The emerging role of the meningeal lymphatic and glymphatic systems in migraine pathophysiology: a systematic review

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Not reported — no meta-analysis performed; findings are qualitative and narrative

• Primary Outcome: Characterisation of meningeal lymphatic and glymphatic system alterations in migraine: DCE-MRI demonstrated changes in lymphatic enhancement in both episodic and chronic migraine; DTI-ALPS showed heterogeneous findings with more consistent abnormalities in chronic and high-frequency migraine; preclinical models showed impaired glymphatic influx and reduced CSF efflux via meningeal lymphatics following CSD, nitroglycerin exposure, and FHM mutations

• Nnt Or Sensitivity: Not applicable — mechanistic/pathophysiological systematic review; no therapeutic intervention assessed; no diagnostic accuracy metrics reported

• Confidence Interval: Not reported

Clinical Application

Current clinical application is not feasible. DCE-MRI and DTI-ALPS are research-grade neuroimaging techniques not routinely available in standard headache clinics. No therapeutic interventions targeting meningeal lymphatics or the glymphatic system have been validated for migraine. The evidence base is insufficient to support any change to current diagnostic or treatment algorithms. In Australia, migraine management is guided by RACGP and Headache Australia frameworks, with PBS-listed preventive therapies including topiramate, amitriptyline, propranolol, and — since TGA approval — CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab) with PBS listing for chronic migraine. This review does not directly inform PBS prescribing or RACGP guidelines at this stage. However, the mechanistic insights into neuroinflammation and glymphatic dysfunction may have future relevance to understanding why CGRP-pathway therapies are effective and to identifying novel therapeutic targets. Australian neuroimaging research centres (e.g., Florey Institute, QIMR Berghofer) may find this review useful for designing translational studies. No TGA-approved therapies targeting meningeal lymphatics currently exist. Adults with episodic or chronic migraine, particularly those with high-frequency attacks or refractory disease where neuroinflammatory mechanisms may be relevant. Findings are most directly applicable to research populations undergoing advanced neuroimaging. Preclinical findings apply to animal models of migraine and require further translational validation before clinical application.

Abstract

BACKGROUND/OBJECTIVE: Migraine is a common, debilitating neurological disorder of unclear pathophysiology. Recent evidence has implicated impaired meningeal lymphatic function and its interaction with the glymphatic system in the development of neuroinflammation and pain sensitization. This systematic review aimed to summarize existing evidence on the role of the meningeal lymphatic and glymphatic systems in migraine pathophysiology. METHODS: Following the PRISMA 2020 recommendations, we searched PubMed, Web of Science, and Scopus from inception to December 15, 2025. Inclusion criteria comprised human or animal studies examining meningeal lymphatic or glymphatic function in migraine or validated migraine animal models. SYRCLE's risk of bias tool for animal studies and the Joanna Briggs Institute (JBI) critical appraisal tools were used for quality assessment. RESULTS: The search yielded a total number of 457 records, out of which 10 articles fulfilled the eligibility criteria. These comprised six imaging studies conducted on human populations and four preclinical studies performed on animal models. Studies using dynamic contrast-enhanced (DCE)-MRI have shown changes in lymphatic enhancement characteristics in both episodic and chronic migraines. Diffusion tensor imaging along perivascular spaces (DTI-ALPS) yielded heterogeneous findings, with abnormalities more consistently observed in chronic and high-frequency migraine. Preclinical models demonstrated that cortical spreading depression, nitroglycerin exposure, and familial hemiplegic migraine mutations impaired glymphatic influx and reduced cerebrospinal fluid efflux through meningeal lymphatic vessels. DISCUSSION: Initial research has shown that altered lymphatic and glymphatic systems may be related to migraine. Nonetheless, there is no existing literature on whether these conditions can be considered causative agents for migraines. There is a need for longitudinal imaging studies in a larger population. REGISTRATION: PROSPERO ID: CRD420251266296.

References

1. 1.Bagheri, K., Sahrai, H., Safari Dehnavi, N., Taheri, N., Norouzi, A., Talebi, M., Mosaddeghi-Heris, R., & Naseri, A. (2026). The emerging role of the meningeal lymphatic and glymphatic systems in migraine pathophysiology: a systematic review. The Journal of Headache and Pain. PubMed ID: 42316010.