Segmental Aqueous Outflow and Trabecular Bypass

5 Segmental Aqueous Outflow and Trabecular Bypass

Alex Huang

Aqueous humor is produced at the ciliary processes, moves into the anterior chamber, passes through the trabecular meshwork (TM) into Schlemm’s canal (SC), and then into collector channels, intrascleral venous plexuses, and finally the aqueous and episcleral veins, where it joins the systemic venous circulation.1–3 This two-dimensional perspective of conventional outflow pathway organization gives the impression that aqueous outflow occurs uniformly around the circumference of SC and then radially away from the limbus, but this is not necessarily the case. The introduction of minimally invasive glaucoma surgery (MIGS) to bypass discrete regions of the TM has made it important and clinically relevant to better characterize the nature of segmental aqueous outflow, during which the outflow rate through different regions of the conventional pathway and around the circumference of the eye may vary.

Segmental outflow has been described in different species and by different methods. Introduction of labeled microbead tracers into the anterior chamber has shown segmental outflow through the TM in species such as rodents, cows, and humans.^4–12 It suggests the presence of high-flow and low-flow regions in the TM attributable to the influence of extracellular matrix components such as proteoglycans and their regulators.^10,11 Even outflow across Schlemm’s endothelium may be segmental and influenced by Rho-kinase inhibition.¹² A unifying funneling theory has been proposed to explain the dynamics of segmental outflow through TM and SC regions.¹³ However, recall that the molecular weight of water is different from that of microbeads, with the latter likely utilizing different cellular mechanisms to facilitate phagocytic transcellular or paracellular movement. Although it is not clear how closely the path of microbead outflow mimics that of water or aqueous humor, it does indicate that segmental passage through the TM is possible.

To study post-TM pathways, canalography and channelography have been performed in real time following injection of tracers through a cannula inserted into SC during human glaucoma surgery.^14–16 Although the delivery of tracers under pressure and the access route used by these techniques may not be physiological, they nevertheless reveal an outflow path from SC onward that agrees with our morphological understanding of the conventional outflow route distal to TM.

Ideally, to capture physiologically relevant segmental outflow, outflow imaging should be performed live, in real time, and at relatively physiological perfusion pressures. Visualization of the aqueous outflow tract around the eye’s limbal circumference should be possible, and findings should reflect outflow behavior in the whole conventional outflow tract from anterior chamber to episcleral veins.

We are developing aqueous angiography as a novel real-time outflow imaging method.¹⁷ The method is based on general principles of retinal intravenous angiography, wherein fluorescein (or other tracer agents) is introduced into the peripheral veins to study retinal and choroidal blood flow. In aqueous angiography, 2.5% fluorescein (as described by the American Academy of Ophthalmology for capsular staining during cataract surgery¹⁸) is introduced intracamerally at physiological pressures. Aqueous angiography in an enucleated pig (Fig. 5.1) and in cow and human eyes demonstrates regions of positive and negative signal, reflecting segmental aqueous outflow in these models. The fluorescein route traversed encompasses the whole conventional outflow tract, including the TM. We are using this technique to determine relative outflow rates around the circumference of the eye ex vivo and in vivo, and the technique may have potential for human translation.

The MIGS trabecular bypass stents are typically placed nasally during surgery, but it is not clear if this approach best exploits segmental outflow in each eye, as the distribution and organization of distal outflow structures and the nature of flow in different parts of the system may vary from eye to eye, possibly explaining the variable success reported of the trabecular bypass procedures. It may be that customizing bypass location to suit segmental outflow features of each eye will enhance the success of these surgeries.