32 - Exploring the Connections Between Sleep and Cluster Headache

¹NEMA Research, Inc., Naples, Florida, USA. ²Uppsala University, Gavle, Sweden. ³Karolinska Institutete, Stockholm, Sweden. ⁴University of Nebraska Medical Center, Omaha, Nebraska, USA. ⁵Temple University School of Pharmacy Practice, Philadelphia, Pennsylvania, USA. ⁶Paolo Procacci Foundation, Rome, Italy

Purpose
The International Classification of Sleep Disorders recognizes four types of headaches related to sleep: cluster headache, hypnic headache, chronic paroxysmal hemicrania, and migraine.¹ The prevalence of cluster headaches is 0.1% and its etiology is unknown.² More men than women suffer from cluster headaches and patients typically exhibit wakefulness, agitation, and a desire to pace during paroxysmal bouts which are characterized by multiple headaches that remit and recur over the course of several hours or days.^3,4 Typically, a headache would last from 15 minutes to 3 hours, resolve spontaneously, and then recur, giving the condition its name of “cluster” headache. Cluster attacks are excruciatingly painful and differ from other types of headache in that the pain is periorbital, unilateral, and the episodes typically involve rhinitis, drooping eyelids, and lacrimation. People experiencing a cluster headache find no relief in sleep and may even prefer to pace or stand up.
Unlike other sleep-related headaches, cluster headaches have a clear diurnal relationship (many patients arise with the headache) and seasonality, such that patients may have months of remission.5 Some patients develop chronic cluster headaches which do not have such periods of remission. Headaches in general are associated with poor quality sleep,⁶ but the association is quite pronounced in cluster headaches. People who suffer from any types of headache are also more likely to report symptoms associated with poor sleep, such as daytime fatigue and insomnia.^7,8 It has been speculated that cluster headaches may be a manifestation of a sleep disorder or that more complex sleep-related mechanisms are involved.⁹
The purpose of this review is to examine the literature on cluster headaches and their relationship to sleep to present the current understanding by the medical community.
Methods
The authors searched the National Institutes of Medicine database, PubMed, for peer-reviewed medical literature on the subject by searching keywords: “sleep headache,” “sleep-disordered headache,” “sleep cluster headache,” and “cluster headache.” The articles were then evaluated to find those which offered insight into the relationship of sleep to cluster headache. In some cases, the bibliographies of relevant articles were searched for supplemental material. The result is a narrative review of the topic.
Results
Cluster headaches have three distinct pathophysiological stages: first, chronobiological aberrations impair the sympathetic nervous system.⁵ Induction is stage two which is promoted by persistent dysfunction of the chemoreceptors accompanied by hypoxia, which may be caused by sleep apnea, vasodilatation, or some other cause. The third and final phase occurs with the signs and symptoms of the attack, resulting in trigeminal nerve stimulation with parasympathetic response. Thus, a neurological process starts the cascade of events that triggers the vasodilatation leading to the painful headache, with vasodilatation the result rather than the cause of trigeminal activation.⁵
Most cluster headache patients report sleep as a headache trigger, ^10,11 and they usually start about 90 minutes into a sleep cycle although the connection between a cluster headache and rapid-eye-movement sleep has been speculated but never established.
Cluster headaches often occur more frequently around summer and winter solstices, and it is speculated that the natural dark/light cycle may play a role as the differences are most pronounced at these times of year.
Hypothalamic activation has been observed in brain scans of cluster headache patients during an attack.^12,13 Magnetic resonance imaging has shown that cluster headache patients have asymmetry of the hypothalamus gland and these patients have more grey matter in the hypothalamus than control patients. The hypothalamus produced hypocretin (a neuropeptide) which is significantly lower in people with cluster headache than controls. Furthermore, melatonin which is produced by the pineal gland and secreted into the hypothalamus to promote sleep is not produced as much in cluster headache patients as others, particularly during attacks.¹⁴
Finally, a study of sleep found that a healthy individual rouses out of sleep 7 to 15 times per hour although sleepers are rarely aware of these momentary arousals¹¹ People with cluster headaches have fewer arousals during sleep, which has been suggested to be caused by reduced hypothalamic activity.
Sleep-disordered breathing has been linked to certain headaches, but may not play a role in cluster headaches.¹⁵ Apnea contributes to many forms of sleep-related headaches, but its association specifically to cluster headaches is unclear.
Most people with cluster headaches do not get adequate treatment and many are never diagnosed at all.¹⁶ In a survey, half of cluster headache patients said they would not tell their employer about their headache history for fear of losing their job.¹⁷
Conclusions
The relationship between sleep and cluster headache has been well known for decades but remains to be more fully elucidated. It is tempting to see sleep as a cluster headache trigger, but the circadian and circannual periodicity of these headaches deserves special consideration. It appears as if cluster headaches involve an intricate synchronization of multiple factors: hypothalamic function in the brain, the light/dark cycle, sleep architecture, trigeminal inflammation, and the response of the autonomic nervous system. Since many people with cluster headache report getting them in their sleep and have a headache upon arising which is not relieved with sleep, cluster headaches were thought to be a form of sleep-related headache, such as migraine. However, evidence seems to suggest that cluster headaches are more likely a brain disorder than a problem with sleep or sleep-disordered breathing.