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Laser Trabeculoplasty

How Does It Work?

Daniel Cotlear, MD; Shlomo Melamed, MD; and Modi Goldenfeld, MD

Laser trabeculoplasty (LTP) is an effective treatment in patients with open-angle glaucoma either as primary therapy or as an adjunct to topical glaucoma medications.¹ The chromophore or target is melanin, which absorbs green light (wavelength of 532 nm) and results in a cascade that ultimately leads to a decrease in intraocular pressure (IOP). A decrease in IOP of up to 30% has been reported, although the effect may be temporary, lasting months to years.^2–5 Several types of lasers are currently used for trabeculoplasty, including argon, diode, titanium-sapphire, and double-frequency neodymium:yttrium-aluminum-garnet (Nd:YAG).^3,6–12

In an attempt to maintain LTP’s efficacy while minimizing the thermal damage and subsequent destruction of the trabecular meshwork (TM) and adjacent tissues, several technologies have been developed and gained popularity. However, argon laser trabeculoplasty (ALT) is still the most commonly used laser treatment for trabeculoplasty around the world^1–5 and is usually applied after maximally tolerated medical therapy has failed to control the IOP.⁵ Although LTP is considered a very safe and effective method, its exact mechanism of action still remains unclear. We will discuss possible mechanisms of action relating to LTP and expand on the clinical use of this treatment modality.

ARGON LASER TRABECULOPLASTY

Clinical Observations Related to the Mechanism

Krasnov¹³ initially described the potential of using laser to treat the TM to decrease IOP in 1973. This concept evolved into the currently used ALT, as described initially by Wise and Witter in 1979,² that has become a standard method of treatment for medically uncontrolled open-angle glaucoma. ALT’s efficacy and safety has been repeatedly confirmed by numerous studies.^6–15 Today, it is widely accepted that ALT reduces IOP in un controlled open-angle glaucoma patients,¹⁶ with success rates of approximately 80% at 1 year, 50% at 5 years, and 33% at 10 years.¹⁵

The following observations reported in clinical studies of ALT may give some hints as to the mode of action of this procedure:

• Increased outflow facility—tonography was performed in patients before and after ALT, and C (outflow) values were substantially increased after treatment.¹⁰ A fluorophotometric study disclosed no effect on aqueous humor inflow.¹⁷ From these studies, it was concluded that ALT mainly affects outflow facility, most probably through the TM—Schlemm’s canal region.
  
• Complete (360 degrees) vs partial (90 to 180 degrees) ALT treatments may be equally effective in IOP control. Additionally, low-dose¹² and low-power¹⁸ ALT has also been ob served to effectively control IOP in glaucoma patients. Such successful results of only minimal or partial treat ment of the outflow system may suggest that a triggered biological process could be involved, affecting nonlasered regions as well.

Some subtypes of open-angle glaucoma are more responsive to ALT than others. Pseudoexfoliative glaucoma, primary open-angle glaucoma, and pig ment dispersion glaucoma are subtypes of glaucoma in which ALT appears to be most beneficial.⁵ The common feature of these 3 diseases may be the wear-and-tear phenomenon. In this concept, particulate matter (pseudoexfoliative material, pigment, or some unknown protein or proteoglycan) is blocking the trabecular spaces and is associated with a diminished number of trabecular cells.19 Reduction in trabecular cellularity may subsequently result in adherence of trabecular beams and total collapse of the TM with increased resistance to aqueous flow. It is conceivable, then, that ALT may affect vital cellular processes related to this wear-and-tear phenomenon, and indeed several studies confirmed such an effect of ALT and will be described later in this chapter.^20–25 In contrast, other types of open-angle glaucoma are poorly responsive to ALT, such as aphakic/pseudophakic glaucoma, uveitic glaucoma, and juvenile glaucoma.⁵

Wise and Witter2 initially proposed this treatment, suggesting that mechanical shrinkage of the trabecular ring following ALT causes widening of the trabecular spaces with subsequent decrease in resistance to aqueous outflow and reduction of IOP. However, to date, no proof for such mechanical stretching of the trabecular sheets has been reported. It has been speculated that in glaucomatous eyes, where the trabecular beams are collapsed, the pattern of ALT may result in scarring of the lasered areas with widening of the trabecular spaces and Schlemm’s canal due to traction of the beams in adjacent regions. However, in a study of 23 pairs of enucleated human eyes,²⁶ no significant change in the cross-sectional area of Schlemm’s canal could be demonstrated after ALT. Because no accurate morphometric analysis has been done in glaucomatous eyes after ALT, the mechanical explanation for its effect still remains theoretical.

Biological Effect of Argon Laser Trabeculoplasty

ALT may be associated with triggering of a cascade of complex biological processes in the outflow system.^{20–25,27,28}

The cellular theory proposes that in response to coagulative necrosis induced by the laser, there is migration of macrophages that phagocytose debris and thus clear the TM from obstruction.²⁹ Recently, an addition to the cellular theory has been suggested. This theory employs facts reported by Wang and colleagues,³⁰ who demonstrated that the TM endothelium shares a similar response to oxidative insults as the systemic endothelial cells and that inflammatory cytokines can play a role in glaucoma. Wang and colleagues³⁰ demonstrated that, in response to sublethal stress performed on TM cells, cytokines such as endothelial leukocyte adhesion molecule-1 (ELAM-1) are released into the aqueous and influence glaucomatous aqueous outflow pathways. Signals such as laser energy promote oxidative stress. The gene for ELAM-1 has receptors in its promoter region that respond to this type of stress, subsequently releasing and activating inflammatory cytokines, such as interleukin-1 (IL-1). IL-1 in turn increases the formation of ELAM-1. Bradley and colleagues^31,32 have demonstrated that IL-1 increases outflow facility and showed that IL-1β and tumor necrosis factor-α mediate ALT-induced matrix metalloproteinases expression. For the first time, it was shown that the humoral pathway can be as important as the mechanical one.

Although the Glaucoma Laser Trial³³ demonstrated the efficacy of ALT, follow-up studies^1,34 revealed that only 20% to 32% of treated patients remained controlled after 7 to 10 years post-treatment. The need for repeat laser therapy was evident, but the fact that ALT creates a scar in the treated TM (Figure 54-1) limited the possibility of repeated treatment. It could thus be inferred that, if the biologic treatment is true, the effects of such treatment are contradicted by the trauma incurred by using thermal energy to influence cytokine release.

Histopathology of Argon Laser Trabeculoplasty

In a series of electron microscopy experiments performed in nonglaucomatous monkeys,^20,21,24 Melamed and colleagues described the acute and long-term cellular changes in the TM and Schlemm’s canal in the treated eyes. Immediately after ALT, the common features of laser effect were coagulative necrosis, disruption of trabecular beams, and dispersion of tissue debris (Figure 54-2). Small fragments of tissue could be found throughout the trabecular spaces, accumulating in the juxtacanalicular region. This accumulation of debris might explain the IOP spike sometimes detected immediately after ALT (in up to 31% of ALT cases).35 Many trabecular cells were rounded up, dislodged from their supportive beams, and some were very actively phagocytic, containing large phagosomes with an excessive amount of fibrillar material. After 4 weeks, the treated, lasered spots were detected as scarred regions with flattened beams. A cellular layer continuous with the corneal endothelium was found to cover these regions. The inner wall beneath these areas was flat with no giant vacuoles present. Rodrigues and colleagues³⁶ and Weber and colleagues³⁷ found similar changes in their studies of trabeculectomy specimens. Early changes consisted of disrupted trabecular beams and accumulation of fibrinous debris. Six months later, treated regions were scarred with a corneal endothelial sheet covering its surface, whereas nontreated regions appeared normal.³⁷

In human eyes, ALT reduces IOP despite scarring of the lasered regions. In a tracer study²⁵ performed in monkeys by using cationized ferritin, the scarred lasered sites were observed to be im permeable to aqueous flow. Gaasterland and Kupfer³⁸ showed that confluent ALT results in chronic IOP elevation due to trabecular scarring. (In fact, it is the best available method still in practice to create a model for glaucoma in monkeys.) One might wonder how, despite all the incurred damage to and scarring of the TM, IOP is reduced after ALT. Several studies^{20,22–25,39,40} may help in resolving this intriguing puzzle by suggesting some biological processes that might be initiated or enhanced by this therapy.

Enhanced Biological and Phagocytic Activity of Trabecular Cells

One of the main tasks of the trabecular cells is to act as the biological filter of the eye. Material obliterating the trabecular spaces is usually engulfed by phagocytes that later migrate away from the beams and the outflow system. After ALT, trabecular cells have been detected in various stages of enhanced biological and phagocytic activity.²⁰ This increased activity might have resulted from the absorption of laser energy itself or could have been triggered by the debris of lasered tissue. It is conceivable that such an effect of ALT might explain its high success rate in the wear-and-tear glaucomas, where the presumed particulate matter blocking the trabecular spaces may be more efficiently removed by trabecular cells activated by ALT, with subsequent reduction of resistance to aqueous flow.

Structural Changes of Regions Adjacent to Lasered Sites

Four weeks after ALT, nonlasered regions adjacent to lasered spots demonstrated an array of significant structural changes.²¹ These regions have wide open intertrabecular spaces with herniations of the juxtacanalicular meshwork and inner wall of Schlemm’s canal into and across its lumen. These herniations contain more vacuoles than in control eyes, suggesting an increased flow of aqueous humor. A tracer study²⁴ with cationized ferritin also suggested this with the demonstration of greater tracer deposition of untreated trabecular spaces, in contrast to nondeposition of tracer in adjacent treated and scarred areas. It was suggested that these changes are a compensatory response to ALT, allowing the aqueous blocked by the scarred spots to be shifted into less resistant trabecular routes, with the net effect of IOP reduction (see Figure 54-2).

Inflammatory Response Initiated by Argon Laser Trabeculoplasty

In humans, ALT usually stimulates an inflammatory response in the eye, requiring the use of anti-inflammatory agents.^8,9 In addition, the TM in monkeys was found to contain an abundance of inflammatory cells, such as lymphocytes, pigment-laden macrophages, and plasma cells.²¹ Such trabeculitis may also be associated with decreased IOP through the release of mediators affecting aqueous outflow, similar to the cytokine-related stress response theories described previously.

Increased Cell Division After Argon Laser Trabeculoplasty

Further support for the importance of the biological response of the TM to ALT was given by a series of experiments evaluating cellular division after treatment.^22–24 Increased trabecular cell division after ALT has been shown in organ-cultured human eyes²² as well as living cats²⁴ and monkeys.³⁹

In organ-cultured human eyes, trabecular cell division and migration were studied by exposure to thymidine. Two days after ALT, nontreated areas of the TM disclosed a marked incorporation of thymidine into the nucleic DNA, indicating increased cellular division.22,23

In the organ-cultured human eyes, thymidine incorporation occurred predominantly in the anterior, nonfiltering region of the TM (which might represent Schwalbe’s line cells). Two weeks later, the labeled cells were more concentrated in the lasered regions, suggesting active migration from the anterior trabeculum into the treated area. In the living cat model, DNA replication in the TM was also demonstrated in response to ALT,²⁵ although no accurate localization to the anterior trabecular region could be made. A significant increase in the mitotic index of trabecular cells in response to ALT was also confirmed by Dueker and colleagues³⁹ in the monkey model. Enhanced DNA synthesis, cell replication, and migration comprise a fundamental biological response of trabecular cells to ALT.

Alteration in Turnover or Synthesis of Glycosaminoglycans After Argon Laser Trabeculoplasty

The hypothesis that ALT causes the release of a factor that induces trabecular cell division or other cellular and extra cellular actions away from the lasered site was tested by Ruddat and colleagues.⁴⁰ In this study, the levels of mRNA for a family of matrix metalloproteinases were measured in response to ALT. These enzymes are synthesized and secreted to release cells from their extracellular matrix, allowing their increased mobility. After ALT, the levels of mRNA were significantly increased, suggesting the release of media-borne signals by ALT, biologically affecting remote, nontreated trabecular regions. In addition, evidence for alteration of turnover or synthesis of glycosaminoglycans after ALT has been reported.²²

Argon Laser Trabeculoplasty Summary

ALT is a widely accepted treatment modality for open-angle glaucoma. Despite its widespread use, we still lack a thorough understanding of its mode of action. With the support of numerous reported studies to date, the mechanical explanation for IOP reduction in glaucomatous eyes cannot be ruled out, but it may be too simplistic and awaits scientific confirmation. In contrast, several biological processes are triggered by ALT and may play an important role in altering outflow pathway conductivity. These biological processes in the TM include early increase in cell division, migration, and phagocytic activity and release of media-borne factors as well as alteration of glycosaminoglycans. Additional structural changes in lasered and adjacent nontreated regions affect ing aqueous flow patterns are also considered. These concepts are summarized in Table 54-2.

ALT is the most commonly used method for trabeculoplasty around the world; however, it is associated with early anterior chamber reaction, local irritation, peripheral anterior synechiae formation, and IOP spikes.^7,10,12 Scarring of the TM that is associated with ALT limits its effectiveness in subsequent applications.^7,12,14–17 For this reason, other laser modalities that have a theoretically lower likelihood of injuring tissues have been explored and will be discussed next.

SELECTIVE LASER TRABECULOPLASTY

Selective laser trabeculoplasty (SLT) was developed as a gentler method of IOP reduction without the scarring of the TM that occurs after ALT.⁴¹ SLT utilizes a frequency-doubled Nd:YAG laser trabeculoplasty (Nd:YAG SLT) to target the pigmented cells of the TM without transfer of significant energy to the surrounding tissue. In this mechanism of action, no thermal damage is inflicted to adjacent cells in the TM.

In contrast to the mechanical theory of ALT (that causes coagulative damage to the TM, which results in collagen shrinkage → subsequent scarring of the TM → tightening of the meshwork in the area of each beam → and reopening the adjacent, untreated intertrabecular spaces; see Figure 54-1),^2,42 the postulated mechanism in SLT is elective photothermolysis that enables the laser to precisely target intracellular melanin granules to activate individual cells while not disturbing adjacent nonpigmented cells. The activated cells release cytokines that trigger a targeted macrophage response to TM cells. The macrophages theoretically reactivate the TM and surrounding extracellular matrix, reducing fluid outflow resistance and lowering IOP.

In published studies,^43–49 SLT is considered to be relatively safe and as effective in lowering IOP as conventional ALT in patients with open-angle glaucoma, while also resulting in less ocular inflammation and fewer IOP spikes after treatment. There is a reported 30% incidence of elevations in IOP greater than 5 mm Hg with ALT compared to an incidence of less than 10% with SLT.⁴³

Because of the lower chance of thermal injury and scarring to the targeted tissue, SLT has the potential (and as of yet unproven) benefit of repeatability.^{29,43,44,50–52}

Mean reduction in IOP post-SLT has ranged from 2 to 14 mm Hg at 1 month and 3 to 6 mm Hg at 3 months to 5 to 7 mm Hg at 6 months. Five-year data sets have also shown that SLT could be as effective as ALT in lowering IOP in eyes with primary open-angle glaucoma receiving maximally tolerated medical therapy.⁵³

The lack of trabecular scarring after SLT may allow repeated treatments in patients with previous ALT. SLT was developed in order to take advantage of the fact that cellular and humoral mechanisms can affect the outflow facility without creating a permanent scar in the TM.^29–32 The energy delivered by SLT is mostly absorbed by pigmented cells and is therefore spatially confined to the pigmented TM cells without incurring collateral thermal damage to adjacent nonpigmented TM cells and underlying trabecular beams. SLT uses a Q-switched, frequency-doubled 532-nm Nd:YAG laser with a short pulse duration of 3 ns. This modality limits the conversion of energy to heat, further minimizing the collateral tissue damage.54 Histological studies⁵⁴ in human cadaver eyes after SLT reveal no evidence of coagulative damage or disruption of the corneoscleral or uveal trabecular beam structure (Figure 54-3). Because of the minimal cytologic damage, SLT offers 2 theoretical advantages: it may be repeat able and it may have a higher safety profile.⁵⁵ Latina and colleagues⁵⁶ were the first to establish the efficacy and safety of SLT by demonstrating a 70% response rate and a 5.8 mm Hg (23.5%) IOP-lowering effect of SLT. In addition, they demonstrated that SLT can be repeated after failed ALT without the risk of post-laser IOP spike. Other studies^57–59 confirmed these findings. Melamed and colleagues⁴⁴ treated newly diagnosed glaucoma patients with SLT and demonstrated a mean IOP reduction of 7.7 mm Hg (30%) while also witnessing a lower incidence of postoperative pressure spikes.

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