Micropulse Laser Trabeculoplasty On Glaucoma Patients: Average 35 Months Follow-Up Results

Background: Glaucoma is a group of eye diseases that can damage the optic nerve and cause vision loss. A novel technology micropulse laser trabecular plasty (MLT) can use duty-circle subvisible laser pulses to treat glaucoma. The aim of this study is to evaluate the ecacy of 360° MLT to alleviate intraocular pressure (IOP) in patients with glaucoma. Methods: This was a single-center prospective study on patients treated with 360° MLT using a Diode True-Yellow 577-nm Laser with MicroPulse technology. All the patients were recruited from the Department of Ophthalmology. Follow-up visits were carried out at 1 day, 1 week, 1 month, 3 months, 6 months, 18 months, and 36 months after the procedure. Best-corrected visual acuity (BCVA), Intraocular pressure (IOP), and vertical cup-to-disc ratio (C/D ratio) were measured during the follow-up. Repeated-measures analysis of variance (ANOVA) and Kaplan–Meier analysis were performed to evaluate the outcomes. Results: A total of 39 eyes from 26 patients were included in this study (10 men/15 women). The average age of patients was 41.47±14.39 years old, and the baseline IOP was 21.13 ± 7.75 mmHg. MLT signicantly reduced the IOP at 1 day (range 15.61–19.01, P=0.0218), 3 months (range 16.47–19.22, P=0.0390), and 6 months (range 15.38–18.56, P=0.0332) compared with the baseline. However, by the end of the study, only 21.88% of patients demonstrated a ≥ 20% IOP reduction, while seven eyes needed further laser or surgical treatment. Conclusions: Micropulse laser trabeculoplasty could reduce IOP in patients with glaucoma or ocular hypertension for a short period, but its lowering eciency was limited up to 6 months of the follow-up period. ANOVA: Repeated-measures analysis of variance; BCVA: Best-corrected visual acuity; C/D ratio: Vertical cup-to-disc ratio; IOP: Intraocular pressure; LTP: Laser trabeculoplasty Laser trabeculoplasty; MLT: Micropulse laser trabecular plasty; OH: Ocular hypertension; RNFL: Retinal nerve bre layer; SLT: Selective laser trabeculoplasty; TM: Trabecular meshwork; VF: Visual eld


Background
Glaucoma is the most frequent cause of irreversible blindness, referred to as a group of eye diseases that can damage the optic nerve and cause vision loss (1).
The managements of glaucoma include anti-glaucoma medications, laser technologies, and ltering and non-ltering surgeries. Laser trabeculoplasty (LTP) has been introduced as a non-invasive procedure to treat multiple types of glaucoma for several years. It applies laser energy to the trabecular meshwork (TM), usually covering 180°-360° range of TM for each treatment (2,3). Micropulse laser trabeculoplasty (MLT) is a newly developed technology, rst described in 2005. It uses duty-circle subvisible laser pulses and focuses on the anterior TM tissue. Considering it's long relaxation time, micropulse laser trabeculoplasty allows the temperature to return to the baseline and avoids heat damage to TM (2). Several clinical trials have been carried out to evaluate the e cacy and safety of MLT. However, the standard protocol for MLT was still not available, and studies continued to explore it (4)(5)(6)(7)(8). Besides, even though some papers evaluated MLT' e cacy, there's still no data showed how long the IOP-reduction effect could last (9). This study aimed to illustrate the effects of 360° MLT's on patients with glaucoma within a longer follow-up period.

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This was a prospective study conducted at the Second Xiangya Hospital from 2015 to 2019. All the patients were recruited from the Department of Ophthalmology.
The inclusion criteria were as follows: (1) patients of Asian origin with glaucoma or ocular hypertension (OH), (2) age older than 18 years, and (3) those who received no surgical or other laser procedures in the recent 3 months. Slit-lamp examination and gonioscopy were performed, IOP was measured using Goldmann applanation, and visual eld (VF) was also tested using the Humphrey Field Analyzer perimeter. OAG was de ned as the open angle on gonioscopy (Shaffer grading > 2 in all quadrants) in the presence of a progressive increase in C/D ratio or VF defects. Patients with higher IOP, typically 21 mm Hg, but no VF or retinal nerve bre layer (RNFL) defects were classi ed as OH (10). Two eyes diagnosed with primary angleclosure glaucoma were included after LPI treatment, with Shaffer grading ≥2 in 360°. Four eyes received ltering surgery before but IOP was not well controlled were also included. Patients went home immediately after the procedure. Nonsteroidal anti-in ammatory drugs (Pranoprofen, 0.1%) was applied four times a day for 1 week. BCVA and IOP measurement were routinely carried out on day 0 and 1 and in week 1, month 1, month 3, month 6, month 18, and month 36. Anti-glaucoma drugs were titrated up or down when the IOP was higher or lower than the targeted one. When multiple drugs were needed, the combination medications were applied to simplify the drug regimen. If the IOP or optic nerve damage was progressed at maximal drug regimen during more than two visit intervals, the patients received additional therapies, such as another laser treatment or ltering surgery.

Ethical Approval
This study adhered to the tenets of the Declaration of Helsinki. Informed patient consent and approval from the Institutional Review Board of The Second Xiangya Hospital were obtained.

Statistical Analysis
Statistical analysis was performed using IBM SPSS Statistics (IBM Corp.) and GraphPad Prism 7 (GraphPad Software, Inc.). Repeated-measures analysis of variance (ANOVA) was used to compare IOP values at different time points with Dunnett's multiple-comparisons test for between-groups analysis. A Kaplan-Meier analysis was performed to tell the time to failure after MLT. For all statistical analyses performed, differences were considered statistically signi cant at P < 0.05. Baseline characteristics N = 39

Visual Field
Visual led index (%) (mean ± SD) 84 ± 25 Mean deviation (dB) (mean ± SD) -5.44 ± 6.69 Pattern standard deviation (dB) (mean ± SD) 5.92 ± 7.51 MLT was completed in all eyes with the laser settings shown in Table 2.  Table 3. During the follow-up period, seven eyes received additional laser or surgical treatment. These procedures included selective laser trabeculoplasty (SLT) in 4 eyes, shunt implantation in 2 eyes, and trabeculectomy in 1 eye. A survival curve analysis is presented in Figure 1, in which mortality is de ned as the presence of progressive IOP elevation or optic nerve damage, due to which the patients received further laser or surgical treatment.
In addition, only patients without MLT treatment failure, who could be evaluated from the beginning to the end of the 35-month observation period, were analyzed. The Kolmogorov-Smirnov test was performed (P > 0.05), which demonstrated that the data was suitable for repeated-measures ANOVA analysis. After 1 day, 3 months, 6 months, and 36 months of MLT, more than 20% patients exhibited a more than 20% IOP reduction, while the mean IOP was signi cantly reduced at 1 day (q=3.12, p=0.0218, DF=31), 3 months (q=2.876, p=0.039, DF=31), and 6 months (q=2.945, p=0.0332, DF=31) visit compared with the pre-MLT level (Table 4,

Discussion
As universally acknowledged, argon laser trabeculoplasty (ALT) exerts thermal damage to the treated TM, causing the shrinkage of collagen bres, stretching and widening the adjacent areas and allow more out ow (11). Compared to ALT, SLT's energy selectively absorbed by pigmented trabecular cells and makes no damage to adjacent structures. Both ALT and SLT provided reliable IOP-lowering effect, but ALT caused obvious damage to TM histologically (11,12). Several clinical trials claimed that SLT was an effective way to control IOP in multiple types of glaucoma (13)(14)(15)(16)(17). However, a wide range of complications, such as redness, photophobia, peripheral anterior synechiae, and cystoid macular oedema were still observed in patients with SLT (18).
Unlike the former laser technologies, MLT is based on a micropulse laser with a 15% duty cycle, which allows the temperature to return to the baseline. Under this condition, both TM and Schlemm's canal could escape from cellular damage, scarring, and morphological changes (19).
Previous research demonstrated that MLT (810nm) was less effective in reducing IOP compared with ALT on a 3-month visit (20). A retrospective review was conducted by Rantala, in which they evaluated 180° MLT (810nm, 180°) on patients with OAG with a minimum follow-up period of 6 months, and found that MLT was a safe but not effective-enough treatment for glaucoma (4). Lee investigated the use of 360° MLT (577nm) for treating patients with OAG. By the end of the 6-month visit, 72.9% of patients were successfully treated(5).
He showed that MLT was as effective as SLT within a 52-week follow-up period (21). Valera-Cornejo conducted MLT (532nm, 360°) on patients with OAG and found that it reduced IOP in a pretty short period(6).
All of the above indicated that both the range and the wavelength of laser applied to patients may affect the results. In the present study, IOP was averagely reduced by 3.73%, and only 21.88% of the patients achieved a more than 20% reduction in IOP by the end of the 35-month visit. This result was not as encouraging as the previous ndings. Recently, several studies claimed that MLT is a safe and effective way to attenuate IOP, while the observation period were relatively short(8, [22][23][24].
The present study had several limitations. Initially, this was a small-sample study. Patients' characterizations, such as the optic nerve condition, might have affected the results. Seven eyes with a C/D ratio range from 0.9 to1.0 were enrolled, four of them underwent trabeculectomy, demonstrating a poor prognosis. The reason why we recruit them is because several anti-glaucoma drugs had been prescribed but not su cient to lower the IOP in these patients. To reduce the glaucoma medications and slow down the progression of optic nerve damage, we decided to perfume MLT to these 4 eyes. Secondly, given the relatively long follow-up period, it was hard for patients to completely following doctors' instructions. Especially, those who still have a relatively good visual acuity, might not apply drugs as routinely as required, leading to an under-estimated IOP-lowering effect.
To our knowledge, this research was one of the longest explorations of the effect of MLT on patients with glaucoma and OH, claiming that a single session of MLT could signi cantly reduce IOP in a pretty short period. Given the repeatability of MLT, it could be used as an IOP-lowering treatment.

Conclusion
In conclusion, MLT is a newly glaucoma treatment based on a micropulse laser with a 15% duty cycle, which could reduce IOP in patients with glaucoma or ocular hypertension for a short period, but its lowering e ciency was limited up to 6 months of the follow-up period. Changes in IOP following MLT with SD bars above and below the mean. MLT=Micro-Pulse laser trabeculoplasty