Aqueous humor circulation is responsible for generating IOP within the anterior chamber of the eye[4].

Aqueous humor gets synthesized by the cells of the ciliary body in a three-step process. First, blood flows into the ciliary processes. Second, the pressure gradient between the blood flow and the ciliary interstitium propels the ultrafiltration of plasma into that interstitium. Finally, the ciliary epithelium actively and selectively transports plasma components from its basal to its apical surface, thereby synthesizing aqueous humor and pumping it into the posterior chamber of the eye. Though the first step in this process depends on blood flow, it is important to note that systemic blood pressure has demonstrated to have no significant effect on IOP. This fact is explainable physiologically in that the percentage of plasma filtered is meager at approximately 4%. The consistency of aqueous humor synthesis is the basis for IOP generation, though IOP also varies with the outflow facility. The resistance inherent in the aqueous humor drainage system determines the outflow facility.[4]

Aqueous humor is drained from the eye by an incompletely understood mechanism. Conventional and unconventional drainage pathways have been proposed. Both pathways begin with the synthesis of aqueous humor, as described above. The humor then flows from the posterior chamber to the anterior chamber by passing through the pupil; this is the point of divergence between the conventional and unconventional pathways.[5]

The conventional pathway continues with the humor draining through the following sequence of structures within the angle of the eye: the trabecular meshwork, Schlemm’s canal, collector channels, and the episcleral venous system. Flow through the trabecular meshwork is entirely passive. Flow through Schlemm’s canal has been demonstrated via paracellular and intracellular pores. Resistance to outflow has been documented in the trabecular meshwork and Schlemm’s canal, though the exact mechanisms are under debate. Flow resistance through these structures has the greatest effect on the outflow facility when compared to all known structures of both the conventional and unconventional pathways.[6] Aqueous humor continues through collector channels until it reaches the episcleral venous system where it gets deposited into the systemic cardiovascular circulation.[5]

The unconventional pathway drains into the ciliary muscle interstitium via the uveal meshwork, instead of the trabecular meshwork. This pathway subdivides into proposed uveoscleral, uveovortex, and uveolymphatic pathways, named for their respective vascular endpoints: orbital vasculature, vortex veins, and ciliary lymphatics, respectively. Each of these leads to systemic cardiovascular circulation. The existence of ciliary lymphatics is a topic of debate. The source of resistance in the unconventional pathway is likely ciliary muscle tone, as demonstrated in experiments involving pilocarpine, which increases tone and decreases unconventional flow, and atropine, which decreases tone and increases unconventional outflow. Further delineation of this pathway remains controversial.[7]

Aqueous humor production and drainage are not directly tested due to a lack of clinical utility. IOP acts as a surrogate measurement due to its association with glaucoma and the availability of cost-effective measuring devices. A clinician may measure IOP indirectly via ambulatory applanation tonometry, whereby air is used to flatten (applanate) an area of the cornea, and the pressure needed to do so is calculated.[8] IOP derives from this pressure. Accuracy of this measurement depends on the skill of the practitioner and the thickness of the patient’s cornea. It is also possible to measure IOP by indentation tonometry, though this is not common in developed nations due to the availability of applanation tonometry. However, this method can be a cost-effective means of bringing IOP measurement to rural areas that may not have access to ophthalmic specialty services. Indentation tonometry tends to underestimate IOP when compared to the applanation gold standard.[9][10] Direct cannulation of the eye is also possible but is not done clinically due to the availability of less invasive methods.[4]

In primary open-angle glaucoma, the secretion of aqueous humor remains normal.[5] However, outflow resistance has been implicated in glaucoma pathophysiology due to its effect on IOP.[6] Investigation regarding the exact nature of this relationship is ongoing. Though elevated IOP is associated with glaucoma, this parameter does not sufficiently explain its pathogenesis: patients with normal IOP may have glaucoma, and patients with high IOP may not have glaucoma.[11][12] Familial history of glaucoma is a known risk factor for glaucoma, but most cases are sporadic and likely multifactorial.[13][14] Genome-wide association studies continue to identify novel loci for further study.[15]

Aqueous humor is clinically significant as it relates to IOP and, therefore, glaucoma, as described above.[13] Screening patients for glaucoma via IOP measurement is controversial. In 2013, the United States Preventative Services Task Force (USPSTF) updated its recommendation on screening primary care patients for glaucoma in patients with normal vision. The systematic review showed insufficient evidence to recommend screening these patients.[16] Contrary to this, in 2016, the American Academy of Ophthalmology (AAO) guidelines promoted a comprehensive medical eye evaluation, including IOP measurement by applanation tonometry, every 5 to 10 years for adults under 40 years old who have no risk factors. The suggested evaluation frequency increased with age: every 2 to 4 years in patients between 40 and 50, every 1 to 3 years in those between 55 and 64, and every 1 to 2 years in those over 65. The AAO made further recommendations for patients who have diabetes mellitus or other risk factors for glaucoma. Yearly examination was recommended for patients with type 1 diabetes, beginning five years after disease onset. The annual examination was also recommended for patients with type 2 diabetes but beginning at diagnosis. Lastly, a biennial examination was recommended for any patient with risk factors for glaucoma, regardless of age.[17]