Introduction to Cluster Headaches

Etiology of Cluster Headache

Although cluster headache was identified more than a century ago, knowledge about the cause and pathophysiology of cluster headache and the mechanisms that are responsible for triggering the headaches remained elusive until now. Historically, there have been two theories regarding the etiology of cluster headache, namely the vascular theory and the neurologic theory. It now appears that both systems are involved in the development of cluster headache and that a neurovascular origin appears to provide the most comprehensive understanding of the etiology of cluster headache.

Vascular Theory

The theory that cluster headache has a vascular origin is based on the presence of inflammation of the walls of the cavernous sinus during an attack. The cavernous sinus is a large channel of venous blood and is important because of its location relative to several cranial nerves, including the trigeminal nerve (fifth cranial nerve) and the oculomotor nerve (third cranial nerve) both of which are involved in cluster headache. Angiographic imaging studies have also revealed that during an attack, a section of the internal carotid artery and of the ophthalmic artery on the painful side of the head is dilated, indicating a loss of vascular tone. Related to vascular irregularity during an attack is the fact that during cluster headache episodes there is a marked increase in sensitivity to substances which cause vasodilation (widening of the blood vessels), such as alcohol, histamines, and nitroglycerin. Based on this information, cluster headaches used to be incorrectly referred to as "vascular headaches".

Neurologic Theory

The theory the neurologic origin of cluster headache evolves from activation of the trigeminal nerve and autonomic nervous system. When the trigeminal nerve is activated, it causes pain in and around the eye. When the autonomic nervous system is activated, this produces the associated symptoms that accompany cluster headache (eye tearing, nasal discharge, etc.). The hypothalamus (the part of the brain that regulates the sleep/wake cycle) is thought to be the trigger that activates the trigeminal nerve and the autonomic nervous system and has recently become a new target in the treatment of cluster headache.

Neurovascular Origin

It has become increasingly clear that both the vascular and neurologic systems are involved in cluster headache. Several aspects of cluster headache, such as the circadian regularity, seasonal relationship, and relapsing/remitting nature of the episodes all point to the involvement of the hypothalamus. Recently, in addition to the vascular involvement described above, imaging studies with PET scans have shown that during a cluster attack, an area within the hypothalamus on the same side as the headache is active and there are signs of increased blood flow to that location. In the absence of a cluster episode, this area is normally quiet. Thus it appears that there is a neurovascular episode relating to the circadian cycle that seems to be fundamental to the development of cluster headache.

As mentioned above, the hypothalamus regulates the internal 24-hour cycle which governs daily life. It is believed that there is a defect in the regulating center of the hypothalamus resulting in an alteration in the biological rhythms of hormone secretions. This is clear since levels of melatonin (a hormone which influences fatigue and sleep-patterns) are abnormal in patients with cluster headache. It is also a highly reliable biological marker of hypothalamic function and of the integrity of the circadian system. In patients who are in the active phase of cluster headache, nighttime melatonin production is lower than when the individual is in remission, and even during remission, the levels of melatonin are lower than in the average individual who does not suffer from cluster headache.

The onset of cluster headache pain seems to be related to the activation of a nerve pathway at the base of the brain, called the trigeminal-autonomic reflex pathway. Activation of the trigeminal nerve stimulates nearby related nerves that cause eye tearing and nasal congestion as well as other autonomic symptoms. The hypothalamus, for unknown reasons, appears to cause stimulation and activation of the trigeminal nerve which is the basis for the excruciating pain that ensues in a cluster headache attack.

Thus, it seems clear that the trigger for cluster headache is in the hypothalamus and that the vascular changes (e.g., increased blood flow of the internal carotid artery, dilation of the ophthalmic artery), are related to the headache but not the cause. Thus cluster headaches are now considered to be "neurovascular" headaches. Cluster headaches are not caused by tumors or aneurysms, although lesions of the brain may present as cluster-like headaches. It is recommended that all individuals with cluster headache should have an MRI of the brain and an MR angiogram looking at the blood vessels in the brain and neck. Some researchers regard cluster headache as a hypothalamic syndrome in which the involvement of vascular and trigeminal nerve pathways may reflect secondary involvement, rather than as a particular type of headache with specific symptoms.