According to the Basic Clinical Science Course Series-Glaucoma, open-angle glaucoma is: “classified as aaaprimary when there is no identifiable underlying anatomical cause of the events that led to obstruction of aqueous outflow and subsequent elevation of IOP”.1 This description is then coupled with a basic diagram showing aqueous production at the level of the ciliary body with arrows depicting the unobstructed flow through the pupil, to the angle and into a nice patent canal, then through the distal collector channels and beyond.
This description is like showing somebody a map of the southern California highway system and letting them know they will get from their hotel in downtown Los Angeles to Disneyland by simply exiting the hotel, merging onto Interstate-5, taking the Disneyland exit, and, hey presto, you’re in the fast-pass ticket lane and ready to take your seat on your favorite vertigo-inducing amusement park ride. It doesn’t consider that there is a movie shoot outside the hotel – or that your car is stuck in valet. And not to mention there is an overturned semi closing off the main on-ramp, three minor fender benders, construction, road closures… and the family of ducks that decided to make their way across the north and south going lanes. You will eventually get to where your desired destination, i.e. Disneyland, but, you just need to understand which highway systems to take, which to avoid, and when to take an Uber.
The conventional outflow system, though not as frustrating as the Californian highway system, has its own share of roadblocks. You see, there ARE underlying anatomical causes that lead to an increased resistance to, or obstruction of, aqueous outflow – and these pathologic changes can emanate from the innermost portion of the trabecular meshwork, all the way through to the episceleral plexus. Yes, the road map for aqueous outflow guides us through the trabecular columns of the uveal and corneal scleral trabecular meshwork, followed by a short trip through juxtacanalicular tissues composed of juxtacanalicular cells interspersed with extracellular matrix proteins. Aqueous must then traverse the tight junction secured, endothelial lined inner wall of Schlemm’s canal before it enters the main aquafer. And just like that, you’re traveling down your favorite waterslide in Disneyland.
Of course, it’s not this simple. The system is a dynamic organ undergoing constant homeostatic changes regulated by pressure-induced tensile changes, hormonal modifications, age, and even iatrogenic or medication induced changes. The trabecular columns are lined by endothelial cells, that like those of the corneal endothelium, are limited in population and once damaged have no hope for regeneration. Over time, like the hair follicles on my head, we begin to lose some of these endothelial cells. This population loss is exaggerated in glaucoma patients and even compounded by the pro-apoptotic effect of benzalkonium chloride, which has been show to induced endotheilial cell drop-out in-vivo and ex-vivo.2,3 As we lose these endothelial cells, adjacent trabecular columns fuse, decreasing the effective filtration area of the trabecular meshwork. We also see an overexpression (or downregulated turnover) of the extracellular matrix proteins within the juxtacanalicular tissue, which also increases the resistance to outflow. But our road blocks don’t end there. One of the enigmas we had for decades was deciphering how aqueous could flow through the inner wall of Schlemm’s canal, given that the endothelial cells that make up this blood-aqueous barrier are fused together by tight junctions. Was it simple pinocytosis? Active transport? Unknown gateways? Although it may be a combination of all the above, one discovery that can help understand how aqueous is able to traverse this intact barrier was the presence of inter- and intracellular micropores within the inner wall of Schlemm’s canal.4 But like the hair follicle analogy, there is an ever expanding drop-out of these micropores in glaucoma patients. Once into the canal, the aqueous is forced through available patent collector channels by our “aqueous pump”5, then into the scleral plexus and beyond. Unfortunately, many of our collector channels are obstructed by external herniations of the trabecular meshwork and inner wall of Schlemm’s canal.6
Despite this pathology in the proximal portion of the conventional outflow system, the system can still be successfully manipulated to enhance outflow. Transluminal viscodilation using the iTrack microcatheter (Ellex, Adelaide, Australia) not only lyses herniations of the trabecular meshwork that obstruct the collector channels and prevent flow into the distal system, it also dilates an attenuated canal (mechanically and via viscodilation). Also, through the work of pioneers including Prof. Robert Stegmann and Prof. Norbert Koerber, we know that the hydrostatic pressure exerted on the proximal system during viscodilation enlarges the spaces between the trabecular columns, but more importantly, creates micro-perforations in the inner wall of Schlemm’s canal, countering the reduced population of inter/intracellular micropores.
Another avenue in dealing with “road closures” in the proximal system is to simply by-pass the diseased area by implanting a trabecular micro bypass microstent, such as the iStent (Glaukos, San Clemente, USA). Though only 250 microns in diameter, proper, targeted stent implantation can be highly effective in enhancing outflow to provide long-term IOP and/or medication burden reduction.7 With both iTrack and iStent, there is limited tissue distortion to the natural architecture, thus allowing further manipulation of the system should the eye’s natural disease state overcome our original modifications. We are using the natural highway system and finding a way to weave our way through the traffic and other roadblocks. These therapeutic options work well in most patients, but not in all. Sometimes, the damage is too entrenched and unamenable to rejuvenation, manipulation or bypass. Sometimes, we just take the subway and use a totally different system, such as the supraciliary space. Or, another option, though not for the Californian highway system, is to simply remove the roadblocks altogether and allow aqueous to have direct access to the collector channels and the distal system.
Ablative procedures are becoming more and more common, principally because the devices are easier to use and more cost effective. They are also highly effective. There are two broad categories of trabecular ablative procedures: focal (or limited to the nasal angle) and complete (360 degrees). Most surgeons are performing the focal ablative procedures as compared to the complete ablation, especially when the procedure is coupled with cataract surgery. Ablative procedures are not new: we have been performing goniotomies and trabeculotomies for longer than I’ve been on this earth (and I’m not a YO, remember). Of course, these procedures have typically been used in the pediatric population. Our forefathers had previously tried transferring these same pediatric techniques to adults but had found them to be ineffective. So, why are we using them now? First and foremost, we have new tools that have changed how the procedures are performed and more importantly, how the tissue is manipulated. With devices like the Kahook Dual Blade, KDB (New World Medical, Rancho Cucamonga,USA), we are no longer simply incising the trabecular meshwork, but rather we are completely removing the actual strip of trabecular meshwork overlying Schlemm’s canal, which, in theory, and what we’ve seen clinically, disallows tissue to scar over the distal collector system and obstructing outflow. The same can be said for the the Trabectome (Neomedix, Tustin, USA), where an electrocautery unit ablates the trabecular meshwork overlying Schlemm’s canal in such a delicate manner that electron microscopic images have shown the endothelial cells of the canal to be left unharmed.
I particularly like using trabecular ablative procedures for outflow manipulation in patients suffering from secondary forms of open-angle glaucoma. As most of the deleterious changes are in the proximal portion of the outflow apparatus, it makes sense to remove the diseased tissue. I know I mentioned in previous blog posts that I like to preserve this tissue because the trabecular meshwork is an aqueous pump and the inner wall of Schlemm’s canal is a blood-aqueous barrier. But, if we are unable to control glaucoma with more conservative measures, it is certainly worth removing this tissue to facilitate improved outflow and achieve our goal—reduced IOP and preserved vision. If the distal outflow system is functioning but the aqueous is unable to adequately reach its conduits, the entire system is relatively useless. (Refertp figures 1, 2 and 3.) With conditions like pigmentary glaucoma and pseudoexfoliative glaucoma, we know there is more resistance to outflow at the level of the trabecular meshwork.8,9 Other secondary forms, like steroid9or anti-vascular endothelial growth factor antibody induced glaucoma10, also show the same exaggerated resistance to outflow and removing the diseased barrier in these patients allows the dysfunctional system to reestablish itself. Both the KDB and the Trabectome are brilliant inventions that serve their function well,– and I am delighted to have both at my disposal, especially for patients with secondary open-angle glaucoma.
Life – and the aqueous outflow system – is a highway and we will encounter many traffic jams from various etiologies. Understanding the aqueous outflow system can help guide us in our decision making when determining which MIGS procedures to choose for each individual patient and their specific disease presentation. Like understanding the complexities of a road map, we need to understand the complexities of the outflow system in order to identify the best route to take to get to our desired destination—vision preservation. Adopting MIGS into clinical practice may only require the scheduling of a handful of patients, but becoming a MIGS expert requires an in-depth understanding of all of the pathologic changes that occur through the drainage angle. Only with this understanding can we provide our patients with the highest level of care. I believe we are en route and on the right path, but we need to continue to garner a much broader understanding of the system in leading us to have our own version of “Google Maps” for the eye. Keep on trucking, my friends.
Figure 1: Heavily pigmented trabecular meshwork overlying Schlemm’s canal in patient with pigmentary glaucoma. Patient had intraocular pressures in the mid 30s on four topical medications.
Figure 2: Following goniotomy using the Kahook Dual Blade, three patent collector channels are highlighted by the regurgitation of blood from the episcleralvenous system into the collector channel ostia and into the anterior chamber (black arrows). Approximately 3 clocks hours of the nasal angle was treated and a full strip was cleaved using the KDB on the left (white arrow) that grasped and removed with MST forceps. To the right, the KDB incised the anterior portion of the TM overlying the canal leaving that region with an intact trabecular meshwork, but with a linear incision, a clear view to the white outer wall of Schlemm’s canal (green arrow), and open collector channels.
Figure 3: Following the focal goniotomy of the nasal angle, viscoelastic evacuation, and pressurization of the eye, one can see the global episcleralfluid venous wave or blanching of the episcleralvenous system, confirming the eye had a patient distal system. Post-operatively, the patient had routine pressures in the low teens without medications, confirming resistance to outflow was within the proximal portion (or trabecular meshwork/inner wall of Schlemm’s canal), and simply removing a small strip helped facilitate outflow, which in turn helped control this patients pressure.