Jorge Alvarado, MD
UC San Francisco
Hawaiian Eye Meeting, 2009
Comments from the author, Brian Francis MD, are in italics.
Dr Jorge Alvarado presented his thoughts and research on selective laser trabeculoplasty (SLT) and laser trabeculoplasty in general. He noted that failure of SLT or a modest reduction in intraocular pressure (IOP) may be explained by competing interactions between laser and glaucoma medications. He hypothesizes that by removing the competing medications, the success of SLT can be greatly increased.
The mechanism of aqueous outflow is a dynamic one, with constant changes in the anatomical shape and position of Schlemm's canal (SC) and the trabecular meshwork (TM) in response to decreased, normal, and increased IOP conditions. The Schlemm's canal endothelium, or inner wall of the canal, acts as a barrier function that opens or closes as IOP changes. The TM endothelium acts as a baroreceptor to modulate this change via various signaling pathways.
SLT supports the signaling of TM endothelium to SC endothelium and results in increased permeability to aqueous outflow. (See Alvarado et al, British Journal of Ophthalmology, 2005 for more information. Briefly, exposure of trabecular meshwork endothelium in vitro was performed, and the culture media added to SC endothelial cells. The SC cells thus exposed showed an increase in gene expression (as measured by PCR) of numerous proteins, including cytokines IL (interleukin)-1α, IL-1β, TNF (tumor necrosis factor)-α, and IL-8. An increase of permeability of SC endothelium of four-fold was seen as measured by flow meters. When the factors listed above were added directly to SC endothelium, this resulted in a similar increase in permeability. Thus, there is a complex signaling pathway between TM and SC that affects aqueous outflow.)
The precise way in which this SC endothelial permeability is regulated is by the formation of filopodia between the cells resulting in a tight junction. When these filopodia are released, this opens a pathway between endothelial cells and allows the passage of aqueous. Dr. Alvarado then showed videos of these cells splitting apart as the filopodia are released.
Experiments with PGA drugs exposed to SC endothelium show a similar opening of this barrier. He conjectures that this suggests that at least part of the function of PGA is through the conventional rather than the uveoscleral outflow pathway. Thus, the effects of SLT and PGA drugs may be quite similar. In addition, the IOP lowering response of an individual to a PGA may be predictive of SLT response. The implications for clinical practice are to discontinue PGA prior to SLT and to use aqueous suppressants as adjunctive medication. This observation is supported by some retrospective studies that have shown a decreased response to SLT in patients using prostaglandin analogues (PGA), although there have not been any prospective, randomized trials to substantiate this.
Dr. Alvarado's experimental data is quite compelling and has many possible ramifications. The first is that the greatest resistance to aqueous outflow may be in the SC endothelium rather than the juxtacanalicular TM, although the two structures are intimately associated. The second is that changes in IOP are detected by the TM (acting as a baroreceptor), and are transmitted via chemical signaling pathways to the SC endothelium, which acts as the actual gateway to control aqueous outflow. This in turn has implications for future drug development. In addition, it suggests that the prostaglandin analogue drugs may in fact act via the conventional trabecular outflow pathway rather than the uveoscleral pathway (or possibly a combination of both).