Meeting the Challenge of Cluster Headache: A Conversation with Andrea Carmine Belin

By Fred Schwaller | February 6, 2024 | Posted in

“In the coming years, we will move into the field of precision medicine. When we have all this knowledge of genetic markers, I think we can use it to see if certain genetic markers are linked to how well a person responds to treatment. Seventy-five percent of patients with cluster headache respond to triptans, but 25% don’t. Why is that? We’re looking to see if this is connected with genetic markers, as well as if genetic markers are connected to certain side effects.” – Andrea Carmine Belin

Andrea Carmine Belin, PhD, is a neuroscientist and geneticist at Karolinska Institutet in Stockholm, Sweden. Her research focuses on cluster headache, in particular aiming to understand its genetic causes. Last year, Belin started the Centre for Cluster Headache at the Karolinska Institutet, the world’s first such center for research on this disorder.

In this Migraine Science Collaborative interview, Belin chats with freelance writer Fred Schwaller about her career, the clinical problem of cluster headache, and recent research that is driving the understanding of cluster headache forward. The interview has been edited for clarity and length.     

Let’s start with your career in the headache field. What led you into the field and what are your goals for your research?

My main goal is to understand what causes cluster headache. Currently, we don’t know what the causes are, and we don’t have a way to cure it. If we can find the causes, then we have better chances of developing better and more effective treatments.

In my lab, we’ve been focusing on the genetics of cluster headache; I’ve always been excited by genetics. At the start of my career I worked on Parkinson’s disease, but all the while there was a pattern of migraine in my family. This personal experience with migraine led me to headache disorders. I knew there was a strong genetic link with migraine, but when I started in the field almost 10 years ago, not much had been done on the genetics of cluster headache, so I thought: I must get started.

Could you explain what cluster headache is and how it differs from other types of headache disorders, like migraine? You wrote in one review that it’s among the most severe pain described by humans – even more intense than gunshot wounds or childbirth. This is astonishing.

Yes, indeed. Cluster headache has been reported to be the most painful thing you can experience as a human being. This comes from a very interesting study where the researchers asked more than 1,600 cluster headache patients worldwide to compare their cluster headache pain to other pain conditions they had experienced. The patients in the cohort who also had migraine said their migraine pain was a 5 on the 0-to-10 pain scale. Kidney stones were around 6. The women in this group who had given birth said labor pain was a 7.2. Cluster headache pain was a 9.7.

What differentiates cluster headache from migraine is that the pain is so much more intense. The attacks are shorter, between 15 minutes and three hours, while migraine lasts more than four hours. And you can have cluster headache attacks several times per day, if you’re unlucky. Cluster headache pain is always on one side of the head, commonly around the eye, and there are also autonomic symptoms like a runny nose, reddening of the eye, and ptosis [drooping of the upper eyelid].

Andrea Carmine Belin

If you have episodic cluster headache, which is 80%-90% of people [with cluster headache], you can have these attacks for weeks or months; that’s when you’re in an “active period.” But then you go into remission, where you can be symptom free for months or years. There are patients who do not have symptoms for five years, and then the symptoms come back. But there are chronic cluster headache patients who don’t have these longer remission periods and have it all the time.

Are there any effective treatments for cluster headache?

A major problem is that no treatments have been developed specifically for cluster headache. There are treatments like triptans, oxygen, and verapamil, but they tend to be administered based on trial and error. These treatments might work for some but not for others, and you can get severe side effects. This is fundamentally because we don’t know what’s causing the disease.

There are also sex differences in cluster headache. How do the symptoms differ between men and women?

Yes, it’s much more common among men than women – up to five times more common. I hear stories from female patients in Sweden who hear, even in big university hospitals, “Oh, you can’t have cluster headache. Only men have that.”

We recently investigated if cluster headache symptoms differed between women and men (see MSC related news story). To our big surprise, we saw that more women than men suffered from the chronic form of cluster headache – twice the number. We also found differences in autonomic symptoms; more women than men have ptosis. We’re looking to investigate the sex differences further, particularly in relation to the hormonal influence on cluster headache, which is known to be linked with migraine. I hear stories from cluster headache patients and clinicians who think there’s some link in cluster headache, too, but very little research has been done in this area.

What triggers cluster headache attacks? 

More than 50% of cluster headache patients say that alcohol triggers their attacks, but only when they’re in an active phase and not in remission. This is very interesting because it indicates there are unique biological changes when you’re in an active phase. Stress is also a trigger, as is too little sleep, but also weather changes. In our Swedish population, about 50% of patients say they have active periods during specific seasons of the year, mostly during spring and fall when there are big changes in the amount of light. About two-thirds of patients also report they have attacks at certain times during the day – usually at nighttime between 2 a.m. and 4 a.m. So we think there’s a role for circadian rhythms in cluster headache.

What are the genetic links with cluster headache?

There are reports on monozygotic twins, where both twins had cluster headache, and the risk of developing cluster headache is reported to be up to 18 times higher if you have a relative with cluster headache. So there seems to be a genetic component.

Cluster headache is a quite heterogeneous disorder, and we won’t identify one single genetic marker giving rise to cluster headache. In addition, you can inherit both protective factors and risk factors. I don’t think we’re there yet in terms of identifying all single nucleotide polymorphisms (SNPs) that carry increased risk of cluster headache, but in our work with the International Consortium for Cluster Headache Genetics, we’re getting closer to identifying all genetic markers linked with cluster headache. Studies have shown that genes involved in alcohol metabolism are connected to cluster headache, but the results have not been replicated in larger studies. We’ve also shown that circadian rhythm genes are involved.

A recent GWAS study of ours identified four regions of the genome that were strongly linked to cluster headache, but these are big regions involving many genes. These results have been replicated by other groups in European cohorts. As with other diseases, there could be different genetic factors that cause cluster headache in other parts of the world, so now we’re trying to recruit more groups as part of our International Consortium for Cluster Headache Genetics as well as characterize the genes in these regions and investigate their possible relation to the development of cluster headache.

The genetic link between circadian rhythm and cluster headache is fascinating. How might genetic variants for circadian rhythm cause cluster headache?

There are about 40 genes involved in regulating the circadian rhythm, and we have investigated some of the core clock genes in relation to cluster headache. We screened a genetic marker in the CLOCK gene that’s been linked to shorter sleep duration, and we could see that this genetic marker was also more common among patients with cluster headache compared to controls. It was even more common among patients who reported a circadian rhythm to their attacks. There are so many genes involved in the circadian rhythm, but I think there’s something there.

What are the most important clinical or research steps in the future that will advance the understanding and treatment of cluster headache?

In the coming years, we will move into the field of precision medicine. When we have all this knowledge of genetic markers, I think we can use it to see if certain genetic markers are linked to how well a person responds to treatment. Seventy-five percent of patients with cluster headache respond to triptans, but 25% don’t. Why is that? We’re looking to see if this is connected with genetic markers, as well as if genetic markers are connected to certain side effects. So with this precision medicine approach, you could just ask the doctor, take a saliva test, and see which genetic markers you have.

For the longer term, if we can identify specific genes linked to the disease and how they’re mechanistically linked, then we can find new drug targets specific for cluster headache.

What research questions are you most excited about now?

We want to see if taking certain treatments at certain times of the day improves treatment outcomes. We’re currently taking skin biopsies from patients and controls, and culturing a cell type called fibroblasts, which have natural circadian rhythms. We can use fibroblasts to investigate if treatments change circadian rhythms in patient and control samples. That’s something really interesting.

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred

Image credit: berya113/123RF Stock Photo.

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Fred Schwaller is a science writer and communicator based in Berlin, Germany. Fred spent a decade in pain research during his doctoral degree at University College London, UK, and his postdoc at the Max Delbrück Centre in Berlin, Germany. After transferring to science communication in 2020, he has been writing and podcasting about life sciences and medicine, specializing in somatosensation and pain. Follow him on Twitter @SchwallerFred.

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