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Practical Aqueous Humor Dynamics

Joel S. Schuman, MD, FACS; Rachel L. Anderson, MD; Malik Y. Kahook, MD; and David L. Epstein, MD, MMM

CLINICAL RELEVANCE

Aqueous Humor Formation

Aqueous humor is produced by the ciliary body and flows into the posterior chamber at a rate of approximately 2 to 3 μL/min.¹ It is believed that at least a majority of this aqueous humor production derives from active secretion by the ciliary epithelium bilayer, which is in continuity posteriorly with the adjacent retinal and anteriorly with the iris epithelia. The outer (sclerad) pigmented ciliary epithelial cell layer lies apex to apex to the inner (vitread) nonpigmented ciliary epithelial cell layer. The base of the latter cells faces the posterior chamber. (Exfoliation material may occur on the base of this cell layer.)

The stroma of the ciliary body (sclerad to the pigmented ciliary epithelium) contains numerous capillaries. This blood supply area as well as the secreting ciliary epithelial cells themselves are potential sites of drug or laser obliterative actions. Although the nonpigmented ciliary epithelium has frequently been identified as containing the enzymatic machinery involved in active aqueous humor secretion,^2–4 the actual process may require the coupling of both the nonpigmented and pigmented cell layers.⁵

The ciliary epithelium is believed to actively secrete bicarbonate into the posterior chamber, carrying water with it and thus representing part of the active secretion of aqueous humor.⁶ This is under the control of the enzyme carbonic anhydrase in the ciliary epithelium (presumably nonpigmented). Thus, carbonic anhydrase inhibitors can reduce aqueous humor formation (up to 40% to 50%).

Beta-adrenergic agonist activity is thought to be involved in active secretion of aqueous humor,¹ such that beta blockade will result in a decrease in this secretion. Many investigators have presumed that the site of beta-blocker activity is at the level of the ciliary epithelium, but a vascular site has not been totally ruled out. The effects of beta blockade and carbonic anhydrase inhibition are not fully additive, suggesting that there are some linkage and interrelated effects.⁷

Apraclonidine, an alpha-2 agonist, reduces aqueous humor formation⁸ and is also partially additive to both carbonic anhydrase inhibitors and beta-blockers, but it is not certain whether the site of action is ciliary epithelial or vascular. (The vasoconstriction that the drug causes might suggest the latter.) Brimonidine is a relatively selective alpha-2 adrenergic receptor agonist. Fluorophotometric studies suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow.

The part of aqueous humor formation that is not active transport has in previous times been called ultrafiltration. However, whether this is a passive pressure-driven process (presumably under vascular control) or some other ciliary epithelial cell process (eg, uncatalyzed hydration of CO₂) is unclear; current data would suggest the former.⁹

Aqueous humor moves from the ciliary epithelium into the posterior chamber, and then through the pupil into the anterior chamber (Figure 3-1). Because there is usually some pupillary resistance to forward fluid flow (which is termed relative pupillary block), the pressure is slightly higher in the posterior chamber than the anterior chamber, resulting in forward iris convexity. In the extreme, this can cause the peripheral iris to move over the front of the trabecular meshwork (TM) and thus cause angle-closure glaucoma (usually due to pupillary block; see Chapter 23). Iris convexity or concavity is thus a useful indicator of relative pressures in the posterior and anterior chambers. (See later discussions of iris concavity in pigmentary glaucoma [Chapter 22] and also various iris retraction syndromes where, for example, there is posterior movement of fluid out of the eye through a retinal hole.)

The amount of aqueous humor in the posterior chamber acts as a force (vector) to move the iris forward in a convex configuration. Agents that decrease aqueous humor formation can, by themselves, act to decrease this iris convexity (see Chapter 23). Thus, these agents are effective in treating the process of angle-closure glaucoma due to pupillary block (independent of the obvious intraocular pressure [IOP] effect itself) but, just as importantly, can lead to confusion in evaluating (usually asymptomatic) narrow-angled eyes by lessening this posterior chamber vector and thereby deepening the angle.

The aqueous humor in the posterior chamber is likely in equilibrium with fluid in the vitreous cavity (see Chapter 30). With retinal tears and detachments, the resulting hypotony most likely occurs because there is net fluid movement out of the eye through the retinal hole. The hyaloid is involved in this fluid exchange between vitreous and posterior chamber. In malignant glaucoma, fluid is retained in an expanded vitreous chamber, and it is commonly required to disrupt the hyaloid barrier (with a yttrium-aluminum-garnet laser or surgically), in order to restore the normal anatomy and allow fluid exchange between the posterior and anterior segments (see Chapter 30).

Diurnal Variation of Intraocular Pressure

We know that there is a diurnal variation in IOP that is believed to be mostly or entirely due to changes in the rate of aqueous humor formation.¹ Although the studies of Kronfeld^10,11 suggested that there might be a small fluctuation in tonographic outflow facility as well, we believe that such possible changes are small and may be explained, at least in part, by the noise in the tonographic technique. There is also a small seasonal variation in IOP,¹² but the mechanism behind this has not been determined. The Ocular Hypertension Treatment Study reaffirmed the prior finding that IOP tends to be higher in winter and lower in summer.¹³ Interestingly, the study also revealed a significantly greater mean deviation on standard automated perimetry in the winter vs the summer.¹³ However, there was no statistically significant association between the magnitude or timing of the peaks of these 2 measures.¹³

What causes the varying rate of aqueous humor production during the day has not been fully determined. It is most common for the highest IOP to occur in the early morning, and, in fact, an IOP spike upon awakening is believed to occur commonly in primary open-angle glaucoma (POAG). On the other hand, the literature describes many patients with other diurnal patterns, and there is much individual variation. The systemic catecholamine burst upon awakening might be implicated in the morning IOP elevation because beta-adrenergic agonists are believed to slightly stimulate aqueous humor formation¹ (see Chapter 13; thus beta-blockers interfere with this and, therefore, act to diminish aqueous humor production), but this has not been unequivocally resolved. Although systemic cortisol levels have been proposed to relate to the diurnal variation of aqueous humor production, recent evidence does not support this.¹⁴

The lowest IOP was previously believed to occur during sleep, again due to decreased aqueous humor formation.^1,15 One might oversimplify this and conceptualize that the pumps in the ciliary body have similarly gone to sleep. However, recent data from sleep labs have contradicted this concept by showing a rise in IOP that happens during the nocturnal period prior to a slow dip in IOP in the early morning hours. See Chapter 72 for further details on 24-hour IOP curves.¹⁶

Some investigators have proposed that patients with glaucoma can show elevated spikes of IOP at odd hours, including while asleep. One of the problems with these data is that it is possible that the act of performing these measurements, by waking people up to take their IOP, may yield measurements that do not accurately reflect their true IOP steady state while asleep. There is a need for new, noninvasive measurements of IOP during the course of a day or during several days in order to provide this important information. As discussed in Chapter 1, our IOP measurements, although extremely accurate, are only one snapshot in time. The field of glaucoma would benefit from a Holter monitor equivalent for IOP measurements, and in recent years, considerable progress has been made to this end. The 3 major categories of long-term IOP measurement strategies include self- or home tonometry, continuous noninvasive IOP measurement, and continuous invasive IOP measurement.17 Multiple commercially available devices currently enable self-/home tonometry, though there are concerns for quality (poor association with Goldmann applanation tonometry, fluctuations based upon patient position), feasibility (such devices do not address the challenge of obtaining IOP measurements during uninterrupted sleep), and, in some cases, safety (certain devices require corneal contact and use of anesthetic drops).^17,18 Contact lens sensors are the mainstay of the continuous noninvasive IOP measurement category, and a commercially available device has demonstrated reliable results and tolerability, though the clinical utility of the device has been limited by its cost and uncertainty about how to interpret the data (which is recorded in mV rather than mm Hg).^17,18 In terms of continuous invasive IOP monitoring, implantable devices have demonstrated favorable tolerability in feasibility trials, but further research and development will be required to demonstrate accuracy of such an approach.^17,19

Another problem with such diurnal IOP data is that the common technique used to obtain it is to do a diurnal curve; that is, to have the patient come to the office (or worse, inpatient setting) for these measurements. It really has not been established that these measurements reflect the patient’s true diurnal curve during the patient’s normal, active day’s schedule.

Conventional Outflow Pathway (Trabecular Meshwork–Schlemm’s Canal)

In adult humans, more than 90% of the aqueous humor fluid in the anterior chamber exits the eye via the TM-Schlemm’s canal system (the conventional outflow pathway) with the remaining 10% existing through the uveoscleral outflow system (see Figure 3-1).^20,21 It is important to note that recent work suggests that the percentage of outflow through the uveoscleral route may be higher than 10%, but this remains uncertain and appears to be age related.^22,23 Schlemm’s canal communicates via a series of collector channels with the aqueous veins, part of the venous system, which are apparent on the outside of the eye (aqueous veins are much less frequently observed in eyes with glaucoma than in normal eyes).²⁴ There is a resistance and a pressure decrease across the inner wall of Schlemm’s canal (either at or just proximal to the inner wall in the juxtacanalicular [JXT] tissue),^25–29 such that the pressure in the TM just proximal to the canal (toward the anterior chamber) is higher than that in the canal. Thus, at elevated IOP, the TM distends, and the inner wall moves toward the outer wall of Schlemm’s canal.^30,31 The locus of abnormal resistance in POAG is believed to be at the same general location (JXT-inner wall Schlemm’s canal)^25,32 as a normal eye, but theoretically, abnormal resistance in the various glaucomas can be added at any place along the aqueous humor outflow pathway.

Relation of Episcleral Venous Pressure to Intraocular Pressure

In conditions with elevated episcleral venous pressure (eg, dural shunt or some cases of Sturge-Weber syndrome), this elevated venous pressure is transmitted back to Schlemm’s canal and then into the anterior chamber (and therefore to the whole eye; see Chapter 47). Although IOP is elevated, the resistance across the inner wall of Schlemm’s canal may be unchanged, and tonographic outflow facility may thus be normal. (In fact, normal outflow facility is observed in fresh cases of dural shunt quite commonly.) Put another way, if the afterload is elevated, the pressure at all proximal points in the system are elevated without need for any change in coefficient of outflow across the normal resistance site. (Outflow facility [C value] is the inverse of resistance.)

Segmental Nature of Outflow: Implications for Angle-Closure Glaucoma

Although Schlemm’s canal extends for 360 degrees inside the limbus, there is considerable resistance to circumferential flow in Schlemm’s canal, at least in adult eyes. It has been calculated that aqueous humor exiting through 1 hour of the Schlemm’s canal circumference effectively has access to only approximately 1 additional clock hour of circumference of Schlemm’s canal on either side.³³ The TM-Schlemm’s canal aqueous drainage system behaves as several separate segmental outflow pathways rather than a freely communicating single-circumferential entity. Thus, in progressive chronic angle-closure glaucoma (due to relative pupillary block), the amount of IOP elevation is roughly proportional (in a progressive way) to the amount of angle closure. Aqueous humor moving through the open portions of the angle cannot move freely into the entire circumference of Schlemm’s canal. Irreversible changes in the TM and Schlemm’s canal can occur as a consequence of peripheral anterior synechiae formation in this condition or possibly after chronic iris touch to the TM without synechiae formation, most commonly after pupillary block is alleviated. In this case, areas of prior appositional closure now become open and once again segmentally drain a portion of aqueous humor, and IOP can thereby be normalized. In fact, with fresh peripheral anterior synechiae formation, using an argon laser to break the synechiae (gonioplasty) can restore normal outflow function.

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