Thursday, September 15, 2016


Aqueous humor (AH) is produced by the non-pigmented epithelium of the ciliary body. It flows into the posterior chamber and through the pupil, enters the anterior chamber (AC).
Aqueous outflow through the AC occurs through the following probable routes:
1.    The “conventional pathway” through the trabecular meshwork (TM) and Schlemm’s canal (SC)
2.    The “unconventional pathway” through the ciliary muscle and other downstream tissues.
3.    Through the iris surface and capillaries.

The uveoscleral pathway is regarded as a minor route for aqueous outflow and shall be discussed here first. Studies however show that aqueous outflow through the unconventional route can vary from 4-60%. The outflow rate through this route tends to decrease with age so that the conventional pathway has to take up more function of aqueous outflow. The outflow through this route is also reduced in exfoliation syndrome, ocular hypertension and during night-time. The outflow is found to increase in conditions like iridocyclitis, glaucomatocyclitic crisis and by prostaglandin analogues which are being used to treat glaucoma successfully.
Unlike the TM/SC, the unconventional/uveoscleral pathway is not a well-defined structural pathway. In this route, AH 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. The uveoscleral outflow is driven by the pressure gradients through the uvea, movements of the ciliary muscles and changes in the extracellular matrix or in the cytoskeleton. 
The conventional route is the major site of aqueous outflow and the resistance produced in this area is responsible for the changes occurring in primary open angle glaucoma (POAG).

Based on anatomical location, the trabecular area can be divided into separate regions which differ in both structure and function. These regions consist of:
1.    The inner uveal meshwork
2.    The middle corneoscleral meshwork
3.    The juxtacanalicular connective tissue (JCT) adjacent to the Schlemm’s canal.  

The uveal meshwork is an irregular, net-like structure with cords connecting its different layers. There are large spaces between the cords which contribute little to outflow resistance. This part of the meshwork consists of bands of connective tissue with irregular openings measuring 25-75µ. The corneoscleral meshwork extends approximately 100µ deeper. It is composed of a number of porous sheets, extending from the scleral spur posteriorly to the peripheral cornea anteriorly. The size of the openings in these sheets decrease progressively as the deeper aspects of the meshwork is reached. These openings are oval shaped and have a greater diameter of 10µ, with a lesser axis of 5µ. Near the SC the lesser axis is reduced to 1-2µ, making the mesh tighter in this region.
The uveal and corneoscleral TM is organized into a network of trabecular beams or lamellae. Each lamella has a core, filled with a fibrillar extracellular matrix (ECM) 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. The matricellular proteins (e.g thrombospondins, secreted protein acidic and rich in cysteine [SPARC], tenascin C, osteopontin and hevin) are non-structural adaptor proteins which modulate the interactions between the trabecular cells and the ECM and modulate tissue remodelling.

Unlike the uveal and corneoscleral meshworks, the 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 3 layers:
1.    Trabecular endothelial layer: This is continuous with the endothelium of the corneoscleral meshwork.
2.    Central connective tissue layer: This consists of parallel, spindle-shaped cells loosely arranged in a connective tissue ground substance having Type III collagen. Connective tissue cells also contain coated pits and coated vesicles in the plasma membrane which are involved in receptor-mediated endocytosis.
3.    Inner wall (IW) endothelium of Schlemm’s canal: This forms the outermost part of JCT. It is a confluent layer of elongated cells attached to one another by tight junctions and lying upon a discontinuous basement membrane. It has a bumpy surface due to protruding nuclei, cyst-like vacuoles and finger-like projections which protrude into the lumen of Schlemm’s canal. The IW endothelium of the SC, it’s basement membrane and the adjacent JCT is known as the “innerwall region”. 

The JCT has a network of elastic fibres which run tangential to the inner wall endothelium, which is also known as the “cribriform plexus”. In response to fluctuations in IOP the JCT undergoes an expansion and recoil, which is an integral part of AH dynamics. Elastic fibers are known to contribute to this mechanism. An acute rise in IOP, as in rubbing of the eyes, is offset by changes in the JCT which brings the IOP back to normal. Histologic examination of the elastic fibres reveals an inner core of cross-linked elastin with an outer sheath of microfibrillar components. There are other proteins associated with elastic fibres including myocilin, fibronectin, vitronectin, versican, tenascin C, decorin, GAG chains, laminin, fibrillin-1, MAGP-1 and Types III and VI collagen.


The IW cells contain unique structures known as “Giant vacuoles”. These giant vacuoles range from 1-10µ in width, 1-7µ in height and 20µ in length. These are not intracellular structures but are out-pouchings of the endothelium caused by the pressure drop across the IW endothelium. The walls of these invaginations are very thin and in the region where the wall is most thin, unique pores are seen to form. Whether giant vacuoles serve as conduits for aqueous entry into the canal in conjunction with pores or function as a mechanism to sense pressure by stretching and allow greater fluid flow in the neighboring intercellular junctions is unknown. In humans, reduced formation of giant vacuoles in the IW endothelium of the SC has been proposed to account for the age-related increase in outflow resistance. 

The inner wall of SC contains approximately 20,000 transcellular pores. These pores permit the flow of aqueous humor into the SC. The majority of these pores (about 75%) are transcellular. Others are located at the border of neighboring cells and are paracellular. IW pores range in size from 0.1µ to more than 3µ with an average diameter of <1µ. The density of pores in the IW endothelium is probably less than 1000 pores/mm2. Some old studies had reported 1000-2000 pores/mm2, but they are now attributed to fixation artifacts.

The SC is an endothelium-cell-lined canal. It runs concentrically around the eyeball at the corneoscleral junction within the internal scleral sulcus. The SC is oval or triangular in cross-section with a greater diameter of 180-250µ. On the posterior aspect it is related to the scleral spur, while the IW of the canal is related to the TM. Occasionally, the SC may break up into branches which coalesce again. 

The lumen of the SC may collapse to a size of few microns or less at higher IOPs which led to speculation that this might be the cause for POAG. However, studies have shown that the collapse of the SC lumen does not produce a flow resistance high enough seen in glaucomatous eyes. It is speculated that the collapse of the canal would make the condition worse and does not in itself cause glaucoma.

AH from the SC drains into the 25-30 collector channels which join the deep scleral venous plexus. From this deep plexus AH drains via an intrascleral- and episcleral-plexus into the anterior ciliary veins. Some of the collector channels bypass the deep scleral venous plexus and pass directly through the sclera. These are called the aqueous veins of Ascher, as they contain AH instead of blood. The aqueous veins ultimately drain into the conjunctival vessels near the limbus.
The SC, collector vessels and aqueous veins are subdivided by septa. These septa are present throughout the SC, but especially so near the collector channels. They bridge the inner and outer walls of the canal. The proximity of these structures to collector channel ostia suggests that their function might be to prevent complete collapse of the canal lumen and occlusion of collector channel ostia.

The collector channels and aqueous veins are relatively large vessels which are tens of microns in diameter and generate negligible flow resistance. However, there is a case report of high IOP after the use of a surgical trabectome, suggesting the existence of considerable flow resistance distal to the SC in human eyes. Most studies, however, confirm that these vessels are not likely responsible for the elevated flow resistance seen in glaucoma. In humans 75% of the resistance to AH outflow is localized in the TM and 25% occurs beyond the SC.

Increase in IOP causes progressive deformation of SC juxtacanalicular cells and trabecular lamellae with progressive enlargement of the juxtacanalicular space. This movement causes cellular elements and ECM to become less compact and reduces the ability of the juxtacanalicular space to participate as a resistance element. With prolonged high IOP, pressure and shear-mediated signals in endothelia initiate a series of responses at the cellular, molecular and genetic levels as well as enable adaptive changes which regulate pressure and flow.

SC= Schlemm's canal; IW= Inner wall; EL= Elastic tendons; TM= Trabecular meshwork; CM= Ciliary muscle

A note on: SCLERAL SPUR:
Immediately outer to the trabecular meshwork is a protruding rim of scleral tissue known as the scleral spur (spur: a device with a small spike or a spiked wheel that is worn on a cowboy or rider's heel and used for urging a horse forward.) It appears as a hook-like process deep to the Schlemm’s Canal. On a meridonial section, it appears as a small triangular area. The base is continuous with the inner surface of the sclera, immediately to the outer side of the filtration angle. The apex is directed forward and inward. To the anterior sloping margin are attached bundles of trabecular meshwork, while from the posterior margin arise meridonial fibers of the ciliary muscle.


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