Originally published in our sister publication, Pain Medicine News.

The rarity of cluster headaches, which affect around 0.1% of the population, has made the condition difficult to research. As a result, clinicians are still largely in the dark as to what causes such headaches.

Research has revealed that cluster headaches may be a symptom of a sleep disorder or that more complex sleep-related factors are involved. However, Rohit Nalamasu, DO, a resident in the Department of Physical Medicine and Rehabilitation at the University of Nebraska Medical Center, in Omaha, and a team of researchers from NEMA Research Inc. in Naples, Fla., believe sleep disturbances and cluster headaches may be symptoms of a specific brain abnormality, rather than a symptom of each other. They presented their research as part of the PAINWeek 2020 Live Virtual Conference (abstract 32).

“Cluster headaches occur during sleep and have a diurnal relationship, so it has been theorized that they have been associated with sleep,” said Nalamasu, who co-led the research. “But as our understanding of the brain expands, we can have new insight into how a lot of stuff works, including cluster headaches.”

An Elusive Cause

Cluster headaches typically set in around 90 minutes into the sleep cycle. Although research has theorized that rapid eye movement sleep is somehow connected to cluster headaches, researchers have not been able to establish a clear relationship. Unlike other sleep-related headache disorders, cluster headaches are unilateral and cause periorbital, droopy or watery eyes, and a runny nose. The unique headaches occur more often in men, who experience more frequent bouts of cluster headaches around the summer and winter solstices, leading past researchers to speculate that the natural light–dark cycle plays a role in triggering the headaches. Cluster headaches also are associated with sleep apnea and other sleep disorders; however, this is also true of other headache disorders, Nalamasu noted.

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For the meta-analysis, his team reviewed 92 studies on cluster headaches—17 of which were included in the PAINWeek presentation—in an effort to better understand what causes the headache disorder. While sleep-disordered breathing has been linked to certain headaches, it may not play a role in cluster headaches, the researchers found. Instead, brain scans showed hypothalamic activation cluster headache attacks as well as asymmetry of the hypothalamus and more gray matter in this part of the brain.

“All those things put together paint a picture that we don’t quite understand yet, but pointing to the possibility that it may not be sleep disorders that are causing cluster headaches,” Nalamasu said. “Instead, we are looking at sleep, sleep apnea and sleep disturbances as a correlation rather than causation, and both could be mediated by a hypothalamic cause.”

Nalamasu noted that various peptides and hormones that originate in the hypothalamus play a role both in sleep and headaches, indicating that both could be caused by one source.

One study included in the analysis found that people with cluster headaches are less often aroused from sleep compared with healthy individuals, which may be caused by reduced hypothalamic activity. Such abnormal hypothalamic activation has been observed in other headache disorders as well, Nalamasu said.

Inflammation May Be at Play

In addition to the hypothalamus, the team focused on hypoxia, which studies have identified as the second of three distinct pathologic stages of cluster headaches. As of now, the research points to cluster headaches being the result of multiple factors including hypothalamic function; the light–dark cycle; inflammation, specifically of the trigeminal nerve; and an autonomic nervous system response.

“We are potentially looking at more of an inflammatory process that we need to better understand,” said Nalamasu, noting that the inflammation may not be related to sleep apnea directly, as research has suggested. “It appears that cluster headaches may actually be a brain disorder rather than a result of sleep problems, as previously thought.”

—Kaitlin Sullivan