything that I read that was so interesting about these relationships is that

they're often described as bidirectional. For example, having an episode of major depressive disorder puts one at higher risk of having migraine and having migraine puts one at higher risk of having major depressive disorder, at least based on some epidemiological studies, like in both directions. That sounds like a horribly vicious cycle. How do you break out of that? Can you? Right. And the same is true for epilepsy. Migraine and epilepsy are these comorbid conditions that seem to similarly have this bidirectional relationship, which maybe suggests some underlying similarity in the pathophysiology, but we don't know. And it's also associated with an increased risk of stroke, especially in the case of migraine with aura, and specifically in the highest risk in people assigned female at birth under age 50. And then there's triggers.

Yeah. When it comes to migraine triggers, there's not really one thing that is true for all individuals with migraine. And we don't know, like because we know so little about the mechanisms of migraine initiation, we don't know how triggers that people may have identified in themselves. trigger a migraine in them or in anyone else. But there are some things that seem to be relatively common triggers for most people that experience migraines. And these are things like stress, which could be emotional or physical stress, lack of sleep or poor sleep quality, including jet lag, and hormonal fluctuations.

In particular, estrogen or a withdrawal of estrogen, compared to where you were at previously. This is often a huge precipitant or trigger, especially for people who menstruate. We have very significant hormone fluctuations on a cyclic basis. So for some people, that means increases in migraines with periods. For some people, pregnancy and breastfeeding causes a decrease in migraine symptoms. And then menopause causes an increase in migraines, whereas postmenopause might be a decrease or an elimination entirely of migraines.

It's like, it's just not complicated at all. It is so straightforward. Yeah. And I'm sure consistent for every person. I know. Yeah, totally. You can predict it, right? Yeah, totally.

And how are hormones thought to be related? Dino. Okay. Oh, Erin, not a clue. I mean, we think that it's estrogen. What is estrogen doing or what is the withdrawal of estrogen doing, like the sudden decrease in estrogen? I don't know, do know, no idea. And it's not like it's universal, right? Not only that not everyone who menstruates has a migraine, but even people who do menstruate who get migraines may or may not have any association with their mencies. So it's not even close to universal. We have no idea what's happening. Yeah. And yet we know so much more. Like it used to be thought that it was all about vasodilation and it was all vascular and it's not.

So we know a lot more than we did. And you're right. We still know so little. The good news is that what we do know has led to the creation of a lot more effective medicines for treatment of migraines. So despite the fact that there's a lot that we don't know, there is good news to be had. And that is that migraines for many people are treatable. There's a number of different medicines. Some of them, like the triptans, work at the 5HT or the serotonin receptors, which cause vasoconstriction and inhibit the release of a whole bunch of neurotransmitters, including CGRP and others.

And then there's newer medications that you've probably seen commercials for if you don't pay for premium Hulu like me. Like UBrelVee and NERTech. These medicines are specifically inhibitors of that CGRP peptide that we talked about. And then we'll talk in the current event section about other modalities that have come up and how much research is being done. Yeah. None of these treatments are perfect. but there are a lot of options. So, Erin, tell me,

how did we get here? How do I even ask that question? Yeah, how do I even answer it? I guess we'll find out after the break. Okay. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something.

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some incredible guests like Kumail Nanjiani. Let's start with your cat. How is she? She is not with a thing. Okay, great, great, great, great way to start. So this is a great beginning and hopefully you'll be able to, I don't know, maybe you will cry. Amanda Seifred. Life is so short.

If you feel something like that, you have that fire in you for this experience. It's not for a guy. It's for the experience of being in love and like it's bigger than a guy. Elizabeth Olson. I love swimming naked so much. And I know you love taking pictures of yourself naked. I love to be naked. I just want to be in my brown underwear all the time.

Ross Matthews. You know what kids always say to me? Are you a boy or girl? Oh my God. That's so funny. I love it. So I'm always like, hi. I try to butcher it up for kids, you know, so they're not confused.

Yeah, but you're butching it up is basically like Doris Day. Right? No, I turn into Be Arthur. Listen to these episodes of Dear Chelsea on the IHeart Radio app, Apple Podcasts, or wherever you get your podcast. Hi, I'm Lisa Trager. And I'm Kara Clank. We're comedians and your favorite overly invested SVU watchers.

And that's messed up, an SVU podcast. We recap iconic episodes, then talk to the stars who live them. Like the legendary Matthew Lillard, who will never forget his time on SVU. I do remember the mustache. I will get a meme of that mustache. Like every like six days, somebody would be like, what was this? Each week, we cover the crimes, analyze the plot holes, and insult the outfits. Benson goes to talk to Kelly to tell her the news, but is wearing a beret.

Not the time for a silly hat, Benson. What are you doing? New episodes drop every Tuesday on the Exactly Right Network. Listen to That's Messed Up on IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. Dund Dun, dun! Migrains. What are they? What causes them?

Who gets them? How do we treat them? Don't worry, Erin. I'm not going to ask you to redo the entire biology section. You're like, wait, I thought that I was done. Like, I answered some of those. Yeah, so you already gave us the answers to what we know or what we think we know about migraines today. But the answers to all of those questions, like whether or not aura has to be present for something to be considered a migraine, or whether

migraines are caused by vascular or neurological changes or if they have a physiological basis at all, those are not going to be the same throughout the history of migraine. And how those answers evolve can tell us more about what was going on in the medical field or even society more broadly than it can tell us about the path of physiology of migraines, to be honest. It can tell us about what new ideas were popular at certain time. or what new discoveries were made. Like, for instance, when allergies or allergens were first identified as a concept, many

physicians thought, hey, maybe migraines are caused by allergens and they try desensitization as a result, like allergy shots. Or when hysteria was a popular diagnosis, it was, you bring this on yourself. And, you know, the advice was just, don't be so stressed out. Don't be so overworked if you want to prevent migraines. Just don't work so hard. Chill out, bro. Just chill out, yeah.

Or when you're finding earthworms crop up as an ingredient for migraine treatment, that's a sign you're probably in the medieval period in Europe. We'll get there. Humans have always tried to explain diseases or other phenomena within the bounds of whatever knowledge we currently have. And the way we treat those diseases is heavily influenced by popular ideas about what their causes are. We still do that. And it's easy to lose sight of that, that our current perception of migraine is only the latest in a long line and is subject to change and likely will change, hopefully for the better. But before you can tell us about what those positive changes might be, let's first go back to the early history of,

migraines so we can see just how far we've come. At least in some ways. And I want to give a huge shout out to the book that I used as my primary source for this history section, and that is Migraine A History by Catherine Foxall. It's a great read, and I'll definitely be quoting from it. It shouldn't surprise you, given just how incredibly prevalent they are, to learn that migraines have been known about, written about, experienced, treated for thousands of years. You can find mentions of migraines in basically any ancient medical text from any part of the world. The Ibrose papyrus from around 1550 BCE describes extreme pain in one half of the skull that should be treated by anointing the head with the skull of catfish fried in oil or fat for four days. Of course. I don't know if that meant

fried for four days or just like anointed. I'm guessing anointed for four days. I would have guessed fried for four days. That's fascinating. Oh, okay. In ancient China, migraines were treated with acupuncture in ancient Greece, bloodletting. And while it has been often suggested that tripaning was done throughout the ancient world to relieve the pain during a migraine specifically. So trapanning like drilling a hole, cutting a hole into your skull. There isn't really much in terms of evidence supporting that, that it was specifically for migraines. It's for dust. Everything I know about tropanin is from golden compass. And trapanning was definitely done, but whether or not it was for migraines, probably we'll never know. If anything, trapanning was used specifically for migraine

more in the 20th century than in ancient times, at least as far as we know. Okay, okay. Of course, I can't leave the Hippocratic texts out of this, and it's in these texts from the 5th century BCE that we find our first clear description of migraine with aura. A young man, Phoenix, with, quote, flashes like lightning in his eye, usually the right. And when he had suffered that a short time, a terrible pain developed towards his right temple, then in the whole head, and then into the part of the neck where the head is attached behind the vertebra, and there was stretching and hardness around the teeth. He kept trying to open them, straining.

Vomits, whenever they occurred, averted the pains I have described and made them more gentle. Phlobotomy helped. Okay. Mm-hmm. About 500 years after this description, Galen originated the term hemocrinia to describe a condition, a syndrome, really. It wasn't like considered a disease. It was more of a syndrome, I guess, where half of your head was in pain and sometimes associated with stomach disturbance. Hemocrinia turned into emigrania in Latin and Middle English, and then to migran in medieval Welsh, and then to magran. And then we see all sorts of variations like megrim, migraine, migraine. But the spellings are all over the place. All wonky. Yeah.

And the French word migraine began to be used more widely in medical literature starting around the 1870s. So, yeah. And the widespread use of these names for migraine and all of the variations of these names, I think it clearly shows that migraine. was not some obscure condition. It was highly recognizable and extremely common. But what was it? What did people think caused it? Aaron, I'm sure you can guess with the leading hypothesis for the cause of migraines from like ancient times until, I don't know, 1700s or so.

Something like humors being off. Yes. I knew that all my talk of the humoral theory of disease has paid off. I thought that so much. I feel like this season, especially. Yeah, basically an imbalance in humors. In the case of migraine, it was attributed to an excess of bilious humors, yellow bile in youth and black bile in adulthood. And so it follows then that treatment involved getting the humors back into balance.

For example, consider this somewhat complicated treatment, aren't they always? from an old English medical text called Bald's Leech Book from 950 CE. I know I want a copy of this. Me too. Quote, For ache of half the head, take the red nettle of one stalk, bruise it, mingle with vinegar and the white of an egg, put all together, anoint therewith. For a half head's ache, bruise in vinegar with oil, the clusters of the lorice,

smear the cheek with that. For the same, take juice of vexedged. rue ring on the nostril which is on the sore side for a half heads ache take dust of the clusters of laurel and mustard mingle them together pour vinegar upon them smear that with the sore side or mix with wine the clusters of laurel or rub fine in vinegar the seed of rue put equal quantities of both rub the back of the neck with that are those for like all just different options yeah you have available to you wow okay right Right? Yeah. And, okay, so first of all, there is actually a logic behind these ingredients because in general, with the humoral theory of disease, you were supposed to treat a condition with ingredients that had the opposite qualities of that disease. Okay. So if migraine was thought to be a cold, moist condition, you would prescribe dry, hot ingredients like nettles and mustard seed. Okay.

Why so very many options? again, there's a reason for it. Not all plant or animal ingredients would have been available year-round. If a recipe calls for fresh nettle and you're in the middle of winter, like, where are you going to get that? Or even if you just run out, right? And the availability of ingredients would have also changed as trade became more widespread and more herbs and spices were introduced, which I think is so interesting to think about. like you can sort of track how trade influenced home remedies for certain conditions over time. Yeah, that's super interesting. Yeah. And the seasonality part too, yeah.

Mm-hmm. So let's see what kind of creative solutions people came up with. So one from 13th century whales is to, quote, eat a baked or roasted hairs brain stuffed with rosemary flowers, followed by sleep, end quote. I uh-uh. I mean, don't do that. I still feel like from our pre-ons episode, like, just don't eat brains. Don't eat brains. That's a pretty good rule. Yeah. Yeah.

Yet another remedy, not sure where it's from. Quote, we anoint the temples, nostrils, and pulsating veins with rose water together with the milk of a woman who is nursing a male child and we induce sleep. End quote. Oh, yie. Okay. Uh-huh, uh-huh. Yep. Yep. How about that? Gargling with all sorts of mixtures of things and bloodletting were also really common treatments and which side of the body you bled from and how much and what time of day, what time of year. All of these things could be adjusted to treat migraines specifically,

which I think is interesting to think about. It's really interesting. I also kind of wonder with bloodletting, like how much blood, I've wondered this for a while, like, how much blood, I've wondered this for a while, like how much blood would they let, number one? And I actually wonder if there would be any benefit if you let out enough that then you had vasoconstriction. That seems like a bad plan. Yeah. I just kind of wonder. So I can't remember.

I have come across actual quantities, but I don't remember anything at this point in time. And I think it was pretty variable. Yeah, it just feels like you would have to do a lot for. it to have any kind of effect. Yeah, and then you're just, you know, inviting a whole host of other problems into your life. Yeah, yeah, et cetera. Yep. Okay.

Okay. But besides bloodletting, which was actually really common, another oddly common ingredient was what I mentioned earlier, earthworms. Yeah, what? Okay. Okay. Quote, take six spoonfuls of the gall of an ox or cow. Put thereto two spoonfuls of the powder of the long worms of the earth and the powder of half a nutmeg grated. Boil all these together upon a chafing dish of coals until it be so thick as you may spread it upon a cloth,

then take a double linen cloth and cut it fit for your forehead and as it may cover the temples. Spread this upon it and lay it to your forehead lukewarm and let it lie until it do fall off itself. So in case you missed it, ground up earthworms, the long worms of the earth, made into a paste that you put on your forehead. With some like goat cow parts and how, stuff, yeah. Yeah. Why? Why? Why?

You can find earthworms in all kinds of remedies for things like constipation, jaundice, fevers, or other diseases of the head and brain, like throughout. the medieval period. Again, why? And I feel like we've come across so many of these, you know, a very strange to us combination of ingredients. And we're just like, ha ha, how weird, moving on. But in this book was the first time that I've actually come across an explanation. Okay. For why earthworms, for example. There is a reason. And honestly, I come. I come kind of like it. I think it's very interesting. Earthworms, because they lived in the dirt, feeding on rotten matter, were believed to also eat or consume the rotting matter in your body that caused whatever disease you had. Huh. And so if migraines were caused by like rotting or toxic

or putrified stuff in your head, then that earthworm paste in theory would have eaten up the putrefying matter. Huh. Yeah. And earthworms weren't alone in this. Like other creatures that were quote unquote bread of putrefaction, like earwigs and snails were also often used in remedies to like get the toxins out of you. How interesting.

Yeah. Okay. Up through the late 1700s or so, it seems like the vast majority of these migraine treatments with the exception of bleeding consisted of recipes that you could make at home. with ingredients that you could find relatively easily. And that's evidenced by the fact that migraine treatments found their way into many home remedy books during the 1500s and 1600s, also showing once again how common migraines were.

In one, there was even a diagnostic tool where you were supposed to be able to, like, I didn't quite understand it, but it was like how much I think of your hand or your thumb you can fit into your mouth. What? During a migraine, because if you can't fit however many knuckles in, then you had a migraine. Because you couldn't like open your mouth? Couldn't open your mouth, yeah. Interesting.

Yeah. The author of migraine history pointed out another interesting aspect of migraine treatments from the medieval and beyond times, which is that while the diversity of treatments, both in terms of methods and ingredients for migraine, seems completely netherly, never-ending, they all share one feature. There are no magical or religious elements in them. Migraines had a physical basis and were treated as such. That's fascinating. Yes, it is because it didn't stay that way. Yeah, I can imagine because I feel like migraine has so much similarity to things that we've covered in the past that absolutely did not have

the consideration of a real physical basis. Uh-huh. It's so amazing to me, given the stigma and the shame and the bias surrounding migraines today, even though we know that there is physical basis for them, how much disregard, how much dismissal there is, when for the vast majority of its history from ancient times through the early to mid-1700s or so, the prevailing medical beliefs around migraines didn't. change all that much. It had a physical basis. It came down to humors. Wow. Yeah. But like we've seen with many other diseases, especially chronic diseases that we've covered on the podcast like asthma and

epilepsy come to mind, once medicine became more centralized and commercialized as people moved into cities in the late 1700s and into the 1800s, perceptions of migraine began to be. to shift. It started with patent medicines, taking the home out of home remedy, and making concoctions available for people to purchase and doctors to patent and prescribe. Then, as hospitals were increasingly built and high population densities in cities meant that doctors could see really orders of magnitude more patients in a year than in past times, they started to observe more about migraines, how frequently they occur, how long they last, what age they usually first happen, the range of symptoms. And armed with these new observations, they began to draw conclusions about

who was getting migraines and why. Were migraines just a cost of social progress, intemperance, sedentary lifestyles, lack of restraint, urban living, all of these things, the negative, the negative side of social progress were thought to contribute to the rise of quote unquote nervous conditions, something that we've absolutely talked about on the podcast in terms of at least gout and asthma. Essentially, the view was that as society grew more corrupted, so did our bodies. Was it a wandering uterus? Perhaps, probably. Was it being too creative? Could be. What? Yeah. Not getting a break from the kids or being afraid to delegate household chores. Oh, God.

Sure, I know, right? I boil. I know. Yep. The perception of migraine, at least among the people writing about them, male physicians, of course, shifted from a legitimate medical condition with a real physiological basis, even if it was thought to be a humoral imbalance, to first a social. and then later on a personal failing.

And part of this was ironically because physicians were paying more attention to this condition and taking note of other symptoms like GI upset or dizziness as pain as the primary feature took a backseat. The delegitimization of migraines in the late 1700s and throughout much of the 1800s shifted who was responsible for managing

this condition. It was no longer the doctor that had to figure out the correct course of treatment. It was now on the person themselves. If only they didn't overeat, if only they ate at more normal times, if only they didn't drink as much, didn't lays around as much, didn't work so hard, exercised more, exercised less, studied more, studied less, slept more, were less ambitious, were less sensitive, less feminine, stronger, than maybe, just maybe, they wouldn't bring this on themselves. Okay. I know.

I know. I'm not surprised by it, but it's still upsetting to her. It's very upsetting. I know. What had once been a humoral imbalance was now a nervous disease. And I'm not talking about like a neurological disease that we think of today. I'm talking about the 19th century idea of a nervous disease, of which there were many different types, and nerves could be affected by any number of things,

according to these physicians, and these things, and thus the nerves themselves, were more under a person's control. But those things, what things affected nerves, of course, depended on the person. And with this increased attention on migraine, physicians began to split them up into different types, often gendered. For example, so-called anemic migraines affected, quote, mothers in the lower classes of life, end quote, whose bodies were, quote, hourly drained by lactation, end quote. But don't worry, if you were a woman in a higher class, you could still get migraine, just called neurologic headache, which were, quote,

undoubtedly hysterical, end quote, in origin. Ay, aye, aye, aye. But also, it was just the domestic life in general that gave women so many migraines. Quote, the anxious forecasting and much serving, which slowly undermined the nervous energies of many wives and mothers. End quote. Those wives and mothers. Working class men got migraine. after being exhausted from quote-unquote excessive hours of labor,

or working in the, quote, unwholesome and ill-ventilated workshops and dwellings of our crowded towns, end quote. But for men of a somewhat higher social grade, it was generally using your brain too much, like reading too much, writing too much, working in legal chambers or the counting house, too much competition, the excitement of the university, and professional life, the anxiety that came from too much ambition, and so on. It could be literally anything. But it's always the person's fault. And the remedies for all these different types of migraine were fairly straightforward, a break from the stressors, which could include maybe a more nutritious diet, not working or studying as much, or for an overworked mother, a forced absence for the home. Yeah, that happened. Okay. And they're just like, you're afraid to delegate. There's tons of people that can help out with your kids. Like, just leave them. And whether or not any of these things

were practical, like let's say that you are working, you know, in one of these factories, it's not like you could just be like, oh yeah, let me just take some days off work. No problem. I'll take a vacation to the countryside where the fresh air, the fresh sea air will do me good. It's not like they were able to use this for like unionizing efforts and actually getting better working conditions. Absolutely not. Yeah. Yeah.

But that didn't, these like practical things didn't matter to the physician prescribing them, right? And the physician's prescriptions, by the way, were not limited to changes in lifestyle. The rise of hospitals and other medical institutions like Asylums provided ample opportunities for physicians to test out experimental treatments, just the latest and greatest, including opium, potassium bromide, arsenic, quinine, and cannabis, which was actually a favorite among many doctors and patients. But nothing reliably worked, as I'm sure you could guess. and contributing to this lack of meaningful progress in migraine research, at least in terms of treatment through the late 19th and into the 20th century, was the lack of certainty in diagnosis. As a quote-unquote invisible illness, people with migraine could appear healthy, even in the midst of a horrific attack, which made it easier for physicians to dismiss their pain or not take it

Seriously. Some physicians saying that, oh, someone who is in that much pain can't be relied upon to recount their experiences accurately. Okay. Not sick enough to be considered chronically ill, but not well often enough to be healthy. Something like that. It was this like middle ground. Pain as a subjective experience couldn't be trusted by these physicians as the sole diagnostic. criterion for migraine. And so they turned to aura. Visual disturbances had long been associated with migraine, but hadn't really been studied in a systematic way until the mid to late 1800s, when two scholarly men, British mathematician, astronomer, and chemist Sir John Herschel, and physician Hubert Erie presented their experiences of quote-unquote ocular spectra at a couple of

scientific meetings. They describe disruptions in visions that could be induced by the shining of a strong light and a, quote, singular shadowy appearance, end quote, that sat at the corner of vision and then came into full view with kaleidoscopic, colorful geometric patterns. Airy also shared a drawing of his visual disturbance, which he called hemopsy. And his drawing, which was jagged, swirling lines on a black background became one of the most famous and recognizable illustrations of migraine aura, which had become front and center in migraine diagnosis and research, as debates continued about whether the condition had a vascular or neurological basis, and effective treatments were, of course, still nowhere to be found.

And that's how things remained for the first decades of the 20th century. The pain from migraines took a backseat to oral. which had become romanticized, especially with people claiming all sorts of historical and religious figures must have had aura and migraine because their religious visions or drawings resembled aura. Hildegarde of Bingen, if that's how you say it, hopefully. A saint who lived in Germany in the 12th century was foremost among these and has been called the patron saint of migraines.

And really her retrospective diagnosis kicked. off a whole bunch more, including Moses, Ezekiel, Daniel, St. John the Divine, Charles Darwin, Pablo Picasso, Redyard Kipling, Virginia Woolf, etc. And I don't know the details of what went into each of these retrospective diagnoses, like, what symptoms did they use? I think for Picasso, they just looked at his drawings and they were like, yeah, sure. Like, did he ever write about pain? Anyway. And of course it is possible that several or even all of these people had migraines. Migrants are incredibly prevalent after all. But the problem with these retrospective diagnoses was how they were used by some people to push this message, which was that A, visual aura was

the defining feature of migraines, and that B, people who had the most extreme. visual disturbances with migraine were the quote clever intellectual people endowed with the creative type of mind end quote yeah and it furthered this idea of there being a quote unquote migraine personality which had evolved from the gender and class stereotypes of the late 19th century prepare yourself oh dear according to the american physician walter alvarez from the mid-20th century or so. The typical migraine patient was female, quote, tense, perfectionist, hypersensitive, easily fatigued, and often depressed or disconnected, end quote. They also had bad periods and quote unquote defective and poorly functioning pelvic organs. What? But don't worry.

She was also, quote, decidedly feminine and sexually attractive. End quote. Ew. Ew. Uh-uh. But with a masculine vibe that, quote, causes her to act independently and to think dispassionately, much as does an able businessman. I cannot. I know.

I know. I hate it so much. Oh, my God. Mm-hmm. Mm-hmm. Alvarez went so far as to claim that he could spot. a migraine patient without even talking to them. I don't like this guy.

And he wasn't alone in his ideas. There's many people you can dislike. In the 1948 book, Headache and Other Head Pain, author neurologist Harold Wolfe wrote that his migraine patients had as children been, quote, delicate, shy, withdrawn, and obedient to their parents, end quote, but also stubborn. And as adults, they were, quote, unusually ambitious and preoccupied with achievement and success, end quote. Unusually ambitious.

They had a hard time delegating. They were impatient and resentful, cold and aloof. Women brought on migraines by not adapting well to situations like going on vacation, just like relax. You can't relax on vacation? You're going to get a migraine. you're going to give yourself a migraine. I want to highlight that you said a book from 1948. Uh-huh.

That was not long ago. No. Yeah. Okay. Another physician from around this time wrote that people with migraines had, quote, a personality that seeks and creates stress and a physiology that handles it poorly. End quote. So, yeah.

It's really interesting because there's evidence now that some of the things that people have historically or even maybe personally identified as like potential triggers or things like quote unquote stress, etc. May actually be part of the prodromal phase of a migraine itself. So like, so it's really even more frustrating to hear like these, oh, you're causing yourself stress. like it could genuinely be that people's brains are increasing certain stress responses or something in a way that's entirely outside of your control. And then a migraine follows. Like it's just, yeah. As though like all of these things are under someone's control anyway.

Right. Like be less stressed. Try not to worry so much. Just like don't worry. That advice has helped no one ever. No. And so when you're met with this kind of dismissal and blame from someone who is supposed to be giving you health care, whom you are paying for health care, whom you look to as an expert, how are you going to feel comfortable asking for help? It's so frustrating because like I said, for the vast majority of human written history, migraines were handled as a, real medical problems with a physical basis, only to have that undermined by physicians who were probably projecting their own insecurities over not being able to effectively treat

migraines or define them. And I have no doubt that contributing to this was the gender distribution in migraines, with women much more likely to experience them. This dismissive attitude towards migraines, the idea of a migraine personality or a taking center stage as a symptom, we're still feeling all of the effects from this today. And there's a book that I didn't get a chance to read for this episode, but I really want to read called Not Tonight, Migraine and the Politics of Gender and Health by Joanna Kempner, that goes into this in much more depth, and I'll link to it on our website. But this downplaying of migraines as just really bad headaches and sort of the casting off of pain, like dismissing pain as the feature for most migraines, has contributed to the gap in

research funds for migraine treatments and the lack of general awareness around the cause and especially the impact of migraines. They can be debilitating. incapacitating, excruciating. Even with stress control, whatever that means, even with sufficient sleep, even with taking a break from the kids, even with medication, even with doing whatever else a doctor tells you not to do so that you don't bring this on yourself, you can't, I'm just so frustrated and I can't help but feel that doctors in the late 19th century in early 20th century, they took one look at migraine and thought, I don't know what this is. I can't treat this. Therefore, it must not be real. Or at the very least, it must not be as bad as they say. Or it's probably

a personal failing on their part because I'm a trained medical professional and I can't admit that I don't know something or can't treat something. Let me read you one final quote from a physician, and then I'll get us off this rage train, maybe. In 1902, J. M. Aiken wrote in JAMA, that, quote, of all the common and much-dreaded nervous diseases we recognize, none are less perfectly understood than migraine, nor is there any other nervous disorder which is so, disastrous to the physician's ability for treatment. It is easy to say what migraine is not, but difficult to define what it is, end quote. I mean, even just the framing of that as like, this is hard for doctors. Oh, yeah. And I didn't even get into like some of the gendered

advertisements from the mid-20th century for migraine treatment where it's like geared towards doctors that are like, it's not just a problem for your female migraine patient. It's also a problem for you, kind of implying like she's complaining to you and she keeps seeking help. So prescribe her this. Wow. Uh-huh. Uh-huh. Oh, wow. It's good stuff. Yeah. In the second half of the 20th century, we did make substantial progress in understanding what migraine was, especially with the introduction of the international classification of headache disorders in 1988, we made progress in what caused it with the neurological framework, sort of overtaking the

vascular one and then kind of being integrated with this new neurovascular framework. And we also made progress, a lot of progress, in how to treat it. First with the introduction of ergotamine and then like migraltarism. tablets, which was a combination of ergotamine, caffeine, and cyclone introduced in the 1950s. And then also another treatment that you mentioned, which was introduced in the 1980s, was the triptans, with the first one being sumatriptan. And so we've come a long way in our understanding and prevention slash management of migraine, but we clearly have so far to go still, not just in treatments and making those treatments accessible

for everyone who needs them, but also in reducing stigma, shame, and blame surrounding migraines, like believing people. What a concept. Why is it so hard? Why is pain the most dismissed thing? I feel like we talked about this in our endometriosis episode. a lot as well. Yeah. Yeah. Also a hugely gendered aspect there. Exactly.

Because you can't see pain. Like when we talk about being able to measure something, right? Right. But we also can't see aura. Yeah, that's true. Or like nausea, but. But you can see vomiting. You can see vomiting.

Yeah. Yeah. I think that I see. spent so much time sort of in the earlier history of migraines because I really did want to get across the point that we used to be better at this. I mean, yes, it was the humoral theory of disease, but it was like, oh, here's this real thing. Here are some real treatments for it. Yeah. Oh, but maybe it's not real. Maybe it's all in your head. And it's just, it's, so many diseases are like this that we've covered on the podcast. You know, we've talked about asthma, we've talked about

lupus, we've talked about epilepsy, we've talked about, of course, endometriosis that have undergone this shift that I think coincides with when medical knowledge was increasing overall, but not necessarily shedding any light on those conditions. And so rather than saying, maybe it's something that we don't know about yet, it had to be put in this box of maybe it's in your head. I'm sure that we'll look back on this period. of time with similar diseases that right now are classified as psychosomatic or whatever it is. You know, like, anyway, I'm at the very end of this. I've gone on this rant and now I should just stop myself and turn it over to you, Aaron.

Oh, but I love it, Aaron. I mean, I hate it. Yeah. Oh, yes. So where do we go from here? Oh, okay, okay. Let's take a break, take a breath. and we'll find out.

Migraine is estimated to affect one billion people worldwide. Depending on the paper that you read and what data you use, meaning if you consider definite and probable migraines based on those ICD criteria, that's between 15% of the global population, or as high as 35% of the general population having migraines each year. 35%, Erin, if you include probable migraine. And that's every year. That's not lifetime.

So this is, yeah, annual prevalence. It's not incidents. We don't have great data on incidents. But that's annual prevalence. Now, across all age groups, prevalence of migraine is significantly higher, usually two to three times higher depending on age, and people who are assigned female at birth compared to people assigned male. And prevalence tends to peak usually in the 30s, but really age 25 to 40. So this is young people being very significantly affected. Among people with active migraine, the median monthly attack frequency, so how many episodes of migraine per month is 1.5.

But a quarter of people have weekly attacks. And remember that the total duration of a migraine attack can last up to a week. Oh my gosh. Right? And up to 5% have chronic migraine, which again means 15 headache days a month, eight of which meet criteria for migraine. So with all of that being said, it should come as no surprise, though this was shocking to me, the World Health Organization ranks migraine as the most prevalent disabling long-term neurologic condition, period. And it's not necessarily because it's the most common. Even in terms of headaches, tension-type headaches are far more common than migraine. But migraine is so disabling that, as an example, while tension-type headache affects almost a billion more people worldwide, like 800 million more people than migraine, Migraine causes six times as many estimated disability-adjusted life years or years lived with disability.

Whoa. Migraine in 2018 caused an estimated 45 million years lost to disability compared to 7.2 million for tension type headache. Oh my gosh. And the data hasn't changed much over the years. That estimate was from a 2018 paper based on 2016. data. Based on 2019 data, it's an estimated 42.1 million years lost to disability. That's, it's obscene. Yeah. Especially because we have treatments. Migraine is the leading cause of disability worldwide for people younger than 50 years,

especially for women. And I don't want to just go based on disability, a adjusted life years or years lost to disability because we know that that's an imperfect metric. But I also have read that in studies that have looked, based on survey data from the U.S. at least, on people's reported effect on their lives, that up to 30% of people who live with migraines say that it affects their careers in some way, 30% say that it affects their parenting in some way, and nearly 50% feel that it affects their relationships. Yeah. That's huge.

And caveat that those numbers are based on U.S. data, so we don't know the, like, universality of that. But it's, I mean, this is not a minor disorder to live with. Right. And like, just living with that uncertainty and that unpredictability and planning. How can you plan around a migraine when you don't know if you're going to have one? Yep, exactly. Oh, my gosh. If you're more interested in money and cost, in Europe, financial costs that are attributed to migraine are estimated at between $50 and $111 billion.

And that was like 15 years ago. And what's interesting is that in Europe, the vast majority of that cost is estimated to be indirect cost, meaning not health care dollars, but dollars lost in other ways because of lost productivity at work, etc. Whereas in the U.S., direct costs are estimated at $11 billion annually and indirect cost $12 billion annually. Wow. So there's a lot of discrepancy there. I'm sure there's a whole podcast about that. So migraine is a massive issue. And most of the data that we have on migraine come from Europe and the U.S. and high-income countries. But migraine is a global phenomenon that affects people across the entire world. And in low and middle-income countries, not only do people tend to lack access to a lot of treatment or even diagnosis options.

people are far less likely to be diagnosed accurately with migraine in low and middle income countries. We also have much less data to guide policy and to guide programs. And part of this is because the focus tends to be in low and middle income countries on other additionally pressing health issues, think things like TB and HIV, which are more common in low and middle income countries. But that's despite the fact that migraine is also causing mass. amounts of disability in these countries as well.

Right. And there's estimates from a whole bunch of different countries that indirect costs alone can be as much as 2% of gross domestic product annually. Whoa. Because of migraine. Yeah. So when it comes to current research, it's a little hard for me to even know where to begin. Is that a good thing?

I don't know. Okay. Sometimes in this section, I'm able to say, like, here's this one new great thing that just happened or is on the horizon. It's about to happen. I don't have that one great thing for migraine. Okay. But that's not because there haven't been great strides made in migraine research. There have been a number of really new drugs in the last year.

really this year in 2023 and in the last couple of years that have come down the pipeline. There have been new monoclonal antibodies that specifically target this CGRP pathway, and many of which are intended to be used as preventative treatment. So especially for people who have chronic migraine or just a high burden of migraine, you know, each week or each month, even if they don't meet criteria for chronic migraine. Preventative rather than just what are called abortive treatments or treatments made to be used when a migraine happens, right? And there have also been other oral medications that includes that whole class called the Jephtents, which are the ones that have commercials right now, like Ubrilvy and Nurtek.

I probably shouldn't use brand names, but whatever. These are things that also target that CGRP peptide. There's also a brand new nasal spray that targets the same peptide. Oh, fascinating. I know. And there's a relatively new, I think in 2019 was when it was approved by the FDA, was a medicine in a class called a dytan, which are very similar to tryptans, but they have less vasoconstrictive effects, which means less cardiac risk, and therefore

more people can probably use it. Cool. And then there are really creative things. like Botox injections, trigger point injections, neuromodulatory mechanisms, and probably a bunch more drugs coming down the pipeline as well. But there isn't like a silver bullet. And a lot of that is because there's still just so much that we don't know when it comes to migraine. Yeah.

So some of the other big areas of research besides just therapeutics are things like identifying biomarkers. either blood biomarkers or imaging biomarkers, things that we can identify on an MRI that can either predict the risk of migraine or predict treatment targets so that we can develop even other types of therapeutics. But in general, there's a lot of mixed results when it comes to a lot of things with migraine research, but especially with this attempt at identifying various biomarkers. I think the thing that gives me hope is I will say that when I was researching for this episode, I found more very recent papers in like well-regarded journals about migraine research than I have found for any of our recent episodes. Oh, wow.

Okay. Like a lot. There's a whole series that came out in the Lancet, three paper series that came out in 2021. there's nature papers and New England journal papers, like a lot of kind of high profile research that's really, really recent when it comes to migraine. So that gives me hope that it's getting a lot more attention because we're recognizing what a massive issue it really is. That's migraine.

Gosh, I hope we did it justice. Yeah, is that enough? I don't know. I don't think so. Tell us. Could it ever be enough? No. Luckily, there's more reading.

There's so much more. Let us tell you about it. I'm going to shout out again, Migraine A History by Catherine Foxhall, and I'll link to it on the website. I have a lot of sources for this episode. A few that I loved were migraine a primer from Nature reviews disease primers in 2022. There was also a paper titled Migraine and the Trigeminovascular system, 40 years in counting, from the Lancet Neurology in 2019. Also, I mentioned already, but there's a great series. It's three different papers about different aspects of migraine from the epidemiology to disease characterization like biomarker research and approaches to management and emerging treatments that all came out in the Lancet 2021.

We'll have a list of this and all of our sources from this episode and all of our episodes on our website. This podcast will kill you.com under the episodes tab. We certainly will. A big, huge, tremendous, incredible thank you to everyone who shared their experience, their story with migraine. We really can't thank you enough. Yeah, thank you. Thank you also to Bloodmobile for providing the music for this episode and every one of our episodes. And thank you to Leanna Skolachi for the amazing audio mixing. Thank you to the Exactly Right Network. And thank you to you, listeners. We hope that you, I don't know, got something out of this episode, learned something? I hope so.

I don't know. We appreciate you. And a special shout-out, as always, to our patrons. Thank you so much for your continued support. We really appreciate it. Yeah, thank you. Well, until next time. wash your hands.

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