Cyclophotocoagulation As A Minimally Invasive Treatment Option for Glaucoma

Abstract

Historically, the complications and inadequate efficacy of prior cyclodestructive procedures limited their role in glaucoma management. Recent advances in treatment techniques and parameters for laser cyclophotocoagulation has expanded its role in today's glaucoma practice. This review summarizes the role of different cyclophotocoagulation techniques, including continuous wave transscleral cyclophotocoagulation and micropulse transscleral cyclophotocoagulation, in the management of glaucomatous optic neuropathy.

Introduction

In the 1930s, cyclodiathermy was first introduced as one of the cyclodestructive procedures, to reduce aqueous humor production through ablation or destruction of the ciliary body epithelium and thereby lowering intraocular pressure (IOP).¹ In the 1940s and 1950s, studies reported cyclodiathermy had a poor safety profile and the clinical response was not encouraging for broad-term application of this technique.^2,3 A review of 100 cases of cyclodiathermy demonstrated that only 5% of cases achieved adequate IOP reduction, while phthisis bulbi occurs at almost the same frequency.⁴

Later in the 1950s, cyclocryotherapy using a freezing technique to ablate the ciliary body to lower IOP was introduced.⁵ Typically, rapid freezing to a temperature of around −70°C will cause the formation of microcrystal cells, which will eventually lead to cellular destruction. In addition to destroying ciliary epithelial cells, cryoablation also leads to occlusion and necrosis of small blood vessels in the ciliary body. The ciliary body ischemia is another cause of decreased aqueous humor synthesis. Cyclocryotherapy was considered to be more effective and less destructive than cyclodiathermy.⁶ However, complications associated with cyclocryotherapy including uveitis, lens subluxation, IOP spikes, hypotony, and vision loss,⁷ made cyclocryotherapy a last-line treatment option after failure of other surgical procedures mainly in blind painful eyes.

Weekers et al. first reported the application of xenon arc photocoagulation on the ciliary body to lower IOP.⁸ Beckman and associates demonstrated that a ruby laser could be an effective transscleral cyclophotocoagulation (TSCPC) treatment modality.⁹ In the following year, the same group reported that the Neodymium: Yttrium-Aluminum-Garnet (Nd:YAG) laser more effectively ablated the ciliary body.¹⁰ Pratesi introduced diode laser in 1984.¹¹ In 1992, Uram used diode laser TSCPC for the first time.¹² When both the Nd:YAG laser (1064nm) and diode laser (810nm) energy are applied through the sclera, the pigmented ciliary epithelium absorbs this energy, resulting in coagulative necrosis of the ciliary body apparatus. The continuous wave diode laser currently replaces the Nd:YAG laser because of its improved safety profile.^13,14

Initially, the micropulse laser was used for retinal laser photocoagulation and then introduced into the field of glaucoma treatment recently. Micropulse lasers apply energy in the form of repetitive pulses of microseconds, interspersed with intermittent rest periods, allowing a gradual build-up of heat energy in the treated cells.¹⁵ This technique theoretically reduces the complications associated with the conventional continuous-wave TSCPC approach.

Cyclodestrctive procedures were historically used in patients with end-stage glaucoma after failure of other incisional surgeries, poor visual potential, or blind painful eyes.¹⁶ However, the advancement in CPC techniques and parameters provided more targeted ciliary processes destruction and safer treatment. Therefore, the role of cyclodestructive procedures in the glaucoma treatment paradigm has expanded greatly.

Continuous wave diode transscleral cyclophotocoagulation (CW-TSCPC) vs. Micropulse transscleral cyclophotocoagulation (MP-TSCPC)

Today, CW-TSCPC and MT-TSCPC are the two most common modalities of TSCPC in the management of glaucoma.

Techniques

In CW-TSCPC, diode laser with a wavelength of 810nm is used. The G-probe used for laser power delivery is positioned approximately 1.2 mm posterior to the limbus. The treatment settings vary according to surgeon preference and patient characteristics. In the conventional “pop-titrated” technique, treatment is started at 1750-2000mW with a duration of 2 seconds until a deep dull “pop” sound is heard, then energy is titrated down, and treatment is initiated using these parameters. However, with slow coagulation (SC) TSCPC, a standardized, fixed lower amount of energy (1250 mw) is delivered over a longer period of time (4 seconds) avoiding the pop sound and thereby preventing over-treatment of the ciliary body.

Compared to CW-TSCPC, MP-TSCPC applies repetitive pulses of energy separated by periods of rest, which gives time to the adjacent non-pigmented structures to recover and prevents them from coagulative damage.^17,18 In addition, the micropulse energy may also stimulate a cellular biochemical cascade, which releases the cytokines in the trabecular meshwork and increases aqueous humor outflow.¹⁹ The most common setting for MP-TSCPC is starting with 2000mW and the laser is “on time” for 0.5 millisecond (ms) and “off time” for 1.1ms. The treatment duration is 90-180 seconds[20-22]. The micropulse probe is moved slowly in a continuous sweeping motion along the arcs around the limbus avoiding the 3 and 9 o’clock meridians. This sweeping motion needs to maintain the same angle and sweeping speed throughout its arc, or variable amounts of energy are delivered. Thus, MP-TSCPC is much more prone to differences in energy delivery within areas of any eye and between eyes with greater technical requirements and thus is more prone to variable outcomes.

Efficacy

CW-TSCPC has provided satisfactory results in the treatment of patients with glaucomatous optic neuropathy. In studies that evaluated conventional ‘pop-titrated’ CW-TSCPC technique, the surgical success rates (IOP≤22mmHg and/or IOP>20% decrease from baseline) were 54-92.3% with a follow-up period of 9 to 80 months.^23-33 Similarly, in patients undergoing MP-TSCPC surgical success ranged from 35 to 96%.^20,22,34-38 However, the World Glaucoma Association proposed restrictive criteria for surgical success evaluation using IOP: IOP≤18mmHg and a reduction of 20% from baseline.³⁹ Under such criteria, Wilensky and Kammer et al. reported a 71.4% success rate using ‘pop’ CW-TSCPC in a 40.7-month follow-up study.⁴⁰ While Tekeli et al. reported a 40% reduction in IOP after 14.2 months of follow up.⁴¹ SC-TSCPC showed encouraging results in the treatment of different glaucoma types with success rates ranging from 60.6-72.2%.^43-48

One possible explanation for the wide range of reported IOP reduction is the preoperative IOP. Vernon et al. reported that in patients with preoperative IOP > 30 mmHg, 94% of eyes had a reduction in IOP of at least 30% at the last follow-up visit, while for those whose initial IOP ≤ 30 mmHg, 75% achieved such degree of the IOP reduction.⁴² Similarly in studies by Shetiliti et al. and Khodeiry et al.,^43,44 success rates of SC-TSCPC were higher in patients with baseline IOP of 21 mmHg or more compared to those with less than 21 mm Hg.

For the MP-TSCPC, Emanuel et al. demonstrated a 59.9% reduction of IOP from a baseline of 27.7 mmHg,⁴⁹ while Garcia et al. reported a 31.1% reduction of IOP from an initial 22.2 mmHg.²⁰

In addition to IOP reduction, pop-titrated CW-TSCPC has proven efficacy in reducing patients’ glaucoma medication use. For example, Vernon et al. observed an 80% reduction in glaucoma medication use.⁴²

After SC-TSCPC treatment, patients had reduction in their preoperative glaucoma medications from 4.1±0.9 to 3.1±1.3 in pseudophakic patients with glaucoma, 3.3±1.1 to 2.0±1.5 in neovascular glaucoma, from 4.2± 0.9 to 1.9 ±1.5 in post-vitrectomy glaucoma, 3.9±1.0 to 2.5±1.2 in aphakic glaucomatous patients and 4.0 ± 1.0 to 2.7 ± 1.4 in patients with post-keratoplasty glaucoma.^44-48

Studies of MP-TSCPC also showed it is effective in reducing both oral and topical medication need for glaucoma treatment. The mean reduction of glaucoma medication is 0.3-1.7 in over 1-year follow-up studies[41, 49-56].^{41, 49-56} Tan et al. demonstrated all patients did not need oral acetazolamide after MP-TSCPC,⁵¹ while Zaarour et al. reported a 26% of patients stopped oral medication postoperatively.²²

The retreatment rate is another important factor to evaluate the efficacy of the cyclophotocoagulation procedures. Retreatment rates in pop-titrated TSCPC ranged from 15.4% to 59.6% with higher retreatment rates in patients with younger age and history of retinal procedures.^{23,24,26-33,42,57}

In SC-TSCPC, the retreatment rates ranged from 7.5% to 14.6%. The highest retreatment rate was noted in pseudophakic patients with glaucoma.^43-48

In the MP-TSCPC studies, the retreatment rates range 0-46%. ^{20, 22, 35, 36, 41, 49-51, 53-56} Tan et al. reported a 35% retreatment rate using 2000mW and 100s settings,⁵¹ and Aquino demonstrated a 46% rate with the same settings.⁵⁰ These two studies used 2000mW and 120s in the retreatment for better efficiency.

Aquino et al. compared the conventional CW-TSCPC and MP-TSCPC in treatment of refractory glaucoma.⁵⁰ With success defined as an IOP between 6 and 21mmHg and at least 30% reduction in IOP with or without medication, the authors demonstrated a significant higher success rate in the MP-TSCPC (75%) compared to the CW-TSCPC (29%) after 12 months. However, at 18 months of follow up the difference in success rates of both groups was not statistically significant. In addition, the complication rate in the CW-TSCPC (60%) group was significantly higher than the one in the MP-TSCPC (12%) group.⁵⁰ It is noteworthy that NVG comprised 29% of cases in the MP-TSCPC group and 50% of cases in the CW-TSCPC, which may have biased results in favor of the MP-TSCPC treatment. Abdelrahman et al. compared the efficacy of MP-TSCPC and conventional CW-TSCPC in pediatric refractory glaucoma treatment.⁵⁸ Six months after treatment, the success rate was 71% in the MP-CPC group and 46% in the CW-TSCPC group, however, the difference was not statically significant. Additionally, at the final visit, the reported complications were more common in the CW-TSCPC group.⁵⁸

Due to the relative novelty of SC-TSCPC, limited studies are available to compare between efficiency of SC-TSCPC and MP-TSCPC. Zemba et al ⁵⁹ studied using MP-TSCPC vs SC-TSCPC in neovascular glaucoma patients and found that the success rates were higher using the SC-TSCPC. After 12 months of follow-up, the mean IOP reduction was 11.95 mmHg in the SC-TSCPC and 8.04 mmHg in the MP-TSCPC group. Similarly, in the SC-TSCPC group glaucoma medications decreased from 2.8 at baseline, to 1.9 at 12 months, and in the MP-TSCPC group from a mean of 2.6 at baseline to 2.1 at 12 months. However, more patients in the SC-TCPC group developed postoperative hypotony.

Complications

The complication rates after TSCPC vary depending on the types of glaucoma, treatment protocol, and other factors. Hypotony, phthisis bulbi, visual acuity reduction, anterior chamber inflammation, postoperative pain, cystoid macular edema, lens subluxation, and scleral perforation have been reported.^13,34,60,61

A decrease in visual acuity (VA) of ≥2 lines is the most common complication of the pop-titrated CW-TSCPC. Based on the literature reviews, the incidence of VA decrease is 3.8%-55.2% with an average of 25% of the cases.^{28,30,32,40,42,45,51,55} Ghosh et al. conducted a 2-year study that included eyes with good VA (≥6/18), they found that 24% of eyes had a decrease in VA (≥2 lines) and half of eyes retained their preoperative VA or better.²⁸ Rotchford et al. reported that 30.6% of the treated patients lost 2 or more lines of VA with good baseline VA (≥20/60) in a 5-year follow-up study.⁵¹ This decrease in VA is similar to the reported rates of VA loss after tube-shunt surgery or trabeculectomy.⁶² The authors also found visual loss was unrelated to baseline VA or IOP level, but probably due to further progression of glaucoma. These data suggest that the CW-TSCPC treatment can be applied to patients with good VA.

In SC-TSCPC, the rates of loss of 2 lines or more of Snellen visual acuity were 12.7-32.6%.^43-48 It was worth mentioning that the incidence of VA reduction was higher in patients with no prior incisional surgeries; the rate of vision loss was 32.6% (15 eyes), but 9 out of the 15 eyes experienced decreased VA due to cataract.⁴³ The most common cause of decreased visual acuity in the remainder of studies was attributed to glaucoma progression and not as a consequence of the laser treatment.^44-48

MP-TSCPC treatment seems to have a lower risk of losing VA. The incidence of VA decrease (≥2 lines) is 1%-26% among different studies.^{20,34,37,41,50,52,53,55,56}

Hypotony (IOP≤5mmHg) is commonly seen after conventional CW-TSCPC treatment, which has been reported in up to 39% of post-surgery patients.²⁹ The reported average rates of hypotony was 9% in patients receiving MP-TSCPC treatment³⁴ and 7.7% in patients post SC-TSCPC.⁴³ The incidence of hypotony seemed to correlate with glaucoma diagnosis. Aquino et al. reported that four out of five neovascular glaucoma (NVG) patients had hypotony after conventional CW-TSCPC treatment.⁵⁰ Ramli et al. observed that a preoperative diagnosis of NVG is associated with a 9-fold increase in the risk of hypotony after TSCPC treatment.²⁹ Spencer and Vernon found that the risk of hypotony was associated with the dosage of laser energy delivered.³⁰ This may explain why patients receiving MP-TSCPC and SC-TSCPC have a lower risk of hypotony since they have less tissue reaction and damage during the off cycle with MP-TSCPC. Additionally, avoiding the pop sound in SC-TSCPC probably limits the risk of overtreatment of the ciliary body and postoperative hypotony.⁴⁴

About 1.9%-20% of cases experienced inflammation after CW-TSCPC treatment ^26,57-60Aquino et al. included 48 patients to receive either TS-CPC or MP-TSCPC randomly, prolonged anterior chamber (AC) inflammation (cell and/or flare > 3 months) occurred in 7 (30%) cases after TS-CPC but 1 (4%) case following MP-TSCPC treatment.⁴⁴ The majority of studies reported an incidence of AC inflammation less than 10% after MP-TSCPC.^{20,36,37,52,53,56} However, Emanuel et al. reported a significant higher rate of 46% of postoperative inflammation at 3 months following MP-TSCPC.⁴⁹ This may be explained by their treatment protocol in which the average duration of treatment was 300 seconds. Therefore, treatment time may be an important factor to influence postoperative inflammation. In addition, the authors also found that race was significantly correlated to prolonged inflammation. Compared with whites, non-white races are 3.6 times more likely to have postoperative inflammation. This may be because the non-white eyes have more pigment in the ciliary body.

One of the advantages of SC parameters is the lower postoperative inflammation rates. The pop sounds are avoided that are believed to represent microdestructive explosive damage to the ciliary body, which can cause greater postoperative inflammation and hypotony.⁴⁴

Phthisis bulbi occurs in approximately 0.8-9.9% of cases following conventional CW-TSCPC procedures, but it is more common in the case of NVG, retreatment, or multiple surgery history.^{26,27,32,55,58,61} No cases of phthisis have been reported following SC-TSCPC.^43-48

In MP-TSCPC studies, the incidence of cystoid macular edema (CME) has been low. Most studies reported incidences ranging from 1% to 3%.^20,21,37 The incidence of CME in conventional CW-TSCPC is 1%-12.4%^24,51,57,63 and 0-8.3% in SC-TSCPC.^43-48 Although MP-TLT has a good safety profile, the rate of subconjunctival bleeding (probably from the tight sweeping motion of the MP probe against the conjunctiva) is a potential problem.⁵³

Encouraging role of SC-TSCPC in certain scenarios

Sheheitli et al.⁴³ conducted a retrospective study to evaluate the efficacy of SC-TSCPC as a primary surgical treatment in patients with no prior history of incisional surgery of any kind. The authors reported a higher success rate of 58.3% in patients with initial IOP greater than 21mmHg compared with 28.1% in patients with baseline IOP21mmHg or less. However, this difference was not statistically significant. Patients required less glaucoma medications after the laser treatment. Although 8.7% of the treated patients required more than one treatment, 7.7% of the patients had tube surgeries for further IOP reduction. The SC-TSCPC technique was associated with minimal complications in those phakic patients.

Post-keratoplasty glaucoma is one of the most complex and medically recalcitrant secondary glaucoma types. Incisional surgeries increase the risk of graft failure after corneal transplantation procedures. In addition, many of these patients have poor or minimal conjunctiva for a trabeculectomy, are not good candidates for tube shunts because of corneal disease, and have closed angles without access for many of the newer angle-based glaucoma surgeries. Khodeiry et.⁴⁷ studied 47 patients with secondary glaucoma after corneal transplant procedures who underwent SC-TCPC. The success of the cohort was 68.1% at 1 year and 66.0% at 2 years of follow-up. There was no difference in success rates between the post-PKP and post-DSAEK groups. A significant reduction in IOP and glaucoma medication dependence was also noted postoperatively. No statically significant changes in central corneal thickness after SC-TCPC was reported. Only one patient (3.3%) out of 30 patients with clear graft at baseline, experienced graft rejection. These findings suggest the viability and safety of SC-TCPC in the management of post-keratoplasty glaucoma.

In a recent study that included 41 patients with adult aphakic glaucoma secondary to complicated cataract surgery, a statistically significant IOP reduction from a mean of 29.6±5.8 mmHg on 3.9±1.0 glaucoma medications preoperatively to 19.0±6.4 mmHg on 2.5±1.2 glaucoma medications were reported.⁴⁸

In addition to safety and efficacy, TSCPC is a cost-effective procedure in many complex patients.^64,65

Conclusions

In summary, TSCPC, especially utilizing the SC parameters, provides glaucoma specialists with a non-invasive, efficacious, titratable glaucoma surgical procedure that can be repeated if needed. TSCPC can be used in different glaucoma types and as a primary procedure, even in eyes with good visual acuity.