The goal of this study was to compare the efficacy and tolerability of conventional transscleral cyclophotocoagulation (CW-TSCP) versus micropulsed diode laser (MPTLT) in the treatment of glaucoma.

In this single-center retrospective study, all patients treated with CW-TSCP or MPTLT between January 2018 and December 2020 at Nantes University Hospital with at least one month of follow-up were included. Intraocular pressure (IOP), glaucoma medications, use of new laser treatment and complications were recorded at 1, 3, 6, 12 and 24 months. Success was defined as an IOP of 6–21mmHg or a ≥20% IOP reduction from the preoperative measurement, with the same or fewer glaucoma medications and no alternative glaucoma surgery.

Thirty-seven eyes treated with MPTLT and 26 eyes treated with CW-TSCP were included. At the last visit (median=16 months), 69% of eyes treated with CW-TSCP and 54% treated with MPTLT met the success criterion (P
                     =0.720). The mean reduction in IOP from baseline was 8.0mmHg in the CW-TSCP group and 2.1mmHg in the MPTLT group (P
                     =0.030). The mean reduction in medications was 1.24 in the CW-TSCP group and 0.6 in the MPTLT group. Among patients treated with oral acetazolamide, 9 patients (69%) in the CW-TSCP group and 3 patients (33%) in the MPTLT group had discontinued the acetazolamide. Persistent hypotony was a significantly more frequent complication in the CW-TSCP group (n
                     =3; 8%) than in the MPTLT group (n
                     =1; 2%).

While both CW-TSCP and MPTLT are effective treatments for lowering IOP over an extended period, CW-TSCP resulted in a more substantial reduction in IOP and greater decreases in the need for glaucoma eye drops and oral acetazolamide, albeit at the cost of a higher incidence of persistent hypotony. Further prospective randomized studies are needed to confirm the superior efficacy of CW-TSCP over MPTLT and to better assess its tolerability.

L’objectif de cette étude est de comparer l’efficacité et la tolérance de la cyclophotocoagulation transclérale conventionnelle (CW-TSCP) par rapport au laser diode micropulsé (MP-TLT) en traitement du glaucome.

Tous les patients traités par CW-TSCP ou MP-TLT entre janvier 2018 et décembre 2020 au CHU de Nantes ont été inclus. Le tonus oculaire (TIO), la prise d’hypotonisants, le recours à un nouveau traitement laser ainsi que les complications, ont été recueillis à 1, 3, 6, 12 et 24 mois. Le succès a été défini comme une tension oculaire entre 6 et 21mmHg ou une baisse tensionnelle d’au moins 20 % et en l’absence d’augmentation du nombre d’hypotonisants et de recours à la chirurgie.

37 yeux traités par MPTLT et 26 yeux traités par CW-TSCP ont été inclus. A la dernière visite (médiane 16 mois), 69 % des yeux traités par CW-TSCP et 54 % des yeux traités par MPTLT ont validé le critère de succès (p
                     =0,72). CW-TSCP a permis une baisse tensionnelle de 8mmHg contre 2,1mmHg pour le MPTLT (p
                     =0,03). La diminution du nombre de molécules hypotonisantes a été de 1,24 dans le groupe CW-TSCP contre 0,6 dans le groupe MPTLT (p
                     =0,045). Parmi les patients traités par acetazolamide oral, 69 % des patients ont pu être sevrés dans le groupe CW-TSCP contre 33 % dans le groupe MPTLT. 8 % des yeux traités par CW-TSCP contre 2 % des yeux traités par MPTLT ont présentés une hypotonie (TIO<6mmHg) (p
                     =0,006).

Bien que la CW-TSCP et la MPTLT soient toutes deux des traitements efficaces pour réduire la PIO sur une période prolongée, la CW-TSCP a permis une réduction plus importante de la PIO, une diminution plus importante du nombre d’hypotonisants, mais au prix d’une incidence plus élevée d’hypotonie persistante. Des études prospectives randomisées sont nécessaires pour confirmer l’efficacité et le profil de sécurité de chaque procédure afin de mieux définir leurs places dans l’algorithme de prise en charge du glaucome.

# Introduction

Glaucoma is now the second leading cause of blindness worldwide, projected to affect almost 80 million patients by 2024 [1]. Elevated intraocular pressure (IOP) is the primary known modifiable risk factor for glaucoma. Its reduction limits the progression of optic nerve neuropathy and, thus, visual field loss. All current glaucoma therapies aim to lower IOP, either by increasing the outflow or decreasing the production of aqueous humour [2].

The ciliary body is divided into two parts: the anterior part, called the pars plicata, and the posterior part, called the pars plana. The pars plicata epithelium is the primary producer of aqueous humour. Destroying the secretory epithelium of the ciliary body via transscleral cyclophotocoagulation (TSCP) is a well-known method for treating uncontrolled glaucoma. In continuous wave TSCP (CW-TSCP), laser energy is transmitted through the conjunctiva and sclera to target the ciliary epithelium and stroma, where it induces a coagulative effect [3]. The contact probe compresses the tissues, enhancing transmission by reducing absorption as the energy passes through the eye's surface. CW-TSCP consistently delivers laser energy during application. When aimed at the pars plicata, the laser induces the contraction of the ciliary processes and thus decreases aqueous humor production. CW-TSCP might also enhance outflow, possibly due to damage to the ciliary body, making it more permeable to the outflow of aqueous humor [4]. Originally, CW-TSCP was used for refractory glaucoma or in eyes with limited visual potential because of reports of severe complications that could threaten vision (hypotonia, phthisis, and intraocular inflammation) [5]. However, more recent studies suggest its use earlier in the treatment process [6].

A more recent method of delivering transscleral laser energy, known as micropulse transscleral laser therapy (MPTLT), applies laser energy to the pars plana through a series of repeated, brief pulses that are interspersed with “off” periods. These “off” periods are believed to allow surrounding tissues to disperse the heat, preventing them from reaching a coagulative state [3,7]. It has also been suggested that MPTLT might partially enhance aqueous outflow by causing the longitudinal ciliary muscle fibers to contract, which tightens the scleral spur and potentially increases trabecular outflow [8]. Studies measuring choroidal thickness on optical coherence tomography (OCT) have also shown that MPTLT increased uveoscleral outflow [9–11]. MPTLT is suggested to be as effective as CW-TSCP but with fewer complications [12,13]. It is being increasingly used, particularly in eyes with better vision than those typically treated with CW-TSCP [14,15].

While MPTLT has shown promising results, few studies have compared it with CW-TSCP, often only over a short period of time [16]. Their results are heterogeneous and incomparable due to a variable definition of success/failure. As glaucoma is a chronic disease, it is also vital to evaluate the long-term effects of treatments. Therefore, this retrospective study aimed to compare the efficacy and safety of MPTLT to CW-TSCP with a homogeneous definition of success over a two-year follow-up period.

# Methods

## Study design

This retrospective study investigated the treatment outcomes of patients who underwent MPTLT or CW-TSCP between January 2018 and December 2020 at Nantes University Hospital (France). Cases were identified from the electronic medical record system (PMSI, Clinicom).

## Eligibility criteria

This study included all patients with any type and stage of glaucoma treated with MPTLT or CW-TSCP between January 2018 and December 2020 and with at least one month of follow-up after the laser procedure. There were no exclusion criteria and the choice of technique was at the discretion of the surgeon, with a total of five different surgeons involved.

## Laser intervention

The laser procedures followed standard protocols used at Nantes University Hospital. All patients received peribulbar block or general anesthesia. CW-TSCP was performed using the IRIS Medical Oculight SLx system (IRIDEX, Mountain View, CA, USA). Initial standardized settings were 2000ms duration and 1500mW power, titrating power down to avoid “pops.” The power used ranged from 1200 to 2000mW, and the duration ranged from 2000 to 4000ms. Between 1 and 3 quadrants were treated with eight applications per quadrant, sparing a clock hour (30°) at each of the 3- and 9-o’clock meridians to spare the long ciliary nerves and vessels. The applications were placed with the front of the probe at the anterior aspect of the ciliary body, as identified by transillumination. For MPTLT procedures, the Quantel Medical Vitra 810 SubLiminal laser combined with the Quantel Medical SubCyclo® probe was used with standardized pre-set powers of 2000mW/cm2 and duty cycle of 31.3% (on for 0.5ms, off 1.1ms). The energy was applied by sweeping the probe in a continuous “sliding” motion. The time applied per hemisphere was between 80 and 90 with a sweep velocity of 10seconds. Both hemispheres were treated for most patients. All patients received dexamethasone drops (0.1%) three times daily postoperatively for at least 10 days, longer at the discretion of the operating surgeon.

## Data

The baseline parameters measured included age at operation, patient-identified gender, glaucoma type, and details of previous ocular surgeries or laser intervention. The following variables were reviewed preoperatively and at 1, 3, 6, 12, and 24 months postoperatively: IOP, number/type of glaucoma medications, complications, repeat procedures, and the need for subsequent alternative glaucoma surgery. We aimed to collect data from appointment records as close to the intended follow-up time as possible, with an approximate maximum of two months. In order to compensate for the variable follow-up of patients, we also looked for the measurement at the last visit over the 26-month period for each outcome.

## Surgical success

The primary outcome was treatment success, which was classified as success at each follow-up time point. Follow-up was categorized into success or failure. Success was defined as an IOP of 6–21mmHg or a ≥20% IOP reduction from the preoperative measurement, with the same or fewer glaucoma medications and no alternative glaucoma surgery. We defined success this way because it is the most often used in studies evaluating CW-TSCP and MPTLT [16], allowing us to compare our results with those in the literature.

The secondary efficacy outcomes were the IOP reduction compared to preoperative IOP, the proportion of patients treated with oral acetazolamide (Diamox®), and the reduction in glaucoma medications (molecules). Patients who required additional surgery were included in our study up to their last follow-up before the subsequent intervention.

Safety outcomes were assessed based on the incidence of specific complications and the overall complication rate. Specific complications included persistent hypotony (minimum duration of 2 weeks), a non-reactive pupil, uveitis, hyphema, phthisis bulbi, corneal epithelial defect, postoperative uveitis, stromal necrosis, and loss of central vision. Hypotony was defined as an IOP of ≤5mmHg. The overall complication rate was defined as the percentage of patients who experienced at least one complication during the follow-up period.

## Statistical analysis

All statistical analyses and graphs were performed using Microsoft Excel. A P-value of ≤0.05 was considered statistically significant. Two independent proportions were compared using Fisher's exact test, and quantitative and independent data were compared using a Mann–Whitney U test. The results are presented as curves or histograms.

## Ethical approval

This audit was approved by the Nantes Ethics Groupe (Groupe Nantais d’éthique). It received a favorable opinion from the Comité d’Expertise pour les Recherches, les Etudes et les Evaluations dans le domaine de la Santé and was authorized by the Commission Nationale Informatique et Libertés. The requirement for informed consent was waived due to the study's retrospective design. All specific patient identifiers were removed. This research complies with:
                           
                              •
                              the French Data Protection Act of 6 January 1978, as amended, and Act No. 2018-493 of 20 June 2018 on protecting personal data;
                           
                           
                              •
                              Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of individuals regarding the processing of personal data and the free movement of such data (RGPD).

# Results

## Demographic characteristics

Table 1
                         summarizes patients’ demographic characteristics, glaucoma etiologies, prior filtering surgeries, and main comorbidities. A total of 26 eyes underwent CW-TSCP and 37 eyes underwent MPTLT. The median follow-up period was 13 and 18 months in the CW-TSCP and MPTLT groups, respectively.

The two groups did not differ significantly in age, self-identified gender, comorbidities, or previous filtering surgery. However, there were some differences in etiology. The CW-TSCP group had significantly more patients with neovascular glaucoma (NVG), whereas the MPTLT group had significantly more patients with post-keratoplasty glaucoma. There were no significant differences in the proportions of other types of glaucoma, although there were slightly more patients with primary open glaucoma in the MPTLT group. Visual acuity was significantly lower in the CW-TSCP group than in the MPTLT group. Since patients were no longer monitored for visual fields due to their very poor vision, the rare MD values are not reported in Table 1. Similarly, patients with optic nerve OCT were not followed up, which was often too impaired at inclusion.

Preoperative IOP was significantly higher in the CW-TSCP group (30.7±9.5mmHg) than in the MPTLT group (24.3±8.2mmHg; P
                        =0.002). Patients also took more glaucoma medications in the CW-TSCP group than in the MPTLT group.

## Overall treatment success

The success rate was similar between groups during the two-year follow-up (Fig. 1
                        ). At the last visit (median=16 months), 69% of eyes treated with CW-TSCP and 54% treated with MPTLT met the success criterion (P
                        =0.720).

## Effect on IOP

Fig. 2
                         shows the mean reduction in IOP from baseline. At most follow-up time points, the IOP reduction was significantly greater in the CW-TSCP group than in the MPTLT group. At the last visit, the mean reduction in IOP from baseline was 8.0mmHg in the CW-TSCP group and 2.1mmHg in the MPTLT group (P
                        =0.030).

## Effect on glaucoma medication

Both interventions reduced the number of medications used (Fig. 3
                        ). At most follow-up time points, the reduction in medications was significantly greater in the CW-TSCP group than in the MPTLT group (P
                        =0.045). At the last visit, the mean reduction in medications was 1.24 in the CW-TSCP group and 0.6 in the MPTLT group.

In total, 13 and 9 eyes treated with CW-TSCP and MPTLT, respectively, required pre-treatment with acetazolamide (Diamox®). At the last visit, nine patients (69%) in the CW-TSCP group and three patients (33%) in the MPTLT group had stopped taking acetazolamide (P
                        =0.860; Fig. 3).

## The proportion of laser-retreated patients

At 24 months, 38% of patients treated with CW-TSCP and 55% of patients treated with MPTLT required further laser treatment (P
                        =0.240; Fig. 4). The mean time to retreatment was 6.5 months in the CW-TSCP group and 8.1 months in the MPTLT group. No laser retreatment was conducted with a different laser type.

## Safety outcomes

Table 2
                         shows the number and proportion of eyes experiencing each complication. There were no cases of phthisis bulbi and hyphema after MPTLT. Persistent hypotony was a significantly more frequent complication in the CW-TSCP group (n
                        =3, 8%, median duration=6 months) than in the MPTLT group (n
                        =1, 2%; duration >12 months; p=0.006).

# Discussion

Our study demonstrated that CW-TSCP and MPTLT are both effective treatments to reduce IOP over a long period. We found similar success rates in both groups, confirming previously reported data (Table 3
                     ) [14,17,20–25]. The variation in the definition of the criterion for success criteria used across studies explains the differences observed in reported treatment success rates. The CW-TSCP and MPTLT procedures also both significantly reduced the need for glaucoma eye drops and oral acetazolamide. Abdullatif and Ahmed El-Saied found similar results, reporting a greater reduction in medications with CW-TSCP than with MPTLT [26]. Reducing medication use is crucial not only for enhancing quality of life but also because poor adherence to medication is common and can significantly contribute to glaucoma progression [27].

In a significant manner, our study observed a greater reduction in IOP (8.0 vs. 2.1mmHg) and a greater decrease in medication (1,24 vs 0,6) in the CW-TSCP group than in the MPTLT group. These clinical data are particularly interesting and suggest that CW-TSCP should be favored over MPTLT when greater effectiveness is sought, albeit at the cost of a higher incidence of persistent hypotony.

A previous study reported that the complication rate was slightly higher with CW-TSCP than with MPTLT [18]. Eyes with POAG better tolerate MPTLT or CW-TSCP than those with other glaucoma types [26,29,30]. In our study, there were more POAG cases in the MPTLT group than in the CW-TSCP group, and this selection bias could partially explain the difference in tolerance between groups. However, there were three times more cases of persistent hypotony (IOP≤5mmHg for more than 2 weeks) in the CW-TSCP group than in the MPTLT group, which could be because patients with NVG exhibit unpredictable IOP responses after any form of treatment, possibly due to significantly reduced outflow caused by secondary synechiae angle closure, while inflow is also reduced but to a lesser extent [18]. Therefore, treatments that affect inflow may disrupt this fragile balance and lead to hypotony [29]. In the CW-TSCP group, of the three patients who developed persistent hypotony, two were treated for NVG. The higher proportion of NVG in this group may have led to overestimating the risk of complications, particularly post-CW-TSCP hypotony.

The exact mechanism of action of MPTLT remains unclear. The proposed mechanisms for its effects include reduced aqueous humor production, enhanced uveoscleral outflow, and increased trabecular outflow [7]. It has been suggested that CW-TSCP success may vary by glaucoma subtype. If MPTLT enhances outflow, it might be more effective in conditions like primary open-angle glaucoma (POAG), where the trabeculum is relatively intact, and less effective in cases of clear obstruction of the normal outflow pathways, such as angle-closure glaucoma or NVG [18,28]. In our study, there were more POAG and fewer NVG cases in the MPTLT group than in the CW-TSCP group, which may have contributed to underestimating the efficacy of CW-TSCP compared to MPTLT. Therefore, this selection bias cannot contradict our results concerning the superiority of CW-TSCP in reducing IOP and medications.

Nevertheless, the small size of the two groups and the variability in patient follow-up represent biases inherent to the retrospective and real-life design of our study. A selection bias was present due to the initial differences between the two study groups. There was a significantly higher preoperative IOP (30.7±10.4mmHg) and a lower visual acuity in the CW-TSCP group than in the MPTLT group (IOP=23.6±8.2mmHg; P
                     =0.002). It is plausible that CW-TSCP was favored for more severe patients whereas MPTLT was preferred for less severe cases.

# Conclusion

While both CW-TSCP and MPTLT are effective treatments for lowering IOP over an extended period, CW-TSCP resulted in a more substantial reduction in IOP, greater decreases in the need for glaucoma eye drops and oral acetazolamide, albeit at the cost of a higher incidence of persistent hypotony.

Considering the selection bias inherent to the retrospective and real-life nature of the study, further prospective randomized studies are needed to confirm the superior efficacy of CW-TSCP over MPTLT and to better assess its tolerability.