Elsevier

Experimental Eye Research

Volume 88, Issue 4, 30 April 2009, Pages 760-768
Experimental Eye Research

Review
Uveoscleral outflow – A review

https://doi.org/10.1016/j.exer.2008.12.012Get rights and content

Abstract

The uveoscleral outflow route was described more than 40 years ago. Part of aqueous leaves the eye through the iris root. The ciliary muscle, and there are large species differences in the fraction of aqueous outflow that leaves the eye through this route. In non-human primates 40–50% of aqueous leaves the eye by the uveoscleral route. In human eyes most data has been collected by indirect calculations, with results suggesting a similar fraction, at least in eyes from younger individuals. An age-dependent reduction in uveoscleral flow in human eyes may explain the initial difference seen between non-human primate and human eyes. Unlike trabecular outflow, intraocular pressures within the normal range have little effect on uveoscleral outflow. This may be explained by the fact that changes in intraocular pressure have little effect on the pressure gradient for flow through the ciliary muscle, which is likely to be the rate-limiting step in uveoscleral outflow. The state of the ciliary muscle is important and contraction reduces while relaxation increases uveoscleral flow. Similar effects are achieved with cholinergic agonists and antagonists. Epinephrine increases uveoscleral flow, most likely through stimulating β2-adrenergic receptors. Prostaglandin F and prostaglandin F-analogues effectively reduce intraocular pressure by increasing uveoscleral flow. This is mediated by structural changes in the extracellular matrix of the ciliary muscle, and is likely to contribute to a valuable excess route for aqueous and proteins during intraocular inflammation. Whether uveoscleral flow plays a significant role in any other eye disease is not clear. Thus, 40 years later we are able to successfully increase aqueous flow through the uveoscleral route, a valuable contribution to glaucoma treatment, but we still have only a limited understanding on its physiological role.

Introduction

In the mid-1960s Anders Bill was investigating how labeled molecules left the anterior chamber. The studies were initiated by a search for a suitable tracer to determine aqueous flow (Bill, 1984). He infused labeled molecules of various sizes into the anterior chamber and collected fluid appearing on the anterior sclera. He found that only about 80% of the total outflow passed through the trabecular meshwork, and into the general circulation (Bill, 1965). In several later studies he confirmed the presence of a second outflow route, the unconventional or uveoscleral outflow route (Bill and Hellsing, 1965, Bill, 1966a, Bill, 1966b). Albumin left the anterior chamber at a higher rate than it appeared in blood, and the part that had not entered the general circulation could be found in the ciliary body, choroid, sclera and episcleral tissues.

Fig. 1 shows the general anatomy of the outflow routes in the anterior segment of a cynomolgus monkey. There is no epithelial barrier between the anterior chamber and the clefts between the ciliary muscle bundles. In young human eyes the inter-muscular connective tissue between the muscle bundles is sparse (Fig. 2A), and in a study on monkeys Inomata et al. (1972) concluded that water and small molecules are able to diffuse through the sclera. Injected into the anterior chamber even 1 μm large latex spheres pass into the muscle. Spheres of 0.1 μm can be found in the loose connective tissue surrounding blood vessels and nerves passing through the sclera, while 10 nm Thorotrast particles readily entered the sclera (Inomata and Bill, 1977). Krohn and Bertelsen, 1997, Krohn and Bertelsen, 1998 have studied the outflow routes through the sclera by injecting methylmethacrylate or stained gelatine into the suprachoroidal space of human donor eyes. They found that transscleral drainage occurred through perivascular spaces (Fig. 3), but they also observed channels (Fig. 4) that they concluded were veins communicating with an intrascleral venous plexus. Thus large proteins can also pass the sclera through perivascular spaces and channels. Most constituents of aqueous can probably pass the sclera independently of scleral pores. The hydraulic conductivity of the sclera is more than enough to handle the small amount of fluid expected to leave the eye through the uveoscleral route. Fatt and Hedbys (1970) and, more recently Jackson et al. (2006), have determined the hydraulic conductivity of the human sclera. Jackson et al. (2006) calculated that the potential transscleral flow was 4.3 μl/min, determined in scleral specimens where no emissary vessels could be seen.

As the vessels of the choroid and the ciliary processes are unusually permeable they permit passage of large proteins into the extravascular space and a constant removal is important to rid the eye of these proteins. Large proteins are normally removed from the extravascular spaces of the tissue by lymph vessels. The transscleral flow has been considered as a substitute for lymphatic vessels, as it has long been accepted that the eye has no lymph vessels. This assumption has recently been challenged (Gupta et al., 2008). Immunostaining for lymphatic vessels revealed numerous fine channels through the ciliary muscle (Fig. 5). Obviously, it remains to determine if these channels are connected to orbital lymph nodes, but it may be the first demonstration of ocular lymph vessels. It should, however, be pointed out that results from studies on the passage of proteins through the uveoscleral route are perfectly compatible with perivascular spaces, veins or lymphatic vessels.

Section snippets

Experimental animals

As uveoscleral flow cannot be sampled from a single outlet indirect techniques have to be used. In the initial studies on uveoscleral flow the anterior chamber was perfused with labeled albumin (Bill, 1965, Bill and Hellsing, 1965). The choice of a large molecular weight tracer is important since a small tracer, such as sodium fluorescein, can be lost by diffusion. Brubaker (1991) calculated that about 10% of sodium fluorescein is lost from the anterior chamber by diffusion into surrounding

Species differences

There are marked species differences in the amount of aqueous that leaves the eye by unconventional or uveoscleral outflow routes. To some extent it seems to depend on the development of the ciliary muscle. Table 1 presents data from several species. The highest values are found in primates (40–60%). In cats the fraction leaving the eye through the ciliary muscle is much smaller, about 3% (Bill, 1966c). In dogs about 15% leaves the eye by the uveoscleral route, while in rabbits, with a much

Physiology

Flow through the uveoscleral outflow occurs by bulk flow (Bill, 1965, Pederson and Toris, 1987). Bulk flow is always pressure-dependent but the unconventional outflow route is often referred to as pressure-independent. The reason is that uveoscleral flow does not depend on the intraocular pressure to the same extent as trabecular outflow. Within the normal range of IOP flow through the trabecular meshwork increases almost linearly, while uveoscleral flow is relatively pressure-independent (

Cholinergic agents

As pointed out above pilocarpine and atropine were the first two agents that were shown to influence uveoscleral flow (Bill, 1967b). In both instances the mechanism of action is regarded as being due to their effects on ciliary muscle tone. Atropine increased the rate of uveoscleral flow in cynomolgus monkeys from 0.90 to 1.07 μl/min (Bill, 1967b). In four animals pilocarpine was given to both eyes and atropine to one eye. In the eyes with only pilocarpine uveoscleral flow ranged from 0.06 to

Clinical significance

The physiological role of the uveoscleral outflow route is not clear. It differs in many respects from the conventional outflow route through the trabecular meshwork. Flow through the trabecular meshwork requires a pressure gradient that results in sufficient pressure within the globe to keep it reasonably rigid during eye movements. As debris pass through the trabecular meshwork it is important that it to some extent acts as a self-cleaning filter. Still, there is a reduction of outflow

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