Understanding Migraine Syndrome And Its Impact on Women: Dr. Regina Krel, Director of Headache Medicine at Hackensack University Medical Center

Michael Carrese

Hi, I'm Michael Carrese, welcoming you to Raise the Line from Elsevier, an ongoing exploration about how to improve health and healthcare.

Migraine is far more than a bad headache. In fact, it's now recognized as one of the leading causes of disability worldwide, affecting more than one billion people and disproportionately impacting women in the prime of their working and caregiving years.

To learn more about this important area of medicine, we're joined by Dr. Regina Krel, a board-certified neurologist and headache specialist, a Fellow of the American Headache Society, and Director of Headache Medicine at Hackensack University Medical Center. Dr. Krel, who is also a Harvard-trained fellow in headache medicine, has authored multiple publications on migraine, including research on its management in women, and she has also advocated for patients nationally through her participation in Headache on the Hill in Washington, D.C.

I'm looking forward to exploring why migraine remains widely misunderstood, how stigma and underdiagnosis affect care, the disability it causes, and the importance of getting proper treatment.

Thanks for joining us today, Dr. Krel.

Dr. Regina Krel

Thank you for having me.

Michael Carrese

So I'd like to start with learning more about you and your background and what first got you interested in medicine and particularly neurology.

Dr. Regina Krel

As far as medicine, I feel like that has been an interest of mine as far back as I could remember. I really never saw myself doing anything else other than medicine. As far as neurology, I think my interest there started during my neuroscience course in my first two years of medical school. I think the neuropathways and the lesion localization made sense to me. So I was very much fascinated by it. And then when I did my neurology clerkship, being able to apply those skills really kind of immersed me and I ran with it from there.

Michael Carrese
Right, right. Go with your interest, right? And what about migraine? Was that something that intrigued you from the beginning or did that come later

Dr. Regina Krel

That came later. In fact, headache and migraine, while I obviously knew existed, I did not know it existed as a separate field. And that interest actually became more in residency. So when I was a neurology resident, we had to choose mentors. Mine happened to be a headache specialist and a lot of our meetings happened during his clinic hours. And so I spent a lot of time hearing patient after patient sharing their journey and their story from getting diagnosed and getting dismissed and then finally what they would explain to me is getting their life back. And I think from that point on, I wanted to be part of the story. I also genuinely do enjoy doing procedures, and I felt that headache medicine allowed me to do the clinical part of it and the procedural part of it and help people in real time.

Michael Carrese

So we should get everybody on the same page here and make sure we understand what you're talking about. When we say migraine, it's really a syndrome. It's not a headache as everyone seems to think. Help us understand what distinguishes it from other types of headaches that people might commonly experience themselves.

Dr. Regina Krel

So migraine, it's a neurological disease and contrary to what many people think, it actually encompasses the whole entire body. So I always say headache is just one piece of the puzzle. Some patients can actually have a migraine attack and really not feel the head pain. It comes on with sensitivity to light, sensitivity to sound. You have brain fog. You can't process as well. Some patients have aura, which are focal neurological symptoms that come along with their migraine. Headache is just a teeny, teeny piece of the puzzle. It might be the one that we hear the most about. It obviously causes the pain, but it's just so much more than that.

Michael Carrese

And to what extent is the headache not the predominant symptom? Is there a way to generalize that? Most people won't have the headache or most people do have the headache?

Dr. Regina Krel

Most people do have the headache, and patients who have migraine can have symptoms in between the headache. So the headache might go away and they'll have what we consider or call the migraine hangover. They'll feel very drained. They still can't function to the tippy top of their ability. They will sometimes experience the sensitivity to light even when they don't have the pain. So yes, headache is there very often. It is very debilitating, but the other symptoms really kind of take over your whole body that make patients dysfunctional.

Michael Carrese

So what are some of the symptoms and neurological processes involved here that people might not understand are connected?

Dr. Regina Krel

Fatigue. So even before a migraine attack may come on, patients may have this experience of not just being tired. A lot of patients will tell me they have excessive yawning. You might not even realize it, but you got a good night's sleep, you feel like things are good, you had your cup of coffee, you go to work and you're yawning incessantly and you don't understand why. Food cravings, mood changes. Some patients will start getting very irritable and you're like, I don't know, the day's okay, it's not that bad. GI symptoms, diarrhea, constipation, balance issues — the patients will tell you sometimes they feel dizzy or everything is moving and they haven't been on a carousel or a merry-go-round. So it's everything. It's your whole body that's involved.

Michael Carrese

And why is that? What's happening in the brain that's causing such widespread symptomology?

Dr. Regina Krel

I like to describe it as a storm. You might get a little storm, a little raindrop that kind of starts and unless you're able to quiet it down, the whole brain becomes involved. It becomes sensitized. So you get this whole storm that's affected and that's why your speech might be affected. That's why all of a sudden you and I are having a conversation, you're physically present, you're looking at me, but you may not be actually processing anything that I'm telling you in the moment because of the fact that the whole brain gets involved.

Michael Carrese

And what's the origin of the storm? Do we know?

Dr. Regina Krel

So there's a lot of theories, and over the years we've kind of moved away from a simplistic, what we call vascular theory of migraine. The old theory was, "Hey, your blood vessels kind of get bigger, you get pain, you take a medication that makes your blood vessels get smaller, pain goes away, we check the box and it's good." But obviously that does not explain all of the other symptoms. So the more recent theory was this neurovascular theory about cortical spreading depression. Something sets off this excitability in the brain. And then you get this massive release of various types of neurotransmitters and peptides, calcitonin gene-related peptide being one of them. It's one of the main players that we get to hear about, especially now and that ends up sensitizing this trigeminal vascular pathway and that is what really is involved in the pounding sensation because we do get blood vessels that dilate on the covering of the brain, on the meninges.

If the blood vessels dilate, you get this pounding sensation, which is what we refer to as peripheral sensitization. And then if the pain goes away because you treated it appropriately in the moment, great. If not, it continues to progress to second and third order neurons, and then you get central sensitization. And that's when you talk to patients and they're like, "I can't touch my head. My hair hurts. I can't lay my head on a pillow. If I touch my body, everything feels achy." That's because that is where the storm really took over the whole entire brain and those are the patients that end up being a lot harder to treat. The more attacks we have per week, per month, the more our brain likes to be in this storm and that's why sometimes it's so hard to bring our chronic migraine patients out of it.

Michael Carrese

What are the treatment options? You mentioned the ones that attack the vascular issue, but what else is in your toolbox?

Dr. Regina Krel

So I think we are in a wonderful place in the migraine landscape today compared to where we were maybe twenty years ago. We do have the old medications where for prevention, some of the antidepressants, anti-seizure meds, they're all older, but they still work. They still have a place. We have triptans, which have been the gold standard for migraine rescue since, I think, the early '90s. 

But more recently, we have the CGRP blocking agents, and these are the calcitonin gene-related peptide medications. So the monoclonal antibodies — there are four of them on the market. Those are used for migraine prevention, and we can use them for both chronic and episodic. And then we have the gepants. The gepants are also CGRP blocking agents, but these are oral medications or intranasal, and they are available for both rescue and prevention as well. 

What's different about these compared to some of the old school ones, except triptans, is that these are actually targeting CGRP, which is what we believe is one of the main drivers of migraine. So these are migraine specific. It's not telling a patient, take a blood pressure medication that has evidence to help with migraine. This is targeting the pathology of migraine. We also have Botox, which is approved only for chronic migraine, which is when patients have fifteen or more headache days per month for three consecutive months and that has been a game changer for us. Sometimes it's independent individual therapy, and sometimes we layer treatments. It's not a one size fits all anymore.

Michael Carrese

So in terms of your own patient base, what's the percentage of patients that you can provide relief for?

Dr. Regina Krel

I'd like to think all of them to some degree.

Michael Carrese

But I guess are there some where it’s just sort of persistent?

Dr. Regina Krel

We do. We do. I always say that my clinic patient population is somewhat biased because being a headache specialist, I do see the ones that have already seen multiple neurologists, multiple primary care physicians, have been even to multiple headache specialists and pain management doctors. So yes, my patient population is skewed, but you know what? I think a lot of migraine management and migraine treatment is really focused on real life education for both the patient and the universe, if you will. It's about understanding the complexity. 

There is no cure for migraine. The majority of patients with migraine, it's due to some sort of genetic cause. There's more than 200 genes that are implicated in migraine, so we can't really pinpoint exactly which one. And because of that, there's this misconception that prevention equals cure. So we always tell patients, "Hey, when we're putting you on a preventative medication, the goal is to reduce attack severity, attack frequency, attack duration. The goal is to improve functionality, get you back to school, work, play, family, life, whatever it is you want to do." And then when an attack does come on, we want to give you a toolbox of saying, "This is what you do when you do get an attack." 

It's not to give false hope of, you will never get one again. And once that mindset changes, even patients see their treatment plan as different because all too often I have patients that came to me and said, "I was given this medication. I took it for a few months. I tolerated it well, but I still got headaches." And I'm like, "But did they get better?" "I don't know, I still got them." And that's when you have to rewire the way the thinking process is going.

Michael Carrese

Yeah, it's sort of a perspective shift that can be helpful. At the beginning, you said that part of what made you interested in this was the opportunity to do procedures. So what are you talking about there?

Dr. Regina Krel

So Botox injections are recommended for chronic migraine and there are injections that are done once every twelve weeks. Patients come into the office. The procedure takes about ten minutes of your time. It's nice because it's obviously not taking a pill every single day. It's very well tolerated. I personally like it as a good layering treatment. So sometimes my chronic migraine patients will start them on Botox. And if we get improvement, but we think we could do better, we'll layer with some of the other medications like the CGRP drugs.

We also do nerve block injections. So occipital nerve blocks, trigeminal nerve blocks are injections that we use with anesthetic. There's no uniformity amongst physicians. So everybody kind of goes based on what they think is effective. We can use bupivacaine, lidocaine, ropivacaine. We sometimes add a steroid, don't add a steroid, but those are good adjuncts for sometimes patients who, let's say, have a lot of medications where we're worried about drug-drug interactions. Sometimes if the patient is in a bad cycle and we really can't figure out how to break them out of that rut, we'll bring them in for nerve blocks. For pregnant patients, sometimes nerve blocks become an excellent treatment plan because they're not really going systemic like some of our meds. 

So those are some of the procedures that we do in the clinic and they work very well and patients are very happy with them when added as part of their treatment plan.

Michael Carrese

Well, it sounds like at least you have options for these folks, which is encouraging. So speaking from a broader lens on this, it is described as an invisible illness and there is stigma associated with it. So talk to us about that for a bit, particularly from your perspective as a clinician. How does that invisibility contribute to the stigma around this condition?

Dr. Regina Krel

So patients who have migraine don't appear sick in the traditional sense of the word, unless maybe you're getting them in the midst of a migraine attack. There's also no way to measure migraine. So it's not like, oh, you have high blood pressure because I took a blood pressure reading and it was elevated, or you have low vitamin D because I did a blood test and that showed it. There is no blood test, there is no blood pressure reading. A lot of the times, even when patients get neuroimaging such as an MRI, it's usually normal or inconclusive. So you can't really see migraine. 

And as we talked about how disabling it is because it can last days to even weeks of just having symptoms, patients feel the need to really push through. A lot of that is really stemming from the fact that if I'm telling you that I have a migraine attack and you can't tell, in your mind it's like, okay, it's a headache, just take an Advil and move on from this situation. But there's so much more going on.

And that leads to, number one, patients really don't talk to their providers about it because they feel like if everyone else is telling me that it's just a headache, then it must just be a headache and I should power through it and move on. There are so many — and I put this in quotes, if you will — more important diseases to focus on. So even though migraine is one of the most disabling, patients worry about, well, hey, the blood pressure being elevated or poorly controlled will kill me. The diabetes will be poorly controlled, it will kill me. Migraine won't kill me, so I won't bother telling my doctor. 

There's a stigma even on the physician side where sometimes you talk to patients and they're like, "Oh, well, my doctor just said it's a migraine. I should have some rest, go to sleep, take some Tylenol." My favorite is drink a Coke and move on. And the patient feels like, okay, maybe it's not real and then they don't get the diagnosis for many years and then they don't get the treatment for many years and the cycle kind of repeats itself year after year. 

Unfortunately there's a stigma even at work for patients who ask for accommodations -- I want the bright lights removed or can I have ten minutes or fifteen minutes to rest after I take my medication to let it kick in -- and there's a lack of understanding there.

Michael Carrese

Well, and it does seem in my mind to be overlapping with what we hear so consistently, which is women are ignored by clinicians.

Dr. Regina Krel

Yes.

Michael Carrese

Even if they do start trying to talk about it, it's sort of dismissed and not heard.

Dr. Regina Krel

Correct.

Michael Carrese

Yeah. Which leads us to the sort of special focus that you have on treating women. As I mentioned, it disproportionately affects women. So what do we know about the reasons behind that?

Dr. Regina Krel

Hormones is kind of the easy answer. In fact, prior to puberty, boys will actually suffer from migraines at a slightly higher rate compared to girls, and that all changes around the time of the onset of menses. Many women will have their first migraine, or their first big migraine that they will recognize as somewhat different than a "regular headache", during their first menstrual attack. And then as their cycles continue, they may have what we call menstrual migraine or menstrually-associated migraine. 

The reason why that happens is right before you get your period, your estrogen level drops and it drops pretty abruptly. That drop in estrogen level is actually thought to raise levels of calcitonin gene-related peptide, which then turns on the storm in the brain and then the migraine attack comes on. And so a lot of this is all centered around the estrogen fluctuations, and so post-puberty, women suffer three times more than men.

Michael Carrese

So how does that feed into the question about management of migraine in women? And what are some things that listeners should understand about that?

Dr. Regina Krel

It's important to listen. Women often don't talk about headache or migraine during their menses because they end up accepting it as par for the course. So they might suffer from these headaches, they might have all of these nausea symptoms, all of these sensitivity to light symptoms, but they kind of accept it as, okay, I'm on my period and so let's move on. 

But it's important to understand that menstrual migraine specifically tends to be more severe and more disabling than migraine outside of the menstrual cycle. They're also usually harder to treat. These are the headache attacks that may not respond to that toolbox that you've already devised with the patient. And so sometimes we do something called spot migraine prophylaxis or spot menstrual prophylaxis, which is if the patient has regular cycles, you can say, "Hey, two to three days before you're about to get your cycle, we're going to put you on this medication." And it could be an NSAID such as naproxen, it could be a long-acting triptan such as frovatriptan, and the patient will continue it through their cycle for about the seven days that they're on it.

There are patients who can also discuss continuous combination birth control, so estrogen-based birth control, and say, "Hey, because your cycles are so regular in terms of triggering migraine attacks, let's put you on a combination pill and have you essentially level out that estrogen without having that drop." The caveat there is it's important to make sure that you have a discussion of whether or not the patient has migraine with aura and that's because patients who have migraine with aura are considered to have a higher stroke risk compared to those who have migraine without aura. And then you don't necessarily want to go the estrogen contraceptive route because estrogen in and of itself has been implicated as a stroke risk.

Michael Carrese

Oh, all right. And what are some other clinical considerations that docs should keep in mind when treating women?

Dr. Regina Krel

So migraines will fluctuate throughout their lifetime, and it's important to listen to them. So obviously for menstrual onset it’s important to probe women and saying, "Hey, are you having headaches during that time? Talk to me about those headaches." It's also important to think that during their lifespan, things are going to fluctuate. So for example, pregnancy tends to be a time of being protective against migraine. Many of our female patients when they get through pregnancy, especially after the first trimester, will have a smooth sailing pregnancy with minimal to no medication. In fact, many of my patients tell me that pregnancy was some of the best times of their life during the migraine. They may have other problems during pregnancy, but migraine-wise, they do very well.

Perimenopause, on the other hand, which can be up to ten years before full-blown menopause, is usually a time of reckoning. And that's because their hormones are all over the place all the time. Things are very unpredictable. Many patients will not even recognize the fact that they have migraine until their forties. When they come to my clinic, they'll tell me, "I used to get regular headaches. They never bothered me, but oh my gosh, now I have to call out from work and now I'm vomiting and I'm wearing those sunglasses and I don't understand why." 

And then again, once they transition into menopause, many women will notice that they are doing better, and that's because the fluctuations of estrogen stop. So it's important to, at any stage in a woman's life, really go in and ask those questions and say, "How are you doing? What are those headaches like? When you treat them, what happens to them?" Because if someone says, "Hey, I had migraines in my teenage years, I took over-the-counter medications, they went away, but now it's not working," you really want to dive in deeper and explore.

Michael Carrese

And for women that are post-menopausal, does it resolve?

Dr. Regina Krel

So I never say there's a cure because we know that there isn't. There are many women that 

will tell you once they hit menopause, they go into remission, if you will. We used to think that that number was much higher. We used to say almost two-thirds of women will go into remission. I think that number is a little bit lower. Not every patient reads the textbook, but yes, many women will notice some improvement, especially those that throughout their life did have that hormonal component. So those women that did have menstrually related migraine, those women that did have improvement in pregnancy or worsening during perimenopause, those women typically will get better post-menopausally.

Michael Carrese

All right. This is fascinating. So we talked about some of the medications available for treatment, but I forgot to ask you about lifestyle factors and behavioral strategies. Fill us in on that.

Dr. Regina Krel

Yes. Migraine is very, very multifactorial. When I talk to patients, I tell them about this kind of migraine triangle of life, if you will. You have your preventative medication, which is what you're going to do on a regular basis to try to prevent migraine attacks from coming on; you have your rescue medication, which is what you do when a migraine attack does come on; and then you have all the lifestyle pieces that you're going to try to do to keep that threshold stable. 

That last category includes consistent sleep. So it's not just about the hours, it's about making sure you have a very good sleep hygiene routine, going to sleep at the same time, waking up at the same time, making sure that you're turning off the electronic devices — which I know no one really does anymore — right before bed to kind of wind down. 

It’s also making sure that you're remaining well hydrated, and not skipping meals. There's a lot of fad diets for migraine, a lot of elimination migraine diets. And while we know that certain foods can be a trigger, it's important to understand that triggers don't cause the migraine. Migraine triggers are things that can lower the threshold for a migraine to come on, and your susceptibility to that trigger will change day to day and hour to hour. And so I don't typically recommend elimination diets for patients. I usually tell them, don't skip meals, keep to a low-processed diet, healthy diets as we would want all the time. And yes, if you do know that there is a particular food or drink that will consistently put you into a migraine state, limit it to the best of your ability.

I think mental health is something that we don't talk about enough when it comes to migraine. Patients with migraine are at a higher risk for both anxiety and depression, and it's very much a bidirectional relationship. So if the mood is not well controlled, patients are more likely to have more migraine attacks. If the migraine is not well controlled, patients are more likely to go into a state of anxiety or depression, and that kind of makes sense. It's very important to make sure that both are addressed. 

It's not always with medication. It can be cognitive behavioral therapy, biofeedback, coping skills, relaxation training, but all of those factors are important and certainly exercise. Countless studies are being published about exercise, both reducing severity and frequency of migraine. So it's all a major piece of the puzzle. It's the triangle.

Michael Carrese

So as we're starting to wrap up here, I'm wondering what's coming down the pike that's encouraging in terms of new treatments and approaches.

Dr. Regina Krel

So we are, again, in a very exciting time for migraine. We are having new emerging treatments for different targets. So for example, a PACAP receptor is being targeted for migraine. So we're moving away from borrowing from other classes and really zoning in on medications that are going to be specific for migraine. 

And then something that I think is also very exciting is neuromodulation. So our whole universe is always focused on medications and pills or injections and our brain functions in two ways. It functions on a chemical level, but it also functions on an electrical level and neuromodulation devices are basically disrupting the electrical circuitry that happens in migraine. There are so many devices that we have available now and there are many more. Many patients have heard of a Cefaly, which kind of goes on your forehead. There's the Nerivio device, which does transcranial magnetic stimulation. 

So it's nice because now we can offer patients non-medication approaches, whether it's because that's what they prefer or because medications just are not appropriate for them, or certainly in pregnancy and adolescence. We have a whole patient population that we really have to be careful about.

Michael Carrese

And do you see them working with your patients?

Dr. Regina Krel

I do. I do. Sometimes I have patients that do them on their own without anything else. I also do love to use them as an adjunctive therapy. Most of these devices are approved for both prevention and for rescue, so you get a dual indication and patients can use them with their preventative, but also they can use it first line as their rescue. And if it takes care of their headache, then it's like, okay, well, now I don't have to use a pill and I don't have to take any meds. I can just use my device, so I think it's exciting.

Michael Carrese

Yeah, it sounds like it. So Osmosis is a teaching company. We really like to find knowledge gaps to fill. One of our favorite questions for guests is, give us some direction here. What video should we make or course should we build around a gap in knowledge or a myth or something that's of importance to you?

Dr. Regina Krel

I think one thing that's very important to me is how to approach a headache patient as a non-neurologist or a non-headache specialist. Oftentimes, obviously depending on where you live and insurance and just availability, neurologists and headache specialists are not going to be the first point of contact that a patient reaches. It might be their GYN, it might be primary care, it might even be pain management. 

So I think a video on how do we approach a patient who has headache as a chief complaint; how do we weed out red flags for potentially dangerous headaches; how do we look for migraine diagnoses. Because part of the gap in migraine is not getting the proper diagnosis. And then if you can't get the proper diagnosis, you're not starting the patient on treatment. So I think an approach to a headache patient from the beginning would be great.

Michael Carrese

We will bring that to the content team for sure. So as we wrap up here, another favorite question of ours, given the fact that we have a younger listening audience, is to get your go-to advice for people who are entering a career in medicine. It's always a complicated career. It seems to be getting more complicated all the time. So what's your advice to folks who are embarking on this?

Dr. Regina Krel

Always stay curious. That is what I tell all of my students and all of my residents. Always ask the “why” questions and keep learning because medicine always evolves. It's not static and it's important that we evolve and grow with it. Nothing will ever replace a very good history and physical exam. That's kind of what separates us from a computer. We are able to take a pertinent history. We are able to perform a thorough exam in order to confidently make a diagnosis and a treatment plan. I think in the age of technology, proper communication and compassion go a long way. 

And something that I think is important that we hear a lot about, and it's very real, is burnout is real. And so it's important to recognize it in yourself, in your colleagues, and it's important to address it in whatever way you see appropriate.

Michael Carrese

Excellent advice. This has been super informative and also encouraging, I think, just in terms of the options you now have that weren't there fifteen or twenty years ago, as you said, and what's coming down the line. So I really appreciate all the information and your time today, Dr. Krel.

Dr. Regina Krel

Thank you. Thank you for having me.

Michael Carrese

I'm Michael Carrese. Thanks for checking out today's show and remember to do your part to raise the line and strengthen the healthcare system. We're all in this together.