Neural Coupling of Intracranial Pressure and Aqueous Humor Outflow Facility: A Potential New Therapeutic Target for Intraocular Pressure Management

Primary open angle glaucoma (POAG) is a chronic progressive optic neuropathy that is characterized by changes in the structure of the optic disc (i.e., optic disc cupping) and thinning of the retinal nerve fiber layer (RNFL), which are accompanied by an irreversible loss of visual function that is initially detectable clinically in the peripheral visual field. Intraocular pressure (IOP) lowering is the only treatment proven to prevent glaucoma onset and arrest disease progression, although glaucoma can develop and progress in patients with statistically normal native IOP. Further, glaucoma can still progress after clinical IOP lowering, as current pharmacological treatments to lower IOP are only partially effective and surgical treatments have a high long-term failure rate. It is imperative that improved treatments be developed to manage this blinding disease.

Glaucoma is among the leading causes of permanent vision loss worldwide, but the mechanisms of damage are not fully understood. The retinal ganglion cells (RGC) and their axons transmit visual information from the retina to the brain, and these axons pass out of the eye through the scleral canal at the optic nerve head (ONH), which is spanned by a fenestrated connective tissue structure known as the lamina cribrosa. The preponderance of evidence suggests that the RGC axons are damaged in the laminar region of the ONH in glaucoma. Among the known risk factors, the most consistent is elevated intraocular pressure (IOP), although the “safe” IOP threshold varies widely among individuals. IOP acts to deform ONH tissues through both direct pressure on the prelaminar and laminar tissues, as well as through expansion of the scleral canal. Retrobulbar cerebrospinal fluid pressure (CSFP) in the subarachnoid space surrounding the optic nerve partially counteracts IOP at the lamina cribrosa through the translaminar pressure (Figure 1; TLP=IOP-CSFP) but does not counter IOP’s effects on the scleral canal.(1) Given this interplay of pressures acting on the ONH, CSFP has been hypothesized as a driving factor in glaucoma and it is likely that translaminar pressure (TLP) is more relevant to glaucoma than either IOP or CSFP alone.(2)

Figure 1:

Diagram of a crossection through the optic nerve head in the posterior pole of the eye, showing the intraocular pressure (IOP) and the cerebrospinal fluid pressure (CSFP) forces on the lamina cribrosa, the site of retinal ganglion cell axon damage in glaucoma. Note that pressurized cerebrospinal fluid in the subarachnoid space (SAS) surrounds the optic nerve, and CSFP is roughly equivalent to intracranial pressure (ICP). The translaminar pressure (TLP) is IOP-CSFP, and the translaminar pressure gradient (TLPG) is TLP/lamina cribrosa thickness.

In addition, since the lamina cribrosa bears the bulk of the net pressure load in the ONH due to its high stiffness relative to the surrounding neural tissues, laminar thickness plays a critical role in the distribution of TLP in the ONH via the translaminar pressure gradient (TLPG = TLP/lamina cribrosa thickness). It is important to note that TLP is different from TLPG, the pressure gradient acting across the thickness of the lamina cribrosa; TLPG takes the laminar structure into account and may prove even more relevant to glaucoma than IOP, CSFP, or TLP.

Retrospective clinical studies have suggested that increased CSFP (and low TLP) is protective for glaucoma and low CSFP (and high TLP) increases glaucoma risk, after accounting for the effects of IOP.(3) Prospective studies have found that CSFP is lower in patients with glaucoma compared to healthy controls and patients with ocular hypertension.(4) A recent study showed that nycthemeral TLP fluctuations are driven primarily by CSFP and not IOP, which is important because prior studies have shown that pressure fluctuations may be important in glaucoma.(5) Experimental and clinical studies have shown that intracranial pressure (ICP) and retrolaminar CSFP are generally similar and so it is reasonable to use ICP as a surrogate for CSFP when quantifying TLP.

In the present study by Ficarrotta and Passaglia, results show that aqueous outflow facility, a measure of the resistance to fluid exiting the eye and hence a determinant of IOP, is coupled to ICP via neural pathways in rats. An increase in ICP was accompanied by a decrease in aqueous outflow facility through the conventional pathway (~2/3 of total outflow), such that a 15 mmHg elevation in IOP drove a 3 mmHg increase in IOP. Outflow facility changes were independent of blood pressure, reversible, scaled with increases in ICP, and were blocked by either neural blockade via eyedrops or death. Given that IOP and/or TLP modulation are the primary treatment modalities for glaucoma, these results reveal a new therapeutic pathway that was heretofore unknown. If this new pathway can be confirmed in humans and leveraged to control aqueous humor outflow facility directly without affecting systemic ICP or CSFP, then therapies could be developed to decrease IOP and TLP as a treatment for glaucoma, or increase IOP and TLP in astronauts to combat spaceflight-associated neuro-ocular syndrome (SANS). This would be a powerful new tool in the clinical management of glaucoma, ocular hypotony, and SANS.