Further Studies on the Canal of Schlemm: Its Anastomoses and Anatomic Relations Georgiana

Intraocular pressure (IOP) is maintained through complex and interrelated systems which control aqueous production and drainage, and it has been suggested that scleral lens (SL) wear may disrupt these vital homeostatic processes. This review provides an overview of anatomical and physiological processes that control IOP, identifies potential effects of SLs on these regulatory mechanisms, and examines studies that have attempted to quantify the effect of SLs on IOP. Lack of access to the cornea during SL wear makes accurate assessment of IOP challenging; therefore, a range of different assessment techniques and instruments have been employed to quantify IOP during and following SL wear. Some studies have evaluated IOP using standard techniques prior to lens application and following lens removal, or through a large central fenestration. Other studies have utilised instruments that facilitate assessment of IOP on the peripheral cornea or conjunctiva overlying the sclera (e.g. Schiotz, transpalpebral, and pneumatonometry). Two studies have recently evaluated changes in optic nerve structure during SL wear. Conflicting results have been reported on this topic, much of which examines changes in IOP in healthy subjects over limited periods of time. Currently, only a few studies have reported on long-term effects of SL wear on IOP in habitual SL wearers (after lens removal). Future research in this area must not only consider the fact that ocular conditions treated with SLs may potentially alter corneal biomechanical properties which can influence IOP, but also that these properties may be further altered by SL wear. Monitoring other risk factors for glaucoma (permanent alterations in optic nerve physiology, visual field defects) could provide a more comprehensive assessment of potentially increased risk of glaucomatous optic neuropathy due to SL wear. Ongoing clinical assessment of optic nerve structure and function is advisable in patients at risk for glaucoma who require SLs.

The distal outflow pathway of the human eye consists of the outer wall of Schlemm's canal, collector channels, and the deep-scleral, mid-scleral and episcleral vessels. It is the last region of transit for aqueous humor before returning to the venous system. While the trabecular meshwork, scleral spur, and inner wall of Schlemm's canal have been extensively analyzed to define their contributions to aqueous outflow, the role of the distal outflow pathway is not completely understood. Collector channels, emanating from Schlemm's canal were previously thought to be passive conduits for aqueous humor. However, recent studies have shown many collector channels contain flap-like appendages which move with changes in pressure. These findings, along with studies demonstrating innervation of episcleral vessels, have led to questions regarding whether other structures in the distal outflow pathway are under neural regulation and how this may influence aqueous humor outflow. This study evaluates the innervation of the outer wall of Schlemm's canal and collector channels, along with the deep-scleral, mid-scleral and episcleral vasculature with microcomputed tomography and 3-dimensional reconstruction, correlative light microscopy, immunohistochemistry, and transmission electron microscopy. Peripheral, autonomic, and sensory nerve fibers were found to be present adjacent to Schlemm's canal outer wall endothelium, collector channel endothelium, and in the different regions of the distal outflow vasculature. Nerves were more commonly identified in regions that contained collector channels when compared to regions without collector channels. These findings regarding the neural anatomy suggest an active neural regulation of aqueous humor outflow throughout the proximal and distal regions of the conventional outflow pathway.

Primary open-angle glaucoma (POAG) is induced by elevated intraocular pressure (IOP) that arises due to increased resistance in conventional aqueous humor outflow pathway (AHO_c) consisting of trabecular meshwork (TM), Schlemm’s canal (SC), and downstream vascular network including collector channels (CCs). Although it has been traditionally considered that most of the outflow resistance lies in TM and the inner wall of SC, recent studies identified that more than one third of the resistance lies on CCs and their connected vascular network. In addition, CCs draw more attention because minimally invasive glaucoma surgery (MIGS) whose success depends upon them has been recently spotlighted in the treatment of POAG. Despite the importance of CCs during the pathogenesis of POAG, glaucomatous changes in CCs of human patients have been only considered as secondary results without direct evidence due to the absence of glaucoma animal model primarily induced by CC impairment as well as difficulty in definitive visualization of AHO_c in vivo. Here, we hypothesize that likewise in TM and SC inner wall, structural and functional impairment of CCs may also primarily contribute to the initiation and progression of POAG. This article introduces a potential strategy to investigate and treat CC-related POAG.

Previous tracer studies have shown segmental outflow in the trabecular meshwork (TM) and along the inner wall (IW) of Schlemm's canal (SC). Whether segmental outflow is conserved distal to SC has not yet been investigated. This study aims to investigate whether the segmented pattern of outflow is conserved in distal outflow pathways by using a newly developed global imaging method and to evaluate variations of active outflow in three distinct regions along trabecular outflow pathway.

Six normal whole globe human eyes were first perfused at 15 mmHg to establish a stable baseline outflow facility. The anterior chamber was then exchanged (5 mL) and perfused with fluorescent microspheres (0.002% v/v, 200 μL) to label areas of active outflow. All eyes were perfusion fixed and dissected into anterior segments. The TM and scleral surface were en face imaged globally. Effective filtration area (EFA) and fluorescent tracer distribution and intensity were analyzed in global images for both the TM and episcleral veins (EPVs). Anterior segments were further dissected into a minimum of 16 radial wedges, from which frontal sections were cut, stained, and imaged, using confocal microscopy. EFA from all three locations along the trabecular outflow pathway were measured and compared. Additionally, TM thickness, SC height, and total number of collector channels (CC) were analyzed and compared between active and inactive areas of outflow. Statistical analysis was performed using Student's t-tests and Wilcoxon signed-rank test with a required significance of p ≤ 0.05.

All three locations showed a segmental outflow pattern. The TM had a significantly higher mean EFA (86.3 ± 3.5%) compared to both the IW (34.7 ± 2.9%; p ≤ 0.01) and EPVs (41.1 ± 3.8%; p ≤ 0.01). No significant difference in mean EFA was found between IW and EPVs. Preferential active outflow was observed in the nasal and inferior quadrants. TM thickness was significantly larger in areas of active outflow (103.3 ± 4.0 μm; p ≤ 0.01) compared to areas of inactive outflow (78.5 ± 6.5 μm), but there was no significant difference in SC height between active and inactive outflow areas. Among all eyes, a total of 80 CCs were counted with 63 associated with active outflow and 17 associated with inactive outflow. A higher number of CCs associated with areas of active outflow were found in the nasal (26 of 63) and inferior (20 of 63) quadrants compared to the temporal (9 of 63) and superior (8 of 63) quadrants.

A segmental nature of outflow is conserved along the trabecular outflow pathway with variations in three distinct locations (TM, IW, and EPVs). IW and EPVs showed a similar mean EFA. Preferential active outflow was observed in the nasal and inferior quadrants of the eye, which are associated with more expanded TM and higher number of CCs. Normal outflow patterns and its variations along the outflow pathway reported in this study will provide the basis for future studies of the outflow changes in eyes with glaucoma.

Primary open-angle glaucoma is the leading cause of irreversible blindness worldwide, and intraocular pressure reduction remains the only proven treatment strategy. Elevated intraocular pressure occurs as the result of impaired aqueous humor outflow. Both a passive model and a dynamic model have been used to explain trabecular outflow resistance. The passive model posits that the trabecular meshwork acts as a static filter that exerts stable and passive resistance to outflow. In contrast, the dynamic model involves a “biomechanical pump.” In recent years, the range of surgical management options for glaucoma has dramatically expanded, particularly the class of procedures known as microinvasive glaucoma surgery. These procedures typically target and enhance specific outflow routes. Optimal patient outcomes with microinvasive glaucoma surgery require a clear understanding of aqueous outflow and a surgical approach that is targeted to overcome the site of abnormal resistance in the individual. We review the anatomy and physiology of trabecular and suprachoroidal outflow that is of relevance to microinvasive glaucoma surgery–performing surgeons.