Corneal nerve alterations in migraine: a systematic review of in vivo confocal microscopy and esthesiometry findings

Objective: To systematically evaluate structural and functional alterations of the subbasal corneal nerve plexus (SBCNP) in adults with migraine using in vivo confocal microscopy (IVCM) and corneal sensitivity testing, and to explore differences according to migraine subtype. Methods: PubMed, Embase, Ovid, LILACS, VHL, and MedRxiv were searched through May 24, 2025, for studies assessing IVCM or corneal sensitivity in adults with migraine. Eligible designs included case-control and cross-sectional studies. Outcomes included corneal total branch density (CTBD), nerve fiber density (NFD), nerve fiber length (NFL), nerve branch density (NBD), tortuosity coefficient (TC), and corneal sensitivity. Risk of bias was assessed using tools designed for each study type, and Certainty of evidence was graded using the GRADE framework adapted to observational studies. Due to substantial methodological heterogeneity across studies, including differences in IVCM acquisition protocols, image analysis software, and mathematical definitions of nerve parameters, findings were synthesized narratively. The protocol was registered in PROSPERO (CRD420251105525). Results: Eight studies, including 370 participants with migraine, met eligibility criteria. Most studies evaluating chronic migraine populations reported lower CTBD, NFD, and NFL compared with healthy controls, although findings remained heterogeneous across studies. Studies of episodic migraine showed contradictory findings, including preserved nerve parameters or isolated increases in TC. Two studies using different neurophysiological approaches to measure corneal sensitivity suggested altered peripheral and central trigeminal sensory processing in migraine individuals. Conclusion: Available evidence suggests that chronic migraine may be associated with structural alterations of the SBCNP, whereas episodic migraine demonstrates more variable findings, including possible increases in nerve tortuosity. Functional studies suggest altered peripheral and central trigeminal sensory processing in migraine.