Noninvasive glaucoma procedures: current options and future innovations.

Noninvasive glaucoma procedures (NIGPs) represent a new dawn in the management of glaucoma. They try to fill the gap between the shortcoming of invasive glaucoma surgeries and antiglaucoma medications. NIGPs were introduced as an adjunct or alternative treatments for glaucoma. Some of these procedures have shown good efficacy with few serious complications. Hence, they are now used as both primary and adjunctive therapy for glaucoma. The most common NIGPS involve laser and ultrasound technologies. Currently, the portfolio of NIGPs includes argon laser trabeculoplasty, selective laser trabeculoplasty, and micropulse diode laser trabeculoplasty. More recent innovations include therapeutic ultrasound for glaucoma, ultrasonic circular cyclocoagulation, and deep wave trabeculoplasty.

INTRODUCTION

Although glaucoma is considered one of the leading causes of blindness worldwide, initial therapy remains debatable. Traditionally, management of open angle glaucoma starts with medical treatment, and then if necessary, proceeds to laser or incisional surgery. However, in Europe, many clinicians perform surgery as the initial treatment for glaucoma, while in the United States, topical glaucoma medications are the first line of treatment. Neither surgeries nor medications are free of potentially vision-threatening complications.12

Researchers have tried to add new modalities to glaucoma management using a variety of noninvasive glaucoma procedures (NIGPs), often using laser and ultrasound. NIGPs fill the gap between medical and surgical treatment and may work synergistically with these options as well. The safety and efficacy of NIGPs are under continuous evaluation in order to understand their role in the management of glaucoma.

Noninvasive glaucoma procedures do not require penetration into the eye and should not be confused with minimally-invasive glaucoma surgeries (MIGS). MIGS requires small incisions and instruments entering the eye. MIGS is also referred to as conjunctival-sparing surgery.3

Currently, examples of NIGPs include argon laser trabeculoplasty (ALT), selective laser trabeculoplasty (SLT), micropulse laser trabeculoplasty (MLT). More recent procedures under investigation include therapeutic ultrasound for glaucoma (TUG), ultrasonic circular cyclocoagulation (UC3) using EyeOP1, and deep wave trabeculoplasty (DWT).

LASER TRABECULOPLASTY

Laser trabeculoplasty (LTP) aims to treat the trabecular meshwork (TM) with laser to improve aqueous outflow facility. It can be used as an adjunct to medications, after failure of medical therapy or as initial treatment for glaucoma.4 LTP is indicated in primary open-angle glaucoma (POAG), pseudoexfoliation glaucoma, pigmentary glaucoma, and ocular hypertension,1245 pseudophakic glaucoma,6 and normal tension glaucoma.7 Some have proposed it as a treatment after failed trabeculectomy.8 Several studies also suggest that SLT can be used as a temporizing treatment and prophylactic procedure in patients with elevated intraocular pressure (IOP) after intravitreal triamcinolone acetonide injection.910 Used in conjunction with medication, SLT has been shown to significantly reduce IOP in patients already on prostaglandin analogue therapy.11 SLT has also been used to treat secondary glaucoma due to silicone oil.12 Contraindications to LTP include extensive peripheral anterior synechiae, uveitis, neovascular glaucoma, and developmental glaucomas.16 LTP is usually contraindicated in eyes with narrow angles. However, cases of primary angle closure and a patent iridotomy with at least 90° of visible TM may benefit from SLT.13 The primary LTP techniques in use today are ALT and SLT. Other options include MLT, titanium sapphire laser trabeculoplasty (TSLT).

Argon laser trabeculoplasty was introduced by Wise and Witter in 1979.14 The glaucoma laser trial (GLT) showed that ALT was at least as effective as initial treatment with timolol maleate 0.5%.15 However, use among comprehensive ophthalmologists was limited due to the visible thermal damage, limited repeatability, late IOP rise, and treatment failure along with the technical skill required to correctly identify angle structures.16 A laser that delivers over 100 times less energy that ALT while providing a similar IOP-lowering effect was developed by Latina in 1995. It is a 532 nm frequency-doubled, Q-switched, neodymium: Yttrium aluminum garnet (Nd: YAG) laser that selectively target the pigmented tissue with minimal collateral thermal damage to the TM. It delivers a 400 mm diameter treatment spot in 3 ns. The large spot size allows greater tolerance for imprecise identification of angle structures during laser application.17 In 2005, Ingvoldstad et al. investigated the use of micropulse diode laser to perform trabeculoplasty.18

The recommended treatment parameters for ALT, SLT, and MLT are presented in Table 1.

Table 1

Characteristics and recommended treatment parameters for laser trabeculoplsasty

The use of lower power is strongly recommended in heavily pigmented angles like pigmentary glaucoma.1 A study found that low-power annual SLT treatment yielded better results compared to ALT and standard SLT.19

Pretreatment with topical anesthetic and prophylactic hypotensive agent such as apraclonidine or brimonidine. Various lenses may be used for LTP including the Goldmann three-mirror lens and the Ritch trabeculoplasty lens.2 The Latina lens was designed specifically for the SLT and had no spot size magnification.2520

LASER TRABECULOPLASTY INTRAOCULAR PRESSURE-LOWERING MECHANISMS

The exact mechanism of action of LTP is unknown. In ALT, the contraction effect of laser burns causes adjacent trabecular beams to open, facilitating aqueous outflow.14 Laser stimulates the trabecular endothelial cells to replicate and remove debris from TM through phagocytosis.15212223

Selective laser trabeculoplasty selectively targets the pigmented cells of the TM with recruitment of macrophages into the outflow system. These macrophages are believed to release chemical mediators that regulate the outflow rate. LTP releases cytokines such as interleukin-1b (IL-1b) and tumor necrosis factor-a. Cytokine release alters matrix metalloproteinases and enhances aqueous outflow. The cytokines may also induce cell division, particularly the in TM cells.11 The biochemical changes that affect outflow after trabeculoplasty take 4-6 weeks to occur. The finding of a delayed response frequently has been invoked by researchers as favoring the biochemical theories of the laser mechanism that enhance aqueous outflow.172425

Alvarado described a junctional disassembly in Schlemm's canal (SC) cells upon exposure to laser irradiation. Similar changes are seen with topical prostaglandin analog treatment. In both cases, endothelial cell junction disassembly is associated with an increase in conductivity. Alvarado concluded that the IOP-lowering effect of SLT and prostaglandin analogs share a common mechanism of action by modulating the barrier properties of SC cells.26

Human TM cell division occurs primarily in the anterior, nonfiltering region. LTP may trigger and increase cell division, as well as cell migration of these anterior TM cells. These migrating cells are theorized to repopulate the burned laser sites, suggesting that they may be stem cells.27

MLT involves the application of repetitive short diode laser pulses. The interval between the pulses provides sufficient cooling time to avoid injury to the pigmented TM and surrounding tissues. These laser applications may produce photo-thermal effects that activate a therapeutic cellular cascade without causing clinically visible damage.182829

CLINICAL RESULTS

In general, in early glaucoma, an IOP of <21 mmHg with a reduction of at least 20% may be sufficient, whereas in moderate glaucoma, an IOP <18 mmHg with a reduction of at least 30% may be required. Numerous studies in the literature have reported IOP reduction within these ranges after LTP.12530

ARGON LASER TRABECULOPLASTY

The GLT compared medical treatment with ALT. At 2-year follow-up, ALT-treated eyes had a lower mean IOP compared to eyes started on timolol.15 After 7 years, the ALT group had a greater IOP reduction and greater sensitivity in the visual field. The results indicated that ALT was at least as good as topical timolol for the treatment for glaucoma and may play a role in decreasing fluctuations in IOP.3132

On average, ALT reduces IOP 20-30% below baseline. The IOP-lowering effect of ALT decreases with time. In long-term studies of 5–10 years, the failure rate after ALT ranges from 65% to 90%. Due to the structural alteration of TM, repeat treatment may lead to a paradoxical persistent elevation in IOP.15212223

Positive predictors for success after ALT include heavy pigmentation of the TM, older age, and certain types of glaucoma such as POAG, pigmentary glaucoma, and exfoliation syndrome.133 Higher baseline IOP is associated with greater IOP reduction after trabeculoplasty.30 ALT is more successful in the hands of surgeons more experienced in the procedure.3435 It is less successful in eyes with no pigmentation of the TM and patients younger than 40 years old.136

SELECTIVE LASER TRABECULOPLASTY

Selective laser trabeculoplasty was first introduced as an adjunctive therapy after medical treatment had failed. The high safety profile of the procedure allowed ophthalmologists to consider its use as a primary therapy with an efficacy equivalent to treatment with a topical prostaglandin analogue.37 Patients who have difficulty instilling drops or who are intolerant to topical medications may benefit from SLT.38394041

The average reduction in IOP after SLT has been reported to be 18–40%.4243444546474849 One hundred and six eyes with POAG were enrolled in a prospective study to evaluate the SLT. At the 18-month follow-up visit, a statistically significant drop in IOP occurred, from 19.55 ± 4.8 mmHg preoperatively, to16.03 ± 2.8 mmHg postoperatively (P < 0.001). There was a statistically significant decrease in the number of medications from 2.25 ± 0.97 medications preoperatively to 1.0 ± 1.3 medications postoperatively (P = 0.004).4 Another study with 36-month follow-up evaluated 157 eyes that were divided into primary and adjunctive therapy, which obtained 28.2% and 25.6% reduction in the mean IOP, respectively [Graph 1]. The difference between the two groups was statistically insignificant.43

Graph 1

Mean intraocular pressure (mmHg) between primary (blue) and adjunctive (red) SLT treatments

Intraocular pressure reduction curves with SLT treatment tend to be reproducible, showing an initial drop in the first 24 h followed by a gradual rise before the IOP stabilizes.15304243

Post-SLT pressure spikes have been reported but are usually transient and can be sustained in some cases.50

Low IOP on day 1 is a positive predictor of success with SLT.51 SLT can be repeated.52 A prospective study that evaluated the reduction in IOP after two SLT treatments to the same area of the TM compared to two SLT treatments to two adjacent regions of the TM. This study found similar reductions in IOP (5 mmHg) in both groups. Interestingly, SLT can be performed by ophthalmic residents reflecting the ease of the procedure.45

Selective laser trabeculoplasty can also be considered in the treatment of cases of failed ALT.30535455

Studies have found that IOP reduction is not influenced by previous ALT treatment.475556 In a pilot study by Latina et al.,17 patients with a failed ALT were treated with SLT and followed-up for 26 weeks. IOP reduction in this group (6.0 mmHg) was not different from a previously untreated POAG group (5.8 mmHg). In a comparative study, Damji et al.21 showed a greater IOP drop with Selective laser trabeculoplasty after failed ALT of 6.8 mmHg versus an ALT retreatment (3.6 mmHg).

Selective laser trabeculoplasty has a statistically significant pressure lowering effect on untreated fellow eyes suggesting a systemic biological response. Studies have reported a decrease in IOP of 9.7%, 8%, and 11.2% in untreated fellow eyes 6-12 months post-SLT.175758 IOP reduction in the treated eye is also predictive of the effect of SLT in the fellow eye.57

MICROPLUSE DIODE LASER TRABECULOPLASTY

A phase II clinical study29 of MDLT treated 32 eyes of 20 consecutive patients with uncontrolled OAG. Criteria for treatment response were IOP reduction ≥3 mmHg and IOP ≤21 mmHg within the 1st week after MDLT.29 The outcomes of this study indicated that 25% of cases had failed and the remaining 75% (15 eyes) had a mean IOP reduction of 22% at 12-month.29 A retrospective study of MLT showed that only three eyes (7.5%) had an IOP reduction of ≥3 mmHg.59

Data for MDLT are relatively limited compared to ALT and SLT. Hence, prospective randomized comparisons are required of MDLT to current IOP lowering modalities.

COMPARATIVE STUDIES

Comparative trials have shown that ALT and SLT are equivalent in terms of IOP lowering and medication reduction.60616263

Three trials showed there was no difference between 360° SLT and medical therapy, with one of the trials indicating greater IOP reduction with latanoprost than 90° and 180° SLT. The 3 trials also revealed no difference between 180° and 360° SLT.64 Others have reported a high failure rate associated with 180° SLT.55

MLT was tested in a short-term, prospective, controlled pilot study in which patients with uncontrolled OAG randomized to either MLT or ALT. At the 3-month follow-up visit, the IOP reduction from baseline was statistically significant (P < 0.05) and comparable in both study arms (18.9% reduction with ALT vs. 18.3% reduction with MLT).18 Another short-term, prospective, randomized trial of MLT versus ALT reported that MLT was less effective than ALT.28 MLT-treated eyes had a mean IOP decrease of 2.5 mmHg (12%) compared to a 4.9 mmHg (22%) reduction in the ALT group at 3-month.28

COMPLICATIONS OF LASER TRABECULOPLASTY

Complications of LTP include transient IOP elevation from 12% to 34% of cases and mild iritis.5 ALT may induce peripheral anterior synechiae.65 SLT may induce endothelial damage in corneas with pigment dispersion on endothelium. SLT has been reported to induce transient corneal endothelial changes without significant impact on the endothelial cell count or visual acuity.666768

TITANIUM SAPPHIRE LASER TRABECULOPLASTY

Titanium sapphire laser trabeculoplasty uses a 790 nm laser with a 7 msec exposure time and a spot size of 200 mm. The near-infrared wavelength is thought to penetrate deeper into the pigmented TM and also have an effect on the juxtacanalicular region and the inner wall of SC. In a study comparing TSLT to ALT, both lasers had a similar efficacy (8.3 mmHg vs. 6.5 mmHg IOP reduction, respectively [P > 0.05]).69

ULTRASOUND TECHNIQUES

Ultrasound applied to the sclera can be used to reduce elevated IOP. Low power ultrasound can be applied such as TUG, or higher power can be applied in high-intensity focused ultrasound (HIFU).

THERAPEUTIC ULTRASOUND FOR GLAUCOMA

The basic idea comes from the fact that phacoemulsification using ultrasound appears to be coexistent with the finding of a decrease in IOP following cataract surgery.70717273

There are three potential IOP-lowering mechanisms of ultrasound: (1) Sono-mechanical or vibratory effect of ultrasound74(2) thermal effect75 and (3) triggering of a cellular integrin response.76

Donald Schwartz worked to develop the technique and the device through three series of studies starting in 2006 with the first human treatment in 2009. The updated system ISonix® was developed by EyeSonix (Long Beach, CA, USA) to deliver low ultrasound and consisted of the function generator, the power amplifier, and a hand piece. The unit is self-tuning with internal safety checks.

Under topical anesthesia, the conjunctiva is marked with a pen and 3 treatments are performed within each treatment quadrant. The present device self-tunes to appropriate the power and frequency. A foot pedal is pressed to activate the ultrasound. A green light changes to a flashing mode indicating that the device is emitting a focused ultrasound. During the treatment, there is no sound and vibration is not obvious to the patient. The tip is placed on the globe at the limbus, and the hand piece is then held firmly against the globe for a 45-s treatment. Human studies were performed in three phases (TUG. 1-3)777879 that coincided with the development of TUG. The clinical trial in TUG.3 involved two groups: (1) Those who were either naïve to pharmaceutical treatment or who had not been on medical therapy for at least 6-month prior to TUG treatment and; (2) subjects who were using pharmaceutical agents. Patient on pharmaceutical agents underwent a washout period of 1-month for the prostaglandins and 1-week for other medications prior to treatment. Twenty-six patients were evaluated for a full year. There were 17 subjects on medication who were enrolled into the study. There were 9 who were in the “naïve” group. The initial results with TUG were promising and comparable to medical treatment with latanoprost. A bilateral response was observed suggesting a biologic effect with systemic cytokine release. The cytokines may promote the production of a matrix metalloproteinase enzyme and the induction of macrophages.77

HIGH-INTENSITY FREQUENCY ULTRASOUND

HIFU, a noninvasive technique producing focal lesions in sclera over the pars plana to treat glaucoma, dates back to 1982. Three mechanisms for pressure reduction were proposed. First, trans-scleral outflow of aqueous humor can occur under the conjunctiva. Second, a focal destruction of the ciliary epithelium can reduce aqueous production this has been documented in experimental animals and is the subject of ongoing studies in treated human patients. Third, scleral scarring has the potential for the separation of the ciliary body from the sclera enhancing uveoscleral outflow. Reported complications include uveitis, lid burn, corneal haze, dellen formation, and cataract. Complications were mostly related to misdirection of the treatment beam.787980

Despite the efficacy of HIFU, its use for ciliary body destruction was abandoned in the mid-1990s, partly due to the bulky design of a commercial system and the relative complexity of the process.

Recently, there has been a revival of the technique with the development of miniaturized transducers. The EyeOP1® device developed by EyeTechCare (Rillieux La Pape, France) allows HIFU to target the ciliary body. Initial animal studies demonstrated a significant reduction in IOP and confirmed histological proof of the destruction of the ciliary process [Figure 1]. Animal studies also demonstrated a fluid filled space between the sclera and ciliary body and between the scleral and adjacent choroid in treated eyes, findings that suggest enhanced uveoscleral outflow.8182

Figure 1

High-magnification (×40) photomicrographs showing ciliary processes with coagulation necrosis, loss of the bilayered epithelium (permission from Florent Aptel)

The EyeOP1 is a portable device, consists of a control module and a probe that uses an HIFU technology at 21 MHz. The rationale of the device is to perform circular ultrasound cyclocoagulation (UC3) in a single step lasting <2 min. The ultrasound waves that are generated last 6 s/sector and are able to heat the tissues resulting in partial coagulation of the ciliary ring at 6 predetermined zones.

Treatment is conducted under local anesthesia. A ring containing six active piezoelectric elements is inserted in a coupling cone. The six transducers are oriented in a particular manner to create a focal zone consisting of 6 elliptical cylinders in a 11, 12, or 13 mm diameter circle superimposed on the ciliary body [Figure 2].8384

Figure 2

The Eyeopt 1 device showing the 6 transducers and its application to the eye (permission from Florent Aptel)

Data from patients treated with UC3 for advanced refractory glaucoma show that the procedure results in a ≥20% reduction in IOP in about 70% of eyes with primary open-angle glaucoma and that the benefit was maintained for at least 1.8586 Melamed et al.87 reported a mean drop in IOP of 38%.Interestingly, HIFU can be compared to diode cyclophotocoagulation; both treat the ciliary processes and reduce the IOP in refractory glaucomas. However, the diode laser has low selectivity for ciliary body processes and is not well-tolerated.88

DEEP WAVE TRABECULOPLASTY

Deep wave trabeculoplasty is a novel noninvasive device that delivers nondestructive sonic energy to the trabecular meshwork. It is designed to enhance aqueous outflow through the TM without causing tissue damage.

The idea behind DWT was inspired from IOP-lowering effect of phacoemulsification. In DWT, mechanical oscillations are delivered to the TM using a handheld instrument positioned along the limbal region that overlies the TM [Figure 3]. The external application of mechanical energy (with much lower sonic frequency than phacoemulsification) causes focal stretching and relaxation of the TM. This induces a proposed IOP-reducing stress response in the TM cells, possibly through activation of an ELAM-1/IL-1/nuclear factor-kB response and release of cytokines. These changes are not associated with heat generation or tissue damage.

Figure 3

Deep wave trabeculoplasty device from ocutherix and its application to the limbus (permission from Robert Atkinson)

Results of an initial human trial in 30 patients revealed that DWT results in a 26% decrease in IOP. IOP decreased from a mean of 24.27 mmHg at baseline to 17.87 mmHg after 3-month with no complications.8990

CONCLUSION

Noninvasive intervention is a new dawn in glaucoma management. It attempts to fill the gap between invasive glaucoma surgeries with its shortcomings and the antiglaucoma medications with its complications, costs, and lack of compliance. Some of these procedures are not being used as commonly (e.g. ALT) other are part of the routine treatment (e.g. SLT), and there are emerging technologies such as TUG, HIFU, and DWT.