IB Uveoscleral Outflow Astute observations led to the notion that there were separate drainage routes for aqueous humor from the eye. First, it was noted that the episcleral venous hematocrit was lower than that of the peripheral venous hematocrit, leading to the idea that episcleral blood was either diluted by a fluid exiting the eye or that blood cells were being removed into the eye.1 The dilutional theory eventually led to the discovery of the conventional trabecular outflow pathway—the first drainage route.2 Anders Bill3 then observed in 1965 that when radioactive albumin (125I-labeled) was injected into the anterior chamber of macaque monkeys, 20% of the total radioactivity could not be recovered from the conventional pathway (Fig. 9.1). Thus, a second drainage route had to exist, and the search for this mystery fraction led to the discovery of the uveoscleral outflow pathway. Today, this second drainage route, or uveoscleral outflow pathway, represents a major medical and possibly surgical therapeutic target for intraocular pressure (IOP) reduction to treat glaucoma.4 Uveoscleral outflow is difficult to measure. The direct method to measure it uses tracers, such as radioactive proteins,3,5,6 India ink,7 and fluorescent dextrans.8,9 A tracer is introduced into the eye, and the final tracer concentration is measured in the peripheral blood. Uveoscleral outflow is then calculated after correction for the peripheral distribution and the amount delivered into the anterior chamber.6,10 The direct method is more easily accomplished in animals than in humans, although it has been performed in a small number of human eyes with intraocular tumors11 prior to enucleation. The direct method has been used to calculate uveoscleral outflow in a variety of animals (Table 9.1). As a percentage of total outflow, some species demonstrate very little uveoscleral outflow (cat and rabbit), some demonstrate intermediate outflow (dog and human), and some demonstrate greater outflow (monkey). As such, it may have been fortuitous that Anders Bill chose to work first with monkeys. To facilitate the measurement and study of uveoscleral outflow, indirect methods that are more feasible for human application have been developed. All indirect methods utilize the Goldmann equation with or without applying aqueous suppressants to calculate parameters of the aqueous dynamic.12 The simplest mathematical model of the basic Goldmann equation (IOP = Fin(R) + EVP)13 predicts IOP as a function of aqueous humor production (Fin; µL/min), resistance of trabecular outflow (R; mm Hg * min/µL), and episcleral venous pressure (EVP; mm Hg), but it does not account for uveoscleral outflow. To account for uveoscleral outflow, a modified Goldmann equation can be formulated where the variable F of the basic equation is expanded to include uveoscleral outflow (Fu). Thus, the Goldmann equation is re-expressed as IOP = (Fin – Fu)(R) + EVP.14 Trabecular outflow is said to be pressure-dependent as it occurs down a pressure gradient (increased outflow with increased IOP), but uveoscleral outflow is considered to be pressure-independent, being little influenced by IOP in a typical physiological range. The pressure independence of uveoscleral outflow does not imply that this pathway is without resistance. Rather, the anatomy of the uveoscleral outflow pathway is such that resistance along this drainage route within the intraocular space is not influenced much by physiologically relevant IOPs so that uveoscleral outflow becomes better modeled by the F variable above. With the modified Goldmann equation, one can calculate Fu after IOP is measured by applanation tonometry, Fin is calculated by fluorophotometry,15 R is determined by Schiotz tonometry,16 and EVP is estimated by manometry.17 Of course, the limitation of this indirect method lies in the assumptions used to determine each of the parameters of the modified Goldmann equation, as all are estimated indirectly. Although the equation estimates uveoscleral outflow, particularly in humans, a critical observer is careful to acknowledge these limitations and potential sources of error when using indirect means to calculate uveoscleral outflow. Uveoscleral outflow, as measured by direct and indirect methods, varies with age. Uveoscleral outflow determined in eyes with tumors in older people (54 and 65 years old)11 was found to be quite low, but subsequent studies have found that uveoscleral outflow may be nearly 40% higher in younger than older people.18 This agrees with Anders Bill’s fortuitous original descriptions of uveoscleral outflow in young macaque monkeys6 that were later confirmed in monkeys stratified by age.19 The influence of age on uveoscleral outflow is relevant, as glaucoma is itself age related. Uveoscleral outflow may also be lower in glaucoma dogs19 and ocular hypertensive humans.20 The term uveoscleral, which has grown out of the variety of methods used to define it, including Anders Bill’s original descriptions, correctly reflects the nature of the pathway. Uveoscleral outflow occurs by bulk flow of aqueous humor through the ciliary muscle into the supraciliary space and then into the choroid and suprachoroidal clefts, subsequently leaving the eye via the perivascular spaces of the emissarial scleral channels or directly through permeable scleral collagen bundles (Fig. 9.2). Various morphological considerations are important to mention. The monkey eye with greater uveoscleral outflow has a ciliary muscle that is well developed, supporting multiple functions with three different portions that are apparent as fibers running in different directions.21,22 Contraction of the longitudinal muscle under parasympathetic control pulls the scleral spur and stretches the trabecular meshwork to increase trabecular outflow capacity. The circular muscle, also under parasympathetic control, contracts the diameter of the circular ciliary muscle ring to loosen tension on the zonules and allow accommodation according to the Helmholtz theory of accommodation.23 While in a relaxed state, the intermuscular connective tissue of the monkey ciliary muscle is sparse with large spaces felt to permit bulk flow down the tract.24 These spaces diminish with muscular contraction, and this may underlie the decrease in uveoscleral outflow seen with pilocarpine (Fig. 9.1); see Contractile Regulators of Uveoscleral Outflow, below.24 By comparison, although histological and electron microscopic studies of the rabbit ciliary muscle show large empty spaces similar to those in primates, frozen sections avoiding the use of organic solvents demonstrate large amounts of hyaluronan filling these spaces, possibly reflecting a barrier to uveoscleral outflow and explaining the monkey and rabbit difference (Fig. 9.3).25 With increasing age, accommodative ability is diminished in primates, and the large intermuscular spaces in the ciliary muscle change. Large clumps of pigmented cells fill these spaces in monkeys (Fig. 9.4).26 In humans, increased connective tissue deposition occurs, and the large intermuscular spaces seen in young ciliary muscle are lost (Fig. 9.5).21 In the distal portions of choroid and sclera, the electron density of the elastic fibers is increased, the choroidal elastin is diminished, and the collagen is more cross-linked and thicker, giving the impression of plate formation in the sclera. Table 9.1 Species Differences in Uveoscleral Outflow
9 Structure and Mechanisms of Uveoscleral Outflow
Species Differences, Direct Measurements, and Serendipity
Age Differences, Indirect Measurements, and Serendipity
Anatomy of Uveoscleral Outflow
Species | Uveoscleral Outflow as Percentage of Total Outflow (%) | PMID Citation Number |
Monkey | 35–60 | 500109612 |
Cat | 3 | 267814713 |
Rabbit | 3–8 | |
Dog (beagle) | 15 | 257875816 |
Human | 4–14 | 513027011 |
Source: Modified from Alm A, Nilsson SF. Uveoscleral outflow–a review. Exp Eye Res 2009;88:760–768.
Fig. 9.3 Uveoscleral outflow in rabbit. (a) The rabbit ciliary body is filled with hyaluronan (pink). AP, aqueous plexus; CB, ciliary body; CC, collector channel; I, iris; R, remnant of vitreous; Sc, sclera. (From Lutjen-Drecoll E, Schenholm M, Tamm E, Tengblad A. Visualization of hyaluronic acid in the anterior segment of rabbit and monkey eyes. Exp Eye Res 1990;51:55–63. Reprinted with permission from Elsevier.) (b) Illustration of normal uveoscleral outflow anatomy and clefts. Red arrow depicts uveoscleral outflow. (c) Illustration of rabbit anatomy with clefts full of hyaluronan (pink). Red arrow depicts uveoscleral outflow.
Interestingly, in glaucoma, ciliary muscle sheaths and tendons are thickened and have plaque-like deposits so that muscle fibers appear fused (Fig. 9.6).27 These pathological changes may explain the uveoscleral outflow abnormalities seen in glaucoma dogs28 and human ocular hypertensive20 eyes, mentioned above.
Taken together, species and age data suggest that large intermuscular spaces in the ciliary muscle represent the starting point of the uveoscleral outflow pathway for aqueous humor exiting the anterior chamber. They may play roles in limiting the rate of outflow and also development of pathology leading to higher IOP.
Contractile Regulators of Uveoscleral Outflow
Key factors in regulating uveoscleral outflow are ciliary muscle contraction and extracellular matrix (ECM) dynamics.
Pilocarpine (a muscarinic agonist) and atropine (a muscarinic antagonist) respectively contract and relax components of the ciliary muscle (longitudinal, circular, and radial), reflecting parasympathetic control of the muscle complex and the unique muscarinic paradox influencing total aqueous humor outflow. In primates, muscarinic activation (pilocarpine) contracts the longitudinal ciliary muscle, opening the trabecular meshwork and increasing outflow facility by the trabecular route.29 However, circular ciliary muscle contraction decreases intermuscular spaces, leading to decreased uveoscleral outflow (Fig. 9.7).11,30 Direct measurements in human eyes show uveoscleral outflow comprising 4 to 14% of total outflow, with this changing to 0 to 3% after pilocarpine and 4 to 27% after atropine.11
