Unconventional aqueous humor outflow: A review

doi:10.1016/j.exer.2016.01.017

Experimental Eye Research

Volume 158, May 2017, Pages 94-111

https://doi.org/10.1016/j.exer.2016.01.017 Get rights and content

Highlights

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Aqueous humor drains through an unconventional outflow pathway that has both a uveoscleral and uveovortex component.
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Tracer-based methods are required to reliably measure outflow through these pathways.
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Indirect estimates of unconventional outflow generally give poor agreement with tracer-based methods.
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The mouse is a promising model for studying aqueous humor outflow.
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There is a need for improved measurements of unconventional outflow in both animals and humans.

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.

Introduction

The pathway of aqueous humor drainage has long been of interest and is of great importance because it provides the fluid resistance that maintains a proper intraocular pressure (IOP). IOP that is too low can impair vision by distorting the retina, cornea, and lens; IOP that is too high can lead to glaucomatous optic neuropathy.

Aqueous humor drainage from the anterior chamber through the trabecular meshwork, Schlemm's canal, collector channels, aqueous veins, and into the episcleral veins was first proposed by Leber, 1873, Schwalbe, 1870, and Knies (1875), and finally demonstrated by Seidel (1921) and Ascher (1942). The latter's observations of clear fluid in aqueous veins established this path as the primary route of aqueous humor outflow from the eye. After exploring aqueous humor drainage in more detail by using tracer molecules, investigators eventually realized that aqueous humor also left the eye through another route, passing through the uvea, the ciliary body and muscle, and into the choroid and sclera. This pathway has been called the uveoscleral, uveovortex, or unconventional pathway to distinguish it from the trabecular pathway, and has been estimated to carry 3–82% of the total aqueous humor outflow in different species. This paper will review the historical basis of our understanding of unconventional outflow, its properties and characteristics, how it is measured, and its significance to glaucoma research.

Section snippets

Historical basis of unconventional outflow

Leber reported in 1903 that tracers introduced into the anterior chamber passed not only into the conventional trabecular outflow pathway but also were found in the suprachoroidal space (Nesterov, 1986). Other early investigators (Nuel and Benoit, 1900, Erdmann, 1907, Seidel, 1921, Kiss, 1943) reported that colloidal tracer accumulated outside the conventional outflow pathway, often deep within the peripheral ciliary body, posterior sclera, and choroid after perfusion with these tracers. These

The anatomy of the unconventional outflow pathway

Because the interstitial spaces of the anterior uvea communicate with the intertrabecular spaces (Fig. 1), a fraction of the aqueous humor outflow that passes into the uveal meshwork can directly enter the interstitial spaces of the ciliary muscle (Henderson, 1950). Perfusion studies with microspheres (Inomata et al., 1972) and fluorescein dextran (Tripathi, 1977, Lindsey and Weinreb, 2002) have demonstrated flow of aqueous humor from this region through the interstitial spaces between the

Methods of measurement

The greatest challenge facing studies of unconventional aqueous humor outflow has been measurement of its flow rate. By definition, this pathway encompasses any outflow of aqueous humor that does not pass through the trabecular (conventional) pathway. Unlike the trabecular route, the path of egress is diffuse and difficult to trace, and this complicates measurement of flow through this pathway.

Measurements of unconventional outflow rate have been classified as: (i) direct, tracer-based methods,

Physiological characteristics of unconventional outflow

Several features of unconventional outflow are particularly interesting from a physiological perspective. These features include the route of aqueous humor drainage along this pathway, the insensitivity to changes in intraocular pressure, the role of the ciliary muscle, and changes in this pathway after death.

Characteristics of unconventional flow in different species

Anatomical [see Henderson (1950) and Tripathi (1974)] or functional differences in the unconventional outflow pathway can affect the drainage of aqueous humor through this route and contribute to differences in unconventional outflow between species. Lower placentals, for example, exhibit a deep ciliary cleft with a relatively undeveloped ciliary muscle that allows open fluid communication to the posterior ciliary body. Primates, in contrast, have a well-developed ciliary muscle without a

Drug effects

Cholinergics, adrenergics, and prostagladins can affect the flow of aqueous humor through the unconventional outflow pathway. The principal site of unconventional outflow resistance is the ciliary muscle. Contraction of the ciliary muscle by cholinergics such as pilocarpine decrease the rate of unconventional outflow (Bill and Wålinder, 1966) while cycloplegics such as atropine increase unconventional outflow (Bill, 1967, Bill, 1969b). However, cholinergics also interfere with accommodation and

Summary and future directions

Anders Bill was the first investigator to explore and characterize the physiologic processes of the unconventional outflow pathways. His pioneering measurement techniques are still the standard for identifying the pathway and estimating the amount of flow through this route. Originally this pathway was a scientific curiosity, but it became clinically important when Camras and Bito found that PGF_2α could profoundly redirect outflow through this pathway from the conventional pathway, reducing

Acknowledgments

NIH E019696 (MJ & DRO), NIH EY022359 (DRO), The BrightFocus Foundation (DRO), Research to Prevent Blindness, New York, NY (JWM), and the Mayo Foundation, Rochester, MN (JWM).

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ReviewUnconventional aqueous humor outflow: A review

Highlights

Abstract

Introduction

Section snippets

Historical basis of unconventional outflow

The anatomy of the unconventional outflow pathway

Methods of measurement

Physiological characteristics of unconventional outflow

Characteristics of unconventional flow in different species

Drug effects

Summary and future directions

Acknowledgments

Aqueous humor dynamics in mice

Invest. Ophthalmol. Vis. Sci.

Uveoscleral outflow – a review

Exp. Eye Res.

Effect of circulation on the disposition and ocular tissue distribution of 20 nm nanoparticles after periocular administration

Mol. Vis.

Human transscleral albumin permeability and the effect of topographical location and donor age

Invest. Ophthalmol. Vis. Sci.

Aqueous veins

Am. J. Ophthalmol.

Reliable measurement of mouse intraocular pressure by a servo-null micropipette system

Invest. Ophthalmol. Vis. Sci.

Prostaglandins increase trabecular meshwork outflow facility in cultured human anterior segments

Am. J. Ophthalmol.

Dissociation of accommodation effects from outflow effects of pilocarpine

Pseudofacility and uveoscleral outflow routes

The mode of action of pilocarpine on outflow resistance in the eye of a primate (Cercopithecus Ethiops)

Invest. Ophthalmol. Vis. Sci.

A pharmacologist looks at medical treatment in glaucoma–in retrospect and in prospect

Ophthalmology

Quantitation of uveoscleral outflow in normotensive and glaucomatous beagles by H-3-labeled dextran

Am. J. Vet. Res.

Pressure dependence of uveoscleral outflow

J. Glaucoma

Influence of molecular weight on intracameral dextran movement to the posterior segment of the mouse eye

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Exp. Eye Res.

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Exp. Eye Res.

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Exp. Eye Res.

Blood circulation and fluid dynamics in the eye

Physiol. Rev.

Basic physiology of the drainage of aqueous humor

Some thoughts on the pressure dependence of uveoscleral flow

J. Glaucoma

Production and drainage of aqueous humor in the cynomolgus monkey (Macaca irus)

Invest. Ophthalmol.

Uveoscleral drainage of aqueous humor in human eyes

Exp. Eye Res.

The effects of pilocarpine on the dynamics of aqueous humor in a primate (Macaca irus)

Invest. Ophthalmol.

Pharmacologic manipulation of conventional outflow facility in ex vivo mouse eyes

Invest. Ophthalmol. Vis. Sci.

Physical factors affecting outflow facility measurements in mice

Invest. Ophthalmol. Vis. Sci.

The influence of genetic background on conventional outflow facility in mice

Invest. Ophthalmol. Vis. Sci.

Review
Unconventional aqueous humor outflow: A review