Clinical Context

Cluster headache (CH) is a severely painful headache disorder characterized by unilateral, orbital head pain often accompanied by autonomic symptoms, such as lacrimation, ptosis, or restlessness. During an active bout, headache attacks lasting between 15 and 180 minutes occur up to 8 times daily. Although CH is considered male-predominant, the reported male-to-female ratio has shifted from approximately 6:1 before 1960 to 5.1-2.5:1 in 2018. This shift may result from lifestyle changes in both sexes and/or from increased CH recognition.

Study Synopsis and Perspective

Women with CH have more severe symptoms and longer headache bouts than men, and they are more likely to have a chronic subtype of the disorder, new research shows.

The study, which is the largest to date involving patients with CH, adds to a growing body of work that suggests that an illness that affects mostly men may actually have a much greater effect on women.

“The main thing from this study is to show clinicians that women can suffer from [CH] too,” senior investigator Andrea Carmine Belin, PhD, associate professor of neuroscience at the Karolinska Institutet, Stockholm, Sweden, told Medscape Medical News.

The findings were published online December 21, 2022, in Neurology.^[1]

Severe and Debilitating

CH is rare, but it is among the most severe and debilitating types of headache. It causes intense pain behind the eyes. The pain has been described as being worse than the pain associated with childbirth or kidney stones.^[2]

In addition, attacks can occur multiple times in a day and can last up to 3 hours.

As reported by Medscape Medical News, a recent study showed that participants with CH were significantly more likely to have comorbid conditions, including mental disorders and other neurologic diseases.^[3]

In the current study,1,484 Swedish individuals were recruited for inclusion into a CH biobank, of whom 874 completed a survey that collected demographic data and information about symptoms, including severity and frequency. The patients included 575 male and 299 female participants with CH.

The study participants were identified between 2014 and 2020 by requesting medical records for International Classification of Diseases, 10th Revision (ICD-10), code G44.0 for CH from all major hospitals and neurology clinics over Sweden, as well as in conjunction with CH outpatient visits to neurology clinics. Study participants were diagnosed with CH and subtype by neurologists through structured interviews and clinical examination according to criteria of the International Classification of Headache Disorders, 3rd Edition.^[1]

Each study participant completed a 3-part questionnaire that included a first part on personal, demographic and medical information. A second part was designed to assess different parts of the disease, and the third included lifestyle questions. For neurology outpatients, the questionnaire was completed in relation to the visit. All data were self-reported except CH diagnosis, which was verified using ICD-10 code G44.0. All participants were genotyped for their biological sex, and it matched their self-reported sex. The age at the time of completing the survey varied slightly between male and female participants (51.3±13.9 vs 49.0±15.0; P=.028)^[1]

Gender Gap Closing?

Women were significantly more likely than men to have headache bouts lasting 4 months or longer and were more likely to have attacks that followed a circadian pattern, with early-morning onset.

Women were more likely than men to experience the onset of CH before age 20 years (23.0% vs 16.2%; odds ratio [OR], 0.64; 95% CI, 0.44-0.92; P=.020). However, there was no difference overall in the average age of disease onset.^[1]

Chronic CH was nearly twice as common in women as men (18.4% vs 9.4%; OR, 0.46; 95% CI, 0.32-0.70; P=.0002). Women were also more likely to have a co-occurring migraine or tension-type headache and to have an immediate family member who had a history of CH (15.4% vs 7.1%; OR, 0.42; 95% CI, 0.27-0.66; P=.0002).^[1]

CH triggered by sleep deprivation, stress, and changes in weather or temperature was also more common in women, whereas among men, attacks were more often triggered by alcohol consumption (56.5% vs 40.5%; OR, 1.91; 95% CI, 1.29-2.81; P=.001).Alcohol was the most common trigger by far (50.7%) for both men and women, and stress was the second most common trigger (26.7%), with more females being affected than males (20.5% vs 37.4%; OR, 0.43; 95% CI, 0.28-0.66; P=.0001). Most of the participants described food items or nonalcoholic beverages that may trigger an attack were chocolate, sweets or food/beverages with high sugar content, coffee/tea, (strong) cheese, food with high salt content, and spicy/pungent food.^[1]

Women were more apt to use oxygen 36.5% vs 27.8%; OR, 0.67; 95% CI, 0.49-0.92; P=.013) for acute attacks and to use preventive medications. They also reported a higher incidence of ptosis (drooping eyelids; 60.5% vs 47.0%; OR, 0.58; 95% CI, 0.43-0.76; P=.0002) and restlessness (53.9 % vs 45.6%; OR, 0.72; 95% CI, 0.54-0.95; P=.024). Menstruation and other hormone-related factors were reported as triggers by 1.2% of women.^[1]

Although CH remains more common in men than women, that gender gap is closing, Dr Belin said. That is in part because of better diagnosis, but also a result of a growing incidence of the disorder in women. Overall, the true number of female patients with CH is probably larger than reported, she added.

“I have patients in our cohort and our clinic who say they go to neurologists with all the symptoms of cluster headache, and the neurologists say that ‘you can’t have cluster headache because you’re a woman,’ “Dr Belin said.

The investigators have created a CH biobank and have DNA samples and clinical data on more than 900 patients with CH. That will make it easier to investigate the underlying cause of the disorder and the reasons for the differences in clinical presentation, they note.

“We’re very interested in learning more about the treatment response in men and women and why chronic cluster headache seems to be more common in women,” Dr Belin said.

Greater Awareness

In an accompanying editorial, Mark Burish, MD, PhD, from UT Health, Houston, Texas, and Richard Lipton, MD, from Albert Einstein College of Medicine, New York City, note that this is one of the most comprehensive CH studies to date.^[4]

The investigators “confirm previous epidemiologic suspicions, provide new insights, and raise important questions into sex hormones and the influence of genetic factors,” Dr Burish and Dr Lipton write.

“This large study of rigorously diagnosed cluster headache patients mandates an elevated index of suspicion for cluster headache in women, and an awareness of possibly more burdensome disease in women,” the editorialists add.

The study was funded by the Swedish Brain Foundation, the Mellby Gård Foundation, the Swedish Research Council, Region Stockholm, and Karolinska Institutet Research Funds. Dr Belin has disclosed no relevant financial relationships. Dr Burish is an unpaid member of the medical advisory board of Clusterbusters. Dr Lipton serves in unpaid positions on the editorial board of Neurology and Cephalalgia and as senior advisor to Headache. Full disclosures are included in the original articles.

Neurology. Published online December 21, 2022.

Clinical Implications

• There are significant differences between males and females with CH, which should be considered at time of diagnosis and when choosing treatment.
• CH is still often misdiagnosed in females, perhaps because certain features of the disease in females resemble a migraine-like phenotype.
• Implications for the Health Care Team: Clinicians should have a greater index of suspicion for CH in women and be aware that women may have more burdensome disease.

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