Glaucoma as a dangerous interplay between ocular fluid and cerebrospinal fluid

Glaucoma is a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma, the most common type, is characterized by progressive degeneration of retinal ganglion cells and their axons in the optic nerve, resulting in progressive deterioration of visual fields. The optic nerve head is generally considered to be the primary site of axonal injury in glaucoma. Although the pathophysiology of glaucomatous optic neuropathy is not well understood, elevated intraocular pressure is considered the most important modifiable risk factor. However, in normal-tension glaucoma, intraocular pressure is not elevated and thus other risk factors must also be involved in the optic neuropathy of primary open-angle glaucoma. Several studies reported significantly lower intracranial pressure in patients with glaucoma compared with healthy subjects, suggesting that low intracranial pressure may result in a high pressure difference across the lamina cribrosa, influencing the physiology and pathophysiology of the optic nerve head by the effect of a mechanical force. Moreover, a rapidly evolving literature suggests the existence of an 'ocular glymphatic system'. This opens up new ways to understand the mechanisms underlying a range of ocular diseases such as glaucoma. In the present paper, I hypothesize that an imbalance between intraocular pressure and intracranial pressure, apart from generating mechanical forces at the lamina cribrosa, may lead to a dangerous interplay between ocular fluid and cerebrospinal fluid resulting in impaired cerebrospinal fluid entry into the optic nerve subarachnoid space and optic nerve perivascular spaces, and the perivascular space surrounding the central retinal artery in particular, thereby inhibiting glymphatic clearance of waste products from the retrobulbar or retrolaminar portion of the optic nerve. Should further research demonstrate that the proposed viewpoint is largely correct, it would hold great potential for our understanding of glaucomatous optic nerve damage and would have important implications for diagnosis and therapy of this devastating disorder.