Unconventional aqueous humor outflow: A review

Abstract

Aqueous humor flows out of the eye primarily through the conventional outflow pathway that includes the trabecular meshwork and Schlemm's canal. However, a fraction of aqueous humor passes through an alternative or 'unconventional' route that includes the ciliary muscle, supraciliary and suprachoroidal spaces. From there, unconventional outflow may drain through two pathways: a uveoscleral pathway where aqueous drains across the sclera to be resorbed by orbital vessels, and a uveovortex pathway where aqueous humor enters the choroid to drain through the vortex veins. We review the anatomy, physiology and pharmacology of these pathways. We also discuss methods to determine unconventional outflow rate, including direct techniques that use radioactive or fluorescent tracers recovered from tissues in the unconventional pathway and indirect methods that estimate unconventional outflow based on total outflow over a range of pressures. Indirect methods are subject to a number of assumptions and generally give poor agreement with tracer measurements. We review the variety of animal models that have been used to study conventional and unconventional outflow. The mouse appears to be a promising model because it captures several aspects of conventional and unconventional outflow dynamics common to humans, although questions remain regarding the magnitude of unconventional outflow in mice. Finally, we review future directions. There is a clear need to develop improved methods for measuring unconventional outflow in both animals and humans.

Keywords: Aqueous humor dynamics; Indirect; Mouse; Primate; Trabecular; Tracers; Uveoscleral; Uveovortex.

Figure 1

Meridional section through the uveal tract of a Macaca fascicularis . Arrowheads show supraciliary and suprachoroidal space. Unconventional outflow passes from the anterior chamber (AC), through the most posterior aspects of the uveal meshwork, enters the open spaces between longitudinal aspects of the ciliary muscle (CM) and then enters the suprachoroidal space. SC -- Schlemm’s canal; PP -- pars plana. (Wood et al. 1990) [Permission Needed]

Figure 2

Light micrograph of fluorescein dextran in the unconventional outflow pathway of a rabbit after intracameral perfusion (AC, anterior chamber). Fluorescence is visible in the conventional aqueous drainage pathway (a), comprising angular meshwork, angular aqueous plexus, and collector channels and aqueous veins, and in the unconventional outflow in the outer aspects of the ciliary body (b) and muscle, and in the suprachoroidal space (arrows). Tracer is also seen in the iris (c), which has been artefactually deflected posteriorly. (Tripathi 1977) [Permission Needed]

Figure 3

Fluorescein concentration in the vortex veins and in general circulation in a rhesus monkey after introduction into the anterior chamber. IOP was held at 20 mmHg for 60 minutes and then increased to 32 mmHg. (Pederson et al. 1977). [Permission Needed]

Figure 4

Flow measured in enucleated human eyes (Pe=0) as a function of IOP (uncertainties are standard errors) (Brubaker 1975). The dashed curve is the best fit of Q=b₁ IOP + b₂ IOP² to the data. Inset shows flow at low perfusion pressure. The solid line is from Equation (4) with flow measured at pressures of 10 and 20 mmHg. The red circle indicates the apparent unconventional outflow (U) erroneously estimated by using Equation (5). This error arises from the modest pressure-dependence of outflow facility that imposes a non-linearity in the flow-pressure relationship (dashed curved) and is not captured by Equations (4) and (5).

Figure 5

Computed tomography oblique sections through the orbital region of an adult rhesus monkey perfused with radio-opaque contrast medium in the anterior chamber. (A) After 1 hour of continuous perfusion while the monkey was alive, contrast medium was confined to the anterior chamber and there was no posterior motion of the medium. Similar images were recorded for up to 8 hours. (B) In the same monkey 35 minutes after death by pentobarbital overdose, contrast medium migrated posteriorly (red arrows). Black voids within the anterior chamber are an imaging artifact. Both images were from the same section plane in the same monkey. The right eye was set to 20 mmHg and left eye to 40 mmHg by using a fluid column. (Butler et al. 1984). [Permission Needed]

Figure 6

Effect of atropine on unconventional outflow in cynolmologus monkey eyes with pilocarpine-induced tone in the ciliary muscle. In eyes with atropine and pilocarpine in the anterior chamber (A), radioactively-labeled albumin entered the uvea and sclera to a larger extent than in eyes with pilocarpine only (B). (Bill 1967) [Permission Needed]

Figure 7

Aqueous humor from the anterior chamber communicates with tissue fluid between the muscle bundles of the ciliary muscle, the choroid, and the suprachoroidal space. Schematic shows how elastic elements in the ciliary muscle, choroid, and suprachoroid help to keep the interstitial spaces open. (Bill 1977). [Permission Needed]

Figure 8

Tracer decoration of the mouse unconventional outflow pathway 60 minutes after injection of 70 kDa dextran into the anterior chamber. (Lindsey and Weinreb 2002) Fluorescence lined the suprachoroidal space (ciliary processes, CP; choroid ,C; sclera, S). High-magnification inset shows some regions of sclera near the suprachoroidal space contained substantial tracer (closed arrows) and other scleral regions contained minimal tracer (open arrow). Retinal pigment epithelium is indicated by a vertical arrow. Tracer did not enter the retina (R). [Permission Needed]

Figure 9

Sagittal section through the anterior ciliary body. (A) Vehicle-treated control eye. CM, Ciliary muscle; I, iris. CP, ciliary processes. (B) After treatment with PGF2α, for 4 days. Note the enlarged spaces between the thin muscle fiber bundles in the prostaglandin-treated eye (arrows). Asterisk: Greeff’s vesicle (Lütjen-Drecoll and Tamm 1988). [Permission Needed]