Glymphatic stasis at the site of the lamina cribrosa as a potential mechanism underlying open-angle glaucoma

Clin Exp Ophthalmol. 2017 Jul;45(5):539-547. doi: 10.1111/ceo.12915. Epub 2017 Feb 27.

Abstract

The underlying pathophysiology of primary open-angle glaucoma remains unclear, but the lamina cribrosa seems to be the primary site of injury, and raised intraocular pressure is a major risk factor. In recent years, a decreased intracranial pressure, leading to an abnormally high trans-lamina cribrosa pressure difference, has gained interest as a new risk factor for glaucoma. New research now lends support to the hypothesis that a paravascular transport system is present in the eye analogous to the recently discovered 'glymphatic system' in the brain, which is a functional waste clearance pathway that promotes elimination of interstitial solutes, including β-amyloid, from the brain along paravascular channels. Given that β-amyloid has been reported to increase by chronic elevation of intraocular pressure in glaucomatous animal models and to cause retinal ganglion cell death, the discovery of a paravascular clearance system in the eye may provide powerful new insights into the pathophysiology of primary open-angle glaucoma. In this review, we provide a new conceptual framework for understanding the pathogenesis of primary open-angle glaucoma, present supporting preliminary data from our own post-mortem study and hypothesize that the disease may result from restriction of normal glymphatic flow at the level of the lamina cribrosa owing to a low intracranial pressure and/or a high trans-lamina cribrosa pressure gradient. If confirmed, this viewpoint could offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.

Keywords: glaucoma; intracranial pressure; intraocular pressure; lamina cribrosa; trans-lamina cribrosa pressure difference.

Publication types

  • Review

MeSH terms

  • Animals
  • Cerebrospinal Fluid Pressure / physiology*
  • Glaucoma, Open-Angle* / etiology
  • Glaucoma, Open-Angle* / pathology
  • Glaucoma, Open-Angle* / physiopathology
  • Humans
  • Intraocular Pressure / physiology*
  • Optic Disk / pathology*
  • Retinal Ganglion Cells / pathology*
  • Tonometry, Ocular