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Abstract
Background/aims This work aims to clarify whether micropulse transscleral cyclophotocoagulation (MPCPC) is gentler in terms of postoperative inflammation and is better tolerated compared with continuous wave cyclophotocoagulation (CWCPC).
Methods Prospective, randomised controlled, interventional, single-centre trial performed at the Ludwig Maximilians University Munich from January 2020 to July 2023. In all patients, a laser flare meter was used to measure anterior chamber flare (ACF). Central macular thickness (CMT) was assessed using optical coherence tomography. To quantify pain perception and quality of life (QoL), patients completed the Visual Analogue Scale (VAS) and the Glaucoma Activity Limitation 9 questionnaire.
Results 60 eyes of 60 patients were included, with 30 eyes in the MPCPC group and 30 eyes in the CWCPC group. A significantly higher increase in ACF was found after CWCPC as compared with MPCPC at 1 day (p=0.004) and 1 week after surgery (p=0). ACF values equalised at week 6 (p=0.270) and month 3 (p=0.610). The increase in ACF at week 1 did not show a significant correlation with the final decrease in intraocular pressure (IOP, p=0.465). Moreover, the CWCPC group showed a markedly higher increase in CMT (165.5 (15–354) µm vs 55.8 (24–141) µm). VAS and QoL scores did not show to be significantly different.
Conclusions Compared with MPCPC, patients treated with CWCPC presented with more marked ACF only in the early postoperative period. ACF did not correlate with final IOP. CWCPC and MPCPC are equally well tolerated in terms of pain perception and QoL, but CWCPC may cause more severe inflammatory macular oedema.
- Clinical Trial
- Glaucoma
- Prospective Studies
- Treatment Surgery
Data availability statement
Data are available on reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
In 2010, the micropulse diode laser (micropulse transscleral cyclophotocoagulation (MPCPC), Iridex, Mountain View, California, USA) was introduced as an alternative to the conventional diode laser (continuous wave cyclophotocoagulation (CWCPC)) to control intraocular pressure in refractory glaucoma, as it is supposed to cause fewer complications while still maintaining the same efficacy. This prospective, randomised controlled study was designed to clarify whether MPCPC is a gentler procedure in terms of postoperative inflammation and is better tolerated by treated patients regarding subjective pain perception and quality of life.
WHAT THIS STUDY ADDS
The study provides novel evidence that a significantly higher anterior chamber flare is seen after CWCPC compared with MPCPC in the early postoperative phase up until 6 weeks after surgery. Additionally, CWCPC may cause more marked postoperative inflammatory macular oedema, which is more likely to require treatment as compared with MPCPC.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
MPCPC may, therefore, be favoured in patients at risk of developing macular oedema or increased ocular inflammation.
Introduction
Continuous wave cyclophotocoagulation (CWCPC) is an established procedure for the treatment of refractory glaucoma.1 Laser energy is used to obliterate the ciliary body in the eye, which leads to reduced aqueous humour production and thus to reduced intraocular pressure (IOP).2 Postoperatively, rare complications such as visual deterioration, prolonged inflammation or persistent hypotony with choroidal detachment can occur.3 Micropulse CPC (MPCPC) is a new procedure in which a pulsed laser is used. The intervals between activity and inactivity are intended to give the tissue in the immediate vicinity of the ciliary body the opportunity to recover and prevent thermal damage. The aim is to achieve a more specific effect on the ciliary body with less damage to the surrounding area.4
The aim of this study is to clarify whether MPCPC is a gentler procedure in terms of postoperative inflammation and is better tolerated by treated patients regarding subjective pain perception and quality of life (QoL).
Materials and methods
For this prospective, randomised controlled, interventional, single-centre trial, 60 consecutive eyes of 60 patients presenting with refractive glaucoma at the Hospital of the Ludwig Maximilians University Munich, Department of Ophthalmology, Germany from January 2020 to July 2023 were included in this study. The study is registered in the DRKS register.
The patients were randomised into two halves: Patients who required diode treatment were alternately assigned to the MPCPC or CWCPC group. The patient and the surgeon were double-blinded for the procedure. Half of the patients were treated with MPCPC (Micropulse P3, Iridex, Mountain View, California, USA), the other half with CWCPC (G-Probe, Iridex). Inclusion criteria include patients with glaucoma requiring treatment due to inadequate IOP despite local pressure-lowering therapy or with eye-drop intolerance with or without previous surgery who are not eligible for another surgical procedure, for example, filtration surgery. Exclusion criteria include silicone oil tamponade, partner eye already included in the study, age younger than 18, need for simultaneous intravitreal injections, selective laser trabeculoplasty within the last 90 days preoperatively. Patients were recruited via the clinic’s outpatient departments.
All patients received a single session of laser treatment by the same glaucoma surgeon (MM). Either retrobulbar anaesthesia with 4% lidocaine and 0.5% bupivacaine (36 patients: 20 in the MPCPC group, 16 in the CWCPC group) or general anaesthesia (propofol) (24 patients: 10 in the MPCPC, 14 in the CWCPC group) was used. A viscous coupling gel (2.2% hypromellose 2 mL) was applied before the procedure. The Micropulse P3 (MP3) probe and the G6 probe (Iris Medical Instruments, Mountainview, California, USA) were positioned perpendicularly at the limbus. Diaphonoscopy using the G6 probe was used to determine the exact positioning of the anterior curved edge in the area of the ciliary body (around 3 mm from the limbus). Laser settings of MPCPC were 2500 mW with 0.5 ms on and 1.1 ms off time (duty cycle of 31.3%). Laser was applied using the MP3 probe throughout 180° (sparing the 3 and 9 o’clock positions (ciliary nerves), previous surgery sites or areas with scleral thinning) in sweeping movements for 50 s, and the same was repeated for the other hemifield. Approximately 2.5 passes of the probe were done per session on both the superior and inferior halves of the globe. The laser settings of CWCPC were a duration of 2000 ms and a power of 1620 mW with 24 burns per eye. The settings were calculated so that the same total power was used for each patient at the end, independent of the CWCPC or MPCPC group. After the surgery, 4 mg dexamethasone was given peribulbarly. In both groups, prednisolone acetate drops 1% were given hourly for the first week and then tapered off over 6 weeks.
Epidemiological data were obtained from each patient, including age, gender, previous ocular comorbidities or procedures and objective refraction-based Snellen chart visual acuity, which was later converted to logMAR for analysis. IOP was obtained using Goldmann applanation tonometry.
These examinations were performed 1 day prior to surgery, as well as 1 day, 1 week, 6 weeks, 3 months and 6 months after surgery.
Treatment success was defined as an IOP>6 mm Hg and<21 mm Hg or achieving 20% or more reduction in IOP from baseline, with or without topical antiglaucomatous medications and no need for the use of oral carbonic anhydrase inhibitors.
Objective measurement of anterior chamber inflammation
Anterior chamber flare (ACF) was assessed quantitatively using a laser flare metre (FM-600, Kowa Pharmaceutical, Nagoya, Japan) after pupil dilation with topical tropicamide 1% 1 day prior to surgery, as well as 1 day, 1 week, 6 weeks and 3 months after surgery. On each occasion, 10 readings with a variation of less than 5% were taken. The highest and lowest values were discarded, and the remaining eight were averaged to obtain the flare measurement. Laser flare values were expressed in photon counts/millisecond (pc/ms) and SD was calculated. Calibration of the laser flare metre was performed according to the manual.
Assessment of inflammatory macular oedema
To assess the presence of inflammatory macular oedema after surgery, a standard macular volume scan consisting of 49 equally spaced B-scans covering 20°×20° centred on the fovea (on Spectralis HRA+optical coherence tomography (OCT), Heidelberg Engineering, Heidelberg, Germany) was performed 1 week and 6 weeks after surgery. Macular oedema was defined as abnormal macular thickening with presence of intraretinal or subretinal fluid in the macula. Central macular thickness (CMT) was recorded from the central 1 mm diameter circle of the ETDRS grid in the thickness map generated by the Spectralis Software (Heidelberg Eye Explorer V.1.9.11.0, Heidelberg Engineering, Heidelberg, Germany). The automatic segmentation of the retinal layers was manually corrected when necessary.
Assessment of pain perception and QoL
Pain perception was assessed using a Visual Analogue Scale (VAS), immediately before the start of the anaesthesia procedure, after completion of the operation on the ward and at 1 week and 6 weeks after surgery. For patients undergoing surgery under general anaesthesia, the pain sensation was assessed before induction of anaesthesia and postoperatively on the ward after the recovery phase. The scale ranges from 0 to 10, whereas 10 represents severe pain and 0 represents no pain.
On week and month 6, QoL was assessed using the Rasch-calibrated Glaucoma Activity Limitation 9 (GAL-9) questionnaire.5 The questionnaire contains nine questions asking about the patient’s difficulty in performing daily activities. The score ranges from 0 to 45 (severe problems in all the categories).
Statistical analysis
All data were gathered and analysed in Microsoft Excel spreadsheets (V.16.23 for Mac; Microsoft, Redmond, Washington, USA). Statistical analysis was performed in SPSS Statistics V.26 (IBM). The level to indicate statistical significance was defined as p<0.05. The Kolmogorov-Smirnov tests were employed to test for normal distribution. Statistical analyses of intergroup differences were performed using the independent and dependent two-tailed Student’s t-test and the Mann-Whitney U Test.
Results
Patient characteristics
In total, 60 eyes of 60 glaucoma patients were included with a male to female ratio of 33:27 and a mean age of 71.2±12.9 (34–87), with 30 eyes in the MPCPC group, 30 in the CWCPC group. Demographic characteristics and the types of glaucoma can be seen in table 1. All patients were Caucasians, except for one patient of Indian origin in the MPCPC group and one patient of Asian origin in the CWCPC group. Regarding previous glaucoma surgeries/laser treatments, 13 patients underwent previous procedures in the CWCPC group and 19 in the MPCPC group (table 1).
Demographic characteristics, distribution of glaucoma types and flare values (at 1 day and 1 week after surgery) of the CWCPC group compared with the MPCPC group
Anterior chamber inflammation
A significantly higher increase in ACF measured 1 day and 1 week after surgery was found in the CWCPC subgroup (1 day: 39.5±43.1 (0.4 to 227.2) pc/ms; 1 week: 45.3±35.6 (−23.6 to 133.7) pc/ms) as compared with the MPCPC subgroup (1 day: 8.2±9.5 (0 to 37.4) pc/ms, p=0.004; 1 week: 15.12±15.6 (–7.8 to 56.4 pc/ms), p=0) (figure 1, table 1).
Differences in anterior flare values at four postoperative time points. Boxplots showing increased anterior flare in the CWCPC group compared with the MPCPC group at different time points after surgery. The differences in anterior flare values were found to be significant at the first two time points, whereas they turned out to be non-significant at 6 weeks and 3 months after surgery. CPC, cyclophotocoagulation; CWCPC, Continuous Wave CPC; MPCPC, Micropulse CPC.
At 6 weeks and 3 months after surgery, eyes after CWCPC still showed higher flare values than at baseline (6 weeks: 35.2±38.4 (–4.8 to 196.1) pc/ms; 3 months: 24.4±42.1 (–30.8 to 199.3) pc/ms) as compared with after MPCPC (6 weeks: 14.0±20.1 (–12.6 to 60.9) pc/ms, p=0.270; 3 months: 27.6±53.9 (–12.6 to 232.4) pc/ms, p=0.610)), yet the difference was not significant.
In both groups, the most pronounced anterior chamber inflammation occurred 1 week after the operation. This was followed by a gradual decrease in inflammation (CWCPC mean flare values at baseline, 1 day, 1 week, 6 weeks and 3 months after surgery: 28±30.3, 67.5±48.3, 73.3±58.8, 63.3±61.3, 53.5±63.3 pc/ms; MPCPC mean flare values at baseline, 1 day, 1 week, 6 weeks and 3 months after surgery: 23.1±18.3, 31.2±19.7, 38.2±23.9, 34.3±26.4, 41.3±49.9 pc/ms).
Regarding all eyes, anterior chamber inflammation after 1 week correlated significantly with IOP6 reduction after 3 months (r=0.386, p=0.008), however, only showed a non-significant tendency to increase with a higher reduction of IOP at 6 months (r=0.112, p=0.465). Flare values of patients showing treatment success compared with patients without treatment success did not differ significantly for all time points (1 day: p=0.99, 1 week: p=0.90, 6 weeks: p=0.94, 3 months: p=0.92). Patients with dark irises (14 eyes) showed a higher increase in flare values as compared with light irises (23 eyes) after 1 week (mean 36.1±36.7 as compared with 24.2±19.8 pc/ms), 6 weeks (mean 29.3±27.5 as compared with 21.0±20.2 pc/ms) and 3 months (42.2±63.7 as compared with 14.7±20.7 pc/ms).
Inflammatory macular oedema
In total, 11 of 51 eyes (21.6%: 4 after MPCPC (7.8%), 7 after CWCPC (13.7%)) presented with new macular oedema (5 eyes) or worsening of pre-existing intraretinal fluid (6 eyes) in the first 6 weeks after surgery. That means that out of the MPCPC group, 15.4% of eyes showed macular oedema and out of the CWCPC group 26.9%. All patients with macular oedema presented with intraretinal fluid, none of the patients exhibited subretinal fluid. Furthermore, all patients developing macular oedema had predisposing risk factors (five patients with presence of an epiretinal membrane, one patient with prior retinal vein occlusion, four patients with previous retinal surgery, one patient with proliferative diabetic retinopathy).7
CMT increased for mean 121.6 µm (15–354 µm) in the first 6 weeks. Eight of the 11 patients (71.7%) showed their peak CMT after 6 weeks.
The CMT increase showed to be markedly higher in the CWCPC than in the MPCPC subgroup (165.5 µm (15–354) vs 55.8 µm (24–141), figure 2). In five patients, additional treatment had to be administered (four out of seven eyes in the CWCPC subgroup (57.1%) and one out of four eyes (25%) in the MPCPC subgroup). All inflammatory intraretinal fluid resolved with treatment. In three patients non-steroidal anti-inflammatory eyedrops (Nevanac 3 mg/mL 1×d) had to be administered. In one patient from the CWCPC subgroup, a peribulbar triamcinolone injection was used to treat the moderate macular oedema. Subfoveal choroidal thickness (SFCT) in the MPCPC subgroup did not markedly increase postoperatively compared with baseline (increase: mean 6.26 µm (0–12 µm) after 1 week, mean 0.75 µm (0–7 µm) after 6 weeks).
Macular oedema after MPCPC and CWCPC treatment. OCT volume scans of one glaucoma patient’s right (A–C) and left (D–F) eye 1 week (A, D), 6 weeks (B, E) and 3 months (C, F) after surgery. The right eye, which was treated with MPCPC only showed minor macular oedema after 6 weeks (B), which did not require additional treatment. The left eye, which was treated with CWCPC at the same time, developed severe macular oedema after 6 weeks (E), which required treatment with a peribulbar injection of dexamethasone. CWCPC, Continuous Wave Cyclophotocoagulation; MPCPC, Micropulse Transscleral Cyclophotocoagulation; OCT, optical coherence tomography.
VAS and QoL
Perception of pain measured by the VAS was highest after completion of the surgery on the wards in both groups, followed by a gradual decline. The increase in VAS did not show to be statistically significant (MPCPC: 1.20±1.99 (0–6) preoperatively and 1.12±1.75 (0–6.5) postoperatively, p=0.13; CWCPC: 0.50±1.32 (0–5) preoperatively and 1.16±2.00 (0–8) postoperatively, p=0.22). The perception of pain did not depend on the type of anaesthesia used (p=0.912). The increase in postoperative pain did not show any significant differences between the groups (after surgery on the ward: MPCPC: 1.12±1.75 (0 to 6.5) vs CWCPC 1.18±2.15 (0 to 8), p=0.904; 1 week after surgery: MPCPC: 0.35±2.4 (–5 to 8.5) vs CWCPC: 0.27±1.15 (–1 to 4), p=0.757, 6 weeks after surgery: MPCPC: 0.075±2.14 (–5 to 6) vs CWCPC: 0.46±1.88 (–1 to 9), p=0.582).
The most troublesome categories regarding QoL were ‘seeing in the dark’ (4.08 (1–5)), followed by ‘moving from dark to bright rooms’ (3.13 (1–5)). The differences in GAL-9 scores compared with baseline were not significant between the two groups (6 weeks after surgery: MPCPC: −0.79±5.63 (−14 to 11), CWCPC: 1±4.01 (−6 to 11), p=0.184; 6 months after surgery: MPCPC: 2.8±4.71 (−5 to 14), CWCPC: 1.46±6.38 (−18 to 11), p=0.436).
Discussion
CWCPC used to be the classical treatment for refractory glaucoma since it is associated with a high rate of severe complications (eg, hypotony, inflammation).8
In 2010, the micropulse diode laser (Iridex) was introduced as an alternative, as it causes fewer complications while still maintaining the same efficacy.9
The present study focused on the inflammatory reaction in the anterior and posterior segment of the eye after MPCPC and CWCPC.
Comparing ACF objectively measured by a flaremeter, the present study found a significantly higher inflammation after CWCPC only in the early postoperative period (until 1 week postoperatively). This may be because MPCPC rather causes apoptosis of the cells by suppressing anti-inflammatory mediators, rather than necrosis of the cells as seen in CWCPC.10 In CWCPC, reduction in IOP is achieved through thermal damage to the ciliary body. CWCPC, in addition, may cause collateral thermal damage to the ciliary body stroma or ciliary muscles,11 thereby further increasing anterior chamber inflammation. MPCPC, on the other hand, is hypothesised to cause inflammation (without consecutive damage) of the ciliary body inducing enhanced uveoscleral outflow.4 In the present study, SFCT in the MPCPC group did not significantly change compared with baseline, but the uveal changes might be too subtle to be picked up on OCT imaging.
The differences in flare levels showed to be nonsignificant in the later postoperative period (6 weeks to 3 months, figure 1). Tekeli and Köse similarly reported significantly different flare values in the early postoperative phase (up to the fourth week after surgery), which then became comparable from the third month onwards.12 However, the treatment regimen in Tekeli’s study differed in that less topical prednisolone was given after the operation. The present study showed that flare values may equalise even earlier at the sixth postoperative week if treated with high-dose topical prednisolone after surgery (all patients received the standard therapy regimen of hourly prednisolone 1% for the first week, followed by a weekly taper for 6 weeks). Under this regimen, no patient had to be treated for prolonged anterior chamber inflammation over a period of 6 weeks.
In alignment with previous work by Kimura et al, the present study found a significant correlation between reduced IOP after 3 months and increase of ACF in the early postoperative phase (after 1 week).13 But as the present study had a longer follow-up than Kimura et al work, it could show that this correlation did not remain significant until 6 months after surgery. Hence, the data of this study are unable to confirm with certainty an association between ACF and final reduction of IOP, as it has previously been published.
This is the first study evaluating postoperative inflammation in the posterior segment of the eye at different time points. Around one-fifth (21.6%) of all eyes developed inflammatory macular oedema after surgery. The increase in intraretinal fluid peaked after 6 weeks and was markedly higher in the CWCPC group compared with the MPCPC group.
In contrast to previous work by Jammal et al, who did not observe the development of macular oedema after MPCPC,14 the findings of this study go more hand in hand with previous work from Williams et al detecting macular oedema in 5% of patients.15 It was exclusively present in patients with known risk factors for macular oedema (epiretinal membrane, prior retinal vein occlusion, previous retinal surgery, proliferative diabetic retinopathy).7 In a quarter of cases after MPCPC, additional treatment was required, compared with 57% of the patients after CWCPC. As reported for macular oedema after cataract surgery (Irvine-Gass),16 macular oedema after CPC also showed to have its peak after 6 weeks following surgery. That is to say that even though the risk of developing significant macular oedema after MPCPC may be lower than after CWCPC and the macular oedema is less likely to be treated, it is worth including regular macular OCTs in postoperative check-ups, especially in patients with known risk factors and especially at a time point of not more than 6 weeks after surgery.
In contrast to previous work by Abdelrahman and El Sayed on a paediatric cohort, stating that postoperative pain may exclusively occur after cCPC,17 this study on an adult cohort found no significant increase in perception of pain after surgery neither in the MPCPC nor in the CWCPC group. This study can support previous studies’ findings that the majority of patients do not experience significant pain after MPCPC9 14 18 and can support work by Falb et al that postoperative pain was not different after CWCPC compared with after MPCPC.19
This is the first study to additionally compare QoL after different types of cyclodiode. Comparable to the VAS scores, there was no significant difference in QoL between the two groups.
This study has several limitations. Even though the total number of all eyes was substantial, studies with a larger cohort of patients with macular oedema after cyclodiode are required to be able to work out differences between different glaucoma types. In this study, the anterior flare was only measured objectively with the help of a flaremeter. It was decided against additional subjective grading at the slit lamp, as examiners may change in the clinic setting.
In conclusion, a significantly higher ACF after CWCPC compared with MPCPC could only be noted in the early postoperative phase until 6 weeks after surgery. Additionally, there was no significant correlation between ACF and final IOP. CWCPC may cause more marked postoperative inflammatory macular oedema, which more likely requires treatment as compared with MPCPC. CWCPC and MPCPC are equally well tolerated in terms of pain perception and QoL.
Data availability statement
Data are available on reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
Institutional review board approval was obtained for this prospective case control study (Identifier: 19-340), and the study adhered to the tenets of the Declaration of Helsinki. All patients provided written consent prior to any study-related procedure.
References
Footnotes
Contributors LFK collected the data, authored the article and created the figures and tables. She is the guarantor of the study. FE collected the data and proofread. MN collected the data and proofread the article. SP proofread. MM conducted the study treatments, authored the article and proofread.
Funding This work was supported by the Munich Medical & Clinician Scientist Program, LMU Munich (grant number for Dr LFK: CS 051) and by Iridex Europe (lending fee flare meter €5000, no funding number assigned).
Disclaimer The funders played no role in study design, data collection, analysis and interpretation of the data or the writing of this manuscript.
Competing interests None of the authors’ financial interests are directly or indirectly related to this work. LFK received previous speaker fees and/or travel expenses from Novartis Pharma, Recordati Rare Diseases, CHIESI, Roche Diagnostics, DORC Holding BV and Santen. FE received previous speaker fees from Novartis Pharma, MN has no financial interests to declare. SP received previous speaker fees and/or travel expenses from Novartis Pharma, Oertli AG, Bayer AG, Alcon Pharma and Pharm-Allergan. MM received previous speaker fees from Sight Sciences, Santen and Abbvie.
Provenance and peer review Not commissioned; externally peer reviewed.