The Glymphatic Hypothesis of Glaucoma: A Unifying Concept Incorporating Vascular, Biomechanical, and Biochemical Aspects of the Disease

Abstract

The pathophysiology of primary open-angle glaucoma is still largely unknown, although a joint contribution of vascular, biomechanical, and biochemical factors is widely acknowledged. Since glaucoma is a leading cause of irreversible blindness worldwide, exploring its underlying pathophysiological mechanisms is extremely important and challenging. Evidence from recent studies appears supportive of the hypothesis that a “glymphatic system” exists in the eye and optic nerve, analogous to the described “glymphatic system” in the brain. As discussed in the present paper, elucidation of a glymphatic clearance pathway in the eye could provide a new unifying hypothesis of glaucoma that can incorporate many aspects of the vascular, biomechanical, and biochemical theories of the disease. It should be stressed, however, that the few research data currently available cannot be considered as proof of the existence of an “ocular glymphatic system” and that much more studies are needed to validate this possibility. Even though nothing conclusive can yet be said, the recent reports suggesting a paravascular transport system in the eye and optic nerve are encouraging and, if confirmed, may offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.

Impaired cerebrospinal fluid dynamics along the entire optic nerve in normal‐tension glaucoma

“…A recent study by Hou et al (2016) in dogs demonstrated if the intracranial pressure (ICP) (measured in the left brain ventricle) falls below a certain level ("breakpoint"), the correlation between ICP and ON SAS pressure (measured in the retrobulbar ON SAS) gets lost. In the latter, a dysfunction of the glymphatic system is favoured as a possible pathophysiological mechanism (Wostyn et al 2017). Third, normal CSF flow also depends on appropriate CSF outflow.…”

“…Recent research suggests a relationship between glaucoma and Alzheimer's disease (AD) (Allingham et al 2009;Liu & Tian 2011). In the latter, a dysfunction of the glymphatic system is favoured as a possible pathophysiological mechanism (Wostyn et al 2017).…”

“…In the last years, the role of cerebrospinal fluid (CSF) has gained interest. Recently, a new hypothesis based on impaired clearance of neurotoxic substances within the ON subarachnoid space (SAS) shifted the focus from mechanical forces to biochemical processes (Wostyn et al 2017). Recently, a new hypothesis based on impaired clearance of neurotoxic substances within the ON subarachnoid space (SAS) shifted the focus from mechanical forces to biochemical processes (Wostyn et al 2017).…”

“…A higher translaminar pressure difference (TLP) has been suggested to be involved in the pathophysiology of glaucomatous damage (Ren et al 2010;Jonas et al 2016); however, the exact mechanism causing ON damage is still not understood. Recently, a new hypothesis based on impaired clearance of neurotoxic substances within the ON subarachnoid space (SAS) shifted the focus from mechanical forces to biochemical processes (Wostyn et al 2017).…”

Current concepts of cerebrospinal fluid dynamics and the translaminar cribrosa pressure gradient: a paradigm of optic disk disease

“…In addition to the lymphatic system, a glymphatic system is believed to be involved in the waste clearing process of the central nervous system, optic nerve, and possibly the eye. 20,74,78,79,202,203 The glymphatic system consists of a network of perivascular tunnels formed by astroglial cells. To enter the glymphatic pathway, CSF courses the perivascular spaces of the brain via the SAS or transependymal resorption from the ventricles (Fig.…”