CHAPTER 1 8 1 Introduction This thesis aims to further unravel the pathophysiology of migraine and cluster headache. Both migraine and cluster headache are disabling primary headache disorders characterized by attacks of severe headache and associated symptoms.1 Cluster headache is one of the trigeminal autonomic cephalalgias.1 By definition, primary headache disorders are not the result of any other underlying disease or process, contrary to secondary headache disorders. Although much progress has been made with unravelling the disease mechanisms of migraine and cluster headache, their pathophysiology remains poorly understood.2, 3 A major hurdle is that there are no diagnostic biomarkers and the diagnosis, therefore, is still made using direct interviews and/or questionnaires based on clinical consensus criteria of the International Classification of Headache disorders (ICHD-3 criteria).1 A shortcoming of the current classification criteria is that it does not take the complexity of disease mechanisms into account. In other words, the ICHD-3 criteria do not fully capture the heterogeneity of the disease, including the underlying neurobiological and genetic factors.4 Understanding the pathophysiology better will improve diagnosis, prognosis, and generate new treatment options. Clinical characteristics Migraine Migraine is characterized by recurrent episodes of severe often unilateral pulsating headache accompanied by nausea, vomiting and/or photo- and phonophobia lasting for 4-72 hours.1 Migraine can be subdivided in two main subtypes: migraine without aura and migraine with aura. For the latter, headaches are preceded by transient neurological symptoms, known as the aura phase, which typically lasts from 5 until 60 minutes.1 Cortical spreading depolarization (CSD) is the presumed underlying mechanism of the aura in migraine.5-8 A typical migraine attack consist of a preictal, ictal (aura and/or headache), and postictal (postdromal) phase.9, 10 Clinically, a patient can be described as interictal, when there is no attack or ictal when an aura and/or migrainous headache is occurring. Migraine is three times more prevalent in women than in men with a peak prevalence of 25%.11, 12 Migraine is associated with several neuropsychiatric disorders, among which depression.13 Migraine is considered a multifactorial (complex) genetic disorder, with a strong familial aggregation.14-16 Complex traits are typically brought about by a combination of multiple genetic variants, each with a small effect size, and behavioural and environmental factors. Hemiplegic migraine (HM) is a rare subtype of migraine with aura, HM is characterized by attacks that are associated with motor weakness that can lead to hemiplegia during the aura phase.1 Cluster headache Cluster headache is a primary headache disorder characterized by excruciating unilateral headache or facial pain accompanied by ipsilateral facial autonomic symptoms and/or restlessness.1, 17 Attacks
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