GENERAL INTRODUCTION 9 1 may last for 15-180 minutes and can occur from once a day up to 8 times or more a day. 1 Cluster headache attacks commonly follow a circadian rhythm with attacks frequently occurring at night and according to a seasonal pattern. The majority of patients have episodic cluster headache, characterized by periods of cluster headache of weeks to months, alternating with attack-free periods of at least 3 months. A small proportion (10-15%) of patients have chronic cluster headache where the cluster periods do not remit for more than three months for at least one year. Cluster headache has a prevalence of around 0.12% and occurs more often in men than women, with a male-to-female ratio of 2:1.18, 19 Of note, smoking and psychiatric co-morbidities are prevalent among cluster headache patients.20 The pathophysiology of cluster headache is poorly understood with current evidence pointing at hypothalamic involvement.3 Genetic predisposition seems to play an important role as illustrated by twin and family studies but no genetic factors have been identfied.21 Pathophysiology Migraine Different disease mechanisms are considered to be involved in migraine pathophysiology, such as neurological, cerebrovascular, and neuroinflammatory mechanisms. The aura phase is most likely caused by CSD, a wave of neuronal and glial depolarization, that is an initial hyperactivity is followed by a prolonged inactivity, resulting in a wave that propagates slowly across the cerebral cortex.22, 23 The depolarization wave classically begins in the occipital (visual) cortex and correlates with a variety of positive aura patterns, as reported by patients.24, 25 Mechanisms of CSD are heavily investigated in animals using various stimuli, such as topical application of KCl, injection of current, or an optogenetic stimulus, and it was shown that CSD can activate headache mechanisms.26 However, there is only limited (neuroimaging) data that can be taken as proof of a spreading depolarization event that qualifies as an aura in humans.27 Also whether the CSD is causally associated with the initiation of the headache phase in patients remains an enigma.28 It is generally accepted that the headache phase involves the activation and sensitization of the trigeminovascular system.29 The trigeminovascular system consists of nociceptive trigeminal afferents from the trigeminal ganglion that surround cranial blood vessels and dura mater projected from the trigeminal cervical complex in the brainstem, which includes the trigeminal nucleus caudalis and the dorsal horns of cervical spinal nerves C1 and C2.30 Following stimulation, the trigeminal afferents transfer nociceptive signals through the trigeminal ganglion to the trigeminal cervical complex. In the brainstem, the signal is modulated and further conducted to the thalamus via ascending pain pathways and reaches the cortex.25 Upon stimulation, the trigeminal fibres release proinflammatory neuropeptides (e.g. calcitonin-gene related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP) substance P and neurokinin A) and other mediators that cause vasodilation of the dural and pial vessels.25 There is ample evidence that vasodilators such as
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