Aqueous humor is drained from the eye via two main pathways1). The conventional pathway passes through the trabecular meshwork and Schlemm’s canal, accounting for 80–95% of total outflow. The alternative pathway is the uveoscleral route, through which 5–20% of aqueous humor flows.
| Item | Conventional outflow pathway | Unconventional outflow pathway |
|---|---|---|
| Route | Trabecular meshwork → Schlemm’s canal → collector channels | Ciliary muscle → suprachoroidal space → sclera |
| Proportion of outflow | 80–95% | 5–20% |
| Pressure-dependent | IOP-dependent | Pressure-insensitive |
The unconventional outflow pathway, also called the uveoscleral outflow pathway, was established in the 1960s by Anders Bill through radioactive tracer studies in monkeys. He demonstrated the flow of aqueous humor from the anterior chamber through the ciliary body, then via the choroid and suprachoroidal space to the sclera.
The main resistance to outflow in the conventional pathway resides in the extracellular matrix of the juxtacanalicular connective tissue near Schlemm’s canal1)2). In contrast, aqueous outflow via the unconventional pathway is non-IOP-dependent, and the tone of the ciliary muscle influences the outflow rate.
In humans, the conventional pathway (trabecular meshwork-Schlemm’s canal) accounts for 80–95% of total aqueous humor outflow, while the unconventional pathway (uveoscleral outflow) accounts for 5–20%1). However, some reports estimate the proportion of unconventional outflow in humans to range widely from 4% to 60%. This reflects differences in measurement methods (direct vs. indirect) and variations due to age and measurement conditions. Notably, there are significant species differences; in primates such as monkeys, the proportion of the unconventional pathway is known to be higher than in humans.
Pathway Flow
Anterior chamber angle: Aqueous humor enters the intercellular spaces at the anterior tip of the ciliary body
Between ciliary muscle bundles: Passes through the connective tissue between muscle bundles in the ciliary body stroma
Suprachoroid: Reaches the connective tissue of the suprachoroidal space
Via sclera: Exits the eye through loose connective tissue around vortex veins, ciliary nerves, and ciliary arteries
Accessory Pathways
Uveal vortex vein pathway: Aqueous humor enters the choroid and is drained through the vortex veins.
Corneal pathway: Outflow through the cornea is negligible.
Iris pathway: Outflow through the iris is also negligible.
Retinal pathway: A small amount of outflow occurs via the pumping function of the retinal pigment epithelium.
There is no limiting membrane at the anterior end of the ciliary body or on the iris surface. Therefore, aqueous humor easily penetrates into the ciliary body and iris stroma. Aqueous humor that enters the ciliary body stroma travels posteriorly along the uvea and exits the eye through the sclera. The rate of aqueous outflow via the uveoscleral pathway has been reported to be 0.2–0.4 µL/min.
The pressure in the suprachoroidal space is lower than the anterior chamber pressure3). This pressure gradient is one of the forces driving aqueous humor from the anterior chamber toward the suprachoroidal space.
A tracer molecule is introduced into the anterior chamber, and the rate of tracer accumulation in ocular tissues and blood is measured. This can quantify both conventional and unconventional outflow, but requires histological analysis and is not noninvasive, making it generally difficult to apply in humans.
Aqueous humor production and outflow through the trabecular pathway are measured independently, and unconventional outflow is estimated from the difference. This method is clinically usable, but because it is an indirect estimate, its accuracy is limited.
Prostaglandin-related drugs are widely used as first-line glaucoma eye drops. Their intraocular pressure-lowering mechanism is primarily the enhancement of uveoscleral outflow. Specific mechanisms reported include reduction of extracellular matrix in the ciliary muscle, increased biosynthesis of certain matrix metalloproteinases (MMPs), relaxation of the ciliary muscle, and changes in the cytoskeleton.
Aqueous humor outflow via the unconventional pathway is influenced by the tone of the ciliary muscle.
Pilocarpine (parasympathomimetic): Contracts the ciliary muscle, reducing the spaces between muscle bundles, thereby decreasing unconventional outflow.
Atropine (parasympatholytic): Relaxes the ciliary muscle, increasing unconventional outflow.
The outflow rate through the unconventional pathway decreases with aging and at night. It is also reduced in exfoliation syndrome and ocular hypertension. Conversely, it increases in iridocyclitis and Posner-Schlossman syndrome.
Prostaglandin analogs lower intraocular pressure by enhancing aqueous humor drainage via the uveoscleral outflow pathway. The mechanisms involve relaxation of the ciliary muscle leading to expansion of spaces between muscle bundles, increased expression of matrix metalloproteinases (MMPs) promoting degradation of extracellular matrix, and changes in the cytoskeleton. These actions improve the permeability of aqueous humor through the ciliary muscle and increase outflow via the unconventional pathway.
Aqueous humor outflow via the conventional pathway is pressure-dependent, increasing with rising intraocular pressure 1). In contrast, unconventional outflow remains constant or increases much more slowly than the conventional pathway when intraocular pressure rises within the range of 4 to 35 mmHg. This property is termed “pressure insensitivity.” Strictly speaking, it is not “pressure-independent” but rather “insensitive to pressure.”
Bill (1977) proposed that the size of the interstitial spaces through the ciliary muscle and suprachoroidal space is determined by the balance between intraocular pressure (which tends to collapse the spaces) and interstitial pressure (which tends to open them). When intraocular pressure rises, the interstitial spaces shrink, increasing outflow resistance, thereby offsetting the increase in driving force. This mechanism is called the “elastic sponge model.”
When intraocular pressure rises, the pressure within the uveal capillaries also increases. Therefore, the change in pressure difference across the capillary wall is much smaller than the change in intraocular pressure. This is another explanation for pressure insensitivity.
When the ciliary muscle is removed by cyclodialysis, most of the resistance provided by the muscle is lost, and unconventional outflow increases more than fourfold and becomes pressure-dependent. This is why traumatic cyclodialysis often causes severe hypotony.
In the main pathway, when intraocular pressure rises, aqueous humor outflow increases proportionally (pressure-dependent). In contrast, in the unconventional outflow pathway, outflow changes little even when intraocular pressure varies in the range of 4–35 mmHg 1). This is thought to be because the interstitial spaces of the ciliary muscle are compressed by the rise in intraocular pressure, increasing outflow resistance and offsetting the increase in driving force (elastic sponge model). However, when the ciliary muscle is bypassed by cyclodialysis, unconventional outflow becomes pressure-dependent and outflow increases more than fourfold.
Based on clinical observations that traumatic cyclodialysis often causes hypotony, the intraocular pressure-lowering effect of the suprachoroidal space has attracted attention. Many new MIGS devices target the suprachoroidal space to achieve appropriate intraocular pressure reduction and minimal hypotony.
In shunt devices that bypass the ciliary muscle, most of the resistance provided by the muscle is lost, and the uveoscleral pathway becomes pressure-dependent. Postoperative intraocular pressure may reach the low teens or even single digits.
Aqueous humor outflow is not uniform; there are regions of high, medium, and low flow 2). In glaucomatous eyes, the area of low flow is increased compared to normal eyes 2). High-flow and low-flow regions differ in molecular composition, and segmental molecular changes occur during homeostatic responses to intraocular pressure 2).
Future challenges:
De Groef L, Andries L, Moons L. The zebrafish as a model for studying aqueous humor dynamics and glaucoma. Annu Rev Vis Sci. 2022;8:349-378.
Acott TS, Vranka JA, Keller KE, et al. Normal and glaucomatous outflow regulation. Prog Retin Eye Res. 2021;82:100897.
Quigley HA, Cone FE. Development of diagnostic and treatment strategies for glaucoma through understanding and modification of scleral and lamina cribrosa connective tissue. Cell Tissue Res. 2013;353:231-244.
