Mark Burish, MD, PhD, on the Role of Family History in Cluster Headache

Cluster headache appears to be an inherited disorder in a subset of families and is likely associated with multiple hereditary patterns, according to a new systematic review of 40 articles.

The review included 22 large cohort studies, 1 twin-based study, and 17 case reports or small case series published between 1985 and 2016. Ultimately, the findings of the review indicated that cluster headache is associated with a family history rate of 0% to 22% (median 8.2%). The review identified 67 pedigrees, and found that the inheritance pattern of cluster headache appeared to be autosomal dominant in 69% of patients and autosomal recessive pattern in 28% of patients.

“Overall, this systematic review supports the notion that familial cluster headache is likely the result of multiple susceptibility genes, as well as environmental factors,” the authors of the review wrote.

Consultant360 discussed the implications of these findings further with study author Mark Burish, MD, PhD, with the Department of Neurosurgery at McGovern Medical School at the University of Texas Health Science Center at Houston.

C360: What prompted you and your colleagues to perform this systematic review of family history and inheritance of cluster headache?

Dr Burish: My colleagues and I were interested in both the clinical and the basic science aspects of this study. On the clinical side, patients with cluster headache will sometimes ask us what the risk is for their children to inherit cluster headache. I think parents understandably never want their children to inherit any of their health problems, but cluster headache appears to be an unusual level of suffering–in fact, it is possibly one of the most painful human experiences.

On the basic science side, we were interested in the genetics associated with cluster headache. Several genetics studies of cluster headache have been performed, but the findings differed, suggesting that susceptibility genes (genes that increase your risk but do not guarantee cluster headache) may be at play. For a full understanding of the genetics, it is necessary to understand heritability patterns.

I should note that we performed a systematic review, but not a meta-analysis. Usually in these studies, a true meta-analysis would be performed. However, we found that the methods in each study included in our review were simply too different to perform a meta-analysis. For example, some studies diagnosed cluster headache among patients in person, while others did so by questionnaire. Some studies personally interviewed as many family members as possible and diagnosed the presence or absence of cluster headache, while other studies simply interviewed only one family member with cluster headache.

C360: In your analysis, you and your colleagues concluded that “cluster headache had a family history rate of 0% to 22%, with a median of 8.2%” and that “the inheritance pattern of cluster headache across 67 pedigrees was consistent with an autosomal dominant pattern in 69% and an autosomal recessive pattern in 28%.” Could you elaborate on the clinical significance of these findings?

Dr Burish: If one has cluster headache, there is about an 8% chance that their child will also have cluster headache, and an approximately 92% chance that they will not. There are likely multiple genes involved in cluster headache, some of which are autosomal dominant and some of which are autosomal recessive. Identifying the specific genes will require additional genome sequencing studies.

C360: How can these findings improve risk stratification and patient referral for cluster headache?

Dr Burish: Cluster headache historically has been associated with long delays in diagnosis. Previous studies have shown that it often takes years for cluster headache to be diagnosed, and in the interim, patients often undergo unnecessary work-ups and procedures. Cluster headache is also associated with an unusually high risk of suicidal thoughts. Those 2 factors–long delay from onset to diagnosis and a high risk of suicidal thoughts–are a dangerous combination. Our findings suggest that both patients and physicians may want to be on the lookout for family members that report headaches that sound like cluster headaches.

C360: What key takeaways do you hope to leave with neurologists on this topic?

Dr Burish: I would want neurologists to know:

  1. The family history rate of cluster headache is higher than previously thought.
  2. The genetics of cluster headache are likely complex, with multiple susceptibility genes involved.
  3. Patients who have a family member with headaches that sound like cluster headache, but have not seen a neurologist, may want to see a neurologist and undergo screening for cluster headache because of the risk of suicidal thoughts in patients with this disorder, which are presumably more dangerous if they do not receive any treatment for their headaches.

C360: What is the next step in terms of future research in this area?

Dr Burish: When we analyzed the pedigrees, we unexpectedly found that there were more women in the pedigrees. The ratio of cluster headache in the general population is about 4.3:1 male:female, but in the pedigrees, it was about 1.4:1–still more common in men, but by a much smaller margin. It may be interesting to perform genetic studies limited to females in the future, because the data on women are otherwise masked by the higher number of men with cluster headache.

—Christina Vogt

Waung MW, Taylor A, Qualmann KJ, Burish MJ. Family history of cluster headache: a systematic review [Published online April 20, 2020]. JAMA Neurol. doi:10.1001/jamaneurol.2020.0682