13 Structure and Mechanisms of Aqueous Production
Aqueous humor, its production and drainage (Fig. 13.1), are essential for maintaining the normal functions of various avascular structures in the ocular anterior segment. A transparent filtrate of the plasma, the aqueous humor provides nutrition to and removes products of metabolism from the lens, cornea, anterior vitreous, and trabecular meshwork. It maintains an optically clear medium to optimize visual function, exerts hydrostatic pressure to maintain the shape of the eyeball, and aids in the circulation of inflammatory cells and distribution of pharmacological compounds.
Suppressing aqueous humor production is a technique to treat glaucoma by lowering the intraocular pressure (IOP). Classes of drugs approved for this purpose include carbonic anhydrase inhibitors, β-adrenergic antagonists, and α2-adrenergic agonists. Other classes under investigation are forskolin, cannabinoid receptor agonists, serotonin, and angiotensin II. These drugs must be dosed several times per day to maintain IOP at a healthy level. Tachyphylaxis, side effects, and lack of patient compliance have limited the IOP efficacy of these drugs. Cyclodestructive procedures slow aqueous production without chronic drug use. By destroying tissues involved in aqueous humor secretion, IOP can be reduced, potentially around the clock. The minimally invasive modern cycloablative procedures are endoscopic cyclophotocoagulation (ECP), ECP plus, and high-intensity focused ultrasound (HIFU). All of these procedures are discussed in this chapter. It is hard to rule out the possibility that the new IOP-lowering drugs and procedures targeting the trabecular meshwork (TM) will also affect aqueous humor production, as the TM and ciliary processes lie in close proximity. This chapter provides an overview of aqueous humor production and describes various interventions that may affect the aqueous production rate.
Anatomic Considerations
The ciliary body (Fig. 13.2) is a small circumferential musculoepithelial structure with a double-layered epithelium overlying the stromal elements and neurovascular structures. The anterior part (pars plicata) has processes extending into the posterior chamber. The posterior region (pars plana) is relatively flat, avascular, and lacks these processes. The double-layered epithelium consists of pigmented epithelial cells toward the stroma and nonpigmented epithelial cells toward the posterior chamber. These layers are oriented apex to apex, forming a specialized unit for aqueous humor secretion1 (Fig. 13.3). The ciliary body is supplied by anterior ciliary and long posterior ciliary arteries. The ophthalmic artery branches off into seven muscular arteries that supply the extraocular muscles and continues as the anterior ciliary arteries. These form the intermuscular circle in the ciliary muscle and minor arterial circle in the iris. Two long posterior ciliary arteries (medial and lateral) arise from the ophthalmic artery; they travel forward in the choroid to form the major arterial circle that supplies the ciliary processes and end in the minor arterial circle of the iris. Four vortex veins drain the ciliary body into the superior and inferior ophthalmic veins. The capillaries of the ciliary processes are leaky, allowing passage of proteins and solutes into the ciliary stroma for aqueous production. Not all substances in the ciliary stroma enter the aqueous humor due to the presence of tight junctions between the nonpigmented ciliary epithelial cells. This and the tight junctions of the iris capillaries form part of the blood–aqueous barrier.
Physiology of Aqueous Humor Production
The production of aqueous humor is a continuous and active process requiring energy. The constituents of the aqueous humor must pass through the ciliary capillary wall, ciliary stroma, and epithelial bilayer before reaching the posterior chamber. The nonpigmented epithelium (NPE) forms part of the blood–aqueous barrier and offers the most resistance to the secretion of aqueous humor. The formation and secretion of aqueous humor into the posterior chamber takes place in the following stages2:
1. Convective delivery of ions, proteins, and water by the ciliary circulation
2. Diffusion and ultrafiltration from the capillaries into the stroma driven by oncotic pressure, hydrostatic pressure, and a concentration gradient
3. Active ionic transport into the basolateral spaces between the nonpigmented epithelial cells followed by water movement into the posterior chamber
Fig. 13.1 Production and circulation of aqueous humor. Aqueous humor that is secreted into the posterior chamber (1) flows across the vitreous cavity (2) or through the pupil into the anterior chamber (3). Fluid circulates around the anterior chamber and eventually drains into the anterior chamber angle (4). Aqueous humor drains from the anterior chamber angle via two routes: the trabecular meshwork, Schlemm’s canal, collector channels, and episcleral veins (5); or the uveoscleral outflow route. The latter route starts with the ciliary muscle. From there, fluid may flow in many directions, including across the sclera (6), within the supraciliary and suprachoroidal spaces (7), through emissarial canals and vortex veins (8), into uveal vessels (9) and possibly into ciliary processes (10), where it could be secreted again. Lymphatic vessels, recently identified in the uvea, also may contribute to ocular fluid dynamics. The exchange of fluid in and out of the cornea and lens (11) does not contribute to aqueous flow. AC, anterior chamber; ACA, anterior ciliary artery; AV, aqueous vein; CC, collector channel; EVP, episcleral venous plexus; LPCA, long posterior ciliary artery; PC, posterior chamber; SC, Schlemm’s canal; TM, trabecular meshwork.
Fig. 13.2 The ciliary body comprises the pars plicata anteriorly and pars plana posteriorly. The ciliary processes are part of the highly vascular pars plicata and are involved in aqueous humor secretion into the posterior chamber. The pars plana is less vascular and as such is the site of entry for intraocular surgery.
Fig. 13.3 Ciliary epithelium as a syncytium. The ciliary processes have a double-layered epithelium. The apices of the nonpigmented epithelium and pigmented epithelium face each other. The ciliary stroma has a rich vascular network with leaky endothelium. The nonpigmented epithelium is rich in mitochondria, which provide energy for aqueous humor secretion. It has rough endoplasmic reticulum and a few pigment granules. The pigmented epithelium has several melanosomes and pigment granules with a few mitochondria. Tight junctions are present between the apices of the nonpigmented epithelial cells to prevent entry of interstitial fluid into the posterior chamber. BI, basal infoldings; BM, basement membrane; CC, ciliary channels; DES, desmosomes; FE, fenestrated capillary endothelium; GJ, gap junction; MEL, melanosome; MIL, mitochondria; RER, rough endoplasmic reticulum; TJ, tight junction.
Fig. 13.4 Overview of aqueous humor formation. Aqueous humor is formed from blood plasma by the continuous and active transport of ions from the nonpigmented ciliary epithelium (NPE) cells into the interstitial clefts. The ions in the interstitial clefts establish an osmotic gradient that draws in water. Various solute pumps are involved in the transport, with Na-K adenosine triphosphatase (ATPase) playing a major role. Apical tight junctions in the NPE cells facilitate movement of water into the posterior chamber.
The formation and secretion of aqueous humor (Fig. 13.4) cannot be measured directly. However, its movement from the posterior chamber into the anterior chamber is calculated by various methods as the aqueous flow rate.3 Over the past few decades, fluorophotometry has become the gold standard for measuring aqueous flow. The rate of aqueous flow is less than the rate of aqueous humor secretion because some of it enters the vitreous cavity or is absorbed by the ciliary body, lens, or iris, and is lost to measurement.
Variations in Rate of Aqueous Flow
Aging
The anterior chamber depth and volume diminish and aqueous humor production slows with age.4 Several key studies reporting an age-related slowing of aqueous flow are summarized in Table 13.1. On average, the aqueous flow decreases by 0.0015 to 0.003 μL/min/year. This correlates with a 2 to 3.5% reduction every decade after 10 years of age.5–7 In people over 60 years of age, this decline accelerates to 0.025 μL/min with each year of life or 1 to 2% reduction every year.8 However, sample size and the age of the volunteers may lead to different conclusions.9
The exact mechanism by which aqueous humor flow decreases with age has been the focus of numerous studies. Light microscopic observations11 show age-related changes in the NPE, stromal blood vessels, and ciliary muscle fibers. The basement membrane of the NPE is thicker in the eyes of subjects between 60 and 70 years of age than in the eyes of subjects younger than 50 years of age. Age-related accumulation of lipofuscin, lysosomes, and lipids occurs in NPE cells. Accumulation of extracellular matrix in the stroma along with thickening of the endothelial basement membrane might impair the supply of nutrients and oxygen to ciliary epithelial cells, thereby reducing aqueous humor formation.12 It is speculated that other factors, such as neural and hormonal autoregulation, NPE cell count, cellular and organelle functioning, and response to cell signaling molecules, might also change as one ages.
Intraocular Pressure
The rate of aqueous humor secretion and flow is relatively insensitive to changes in IOP. When healthy subjects are tilted to a head-down position for 30 minutes to 8 hours, the IOP increases rapidly, remains elevated while in the head-down position, and returns to normal a few minutes after returning to a head-up position. Fluorophotometric aqueous flow remains unchanged despite the short-term variations in IOP associated with body position.13 Even with chronic IOP elevation, such as in exfoliation syndrome, primary open-angle glaucoma (POAG), and ocular hypertension (OHT),14–17 the aqueous flow remains relatively constant. Increasing the outflow facility to lower the IOP does not change aqueous production.18,19 In abnormal reductions of IOP (ocular hypotony), one can find reductions in aqueous flow especially when the hypotony is related to inflammation such as iridocyclitis. When the hypotony is related to injury, such as cyclodialysis cleft, aqueous flow remains normal. Clearly, aqueous humor production is not the regulatory mechanism controlling IOP.
Twenty-Four Hour Rhythms of Aqueous Humor Formation
The aqueous flow shows a predictable rhythm over a 24-hour period (Table 13.2). The daytime aqueous flow is 2 to 4 μL/min and at night it slows by almost 50% in healthy volunteers.5,20 This 24-hour rhythm is maintained in all age groups despite an age-associated decline in aqueous humor production.21,22 Daytime aqueous flow is normal in OHT and POAG.23,24 The nocturnal decrease of aqueous flow is present in OHT, but in POAG there is some evidence that the aqueous flow is not decreased as much as in healthy age-matched control subjects.16,25
Various hypotheses as to what regulates this 24-hour rhythm of IOP and aqueous flow have been proposed. Downregulation of β-adrenergic activity during sleep might contribute to the nighttime slowing of aqueous flow. This is supported by the finding that β-adrenergic antagonists do not lower IOP at night.29 Adrenergic agonists such as epinephrine, norepinephrine, isoproterenol, and terbutaline affect aqueous flow but not in a consistent manner. Patients with Horner’s syndrome30 (oculosympathetic palsy) or bilateral adrenalectomy31 have no variations in the diurnal or nocturnal aqueous flow when compared with healthy subjects. Corticosteroids, melatonin, cyclic adenosine monophosphate (cAMP), adenosine, arginine-vasopressin, and dopamine have some effect on the daily variations in aqueous flow. Apparently, a complex interaction between the neurohormonal milieu and specialized cells in the ciliary body and suprachiasmatic nucleus determine the aqueous flow rate at any given time.
Aqueous Humor Formation in Pathological States
The major contributing factor to elevated IOP is increased resistance to aqueous outflow through the trabecular meshwork. Studies of various glaucomatous conditions and associated systemic predispositions indicate that aqueous flow is not a contributory factor to the pathology (Table 13.3). In a glaucomatocyclitic crisis, aqueous flow measured before the availability of fluorophotometers showed varied results. The presence of flare and cells in the anterior chamber during attacks interferes with fluorescein detection and might have been the reason behind an apparent delay in fluorescein clearance with fluorophotometry. The acute attacks in this condition are not associated with increased aqueous flow rates.32,33 Aqueous flow is low in eyes of monkeys with experimental iridocyclitis.34 In addition to enhanced uveoscleral outflow, a low aqueous flow might explain the occurrence of ocular hypotony in patients with long-standing uveitis.35
Topography of Aqueous Humor Formation
To aid in conceptualizing aqueous humor formation and calculating secretion rate, the formation of aqueous humor is assumed to be uniform over the entire surface of the ciliary epithelium. However, regional differences in expression of proteins such as Na-K adenosine triphosphatase (ATPase) in the human ciliary processes,47 and a preferential secretion by the posterior ciliary epithelium and absorption by the anterior ciliary epithelium in rabbits, support the idea that there might be topographic variations in aqueous humor secretion.48 It is tempting to hypothesize that the topographic variations in aqueous production may be associated with segmental flow of aqueous humor through the trabecular meshwork.
Modifying Aqueous Humor Flow
Pharmacological Modification of Aqueous Flow
Slowing aqueous humor production is an effective way to lower IOP. This is accomplished by carbonic anhydrase inhibitors (CAIs) and β-adrenergic antagonists. Depending on the duration of treatment, α-adrenergic agonists have a combined effect on production and drainage.
Carbonic anhydrase inhibitors are sulfonamide drugs that have been used systemically for decades to lower IOP. Inhibition of the carbonic anhydrase enzyme in ciliary epithelium blocks the active transport of sodium, chloride, and bicarbonate into the posterior chamber, thereby slowing the osmotic movement of water and hence reducing aqueous humor formation. The newer topical CAIs are less efficacious than oral CAIs but have fewer side effects and are additive when combined with IOP-lowering drugs of other classes.49
β-adrenergic antagonists inhibit the synthesis of cAMP in the ciliary epithelium to reduce aqueous humor formation. Long-term therapy is associated with tachyphylaxis and “drift,” wherein almost 50% of patients treated with β-blockers as monotherapy will require addition of a different class of drug to maintain the target IOP.50
Epinephrine stimulates both α- and β-adrenergic receptors. Ciliary muscle contraction with improvement in trabecular outflow facility is thought to be the primary IOP-lowering mechanism. Reduction in aqueous flow secondary to vasoconstriction has been documented by several studies, but the effect has not been consistent. The final rate of aqueous flow with epinephrine treatment is likely to entail the combined activation of several different adrenergic receptors at any one time. However, epinephrine is no longer commercially available for ocular use in the United States. Dipivefrin hydrochloride, a prodrug of epinephrine, has the same IOP-lowering effect with a better adverse effect profile. This class of drug is rarely prescribed today because of better options from which to choose.
Apraclonidine is an α2-adrenergic agonist with some α1 activity. IOP reduction is secondary to vasoconstriction and decreases in aqueous flow. With continued use, it increases trabecular outflow facility and lowers episcleral venous pressure.51 With time the IOP effect diminishes and side effects intensify. This has limited its usefulness to less than 1 month of treatment.
Brimonidine is a highly selective α2-agonist that reduces aqueous flow due to ciliary vasoconstriction. This effect is lost within 1 month of use, after which an increase in uveoscleral outflow is the main IOP-lowering mechanism.52
Several new classes of aqueous flow suppressants are under investigation for potential glaucoma therapy. Forskolin increases intracellular cAMP, thereby reducing aqueous humor production.53 Cannabinoid derivatives act on the CB1 receptor, the main cannabinoid receptor expressed in the inflow and outflow pathways. The main hypotensive effect is thought to be increased outflow facility secondary to Schlemm’s canal dilation. Because the receptors are present in the uveal tract, cannabinoids might also modulate aqueous flow and uveoscleral outflow.54 Serotonergic compounds and angiotensin II have a combined agonist- antagonist action and target multiple sites. They are thought to lower IOP by either increasing uveoscleral outflow or reducing aqueous flow. Their derivatives act preferentially on select receptor subtypes resulting in the observed effects. Table 13.4 lists the pharmacological agents that reduce aqueous humor formation.
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