CHAPTER 1 10 1 prostaglandins may be pivotal in the development of migraine attacks.7, 31, 32 Increased sensitivity of the trigeminal system is believed to be an important underlying mechanism in migraine pathology. The mechanisms underlying this hypersensitivity during a migraine attack remain unclear. Additionally, the hypothalamus is believed to be involved in the prodromes (symptoms that precede the migraine headache).33 Clinically this is evident by increased fatigue, food cravings, yawning and irritability in the patients. Therefore the phase before the migraine attack can also give insights into the pathophysiology of migraine. Cluster headache Various mechanisms/structures, e.g. the trigeminovascular system and the hypothalamus, are believed to be involved in cluster headache pathophysiology and it is thought that the interplay of these systems is responsible for the clinical presentation.34, 35 However, how these structures interact with each other and the mechanisms on the initiation of an attack remain unclear. Similar to migraine, also in cluster headache the trigeminovascular system is believed to be involved in pain processing.34, 35 Different divisions of the trigeminal nerve are primarily responsible for the innervation of cranial structures. Stimulations of the different divisions produce pain in different locations, activation of the second-order trigeminocervical neurons at the ophthalmic division is in line with the clinical presentation of pain in the peri-orbital region.35 The trigeminal-autonomic reflex is also associated with the physiological and anatomical landmarks of a cluster headache attack. This reflex is activated upon irritation and produces parasympathetic symptoms, such as nasal congestion and lacrimation.36 The reflex travels from trigeminal nerve endings to second-order trigeminocervical complex, that projects to the superior salivatory nucleus located in the pons.34, 35 These projections in turn synapse in the peripheral sphenopalatine ganglion and postganglionic parasympathetic nerves and then innervate nasal, pharyngeal and lacrimal glands, inducing autonomic symptoms.35 Activation of the trigeminovascular system and the trigeminal-autonomic reflex leads to release of neuropeptides (e.g. CGRP and PACAP). In addition, the hypothalamus is believed to be a key player in cluster headache pathophysiology. The hypothalamus is involved in the regulation of sleep and circadian rhythms.37 The hypothesis that the hypothalamus is involved in cluster headache is supported by the clinical feature of a circadian rhythm in cluster headache and the finding that the hypothalamus shows increased activation during glyceryl trinitrate (GTN) induced attacks of cluster headache.38 Rationale for biochemical studies Identifying biochemical markers, biomarkers, can help uncover the metabolic underpinnings of human disease. Validated biomarkers can improve diagnosis, prognosis and assess the effectivity of
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