Thank you very much Dr. James Tsai for your thorough and sophisticated discussion. Dr. Tsai asked me to clarify whether our clinical study is retrospective or prospective in nature. Our study was not formally conceived as a prospective clinical trial, although in reality it represents a consecutive series of cases treated with SLT, and in that sense it could qualify as a prospective study. There are exclusion criteria described in the paper, including age, previous ocular surgery, and secondary glaucoma. The patients listed in received the SLT procedure consecutively. In view of the improved success achieved during the treatment of the first ten patients or so, we adopted this laser treatment protocol as our new standard. Today, candidates for an SLT procedure are routinely asked to stop using prostaglandin analogues (PGAs) and usually return for an IOP check every two weeks. During this time, the IOP increases progressively to reach a maximum level around four weeks in most cases. This elevated pressure is taken to represent the baseline IOP value while not using PGAs. The patient is scheduled to have the SLT performed shortly thereafter, and subsequently, the PGA use is reinstituted for two to four weeks post SLT. By this time, the SLT becomes functional and the PGAs can be safely discontinued. According to our limited studies, an IOP rise after discontinuing the PGA predicts both a positive SLT outcome, and the level of the IOP lowering to be expected. In our hands today, we obtain approximately a 29–30% IOP reduction on the average. This response is far greater than what we achieved before implementing this new protocol.
I want to thank Dr. Allan J. Flach for his gracious comments, and for responding to my request, extended as I was running out of time during the presentation, to remind me to discuss the situation in patients receiving SLT for 180° and PGAs. Scherer (Reference No. 4
cited above by Dr. Tsai) has proposed that “PGA use made SLT more effective,” which is contrary to our proposal that PGAs and SLT do not seem to be additive to each other in lowering the IOP. Scherer made the SLT/PGA comparison at only one month after SLT. At this time, and depending on the baseline IOP, the SLT effect is only starting to become apparent, while the PGA has been fully functional all along. In fact, we routinely keep our patients on PGAs during the early post-SLT period to protect them from any IOP elevation, as it is often observed during this time. Thus, we believe that waiting three months after SLT is preferable, and withdrawing the PGA at that time may yield a different outcome compared to the situation at one-month after SLT. In our cases, we have observed that the IOP upon discontinuation of the PGAs is maintained at nearly the same level as measured when the PGAs were on board.
In addition, when only 180° of laser irradiation is used, the untreated trabecular meshwork (TM) in the other 180° remains fully available for the PGAs to have their effect in promoting outflow of aqueous. In fact, when treating for 180° with only 50 laser pulses, the untreated TM tissues between the laser shots also remain available for the PGAs to lower the IOP. If this is truly the case, even when treating for 360° and delivering the customary 100 laser pulses, the addition of PGAs should also induce an additional lowering of the IOP, albeit this might be a decrease of perhaps only 2–3 mm Hg. Following the same reasoning, one may predict that by delivering 150–200 low-power pulses instead, approximately 0.6 mJ, for 360° would reduce or perhaps even eliminate the additional IOP lowering induced by PGAs. That is, when the TM is truly lasered fully, and if the PGAs and SLT have a common effect, then the addition of PGAs might be expected to be superfluous. Thus, perhaps we have serendipitously stumbled on a novel way to determine empirically the number of laser shots, for example, 100 versus 150 or more, that constitute a complete laser-irradiation treatment. Determination of that maneuver was unavailable before this investigation.
Dr. Malcolm R. Ing’s first question refers to our published work (reference #17 in this paper) in which we showed, as he mentioned, that the conventional aqueous outflow pathway has an elaborate cell-to-cell signaling pathway, whereby the various cell types in this pathway communicate with each other to maintain aqueous outflow homeostasis. In another paper, recently submitted, we have also pointed out that monocytes, which can be recruited to the TM by chemoattractant factors secreted by trabecular meshwork endothelial cells (TMEs), also participate in aqueous outflow homeostasis by modulating the barrier property of Schlemm’s canal endothelial cells (SCEs). His second question refers to the specifics of our SLT treatment protocol, which he very well described already, and which is now described above in my reply to Dr. James Tsai’s and below to Dr. Stamper’s comments.
Dr. Robert Stamper wants to know how long before the SLT would we recommend stopping the prostaglandins before proceeding with treatment. Again, this issue is covered above in my reply to Dr. Tsai’s comments. Bob, I generally wait four weeks so that I can obtain a measure of the PGA IOP lowering effect. This measurement helps to reassure the patient that the SLT procedure is highly likely to be effective, and to give the patient a ballpark value as to what the IOP-lowering effect of the laser procedure is likely to be. However, in general practice, one does not generally need this information, and I think it would be perfectly reasonable to treat even while the patient is still using PGAs. The disadvantage might be that the treating physician might detect only a modest IOP lowering effect, as we have done in the past. Again, another advantage, as mentioned above is that the treating physician, by stopping and restarting the PGA use, might learn whether the SLT procedure, and specifically the number of shots delivered, treated the entire TM fully.
With regards to the important issues raised by Dr. Paul K. Kaufman, we agree wholeheartedly that the in vivo situation is immensely more complex than that encountered in the laboratory. However, we remain much more encouraged than he does for several reasons. We tested the responses of SCEs in vitro, both in terms of any effects on permeability and the disassembly of intercellular junctions, to timolol, brimonidine, brinzolamide, and three commonly used PGAs. Among all of those several agents, only the PGAs, which represent the one glaucoma therapy that increases aqueous outflow, turned out to be the agents that uniformly increase the conductivity of the SCEs and the disassembly of their barrier. Additionally, after learning that media conditioned by lasered TMEs have a very similar effect, as do PGAs, we proceeded to show that clinically the IOP lowering effects of laser irradiation and the application of PGAs are remarkably similar. Thus, while translating findings in the laboratory into the clinical arena is seldom possible, in the circumstance of SLT and PGAs it may be possible to ascertain whether the effect of each approach is more or less the same, or nearly identical. In fact, we hope that others will be encouraged to learn whether the similar clinical responses to the SLT and PGA therapies merely represent a baseline related effect, as suggested by Dr. Kaufman, or reflect the existence of a common mechanism of action. Finally, Dr. Kaufman wants to know the dosage of the agents used, which actually were in the “single digit” μM levels for latanoprost (Xalatan, Pfizer Ophthalmics, New York New York) and travoprost (Travatan, Alcon Laboratories, Inc., Ft. Worth, Texas) (i.e. 3.5 and 2.4 μM respectively) and in the double-digit level for bimatoprost (Lumigan, Allergan, Inc. Irvine, California) (i.e. 20 μM). I think that these answers take care of all the questions. Thank you very much.