The pathophysiology of cluster headaches is much less understood. While there appears to be a genetic component, no gene has been clearly identified.8

Cluster headache is currently considered to involve a dysfunction of the hypothalamus, but not involve brainstem activation, unlike migraine. One theory is that the hypothalamus is the determinant of whether an episode will be initiated, but the peripheral nervous system then has to be activated for an attack to occur.6,18

Imaging can show which parts of the brain are active in cluster headaches, supporting the involvement of the hypothalamus and other brains areas in the pain matrix. Imaging has also shown the autonomic (parasympathetic and sympathetic) activation of the trigeminovascular system.19

In common with migraine, cluster headaches will involve the trigeminal autonomic response, with the superior salivatory nucleus (SuS) being activated. The SuS is linked to the hypothalamus, and neurons projecting from the SuS release a neurotransmitter, vasoactive intestinal polypeptide (VIP), during cluster headaches (and in around 70 per cent of migraine cases). This results in cranial autonomic symptoms such as facial flushing, eye lid droop, congestion and tear production.6,20