Micropulse Transscleral Cyclophotocoagulation: One-year Results and Comparison of two Different Laser Settings in Severe Glaucoma

Francesca Chemello University of Verona: Universita degli Studi di Verona Guido Barosco (  guido.barosco@gmail.com ) Universita degli Studi di Verona https://orcid.org/0000-0003-2516-4127 Anna Rodella University of Verona: Universita degli Studi di Verona Piero Ceruti University of Verona: Universita degli Studi di Verona Roberta Morbio University of Verona: Universita degli Studi di Verona Mattia Marcigaglia University of Verona: Universita degli Studi di Verona Giorgio Marchini University of Verona: Universita degli Studi di Verona


Introduction
Ophthalmologists have always identi ed in the cycloablation of the ciliary body an effective solution for lowering the intraocular pressure (IOP) reducing the production of aqueous humour [1].
Many different approaches have been used to reach this objective, from the cyclo-diathermy and freezing technique through different types of laser's energy such as Xenon laser, Nd-Yag laser and ruby laser [2].
Continuous-wave transscleral cyclophotocoagulation (CW-CPC) using the diode laser energy has been introduced in 1993 and became the preferred procedure owing to its cost, e cacy and portability [2,3]. Target of this laser is the pigmented epithelium of the ciliary body: the wavelength employed (810 nm) is selectively absorbed by these cells, but still, the energy delivered caused a coagulative necrosis of the surrounding tissues as well [4]. In the face of a proven e cacy, the high ratio of serious complications such as macular oedema, vision loss and prolonged hypotony limits its use to refractory glaucoma with low vision potential [1,[5][6][7]. All these dangerous complications are secondary to the damages of the surrounding tissues such as the ciliary muscle, the non-pigmented epithelium and the ciliary body stroma [8].
The micropulse laser transscleral cyclophotocoagulation (MP-CPC, IRIDEX, CYCLO G6 Glaucoma Laser System, Mountain View, CA) represents the latest news in this panorama. The type of energy and powers are the same of the CW-CPC. The difference stands in the duration in which the energy is provided: the device delivers the energy in a pulsatile wave operating in an "on" and "off" cycle mode with a xed 31.33% duty cycle. During the "on" cycle multiple milliseconds repetitive bursts of energy are emitted by the device and absorbed by pigmented tissue, during the "off" cycle non-pigmented tissues and the surrounding stroma have the time to cool off and do not attain the coagulative threshold [9][10][11][12]. Beside the primary mechanism based on the reduction of aqueous humour production secondary to the coagulation of ciliary body's pigmented tissue, also an increase of the trabecular out ow as well as the uveo-scleral out ow have been assumed [1,10,13,14]. The latest studies suggest a maintenance of the e cacy with a lower incidence of complications compared to the CW-CPC [8,9]. The settings on the machine leave the operator free to decide the power of the laser, the duration time of the treatment and the motion of the probe on the patient's conjunctiva.
Literature is still not agreed in terms of e cacy and safety of the procedure as well as duration of treatment and laser parameters to set, in uencing the predictability of the treatment [15,16]. The rst aim of this study is to evaluate the e cacy (considering the amount of reduction of both IOP and antiglaucoma medications) and the safety (considering the rate of complications) of MP-CPC after a follow-up period of 12 months. We also compare 2 different durations of treatment looking for any difference in terms of e cacy and safety of these 2 protocols.

Methods
This retrospective study involved 40 eyes of 40 adult patients (age ≥ 18) with different types of severe glaucoma. The data were collected reviewing the computerized charts of the rst 20 patients consecutively treated with a 90 sec/hemisphere duration and the rst 20 patients consecutively treated with an 80 sec/hemisphere duration at the University Eye Clinic of Verona during the rst 8 months of usage of the MP-CPC between January and August 2018.
Our Ethical Committee Board approved this study. The research followed the tenets of the declaration of Helsinki. Informed consent to use anonymously the data was obtained from all the subjects. At baseline and at every follow-up visit eye examination, IOP, visual acuity, topical medications, and oral carbonic anhydrase inhibitor (if present) were recorded. In case of failure, re-treatment or other procedures were evaluated from three months from the laser procedure.
These data are referred to our rst experience with this new and still not standardized technology and the selection of the patients was linked to our past experience with CW-CPC and with his side effects.

Surgical Technique
The procedure was delivered by the same two glaucoma specialists (GM, PC) in our operating theatre, all patients received retrobulbar block of 1:1 bupivacaine and mepivacaine before starting the treatment. Methylcellulose gel was applied on the conjunctiva to ensure a better sliding motion of the probe and to properly transmit the energy. The power used was 2000 mW, delivered for either 90 or 80 seconds per hemisphere (superior and inferior) based on the surgeon choice at the day of the treatment, for a total of either 180 or 160 seconds per eye respectively, at 31.3% of duty cycle. During the procedure the probe was swiped 4 times per hemisphere in the 90 seconds group and 3 times per hemisphere in the 80 seconds group (both superior and inferior), maintaining the perpendicularity with the scleral surface and sparing the 3 and 9 o'clock to avoid the risk of damaging the ciliary nerves. One drop of topical xed combination of Dexamethasone 1 mg/ml and Netilmicin 3 mg/ml were administered to the patients at the end of the treatment. Patients were tapered with topical Dexamethasone 1 mg/ml for one month after the procedure. All the medications were maintained and eventually modi ed depending on the need of the patient evaluated at every control visit. Prostaglandin (if present) was suspended for the rst 7 days after the procedure, as a standard.

Patients' characteristics
The study involved 40 eyes of 40 adult patients (age ≥ 18) affected with different types of glaucoma de ned as severe stage according to the Hodapp Parish Anderson classi cation [17]. Demographic and clinical characteristics were recorded at baseline. All patients treated at the time of the procedure had uncontrolled IOP, out of their target values and have no previous history of eye surgery within 6 months from the enrolment or any other cyclodestructive treatment. The duration of treatment received was independent of the preoperatory criteria and up to the surgeon choice. All patients shared clinical and functional indication for the MP-CPC treatment.

Primary Outcomes
Target IOP was de ned as an IOP between 6 and 21 mmHg or a reduction greater than 20% with or without medications. Treatment success was set as the achievement of the target IOP with or without medications at 1, 3, 6, 12 months follow-up visit. IOP was measured at baseline and at every control visit using the Goldman applanation tonometer (AT 900 ® , Haag-Streit International AG, Koeniz, Switzerland).
Patients who did not reach their target IOP for ≥ 2 consecutive visits were scored as failure. Topical drugs reduction from baseline was evaluated at 1 week and 1, 3, 6, 12 months follow-up visits.

Secondary Outcomes
Complications were evaluated at 1, 3, 6, 12 months follow-up visits and included: loss of visual acuity, anterior chamber in ammation, corneal oedema, macular oedema, prolonged hypotony, phthisis bulbi, sympathetic ophthalmia, and any other pathological ndings connected to the laser treatment.
A comparative analysis between the 90 seconds/hemisphere treatment group and the 80 seconds/hemisphere treatment group has been conducted to nd any difference in terms of IOP reduction, drugs reduction and rate of complications at 1 week and 1, 3, 6, and 12 months follow-up. Oral carbonic anhydrase inhibitor was the rst drug (before topical ones) to be suspended in case of controlled and IOP.

Statistical Analysis
Data analysis was performed using SPSS for MacOS (version 25.0; SPSS, Inc., Chicago, IL). Normali ty for data samples was evaluated with the Kolmogorov-Smirnov test. If parametric analysis was possible, the Student's t test for unpaired data was used to compare data between the 80 and 90 seconds/hemisphere groups, whereas for nonparametric anal ysis the Kruskal-Wallis test was applied to assess the signi cance of data related to IOP modi cations and number of topical drugs needed, post-hoc analysis was conducted performing the Mann-Whitney U-Test and applying the Holm-Bonferroni Correction on the p-value obtained. For all statistical tests, a p value of less than .05 was considered statistically signi cant.

Discussion
The advantages of the CW-CPC are usually offset by the very severe disadvantages of this procedure, encouraging to look for a safer and more predictable strategy. Our cohort was made by refractory severe glaucoma, at baseline most of them had already undergone other eye surgical procedures as resumed on Table 1 and would have been good candidates for a CW-CPC, which represented an easy, effective and dangerous option [18][19][20]. These patients have been treated with the MP-CPC as an alternative to the CW-CPC as a result of the latest evidences of e cacy and safety of this treatment [8, 9,[21][22][23]. The mean percentage of IOP reduction was 33% after 1 month, 41% after 3 months, 33% after 6 months and 34% after 12 months ( Fig. 1 and Table 2). Our results are concordant with what reported by surgeons who used comparable laser settings and patients' follow-up times [24,25].
Our success rate did not greatly differ to success rate of Williams et al (67% at 8 months) as well as success rate of Tan et al (73% at 18 months ) and of the adult group of Lee et al (72% at 12 months); this evidence is corroborated by the percentage values of IOP reduction reported by these three authors, comparable to ours [22,24,25]. The reduction on topical medications showed a statistical signi cance only at month 3 (p = 0.016), though, this reduction has a negligible clinical relevance, changing from a mean 3.4 (± 1.0) to 2.9 (± 1.0). The IOP recorded a higher de ection after 3 months and then slowly increased at month 6 and 12 as recorded on Fig. 2. This observation withstands the mean timing of retreatment in our cohort that was 6.3 months, similar to the mean re-treatment time reported by Aquino et al (6.8 months) [8]. This evidence, if con rmed, induces to think a maximal effect around month 3 based on a balance of aqueous humour reduction, resolution of the in ammation and bio-activation of the drainage pathways, with a downgrading e cacy by the time [8,12].
As far as the complication rate, we had 5% of complications represented by 1 case of macular oedema and 1 case of IOP spike, successfully managed with a second MP-CPC treatment. This data are closed to the data reported on other studies where similar laser settings have been used [9,25,26]. From the charts did not emerged any cased of pathological increase of in ammation secondary to the laser treatment.
The comparison between the group who received 90 seconds/hemisphere and the group who received 80 seconds/hemisphere did not show any statistically signi cant difference in terms of IOP, medications reduction and rate of complications ( Fig. 3 and Fig. 4).
The absence of differences in our two groups could be due to a similar outcome-range of the two durations as supposed from Sanchez et al. [15] Our comparative analysis could suggest that using shorter duration do not greatly affect the e cacy of the treatment. This trend is validated by the results of Sarrafpour et al. who obtained same laser e cacy (30% IOP lowering) using 2000 mW for 50 seconds/hemisphere [27]. It is more practical thinking in terms of energy delivered (measured in Joule). These results leave the eld to some speculations: maybe is not a matter of total energy delivered, but of su cient energy per duty cycle to reach the threshold by the pigmented epithelial cells of the ciliary body, sparing the surrounding stroma. The di culties putting it into practice and in standardizing the procedure are due to the hidden position of the ciliary body, the interindividual difference in pigmentation that changes the velocity to gain the threshold and the not yet completely de ned mechanism of action [28]. Based on our results and on the photophysical response seems reasonable to think about a temperature to reach during a single duty cycle, setting the minimum useful power and exposing the ciliary body to the shorter effective duration.

Conclusion And Study Limitations
In our series the MP-CPC appears a promising technique combining a satisfying e cacy and safety pro le with a good manageability in refractory advanced glaucoma. The di cult aim of the user is to set and maneuver the laser to maximize e cacy minimizing complications. Our comparative analysis suggests that shorter treatment, using the same power setting could maintain the e cacy. More studies should be conducted to better enlighten the right machine settings and to standardize the technique as well as to gain more knowledge about the biological modi cations induced by the treatment. A limitation of the study is represented by the variability of the patients' characteristics. Must be noted that to select our subjects we focused the attention on the stage of the disease, regardless of the age of the patients and the type of the glaucoma, since this treatment is mainly reserved to refractory glaucoma, therefore we aimed to investigate it speci cally on this category of patients. The absence of randomization proper of a prospective study could be prone to selection bias when it comes to typify different durations of treatment, unfortunately this source of error is intrinsic to the retrospective nature of our investigation. Further prospective studies are needed to con rm our results about the effects related to the duration used.

Declarations
Funding: Not applicable. Comparison of number drugs needed between the 80 sec/hemisphere group and the 90 sec/hemisphere group at baseline and at follow-up visits. Error bars correspond to standard deviation