Unconventional Aqueous Outflow
Maintaining healthy aqueous humor outflow (AHO) is important for intraocular cellular health and stable vision. The impairment of AHO can lead to increased intraocular pressure, optic nerve damage and concomitant glaucoma. The pathway of aqueous humor drainage provides the fluid resistance that maintains a proper intraocular pressure (IOP). This is dependent on both aqueous humor production (inflow), and aqueous humor egress rate, (outflow’s balance). Low IOP can distort retina, cornea, lens; impairing vision. High IOP may lead to glaucomatous optic neuropathy.
Outflow rate through the unconventional pathway tends to decrease with age, and at night. This also happens in the presence of exfoliation syndrome, and ocular hypertension. Also, outflow rate through said pathway increases with iridocyclitis, glaucomatocyclitic crisis, and by prostaglandin analogs, which are being used successfully to treat glaucoma. Passage of aqueous humor outflow through the uveoscleral route was considered a passive and minor route until recently. In humans, it is reported that it can vary from 4-60%. Leber (1873), Schwalbe (1870), Kneis (1875), shown by Seidel (1921), and Ascher (1942) found aqueous humor drainage from anterior chamber through trabecular meshwork, Schlemm’s canal, collector channels, aqueous veins and into the episcleral veins. Later, this route was established as the primary route for aqueous humor outflow from the eye. Leber (1903) found that tracers from the anterior chamber passed into the conventional trabecular outflow pathway and in suprachoroidal space. Notice was taken of colloidal tracers accumulated outside conventional pathways (often deep within peripheral ciliary body, posterior sclera, and choroid after perfusion) with these tracers led to the inferred existence of a secondary aqueous humor outflow pathway (unconventional). Anders Bill (1960s) conducted studies with monkeys to solidify the understanding of unconventional outflow. This was done by flushing radiolabeled molecules of various sizes throughout the anterior chamber and examining different pathways the tracers left the eye. He concluded (because tracers accumulated constantly in sclera and more, and this was independent of the tracers diffusion coefficient) that there must be flow from anterior chamber through uvea, and into sclera by choroid and suprachoroid. This is the ‘unconventional route’.
Aqueous humor flows out of the eye primarily through the conventional outflow pathway that includes the trabecular meshwork and Schlemm’s canal. The Trabecular Meshwork regions include: the inner uveal meshwork (irregular net like structure with cords connecting different layers, and large spaces between the cords hardly contribute to outflow resistance), middle corneoscleral meshwork (organized into a network of trabecular beams or lamellae. Each lamella has a core, filled with a fibrillar extracellular matrix and covered by endothelial-like flat trabecular cells. The ECM is made up of an intricate arrangement of type IV collagen, versican, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs-4), laminin, fibronectin, metalloproteins (MMP-2 and 14), glycosaminoglycans (GAGs), and matricellular proteins.), Juxtacanalicular connective tissue (JCT) (adjacent to the SC, JCT is not arranged into beams/lamellae, but is rather composed of a loosely arranged ECM in which a sparse number of cells are embedded. Histologically, the JCT can be divided into three layers: Trabecular endothelial layer, Central connective tissue layer, and Inner wall (IW) endothelium of SC.) A portion of outflow goes via an ‘unconventional’ route, and this portion is likely to be more than small in healthy eyes, as it can vary from the wide range total aqueous outflow (likely 4-60% in humans). This route includes the ciliary muscle, supraciliary, and suprachoroidal spaces. After, it could drain through Uveoscleral pathways (aqueous drains across sclera to be reabsorbed by orbital vessels). Aqueous humor exits through the root of the iris, seeps through and around tissues, including the supraciliary space, ciliary muscle, suprachoroidal space, choroidal vessels, emissarial canals, sclera, and lymphatic vessels. Uveoscleral outflow is thought to be driven or changed by pressure gradients through the uvea, by movements of the ciliary muscle, and by cytoskeletal alterations or changes in the extracellular matrix within the drainage tissues.
It could also use the Uveo vortex pathway, where said aqueous humor enters choroid to drain through vortex veins.
The unconventional pathway is estimated to carry 3-82% of total aqueous humor outflow in different species. Trabecular outflow accounts for 70% to 95% of the aqueous outflow, and remaining 5% to 30% by uveoscleral outflow. Aqueous humor enters the ciliary muscle and exits through the supraciliary space. It may also cross the anterior or posterior sclera and subsequently pass through the emissarial canals around the vortex veins or into the choroidal vessels. Pressure gradients through the uvea, movements of the ciliary muscles, and changes in the extracellular matrix or in the cytoskeleton drive the uveoscleral outflow. Unconventional outflow must pass through the interstitial spaces of the ciliary muscle. The unconventional route is not the trabecular pathway, it includes the corneal route (negligible), iridial route (negligible), retinal route. With the retinal route, flow is generated by pumping capacity of retinal pigment epithelium (considered small unless retina detaches). Pilocarpine causes ciliary muscle contraction, decreases the space between muscle bundles, and decreases the unconventional outflow. Atropine is a ‘muscarinic antagonist’, which relaxes the ciliary muscle, thus increasing the unconventional outflow. Bill et al found that as IOP increased between 4 mmHg and 35 mmHg, unconventional flow either remained constant or increased at a much slower rate than did conventional outflow. Pedersen (1977) and Suguro (1985) also found unconventional outflow to be relatively pressure insensitive. It is important to note that in these studies, unconventional flow was not found to be pressure-independent, only pressure insensitive. In 1977 Bill suggested that the sizes of the interstitial spaces that carry unconventional flow through the ciliary muscle and suprachoroidal spaces are determined by a balance between Intraocular Pressure (tends to collapse these spaces and elastic elements), and interstitial pressure within the spaces, that tend to keep them open. As IOP increases, these spaces become smaller, and therefore increasing their resistance to flow. Bill referred to this as an “elastic sponge model” because of its similarity to channels in a sponge. In order for the elastic sponge model to explain the pressure-insensitivity of uveoscleral outflow, the resistance to flow through the ciliary muscle and suprachoroidal space must be much greater than the resistance to flow across the sclera. However, a large resistance in the ciliary muscle is not consistent with the observation that the resistance to flow through the sclera is comparable to total unconventional outflow resistance (Fatt and Hedbys 1970; Kleinstein and Fatt 1977; Jackson et al. 2008). Flow through the uveo vortex pathway offers another explanation for the pressure insensitivity of unconventional outflow. When IOP increases, even over the range of 4 to 35 mmHg, pressure in the uveal capillaries also increases, and therefore, the pressure difference across the capillary wall increases by much less than does a change in IOP. Bill (1977) suggested that compression of the ciliary muscle with increasing IOP could increase its flow resistance and thereby contribute to pressure insensitivity of unconventional outflow. When the ciliary muscle is removed by cyclodialysis, most of its resistance is lost and unconventional outflow increases four times more and becomes pressure dependent. Outflow facility and uveoscleral outflow also decreases with age and glaucoma. Studies done in aging eyes with glaucoma show an increase in extracellular material within ciliary muscles and trabecular meshwork, and also a loss of meshwork cells. All of this contributes to a reduction of outflow and an increase in IOP.
Aqueous humor outflow is a measurement of flow rate. Unlike the trabecular route, exit is diffuse and challenging to trace. The unconventional rate is measured with direct/tracer-based methods, and indirect methods. Direct methods are used to estimate both conventional and unconventional outflow via ocular tissues by looking at the rate of accumulation of a tracer molecule and in the blood after introducing the tracer in the anterior chamber. Most accurate, but may require a histologic analysis and are not non-invasive, so they are considered generally not suitable for use in humans. Indirect methods are used to infer unconventional outflow by finding the difference between aqueous humor production and aqueous humor outflow through the trabecular pathway, each one is determined independently. There is a need for new techniques for the measurement of uveoscleral flow.
Using the uveoscleral pathway for therapeutic purposes could involve both lowering of IOP and drug delivery via a transscleral approach. The current understanding of the mechanism of the IOP decrease caused by prostaglandin treatments involves permeability changes in the ciliary body. Many agree that prostaglandins lower intraocular pressure by increasing uveoscleral outflow. The growing use of prostaglandins to lower intraocular pressure has led to a growing interest in uveoscleral outflow. Mechanisms that may contribute to the prostaglandin-mediated increase of uveoscleral outflow include activation of a molecular transduction cascade, an increase in the biosynthesis of certain metalloproteinases (which leads to the reduction of extracellular material in the ciliary muscle), relaxation of the ciliary muscle, cell shape changes, cytoskeletal alteration, or compaction of the extracellular matrix within the tissues of the uveoscleral pathway.
Glaucoma and Surgery
To reduce IOP with a more rapid postoperative recovery and better safety ratings compared with traditional filtration surgery, minimally invasive glaucoma surgical devices are able to exploit different aspects of aqueous outflow. The potential IOP-lowering effect of the suprachoroidal space on the uveoscleral route is evident from clinical observation that a cyclodialysis cleft from trauma often leads to hypotony, an IOP of 5 mmHg or less. Hypotony’s adverse effects can damage the eye in several ways. Harnessing a cyclodialysis cleft to control IOP is challenging due to uncontrolled low pressures and pressure spikes on closure of the cleft. Many new minimally invasive glaucoma surgical devices target this space with the goal of obtaining a controlled IOP with suitable pressure reduction and minimal hypotony. The pressure-dependent trabecular outflow system has been the primary focus of the majority of surgical targets to lower IOP. However, once the ciliary muscle is bypassed through a shunt or a cyclodialysis cleft, most of the resistance the muscle offers is lost and the uveoscleral pathway becomes pressure dependent. This increases the amount of outflow by four times When the uveoscleral pathway is made pressure-dependent, its capability of lowering IOP is so significant that postoperative IOP may reach the low teens or single digits. Better understanding the unconventional route could prove to be extremely beneficial in treating glaucoma through surgical means.
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