CGRP-provoked headache is associated with a neuroimmune signature in idiopathic intracranial hypertension

Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure and disabling headaches, yet its underlying mechanisms remain poorly defined. Calcitonin gene-related peptide (CGRP) is a key neuropeptide implicated in migraine and headache attributed to IIH. CGRP-driven neuroinflammation is implicated in migraine generation but whether CGRP-provoked headache in IIH is accompanied by dynamic neuroimmune activation during the ictal phase remains unknown. We aimed to characterise cytokine alterations during experimentally-induced IIH headache attacks provoked by CGRP. In a randomised, double-blind, placebo-controlled, two-way crossover study (IIH Provoke: ISRCTN13251508), 16 women with IIH underwent two inpatient visits receiving intravenous CGRP (1.5 µg/min for 20 min) or placebo (isotonic saline). Blood samples were collected at baseline and either at peak headache or at the end of the visit, if no headache occurred. Plasma cytokines were measured using the Olink ® Target 48 Cytokine Panel. CGRP induced a typical IIH headache attack within the sampling period in 7/16 participants. Compared with baseline, eight cytokines were significantly elevated during CGRP-provoked headache attacks: C-C motif chemokine 4 (CCL4), CCL8, interleukin-6 (IL-6), IL-17C, IL-27, oncostatin M (OSM), hepatocyte growth factor (HGF), and transforming growth factor-α (TGF-α) ( P < 0.05). These changes were not observed after placebo or in participants who received CGRP without developing headache. CGRP-provoked IIH headache attacks were associated with elevations in pro-nociceptive mediators (IL-6, CCL4, OSM) and immune-related cytokines (IL-17C, IL-27, HGF, TGF-α). These findings suggest that CGRP-provoked headache in IIH is associated with changes in circulating cytokines consistent with a neuroimmune response during the ictal phase. Larger cohorts are required to validate these observations and explore neuroinflammation as a therapeutic target in IIH headache.