Hallmarks of primary headache: part 1 - migraine

Abstract

Background and aim: Migraine is a common disabling conditions which, globally, affects 15.2% of the population. It is the second cause of health loss in terms of years lived with disability, the first among women. Despite being so common, it is poorly recognised and too often undertreated. Specialty centres and neurologists with specific expertise on headache disorders have the knowledge to provide specific care: however, those who do not regularly treat patients with migraine will benefit from a synopsis on the most relevant and updated information about this condition. This paper presents a comprehensive view on the hallmarks of migraine, from genetics and diagnostic markers, up to treatments and societal impact, and reports the elements that identify migraine specific features.

Main results: The most relevant hallmark of migraine is that it has common and individual features together. Besides the known clinical manifestations, migraine presentation is heterogeneous with regard to frequency of attacks, presence of aura, response to therapy, associated comorbidities or other symptoms, which likely reflect migraine heterogeneous genetic and molecular basis. The amount of therapies for acute and for prophylactic treatment is really wide, and one of the difficulties is with finding the best treatment for the single patient. In addition to this, patients carry out different daily life activities, and might show lifestyle habits which are not entirely adequate to manage migraine day by day. Education will be more and more important as a strategy of brain health promotion, because this will enable reducing the amount of subjects needing specialty care, thus leaving it to those who require it in reason of refractory condition or presence of comorbidities.

Conclusions: Recognizing the hallmarks of migraine and the features of single patients enables prescribing specific pharmacological and non-pharmacological treatments. Medical research on headaches today particularly suffers from the syndrome of single-disease approach, but it is important to have a cross-sectional and joint vision with other close specialties, in order to treat our patients with a comprehensive approach that a heterogeneous condition like migraine requires.

Keywords: Aura; CGRP; Calcitonin gene-related peptide; Ditans; Gepants; Medication overuse headache; Migraine; Productivity loss; Triptans.

Fig. 1

Overview of migraine genetics. Notes. An overview of the complex genetic architecture of migraine, from polygenic model on the left, to monogenic model on the right

Fig. 2

Role of CGRP and Amylin in the trigeminovascular system. Notes. Representation of the key elements of the trigeminovascular system, comprising meningeal blood vessels, local mast cells and trigeminal nerve fibres during a migraine headache attack. Binding of CGRP and amylin to their receptors results in dilation, and shear stress in the meningeal vessels. CGRP additionally activates mast cells, triggering the release of a plethora of pro-nociceptive compounds such as serotonin, histamine, leukotrienes, prostaglandins, ATP, and NO, further exciting the nociceptive fibres and promoting more CGRP release. ATP, adenosine triphosphate; CGRP, calcitonin gene-related peptide; NO, nitric oxide

Fig. 3

Molecular pathways underlying the pathophysiology of migraine headache. Notes. Activation of the trigeminovascular system results in the release of CGRP, amylin and PACAP from c-fibers, and their release can be modulated via de activation of presynaptic receptors. Binding of these peptides to their receptors results in changes in vascular tone and nociceptive transmission. These responses can be regulated by modulating the different components of their signalling cascades, which has been studied using provocation models, in which potential trigger molecules are used to induce migraine attacks in humans. ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CGRP, calcitonin gene-related peptide; CGRPR, CGRP receptor; GTP, guanosine triphosphate; NO, nitric oxide; PACAP, Pituitary adenylate cyclase activating polypeptide; PDE3, phosphodiesterase 3; PDE5, phosphodiesterase 5; VIP, vasoactive intestinal peptide

Fig. 4

Neurophysiological hallmarks of migraine: peripheral to central processes