Exploring the Circadian Patterns of Cluster Headaches and Sleep Phenotype

The trigeminal autonomic cephalalgias are a group of headache disorders that appear similar to each other and other headache disorders but have important differences. Proper diagnosis is crucial for proper treatment.

 In this episode, Gordon Smith, MD, FAAN, speaks with Mark Burish, MD, PhD author of the article “Cluster Headache, SUNCT, and SUNA,” in the Continuum April 2024 Headache issue.

Dr. Smith is a Continuum Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Burish is an associate professor at UT Health Houston in Houston, Texas.

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Read the article: Cluster Headache, SUNCT, and SUNA

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Host: @gordonsmithMD

Full Transcript Available

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the Show Notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. AAN members: stay tuned after the episode to hear how you can get CME for listening.

Dr Smith: This is Dr Gordon Smith. Today, I'm interviewing Dr. Mark Burish on cluster headache, which is part of the April 2024 Continuum issue on headache. Dr Burish is an Associate Professor of Neurology at the University of Texas Health Science Center at Houston, which is located in Houston, Texas. Mark, thanks so much for joining me today on Continuum Audio. I was really excited to be asked to talk with you about this article. When I recertified from my boards the last time (and actually, it will be the last time I have to take the exam), I did the AAN course on all of neurology. And I'm a neuromuscular guy, right, and so I was actually kind of worried about the headache part because I thought, “How interesting could that be?” And I was blown away at how fascinating headache has become, and in particular, your topic (cluster, SUNCT, SUNA, the trigeminal autonomic cephalalgias) - such a great topic. But before we start talking about them, I'd love to just hear more about how you got interested in this area - both headache, this topic in particular. What's your story, Mark?

Dr Burish: Well, thank you very much for having me. I’m honored to be part of this. I got into headache probably the way many people do; is, in residency, you figure out what you like, and your residency clinic tends to start collecting patients that you like (not that you're trading them with other residents, but you see certain patients). And mine (by the end of residency) had a lot of headache and pain patients into it. Then, I was very fortunate and had the opportunity to do some research as part of my career. I'm an MD-PhD, and I spend about half my time now doing research on cluster headaches, so I'm very fascinated by these types of diseases.

Dr Smith: Can you tell us really briefly what you're working on in your research?

Dr Burish: Cluster headache is such a poorly researched area. There's not a lot of people in it, so we do a little bit of everything: we have a clinical trial going; we do some basic science on the circadian mechanisms (cluster gets this very weird timing to it, where the headaches happen same time every day); and we do a little bit of starting to wade into the genetics.

Dr Smith: Well, super exciting. I was actually blown away by the statistics on cluster (as common as multiple sclerosis), and the severity of pain I was amazed to learn is above that of childbirth (it was, like, between nine and ten out of ten, which is really crazy). And I'm worried that I missed these patients in my neuromuscular clinic. So, maybe we can begin by - just tell us what you think our listeners need to know. If they have to drop off right now, what message do they need to remember from our conversation?

Dr Burish: I think there's two things. First of all, the first-line treatments for these headaches have not changed recently. For cluster headache, you still treat it with oxygen, the triptans (the faster triptans; not the oral ones, but the injectables and nasals), and you prevent them with verapamil. For SUNCT and SUNA, you use lamotrigine. So, those have not changed over time. There are some new treatments, which we'll talk about later. Then the second point is, there are four different types of headaches in this family and they all look very, very similar (one-sided pain, autonomic features, ipsilateral lacrimation, rhinorrhea - that type of thing). They differ in the treatments and how long they last. If you get them wrong (if you misdiagnose them), you're probably not going to give them correct treatment. Indomethacin works very well for two of them (the ones with hemicrania in the name, so not the ones we're going to discuss today). And then SUNCT, SUNA, and cluster headache - indomethacin does not work very well. So, it's important to distinguish them and get them right.

Dr Smith: Maybe we can start there, Mark. I mean, I was kind of appalled to learn that the average delay in diagnosis is four to nine years in your article, and given the severity of pain and the impact it has on these patients, that's clearly a challenge. What's so hard about this? And do you have pearls on how we can recognize these patients? And how do you sort this out practically in clinic?

Dr Burish: For cluster headache patients especially, it is a lot more common than we would think it is, but it still goes misdiagnosed, partly because most cluster headache patients are episodic. So, there's an episodic version where you get them every day for a few weeks and then they might go away for a year. So, I think what happens is that patients start to get into a cycle and they either get confused for sinusitis (because it happens in the spring), or they schedule a visit with a neurologist or somebody else, but the headaches are over by the time they see them, and they cancel the visit. So, I think they get misdiagnosed partly because it's either confused or they don't see doctors fast enough. I think a little bit more awareness of what this disease is and then, somehow, a mechanism to get these patients in a little bit more urgently is probably what's necessary.

Dr Smith: Well, Mark, access is a real issue in neurology more broadly, and I'd love to talk to you about that in a moment, but I wonder if we could go back. You talked about how similar these are to one another, yet the treatments are different. How do you sort out the diagnosis when you're seeing a patient? Let's say you have someone who comes in who has episodic, unilateral, very severe pain and some of these autonomic features. What are the pearls for differentiating cluster, SUNCT, and SUNA from each other?

Dr Burish: The big difference between all these different headaches is the timing. As a general rule, SUNCT and SUNA attacks last seconds (they're very similar to trigeminal neuralgia); paroxysmal hemicrania (that's one of the hemicrania ones, where indomethacin helps) - those attacks last minutes; cluster headache attacks last about an hour; and the hemicrania continua is constant (that's the other hemicrania one where indomethacin works). The other part is how often they happen. Again, SUNCT and SUNA - very similar to trigeminal neuralgia, may happen hundreds of times a day; paroxysmal hemicrania - dozens of times a day; cluster headache - maybe a handful of times; and then, hemicrania is constant. Based on how long the attacks are and how frequent the attacks are, you can generally separate them out. And if you're not sure, just try indomethacin. And then if it doesn't work, you're trying to distinguish between SUNCT and SUNA, which lasts seconds, and cluster headache, which lasts an hour, so fairly easy to distinguish those.

Dr Smith: How long does it take to medicine to work in a patient with hemicrania continua or paroxysmal hemicrania? I’ll remind our listeners - there's a separate article in the same issue of Continuum on that topic - but for our purposes, let's say you try that; how long do you need to try it?

Dr Burish: Yeah, there's a great, another article about how much to give and how it works. It is generally pretty quick. I have noticed with most patients that the onset is twenty-four to forty-eight hours. And then, if you stop the medicine, the same thing - offset is kind of twenty-four to forty-eight hours. So, patients know pretty quick whether it's going to work.

Dr Smith: Wow - that's awesome. One of the things I was interested in was so-called “secondary cluster.” So, you've seen your patient and let's say you've diagnosed them with cluster (primary cluster). Do you do additional testing? Do they need imaging or other laboratory workup?

Dr Burish: Yeah. The differential for cluster (and cluster is the one that we know the most about; it is the most common of all the trigeminal autonomic cephalalgias) - it's a fascinating differential. If you don't know much about them, migraine is probably the most common. If you do know a lot about them, hemicrania continua and paroxysmal hemicrania are very common. But there's all these secondary headaches that can look identical to cluster headache; these pituitary hormone-secreting tumors (prolactinomas) - things like that. So, because all these other secondary causes can happen, they generally recommend everybody gets an MRI of the brain, with or without contrast. If that is normal and the patients continue to not respond to the medicines like you expect them to (verapamil doesn't work, oxygen doesn't work, and so forth), then you might do some additional testing for pituitary bloodwork. So, just kind of a panel of hormones, looking at blood vessels (because there are some cases that dissections or AVMs can cause cluster headaches). And then sometimes get imaging of the apex of the lung because there's some data that - with the Horner syndrome - that that might be relevant.

Dr Smith: I'll refer our listeners to your article, just in general, because they really need to read it. It's fantastic. But your discussion about the neuroanatomy is really cool, and probably more than we want to get into right now, but the intersection of the neuroanatomy with therapeutics, and some of these other potential etiologies. So, one thing I was really amazed by (or appalled by, frankly) was the frequency with which these patients have suicidal ideation, given the severity of the pain and, I assume, the long time it often takes to get this sorted out. How do you handle that in clinic? Do you have conversations with people about this? How often do you appreciate it? And any words of wisdom for those of us who might encounter these patients?

Dr Burish: Yeah. It's not hard to imagine why patients would be suicidal with this. When you have pain that is a ten out of ten - and patients who have also had childbirth and cluster, they consider childbirth more around a seven - so you can imagine how painful this is and what thoughts might be going through people's heads. It tends to be (in my personal experience and some emerging data) that they are suicidal during a cycle. So, for these episodic patients (most patients are episodic with cluster headache for a few weeks), they are suicidal during those weeks. And when the headaches go away, much less risk of suicide. So, during the cycle, I try to get my patients in as fast as possible, get the medications in as fast as possible, but basically just be there to let them know that we have options, and so that they consider me as their first option, rather than something darker.

Dr Smith: How successful is first-line therapy in these patients and what's your success rate with your initial attempt at treatment?

Dr Burish: On the acute side, the as-needed medicines (sumatriptan, oxygen) - if you give an injection (not the oral; that takes too long) - incredibly effective; for most patients, one or both of those will work. We usually prescribe both because the injections - usually you can't get that many (they can be quite expensive, realistically speaking). But also, just practically speaking, patients can have headaches up to eight times a day and you're not really supposed to be taking sumatriptan eight times a day, so we also give oxygen (but then again, oxygen is not very portable, so that's where the sumatriptan comes in). On the preventive side - not great. There's been some studies suggest maybe fifty percent is as good as any preventive is going to work for you, and that's not considering side effects and other things that patients might stop them. So, we do need to have a few different preventive options and you may have to go through a few different things. Chronic cluster headache (which is the more rare version, where patients have them year-round) is anecdotally much more refractory to treatment.

Dr Smith: Can you talk a little bit about bridge therapy? You differentiate bridge from prophylactic therapy in your article.

Dr Burish: Yeah. When you're approaching one of these patients - let's say they're completely naive to any medications - usually we will give them a couple of as-needed, acute medications (sumatriptan injections and oxygen). We’ll give them a preventive like verapamil, but the verapamil takes a few weeks to kick in. So, the obvious question is, “What am I supposed to do in the meantime, while you're ramping it up and it's kicking in?” So, we use these short-term preventives, which we call bridge therapies or transitional therapies. These are short-acting preventives; they kick in quick, but you can't take them for very long. The most common by far is prednisone. Or an occipital nerve block with some sort of steroid (so, steroids in some sort of fashion). We will usually give them right at the beginning of a cycle (right at the beginning of a flare for chronic cluster headache patients) while we are uptitrating something like verapamil.

Dr Smith: This may be a really silly question, but the next time I see one of these folks and I want to start oxygen, how do I do it? What are the logistics of giving someone oxygen for this, and how do patients navigate that, right? If you're having eight attacks a day during a cluster and you work as a nurse in the headache clinic, you probably have oxygen there. But you get where I'm going, right? - it's logistically challenging. How do you order it, and do you have words of wisdom to make it easier for patients to use?

Dr Burish: There's a whole kind of system of oxygen, durable medical equipment - stuff that I've had to learn. To boil it down, there are basically two types of oxygen. There's a concentrator - kind of just a machine that takes room air and turns it into about ten percent oxygen - that is sometimes effective for patients. But sometimes ten liters per minute (which is the highest that can give) is not enough and you need fifteen liters per minute. In that case, you need an oxygen tank (the big metal cylinders that you see with a extra device on top called a regulator, that can crank it up to fifteen liters a minute. For both of these - fifteen liters a minute - you're going to need a mask. The nasal canula is just - it doesn't get up to fifteen; it's not going to be enough, so we give you this bag mask (the non-rebreather mask, or the bag hanging out below it). You really need high dose, pure oxygen for these things to work, so you have to write orders that say, “fifteen liters a minute, with regulator and non-rebreather mask.”

Dr Smith: I'll refer our listeners to your Continuum article. I know a lot of our listeners use Continuum at point of care. And, of course, you can access it electronically, so there's really great pearls there. Another question for you: CGRP agents have really transformed migraine; what role do they play, if any, in management of these headaches (cluster, SUNCT, and SUNA)?

Dr Burish: I think this is a fascinating emerging area of cluster headache research. One of the studies in the last three years came out that it was successful for episodic cluster headache, called galcanezumab, and it did not work for chronic cluster headache. Meanwhile, a couple other CGRP companies have tried them and they were unsuccessful, at least according to the data on ClinicalTrials.gov. And some other CGRP studies are still emerging. We know that both migraine and cluster headache work on the trigeminal system (I mean, this is a trigeminal autonomic cephalalgia - it's in the name) and CGRP is involved in the trigeminal system. That's probably where the commonality between migraine and cluster headache come from - they both work on the same pain system. But why all of them seem to work for migraine and only some of them – you know, some of these medicines work for cluster headache - is a fascinating thing. Does that mean that we don't have the dose right? Does that mean that we don't have the timing of these clinical trials right? Does that mean it's just not as effective? And there's other things that are involved in cluster headache - it's an interesting mechanism that we can start to explore.

Dr Smith: I wanted to learn more about the circadian aspects of this - I found that really interesting, and you commented that you're interested in that in a research perspective. Can you describe that phenomena a little bit and just tell us what your thoughts are?

Dr Burish: The interesting thing about cluster headaches, specifically, is that the headaches happen, for most patients, the exact same time every day – so, within an hour each day. So, my patient usually will say, “They're at two AM.” Across different time zones, every study that’s been done - well, not every study, but many studies have been done - two AM is the most common time of day. But if you ask an individual patient, patient number one will say, “They happen every day at two AM; patient number two will say, “They happen every day at three in the afternoon.” I had a patient who was, I think, kind of getting fed up with all the questions I was asking about his headaches, and he said, “Dr Burish, it's three o’clock; if you want to wait until three fifteen, I'm going to get a headache - you can see what it's like.” That's how sure he was about when the headaches were going to happen. And other than maybe hypnic headache, there are a few other headaches that have that level of circadian predictability. So, it's just an odd, curious, unique thing to these headaches and we don't quite understand why yet.

Dr Smith: So, I'm curious if the time of day patients get their headaches is in any way correlated with other aspects of sleep phenotype, right? There's broad variability in your sleep phase - the length of it, when it starts and ends. Is there any relationship, in your experience, between the time of day (two AM, ten PM) and other aspects of their sleep?

Dr Burish: We haven't seen that, to my knowledge. People have looked, for example, at sleep studies while patients are having attacks. These attacks occur out of REM sleep, non-REM sleep - it doesn't seem to matter. Anecdotally, patients will say, “My cycle last year - I had headaches every day at two AM. But my cycle this year - I have headaches every day at five in the afternoon.” So, even a same patient who, theoretically, is not having big sleep changes over different years, has different timing of attacks.

Dr Smith: Mark, what's the latest thing? What's most exciting in the field that you can tell our listeners about?

Dr Burish: There are a lot of new treatments for cluster headache. There's the galcanezumab, which we discussed a little bit. There is a new dose for prednisone. We weren't sure how effective it was; now we're using kind of neuroimmunology-level doses of prednisone (100 milligrams daily; kind of titrating down from there). And then there's an occipital nerve stimulator for the chronic cluster headache patients. Since the last Continuum review on this topic, these three trials have been successful, and I think what gets lost is how impressive each one of these is in different ways. The prednisone study is impressive because you had to study that medicine (which we thought worked but didn't have a good clinical trial), and it's really hard to enroll patients in a placebo-controlled study where you already think it works. Another was done by a large pharmaceutical company. This is not an advertisement for or against, but these companies have rarely ventured into studying cluster headache until recently. The third study, the stimulator study, was a ten-year, multisite study involving surgeons and neurologists - just a monumental effort. It's because of these impressive studies that we now have data on how to treat the patient.

Dr Smith: Just so interesting. I tell you what - I mean, if you told me twenty years ago I would be this interested in headache, I would have said, “You're crazy.” But now I see why our residents are so interested in it and why you are. This is fascinating. I could keep going for another hour or two asking you questions, Mark, but maybe we can pivot back to where we began. You told us your story about enriching your resident clinic - and for those residents listening, those are words of wisdom right there, my friend. But here's my question for you: we've already talked about access to care and how you manage access for these patients, but we have a huge access issue in neurology broadly and we desperately need more neurologists. As you're probably aware, there are some of our colleagues that don't think pain is neurology (I'm not one of them, but I know some of them and respect them otherwise). If there's an access issue for neurology, there's a access crisis for pain neurologists. And you don't just see headache, as I understand it; you see other patients with pain. So, I want to give you the last few minutes of our Continuum Audio episode to do your pitch, right? What do you have to say to the residents that are listening to us (or students) about why you find managing pain so rewarding and why they should consider this as a field?

Dr Burish: Yes - I also did a fellowship in pain medicine, in addition to my headache research, so I see a little bit of both. For me, the patients are very appreciative because you are talking with them about what they are interested in. They are not interested in the change in the MRI between last time - I mean, they are interested in it, but not as much as, “I hurt today.” So, patients are more than happy - they're very grateful that you are addressing their primary concern, the thing that they're going home with that day that they're worried about. For me, seeing these patients has been very rewarding. From the research side. I think it's fascinating that there's just not enough research in this area - you can create your own niche; you can look into your own mechanisms - there's just not a lot of people in this field. And then, I think from a clinical side, other than the rewarding nature of it, there's a lot of options that we have. There's all of these neuropathic medications; there's all these different headache medications. If you want to wade into the procedural side of things (which I did with pain management), you can get into fluoro-guided procedures and spinal cord stimulators and all these different options that we have for these patients that help them, in addition to whatever they're going through. I have patients that then come back and say, “Well, by the way, I have these seizures; do you mind helping me kind of just go through my antiepileptics.” And they're generally well controlled and they consider me kind of a general neurologist for them. So, I’ve found it extremely rewarding and I wouldn't do anything different.

Dr Smith: Well, that's really great information and I hope our resident listeners will take that to heart. Your article is truly amazing, Mark. I can't tell you how much I was impressed with it, and for our listeners - you gotta check it out. I've got a list of ten other things on my piece of paper here I could ask Mark about, but I think we're probably at time. So, Mark, thank you so much. Congratulations on an amazing article and really fascinating and exciting area of neurology.

Dr Burish: Thank you. Thank you very much for having me.

Dr Smith: Again, today we've been interviewing Dr Mark Burish whose article on cluster headache - appears in the most recent issue of Continuum, which is on headache. Be sure to check out Continuum audio podcasts from this and other issues, and thank you very much to our listeners for joining us today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice. Right now, during our Spring Special, all subscriptions are 15% off. Go to Continpub.com/Spring2024 or use the link in the episode notes to learn more and take advantage of this great discount. This offer ends June 30, 2024. AAN members: go to the link in the episode notes and complete the evaluation to get CME. Thank you for listening to Continuum Audio.