Introduction

See Video

In 1974, Worthen and Wickham first described a laser procedure for the treatment of open angle glaucoma (OAG)1. The laser was directed at the trabecular meshwork and they believed the procedure to be a trabeculotomy. Soon thereafter, Krasnov demonstrated a decrease in intraocular pressure (IOP) using a Q-switched laser to perform ‘goniopuncture’2. In 1979, Wise and Witter introduced the technique and parameters for an enduring procedure called argon laser trabeculoplasty (ALT)3. Since then, different techniques such as trabeculopuncture have been tried with limited long-term success. Interestingly, laser irradiation of the trabecular meshwork (TM) with the neodymium : YAG laser (1064 nm), diode laser (810 nm), and krypton laser (red 647.1 nm or yellow 568.2 nm) also reduce IOP comparably with ALT. Since these lasers interact with the TM in different ways, it suggests the hypotensive effect of laser trabeculoplasty (LTP) is multifactorial. In 1998, Latina published a pilot study using a Q-switched 532-nm Nd : YAG laser to perform trabeculoplasty that lowered IOP without causing coagulative damage to the TM4. This method was coined ‘selective laser trabeculoplasty’ (SLT). SLT and ALT have become the two most common forms of LTP performed for OAG and will be the focus of this chapter.

Epidemiology

The Early Manifest Glaucoma Trial was the first large randomized clinical trial to show that reduction of IOP with a combination of a beta blocker and ALT can slow disease progression in patients with manifest OAG5. Lowering IOP, medically or with laser or filtration surgery, remains the only viable approach to favorably alter the course of OAG. Therefore, the focus of glaucoma treatment remains centered on IOP control at an estimated cost of $623–2511 per patient per year in 20046. In the US, the direct medical cost of glaucoma, including medical treatment, surgical procedures and outpatient visits, was $2.86 billion in 2004. Medical therapy accounts for 38–52% of direct costs7. While real world data on the cost effectiveness of LTP are lacking, studies using simulated models that make assumptions about treatment efficacy suggest that LTP lowers yearly treatment costs for OAG. In one study, the cumulative 5-year cost of treatment with medication alone was $6571, while treatment with LTP reduced the cost to $4838, (including the cost of the procedure), therefore offering a 5-year saving of $1733 or a yearly savings of $346 per patient8. Clinically, the Glaucoma Laser Trial showed that initial treatment with ALT was as effective as initial treatment with topical medication9. Therefore, the use of LTP as treatment, compared with topical medications or in conjunction with medications, may be a reasonable option for selected OAG patients. Using a Medicare database, the numbers of LTPs peaked in 1992 with 176 670 procedures performed10. LTP numbers declined steadily until 2002, when the rates started to increase again to 169 680 in 20067. Given the trend of increased use, along with data regarding clinical efficacy and favorable economic impact, we need to review our understanding of the fundamental principles and describe the techniques of ALT and SLT.

Fundamental principles

The mechanisms of action of ALT and SLT are not completely understood, but are thought to be different from one another. A comparison of the morphological changes in the TM of eight human eye bank eyes after these procedures offers some insight. After ALT, scanning electron microscopy (SEM) revealed crater formation in the treated areas, measuring approximately 70 µm. Coagulative damage was evident along the base and edges of the craters, with disruption of the collagen scaffolding and scattered debris derived from disrupted trabecular beams. Intracellular changes were evaluated with transmission electron microscopy (TEM). TEM also revealed disrupted trabecular endothelial cells with coagulative damage. In contrast, evaluation with SEM of eyes treated with SLT revealed no evidence of crater formation or coagulative damage. There was minimal evidence of mechanical change, with only rare crack-like defects of the corneo-scleral meshwork identifiable. TEM revealed no coagulative damage to trabecular cells, but revealed disrupted intra-cytoplasmic pigment granules within pigmented TM endothelial cells11. See Figure 43.1.

Fig. 43.1 100× magnification photomicograph of monkey TM 1 day after SLT, showing macrophages within the TM and no thermal damage to the trabecular beams or cells.

Courtesy of Mark Latina, MD.

Postulated mechanisms of action of ALT include: mechanical, cellular, and biochemical. The mechanical theory suggests that coagulative damage causes shortening or ‘tightening’ of the inner trabecular lamellae. This trabecular tightening may increase outflow by preventing trabecular beams from collapsing. In 1972, Nesterov performed perfusion studies on 20 cadaver eyes and proposed that collapse of the trabecular lamellae upon each other and onto Schlemm’s canal may contribute to primary open angle glaucoma (POAG)12. Thus, the mechanical theory of ALT proposes that the tightening of the trabecular lamellae prevents or delays collapse of the lamellae or Schlemm’s canal allowing for increased outflow. The efficacy of a new procedure, canaloplasty, provides some construct validity for the mechanical theory of ALT. In canaloplasty, a 10-0 suture is threaded into Schlemm’s canal for 360° and a knot is tied to tighten the trabecular ring. This vaults Schlemm’s canal inwards and in one study the degree of this effect was proportional to the magnitude of IOP lowering13. The mechanical theory explains IOP lowering based on changes in anatomic conformations.

The cellular theory, or the ‘repopulation’ theory, suggests that LTP stimulates TM cell division and repopulates the trabecular beams with healthy cells that contribute to an improved outflow facility. In support, a histological study that measured TM cellularity in patients with POAG compared with that of non-glaucomatous individuals found that the TM from POAG patients had lower cellularity than age-matched normals¹⁴. Laser may stimulate repopulation by cells that are derived from a stem cell population in the anterior, non-filtering region of the TM15. LTP may also trigger macrophage infiltration of the TM aiding removal of cellular debris and thereby increase outflow facility16.

The cellular theory links to the biochemical theory due to the altered biochemical profile of healthier cells that repopulate the TM. Furthermore, infiltrating macrophages may also degrade extracellular matrix, further improving outflow facility. The biochemical theory focuses primarily on the alterations in the extracellular matrix, particularly the juxtacanalicular tissue, which allows aqueous to enter Schlemm’s canal. Such changes are of particular interest for the mechanism of SLT, since SLT produces minimal mechanical and coagulative changes in the TM, yet results in a significant IOP lowering effect. The trabecular surface and intratrabecular spaces are lined with mucinous glycosaminoglycans (GAGs). GAGs are important contributors to aqueous outflow resistance in the juxtacanalicular connective tissue and regulate fluid outflow by forming gel-like solutions. Laser treatment has been shown to alter the expression of GAGs by the TM cells17. Whether the modulation GAGs directly changes the extracellular matrix to allow for more outflow, or if it allows the TM cells to respond to biophysical cues and further modulate the matrix to then increase outflow, is yet to be elucidated18,19. Studies of other factors released by the TM that regulate Schlemm’s canal permeability are also contributing to the understanding of the mechanisms of LTP. SLT results in the release of interleukin-1α, 1β, and tumor necrosis factor-α into the aqueous humor. These cytokines bind to TM cells near the juxtacanalicular tissue and increase flow across the extracellular matrix tissues by inducing the release of matrix metalloproteinases19. Therefore, the IOP lowering effect is not due to one factor but likely due to the interactions of many mechanisms and enzyme cascades.

Preoperative assessment

Determining which patients are good candidates for LTP requires assessment of multiple factors. These include age, race, angle anatomy, TM pigmentation, and the mechanism of glaucoma. Some secondary glaucomas such as pigmentary20, exfoliative21, or steroid-induced22 can be treated successfully with LTP, while others such as uveitic, angle-recession23, and those associated with irido-corneal endothelial syndrome show minimal benefit with LTP. Congenital or juvenile glaucomas or glaucomas associated with angle dysgenesis and malformations also do not respond well to LTP.

Preoperative gonioscopy is essential when LTP is considered as a treatment modality. This not only determines the status of the angle structures but allows assessment patient cooperation as well, since the procedure will require adequate intraoperative patient positioning and lens placement. Anecdotally, we have found that patients with severe blepharospasm and small lid fissures may require a pediatric Goldmann lens for successful LTP. It is advantageous to recognize such challenges preoperatively rather than in the laser suite. During gonioscopy note the amount of TM pigmentation, as this dictates the power necessary at the time of LTP. For both ALT and SLT, increased pigmentation likely leads to increased absorption of laser energy by pigmented TM cells. Eyes with increased TM pigmentation are at higher risk of post-LTP IOP spikes (particularly SLT24). In order to reduce this risk, use lower energy settings or fewer laser applications.

Procedure

The preoperative preparations for both ALT and SLT require the following:

Fig. 43.2 The various lenses used in LTP. (A) the Goldmann three-mirror lens; (B) the Ritch lens; (C) the Latina lens.

The operative eye should be treated with a drop of topical anesthetic. Some surgeons place a drop in both eyes to maximize patient comfort. The use of pilocarpine to constrict the pupil and facilitate the view of the angle structures is optional and should be considered if the angle appeared slightly narrow on preoperative gonioscopy. Application of either apraclonidine or brimonidine prior to laser treatment reduces the likelihood of a post-treatment IOP spike25.

Operative procedure

Argon laser trabeculoplasty (ALT)

The methylcellulose agent should be placed directly on the treating lens to facilitate its coupling to the eye. It is helpful to place the lens on the eye such that the appropriate mirror is in position to visualize the quadrant to be treated. This minimizes lens manipulation at the time of treatment. If the Ritch lens is used, the spot size applied is actually one-half the size of the spot with the three-mirror lens. Once the lens is in place with the patient sitting at the laser-slit lamp system, the position of the aiming beam should be noted. It may be easiest to place the beam superiorly at the 12 o’clock position so the treatment is begun at the 6 o’clock inferior angle. The angle is usually widest at this point and has some pigment, facilitating distinction of angle landmarks.

Typically the continuous wave argon laser with the blue-green light wavelength is used, though the green only as well as the krypton red settings have been used. Determination of laser energy involves titration of the power either up or down until a faint blanching of the treatment site is noted. A typical starting point for the power is 600–800 mW. The standard lasers settings are 50 µm for spot size and 0.1 seconds duration.

The application should bridge the area between the pigmented and non-pigmented trabecular meshwork. The spots should be evenly spaced, so there are approximately 25 spots per quadrant. The space between spots should be about three to four times the size of the spot itself. Use of a consecutive pattern of applying spots between areas where the lens is rotated prevents confusion that may lead to re-treatment or omission of an area. To apply consecutive spots the lens should be turned in the direction opposite to that in which the laser spots are applied. For example, if the laser spots are applied in a clockwise fashion, the lens should be rotated counterclockwise (Fig. 43.3).

Fig. 43.3 The direction of treatment application and lens rotation.

For both ALT and SLT there is no consensus whether it is best to treat 180° initially or 360°. Generally, there is a higher risk of inflammation and postoperative pressure spikes if 360° are treated26. Several studies report equal efficacy of IOP lowering with treatment of 180° versus 360°27, while others report greater IOP lowering with treatment of 360°. In one study, there was less inter-visit IOP fluctuation when 360° were treated versus treating 180°28.

Post-procedure management

Tonometry may be performed approximately 1 hour after either ALT or SLT to check for a pressure spike. Any concerning elevation of IOP should be treated prior to discharge. On discharge, it is recommended that all prior glaucoma medications be continued. Non-steroidal anti-inflammatory agents can be used postoperatively if the patient feels discomfort; otherwise surgeons generally do not prescribe them postoperatively because they may dampen the therapeutic effect of LTP. Postoperative follow-up is scheduled for 1 to 6 weeks after LTP.

Complications

Immediate intraoperative complications of LTP with ALT or SLT are generally not seen. Aside from mild conjunctival injection, the most common postoperative complication is an IOP spike. IOP spikes usually occur 1–3 hours after the procedure with the incidence reported anywhere from 9.2% to as high as 53% after ALT. This large range is partly due to the variation in criteria of IOP spike, defined as anywhere from 5 mmHg to 10 mmHg. The GLT reported 34% IOP spikes after ALT, compared with lower rates reported for SLT around 2.4%, though many other studies report similar rates for ALT and SLT. As discussed previously, the modifiable factors to reduce risk include preoperative or immediate postoperative use of an alpha-agonist agent as well as judicious titration of laser power intraoperatively. Treatment of 180° as opposed to 360° may also reduce the risk of postoperative inflammation and IOP spikes.

A patient may have postoperative inflammation with or without some mild discomfort after LTP. As mentioned previously, the use of a topical non-steroidal anti-inflammatory agent can address this issue. Peripheral anterior synechiae (PAS) are a known side effect of ALT but not SLT. The rate of PAS can be reduced by properly placing laser spots at the junction between the filtering and non-filtering portions of the TM.

Less common, but reported complications of LTP include hyphema30, cystoid macular edema31, corneal edema32, and choroidal effusion33.

Assessment

There are varied reports regarding the success of LTP, in part due to different criteria used to define success. The Glaucoma Laser Trial reported a mean reduction in IOP of 9 mmHg in eyes undergoing primary ALT versus 7 mmHg at 1 year, in eyes initially treated with medications9. The various other clinical studies on ALT reveal an average decrease in IOP at 1 year between 6 and 9 mmHg. One 10-year follow-up study reported the average IOP decrease to be 8.9 mmHg at 1 year, 10.0 mmHg at 5 years, and 8.9 mmHg at 10 years34. Success rates in this study were reported at 77% at 1 year, 49% at 5 years, and 32% at 10 years. Success was defined as a decrease in IOP of 3 mmHg or greater, IOP of 19 mmHg or less, and stable visual fields and optic nerve with no other laser or surgical intervention. The failure rate according to the aforementioned success criteria was found to be highest in the first year, at about 23%, and then ranged from 5 to 9% per year thereafter. Another 10-year study by Wise reported that the percentage of eyes with IOP less than 21 mmHg was 61% at 5 years and 70% at 10 years35.

Latina et al. published the first study demonstrating the efficacy of SLT in 19984. This multicenter, pilot study showed 70% success in lowering IOP by at least 3 mmHg. The mean IOP reduction at 26 weeks was 5.8 mmHg. One year postoperative data from clinical trials comparing ALT with SLT found the mean decrease in IOP to be around 6 mmHg for both procedures with no significant differences in the rate of complications36. There are no 10-year data available comparing SLT with ALT, but studies with up to 5-year follow-up for both forms of LTP demonstrated equal success rates. Success rates, defined as a decrease in IOP of 3 mmHg or more, were 68%, 46%, and 32% at 1, 3, and 5 years respectively for SLT. The comparable success rates for ALT in the same study were 54%, 30%, and 31%37. See Table 43.2.

Table 43.2 Comparison of ALT and SLT outcomes

The only statistically significant difference in success rates of ALT and SLT was in repeat laser procedures after previous ALT. SLT appears to be better than ALT in lowering IOP in eyes with prior ALT38.

There are some interesting trends in the response to treatment for the various OAG subtypes. For example, young patients with POAG may not have as much of a response to ALT as older patients. In contrast, pigmentary glaucoma patients younger than 40 years of age may have a better response to the treatment than older patients with the same condition20. Also, patients with exfoliation glaucoma have a high success rate with ALT (perhaps even higher than patients with POAG), though over time the success rate regresses to a level comparable with that of POAG patients21. Furthermore, there are isolated reports of success in lowering IOP in steroid induced glaucoma. LTP may be a good temporizing measure in these cases where the IOP spike may be temporary and thus may spare the patient an incisional procedure22.

There have been some theories that the effect of SLT may be dampened if the patient is already on a prostaglandin analog. This was thought to be true if the pathway of prostaglandin analogs lowering IOP overlapped with the mechanism of SLT lowering IOP. Studies that compare the effect of SLT on patients using a prostaglandin analog versus not using an analog have not supported this theory. They have found that in fact the effects may be additive and that the IOP is lower with SLT in conjunction with prostaglandin analog treatment39.

There are several opportunities to expand our knowledge in the area of LTP. There is no confirmation that LTP actually improves outflow facility. Since the SLT spot straddles the entire filtration angle, it could have an effect on uveoscleral outflow and this would be important to document. The discovery of the molecular mediators involved in the therapeutic effect of LTP could lead to new drug targets for glaucoma. Selective targeting of pigmented trabecular endothelial cells has benefited our patients but perhaps selective targeting of stem cells would yield even more robust results in LTP patients. While SLT produces minimal structural effect on the filtration apparatus, the question of how repeatable SLT is remains open. While LTP is safe and effective in newly diagnosed glaucoma there are no real world data to indicate that early performance of LTP favorably impacts the ophthalmic pharmacy costs for glaucoma.

In conclusion, LTP provides an option for the treatment of many kinds of OAG. The success rates of SLT and ALT are comparable in POAG. The choice of which laser to use varies according to the individual situation. ALT may be preferable in patients with pigmentary glaucoma or exfoliation glaucoma. In contrast, SLT may be the procedure of choice for a fairly young patient with POAG. Furthermore, in patients undergoing a repeat LTP treatment, SLT may be more favorable. Patients may feel less discomfort with SLT than ALT during the treatment itself40. SLT remains an easier procedure to master due to the larger spot size but the investment in a separate laser for a single procedure still keeps ALT a popularly performed procedure. Optimization of the indications for LTP, preoperative preparation, laser surgical technique, and postoperative care has much to offer OAG patients worldwide.