The largest study so far of sex differences in cluster headache reports that more women than men experienced the chronic form of this condition, as well as longer bouts.
Researchers and clinicians know that cluster headache (CH) is more common in men than in women. But women experience this painful condition too, and there is evidence that they may differ from men in their clinical presentation. The largest study to date of sex differences in CH now confirms and extends those previous observations, providing a picture of how this difficult-to-treat disorder differs between men and women.
Researchers led by Andrea Carmine Belin, Karolinska Institutet, Stockholm, Sweden, report that more women than men experienced chronic CH, and had longer CH bouts, in a clinical study including 874 participants. Women also experienced ptosis (when the upper eyelid droops over the eye) and restlessness more frequently than men did, among a number of other findings distinguishing the sexes in their CH symptoms.
The attribute that most sets the current research apart from previous work is the sheer number of study participants, according to Shivang Joshi, Community Neuroscience Services, Westborough, US, and the University of Massachusetts.
“It’s hard to find a large population of cluster headache patients in one practice, so the greatest strength is the population size of this study,” according to Joshi, a headache specialist who has investigated CH in several studies. “This study corroborates previous findings, but there are some sex differences that stand out and that are important to continue to monitor as we move forward looking at designing future studies,” he added.
The authors have published “one of the most comprehensive studies of sex differences in cluster headache; they confirm previous epidemiologic suspicions, provide new insights, and raise important questions into sex hormones and the influence of genetic factors,” wrote Mark Burish, UT Health Houston, US, and Richard Lipton, Albert Einstein College of Medicine, Bronx, US, in an accompanying editorial.
The research and editorial appeared online ahead of print December 21, 2022, in the journal Neurology.
Lots of sex differences
The impetus for the new research, Carmine Belin told Migraine Science Collaborative, came from human genetic studies of CH that she conducts with collaborators, along with a desire to raise awareness of the condition.
“Cluster headache has been the typical male disorder, but we do a lot of genetic studies on cluster headache, and we had a feeling that there are a lot of women out there with it, and also that they might have a more severe form or be different in some way. Many women with cluster headache who participate in our genetic studies have told me that when they go to their neurologist or general practitioner with very clear symptoms of cluster headache, they still hear, ‘Oh, no, you can’t have cluster headache because you’re a woman.’ One part of our work is to increase awareness of cluster headache and that women can have it, so that’s why we started off with this study.”
So Carmine Belin, first author Carmen Fourier, and colleagues screened medical records from Swedish hospitals and neurology clinics to identify people who had been diagnosed with CH based on the International Classification of Headache Disorders (ICHD), 3rd edition. Through a questionnaire, study participants provided information about clinical aspects of their condition as well as their lifestyle. The study would ultimately include 874 people (66% men, 34% women).
The authors would go on to identify a number of sex differences. It turned out that more women than men (15% vs. 7%) reported a family history of CH, translating to 58% lower odds of a family history in men compared to women (an odds ratio [OR] of 0.42). Women were also more likely than men to have chronic CH (18% vs. 9%), with the latter being 54% less likely to present with that clinical symptom than women (OR: 0.46). That finding stood out to Carmine Belin, though why this difference is present remains a matter of speculation.
“One idea is that it could be that women with the chronic form of cluster headache easily get a diagnosis because they have very clear symptoms, and the ones with episodic cluster headache might get a migraine diagnosis at the start; I got the feeling from study participants that cluster headache was initially misdiagnosed as migraine,” Carmine Belin said.
While there was no difference between the sexes in the frequency or duration of CH attacks each day, CH bouts (measured in months) were longer in women than in men.
Ptosis was also more common in women than in men (61% vs. 47%), as was restlessness (54% vs. 46%). Women were also more likely than men to report a diurnal rhythmicity to their CH attacks, that is, a CH attack distribution that varied according to the time of day (74% vs. 63%); women were more likely to have CH attacks at night and during the early morning hours.
The researchers also saw a difference in chronotypes, with women more often reporting that they were morning types, and men more often saying that they were evening types. Further, while the proportion of women versus men using abortive medications was similar, the former more often used oxygen than the latter did (37% vs. 28%). More women than men (60% vs. 48%) used preventive treatments. Also, women had migraine and tension-type headache more often.
Finally, in terms of trigger factors, while alcohol was the most common trigger reported by both women and men, it was men who more often listed alcohol as a trigger of their CH attack (54% vs. 48% for women). After alcohol, stress was the next most frequently reported trigger, with more women than men reporting this trigger (37% vs. 21%). More women than men also reported a lack of sleep as a trigger (30% vs. 20%).
Keeping researchers busy
There is no shortage of questions to keep CH researchers occupied in the future. To start, the reasons for most of the sex differences identified in the study are unclear. “We need more research,” Carmine Belin said.
Further, one area of particular interest to Carmine Belin is sex differences in treatment effects – why do some people with CH respond to certain drugs but others do not? Perhaps side effects might explain why.
“We are already looking at different genetic markers that have been linked to triptan response in migraine to see how this looks in cluster headache,” she said.
Considering the idea that dysfunction in the circadian system may play a role in CH, and that maybe this might explain why some people don’t respond to triptans, she is also doing sleep studies in people with CH.
“We have followed 40 patients and 40 controls with an actigraphy unit, looking at their sleep. We are digging into that data right now, looking at how patients sleep when in an active phase versus remission. It looks like, even when in remission, they have lower sleep quality compared to controls,” Carmine Belin said. She noted that the circadian system could potentially be targeted by improving sleep, or by providing preventive treatment – at the right time in the circadian cycle – for a better drug effect.
Another area ripe for investigation is the role of hormones in CH. Speaking of which, how menopause may affect CH is also a question of interest to Carmine Belin.
Notably, Joshi said it would be interesting to learn if there are sex differences in the response to neuromodulation devices; non-invasive vagus nerve stimulation is currently approved by the US Food and Drug Administration (FDA) for use in CH.
An encouraging outlook
The current study is an encouraging one for the CH field: Not only does it advance knowledge of CH, but it also has the potential to raise awareness of this condition among clinicians, and especially that women can suffer from it. That is sorely needed, considering that it can take up to a decade for some with CH to get a correct diagnosis.
But the news gets even better when looking at the prospects for CH research more broadly.
For instance, while there are abortive treatments for CH, including triptans and oxygen, as well as preventive treatments including lithium and the calcium channel blocker verapamil, it’s clear that additional therapies are needed. But Carmine Belin said that genetic studies of CH suggest that the development of successful new drugs for the condition is a realistic possibility.
In particular, while well over 100 genetic variations – usually with only small effects – have been linked to migraine, a recent genome-wide association study she performed with collaborators in the United Kingdom identified just four genetic loci that were all strongly linked to CH, making the search for new drug targets more manageable and perhaps more likely to bear fruit. Another study of Dutch and Norwegian patients reported similar results.
Carmine Belin added that a new consortium called the International Consortium for Cluster Headache Genetics, which aims to involve groups outside of Europe in CH genetic studies, is looking into what the genes linked to CH are doing and whether they could be drug targets.
Another reason to be optimistic for the future of CH research and care: Carmine Belin’s lab recently received a large donation to launch a center for CH research. “It’s the first center for CH in the world,” she said. The center will collaborate closely with clinicians at Karolinska University Hospital, which sits right next to the new center.
In the meantime, when asked what she thinks is the most important contribution of her current study, Carmine Belin had a clear answer.
“Women can get cluster headache, too. That’s our main message.”
Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on Twitter @NeilAndrews
Sex differences in clinical features, treatment, and lifestyle factors in patients with cluster headache.
Fourier et al.
Neurology. 2022 Dec 21. Online ahead of print.
Cluster headache: Worse in women.
Burish MJ, Lipton RB.
Neurology. 2022 Dec 21. Online ahead of print.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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