The efficacy and safety of micropulse transscleral laser treatment in glaucoma: a systematic review and meta-analysis

The microPulse P3 ® Delivery Device (IRIDEX Corporation, Mountain View, CA, USA) contains a customized contact MP3 probe and a Cyclo G6 Glaucoma Laser System that emits 810 nm infrared radiation [8]. It delivers repetitive micropulses of diode laser energy with a standard 31.3% duty cycle, a short working cycle ‘on’ and a longer rest cycle ‘off’. This special modality could make melanin in the pigmented ciliary epithelium absorb the energy from the 810 nm laser and transmit the energy to the surrounding tissue during the “on” cycle, and gradually cool the ciliary body during the “off” cycle, resulting in reduced the cyclodestructive damage histologically [8, 9], potentially achieving fewer complications clinically. Despite the confirmed efficacy of CW-TSCPC, excessive laser energy may cause collateral damage to the surrounding tissue, leading to persistent hypotony, intraocular inflammation, hyphema, or phthisis bulbi as clinical manifestations. The definite mechanism in CW-TSCPC is to suppress aqueous humour production by ciliary body destruction, while that in mTLT remains unrevealed. The possible mechanisms have been hypothesized.

During the ‘on’ cycle, the pigmented epithelium of the ciliary body absorbs the energy from the 810-nm laser and subsequently transmits it to the surrounding tissue. During the ‘off’ cycle, the pigmented ciliary epithelium, non-pigmented epithelium, and ciliary stroma can be cooled and protected from significant destruction as confirmed by macroscopic and histological evaluation at a low energy level. However, partial disruption of nonpigmented and pigmented ciliary epithelium layers, and stromal destruction in the pars plicata were observed at higher levels of energy in normal porcine eyes. As a result, the limited temperature rise could reduce the aqueous humour production and cyclodestructive damage simultaneously. In addition, it has been reported that the depigmented areas in the pars plana, coagulation of collagen and destruction of ciliary body stroma in mTLT were milder than those in CW-TSCPC in the adult cadaveric eyes [10, 11]. These findings suggested that mTLT was associated with reduced aqueous humour production.

A thicker choroid could be noted in the responsive patients after mTLT treatment by optical coherence tomography angiography in some studies [12]. In addition, Nemoto et al. obtained the direct signal from the uveoscleral outflow tract by a fluorescent tracer in Dutch belted rabbits treated with mTLT. Moreover, they suggested that uveoscleral outflow was dependent on the laser settings [13]. The correlation between the increase in choroidal thickness and the IOP reduction was significant, which suggested that the uveoscleral outflow pathway might be one of the important mechanisms [12].

The third possible mechanism is the trabecular meshwork outflow. Ahn et al. examined the histologic changes in the pars plicata and ciliary muscle in normal porcine eyes at different energies and found that the trabecular meshwork became longer in length after mTLT treatment at 1 month postoperatively. In addition, the expression of α-smooth muscle actin (α-SMA) reflected that the activation of myofibroblasts gradually increased in stromal myofibroblasts of ciliary muscle with enhanced laser energy after mTLT treatment, meaning that one of the mechanisms of mTLT might be the trabecular meshwork outflow pathway by ciliary muscle contraction and scleral spur displacement and this effect was energy-dependent [11].

In this meta-analysis, mTLT was compared with CW-TSCPC in regard to IOP reduction, NOAM reduction, retreatment rate, and complications. mTLT seems to be superior in safety and retreatment. However, a relatively high level of heterogeneity among the included studies was present in the comparison of IOP reduction and NOAM reduction. The diversities in baseline patient characteristics across different studies might explain this discrepancy. The baseline IOP in mTLT was lower than that in CW-TSCPC, and glaucoma type, glaucoma stage, laser parameters, age, previous history, and race were dissimilar among studies. Only the baseline of NOAM had no significant difference.

The results of this meta-analysis provided evidence that mTLT could be recommended as a new approach for glaucoma treatment. Compared to CW-TSCPC, mTLT has more advantages. First, unlike ciliary body destruction, which suppress aqueous humour production in CW-TSCPC, mTLT only slightly destroys the ciliary body, and improves the aqueous humour outflow through the uveoscleral and trabecular meshwork outflow pathway. Second, with the superiority of safety, mTLT widens the indications, not just for advanced stage glaucoma patients. Third, the repetitive treatment with mTLT enables the performance of invasive surgery in the future especially for younger patients with high surgical failure rates. Our results showed that mTLT could significantly lower the IOP with or without medicine in 12 months. In our included studies, the mean IOP reduction was 23.9–63% at 6 months, and 23–31% at 12 months, while the success rate was 60–70% at 6 months, 33-87.5% at 12 months, and 52% at 18 months. However, the efficacy might be influenced by several factors. First, the efficacy may be related to the type of glaucoma. After mTLT, all three mechanisms of IOP reduction might be activated, but with the differences in mechanisms of IOP elevation among various types of glaucoma, the effects of IOP lowering remain different to varying degrees [14‐17]. As most studies have reported, neovascular glaucoma seemed to be less effective in controlling IOP by mTLT [14, 18]. However, which type of glaucoma could achieve a better result requires more evidence in the future. Second, the higher parameters of laser settings and durations are considered to have a more powerful IOP lowering effect in cyclophotocoagulation treatment, as a cause of a better efficacy [19]. Third, the age affects the effectiveness. The variations in ciliary body position leading to laser failure to the ciliary body and the excessive repair capacity of non-pigmented epithelial cells in children could result in a lower success rate than that in adults [20‐22]. Fourth, the various sensitivities to mTLT treatment might also depend on the base condition including prior surgical history and baseline IOP [23‐25]. Moreover, for different races, the various contents of pigment cells might also lead to different efficacies [26‐29].Commonly, the antiglaucoma medications are mandatory postoperatively because of the delayed IOP-controlling effect in mTLT. As reported, most of the patients could reduce their medical burden but could not be completely freed from it. The number of medications could be reduced to a certain extent, but the decrease gradually decreased over time. We hypothesized that the progressive repairment in mild histological destruction [10] of mTLT and gradual diminishment in the reversible effect of increased aqueous humour outflow might contribute to this outcome. In this meta-analysis, ocular hypertension and several types of glaucoma, such as primary open-angle, primary angle-closure, neovascular, pseudoexfoliative, congenital, uveitis, pigmentary, postkeratoplasty, postvitrectomy, aphakic, and iridocorneal endothelial (ICE) syndrome glaucoma at various stages were included. In traditional treatment, only those who suffer from refractory glaucoma at the end stage are suggested to undergo cyclodestructive procedure as the last resort due to the high risks of complications. These limitations promote the development of cyclodestructive modalities. The superiority of fewer side effects related to mTLT produce drives its application in an increasing number of patients. Venkata et al. first reported the implementation of mTLT in patients with good central vision BCVA of ≥ 20/60. After treatment, their BCVA had no significant change, with a mean IOP reduction of 40.2% and a mean antiglaucoma medication decline of ≥ 1 from baseline to 12 months postoperatively, laying a foundation for application in early-stage glaucoma [30]. Subsequently, Abdullatif et al. reported a 23.9% IOP reduction and 60% success rates in the nonrefractory medically uncontrolled patients, providing evidence for the reduced burden of anti-glaucoma medication in mTLT [28] at nonrefractory glaucoma. Since the opaque cornea increases the surgical difficulty in the postkeratoplasty refractory glaucoma and filtration surgery usually leads to high rates of graft failure, Zemba et al. tried to apply mTLT to patients after penetrating keratoplasty. They obtained a satisfactory result, in which the success rate was 76.9%, and the median IOP dropped from baseline 29 mmHg to 18 mmHg at 12 months postoperatively [31]. Collectively, mTLT treatment has been gradually applied to various types of patients with acceptable consequences.

In fact, those who are not candidates for incisional glaucoma surgery or reject incisional surgery, those who have a history of incisional surgery, those who are refractory glaucoma patients, and those who wish to decrease the medical burden with a controlled IOP could be taken into consideration for mTLT treatment [15, 16, 23‐25, 32‐34]. However, mTLT is not suitable for every individual. For patients with scleral thinning secondary to glaucoma surgeries or rheumatoid arthritis, the area of scleral thinning should be avoided, and the energy should be limited to lower the energy transmission. Moreover, mTLT treatment is generally not recommended in patients with > 1 clock position of scleral thinning among the publications [35]. In addition, anti-inflammatory therapy is central to those who are at high risk of postoperative inflammation after treatment [36, 37]. The standard protocol for mTLT treatment is a laser setting of 2000 mW and a duty cycle of 31.3%, while the 3 and 9 clock positions are not treated [25]. Actually, the parameter settings were mostly dependent on surgeons’ clinical experience and patients’ preoperative IOP level, medical and surgical history and so on. Tekeli et al. tried to compare the outcomes between different laser durations (160 and 240 s) in 76 patients with good baseline visual acuity. The visual acuity and visual field values remained statistically unchanged from baseline to endpoints in two groups. However, the retreatment rates were higher in 160 s group (37.6%) than 240 s group (15.9%) at 12 months [19]. On the other hand, Niten Vig et al. lowered the energy (a duration of 80–90 s, a laser setting of 2000 mW and a duty cycle of 31.3%) for refractory glaucoma, and the success rates were 75.9% at 1 month, 79.3% at 3 months and 58.6% at 6 months [38]. It seemed that a longer duration could result in better IOP control and a lower retreatment rate. However, the balance between short-term and long-term efficacy and safety also needs to be taken into consideration during mTLT treatment. Some patients needed repeated mTLT treatment owing to uncontrolled IOP or failure to achieve target IOP, and the success rates gradually decreased over time in the included articles. Some studies showed that retreatment seemed to be helpful in further IOP control. In 2019, Lim et al. reported the results of repeated mTLT procedure in 43 Asian patients with refractory glaucoma. All of them received ≥ 2 episodes of mTLT with a mean IOP of 35.2 ± 11.0 mmHg preoperatively, 31.8 ± 13.2 mmHg at 3 years, and 27.1 ± 13.8 mmHg at the latest follow-up. Moreover, the average number of medications was reduced from 3.3 ± 0.9 preoperatively to 2.8 ± 1.3 at the final follow-up with few complications, including prolonged hypotony in 3 eyes (7.0%) and phthisis bulbi in 2 eyes (4.7%)[39]. In addition, repeated mTLT treatment could increase the success rates from 36.5 to 58% [20] and from 65 to 80% at the last follow-up [33]. However, the high level of baseline IOP, a younger age, and a prior CW-TSCPC might be associated with a mildly elevated risk of failure and complications [20, 27], while neither sex, race, visual field, type of glaucoma, nor a glaucoma family history might contribute to treatment failure [27, 40]. These findings demonstrated that glaucoma patients could benefit from repeated mTLT treatment without causing more side effects.

In our results, mTLT seems to be low-risk but with fewer included publications. The complication rates varied between the studies mostly because of the diversity in energy settings. It could be believed that a higher level of energy is associated with more severe and prolonged complications. Worsening of visual acuity, and phthisis bulbi are rare and considered severe complications. However, the decrease in sight might be mainly caused by aggravated cataracts [30], which could be resolved through cataract surgery. Common complications, such as mydriasis, superficial punctate keratitis [20], anterior chamber inflammation, hypotony, and pain seldom need more surgical intervention and can be recovered spontaneously or by medicine. Rare complications (IOP spikes, hyphema [28], scleral thinning [41], choroidal detachment [28], neurotrophic keratitis [42], and suprachoroidal haemorrhage [43]) can be alleviated after appropriate treatment. These findings reflected that mTLT treatment seems to be a safe option for glaucoma.