Novelty in Inflammation and Immunomodulation in Migraine.

[BACKGROUND] Migraine is a diffuse and disabling disease. Its pathophysiology is complex and involves both central and peripheral dysfunctions.

[OBJECTIVE] This review will discuss the pathogenesis of migraine from the origin of the neuro-inflammatory theory, to the modern pathophysiological model and the latest therapies.

[METHODS] PUBMED and EMBASE (up to May 2019) were searched for: migraine, inflammation, immunomodulation. An additional search was carried out from the bibliography of previous review articles.

[RESULTS] Migraine was thought to be mainly a vascular disorder, according to the so-called "vascular theory". Based on animal models, a new hypothesis called "the neuro-inflammatory" was conceived at the end of the 20th century. The growing knowledge about the trigeminovascular system and its role in the inflammatory-pain pathway, allowed to identify other specific neurotransmitters, such as the Calcitonin Gene-Related Peptide and Pituitary Adenylate Cyclase-Activating Peptide. Evidence was provided that the inflammatory-pain system could become sensitised and, due to this sensitisation, the pain could also perpetuate, even in the absence of any triggers of the migraine attack. At last, brain immune cells modification during cortical spreading depression in migraine was demonstrated, along with the existence and function of the glymphatic system. The better comprehension of the immune system abnormalities allowed the development of new immunomodulating drugs: the monoclonal antibodies against the CGRP or the CGRP receptor. Moreover, new insights into the molecular mechanism of CGRP, and the function of C-fibres and Aδ-fibres, highlighted the mechanism of action of Botulinum Toxin type A in the treatment of chronic migraine.