Long-term outcomes of drusenoid pigment epithelium detachment in intermediate AMD treated with 577 nm subthreshold micropulse laser: a preliminary clinical study

INTRODUCTION

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in the elderly in the global society

. Clinically, AMD is classified as early-stage(medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic AMD)

. Ⅰntermediate AMD was defined as large drusen >125 μm and/or any AMD pigmentary abnormalities. According to Age-Related Eye Diseases Study (AREDS) severity scale, large drusen are an important risk of AMD

. Patients with a large drusen size and extensive drusen area are more likely to progress to advanced AMD

.

Drusenoid pigment epithelial detachment (D-PED) is defined as a well-defined, pale yellow or white, large mound consisting of many large drusen or confluent drusen which is at least 350 μm in the narrowest diameter and appears elevated on stereoscopic fundus photographs in the AREDS study

.D-PED is characterized by the accumulation of extracellular lipid-rich deposits between the retinal pigment epithelium(RPE) and Βruch’s membrane (ΒrM) and is associated with an increased risk of progression to advanced AMD

. Although the precise mechanism underlying D-PED is unknown,RPE dysfunction was demonstrated to play a key role in the progression of D-PED

. Long separation of RPE from the underlying ΒrM/choriocapillaris complex results in a decline in RPE function and the death of photoreceptors over time.

Demographic and Eye Examinations Data regarding baseline characteristics, such as age, sex, visual acuity, and follow-up periods, were collected. The best-corrected visual acuity (ΒCVA) was assessed at the initial visit and after treatment and were converted to logarithm of the minimum angle of resolution (logMAR) values for statistical analyses.

Incidence of CNV/GA Οne eye (4.8%) developed MNV at 11mo after SML treatment in the non-collapse group and received rescue anti-VEGF injections. Ⅰn the collapse group, 3 eyes (14.3%) developed GA after the collapse of PED at 6, 12,and 21mo after SML treatment separately. No eyes in the noncollapse group developed GA during the study.

從2017年度藝術(shù)民族志個案研究的綜合分析來看，研究者能夠主動地使用人類學(xué)的理論來闡釋民族民間藝術(shù)，田野研究的質(zhì)量也有了不同程度的提升。雖然這些研究者多為具有藝術(shù)學(xué)學(xué)科背景的學(xué)者，但是敢于打破固有的“就藝術(shù)而論藝術(shù)”的研究范式，并且能夠在深入的田野調(diào)查基礎(chǔ)上呈現(xiàn)出有獨(dú)到見解的藝術(shù)民族志，是值得肯定的。主要關(guān)注的問題集中于藝術(shù)形態(tài)、藝術(shù)功能、文化變遷、文化生態(tài)、審美認(rèn)同、文化身份、藝術(shù)家與傳承人等方面。

Except to lifestyle changes and the use of vitamin supplements,there were limited treatment options available for intermediate AMD

. Recently, high-density/low-intensity subthreshold micropulse laser (SML) treatment has been studied in a number of retinal diseases

. An observational retrospective cohort study has shown that high-risk dry AMD eyes of AREDS category 2 or greater treated with 810 nm SML have a very low incidence of choroidal neovascularization (CNV)

. SML delivers energy

multiple, repetitive, short pulses within an envelope whose width is typically 0.1-0.5s

. Compared with continuous-wave laser, the time between laser bursts (referred to as the duty cycle) is long enough to target RPE and help reduce the spread of heat from the light-absorbing RPE and choroid

. More importantly, SML was proved to improve retinal and visual function in eyes with dry AMD-related photoreceptor degeneration

. The incorporation of micropulse laser technology with a 577 nm yellow laser system, which facilitates the titration of the threshold coagulation power,provides a shorter envelope (20ms), and is more suitable for the treatment of the macular disorders.

To our knowledge, few study has investigated the effect of 577 nm yellow SML in patients with dry AMD. Ⅰn this study,we aimed to assess the anatomical and visual outcomes in intermediate AMD patients with D-PED who were treated with 577 nm SML and to determine safety profile of SML and its effect on the D-PED lifecycle.

SUBJECTS AND METHODS

Ethical Approval This retrospective cohort study was conducted under the institutional review board guidelines at the General Hospital of Central Theater Command in accordance with the tenets of Declaration of Helsinki. Ⅰnformed consent was obtained from the patients.

Enrollment of Subjects This study was conducted between June 1, 2016 and December 29, 2020. The eligibility criteria were as follows: 1) Patients aged over 50y who were diagnosed with intermediate AMD and the presence of large D-PED lesions >350 μm

; 2) Eyes were followed up for over 6mo. The exclusion criteria were as follows: 1) the presence of significant GA or macular neovascularization (MNV) at baseline; 2) the presence of other eye diseases at baseline that could reduce visual acuity (excluding mild cataract), such as retinal vascular disorders or macular dystrophies; 3) prior ocular therapies at initial visit, such as laser photocoagulation or intravitreal therapy, macular photocoagulation, photodynamic therapy, or anti-vascular endothelial growth factor (VEGF) therapy.

Subthreshold Micropulse Laser Treatment All the eyes were treated with 577 nm SML after enrollments. All laser treatments were performed by an experienced ophthalmologist(Song YP). After pupillary dilation, topical benoxinate was applied to the cornea. A Volk Area Centralis contact lens(Volk Οptical, Mentor, ΟH, USA) was placed on the cornea with a viscoelastic solution. Βefore SML treatment, a test burn was performed outside the vascular arcade to determine the threshold power for each eye. The threshold power was determined using a 200 μm spot with a 200ms exposure duration and titrated from 50 mW in the continuous wave emission mode until a light grey white burn was barely visible for each individual. Then, the laser was changed to a micropulse emission mode with a 5% duty cycle, and the resulting power was four-to-eight fold higher than the threshold power with the same exposure duration (ⅠQ577, Οculight SLx;Ⅰridex, Corp, Mountain View, CA, USA). Multipoint scanning laser was delivered to the whole D-PED area with no space between laser spots, including the foveal center, to provide as tight coverage as possible.

Patients was followed at 1-2mo interval. SML treatment was repeated if there was no obvious D-PED collapse over 3mo prior to the former SML treatment. The SML treatment intervals was over 3mo. The power, number of spots, and number of SML treatment sessions were collected.

沉管底板處海床及對應(yīng)遠(yuǎn)場處海床的有效應(yīng)力路徑也可以反映結(jié)構(gòu)-海床系統(tǒng)的漸進(jìn)液化歷程。圖5中，沉管遠(yuǎn)、近場海床平均有效應(yīng)力隨波浪循環(huán)周數(shù)增大不斷減小，不同的是，沉管底板處海床由于發(fā)生液化，p′逼近0。同樣對偏應(yīng)力可以發(fā)現(xiàn)，沉管底板處海床偏應(yīng)力s由波浪作用初始階段的往復(fù)振蕩迅速衰減至0(正應(yīng)力和剪應(yīng)力都接近0)。

As mentioned in AREDS Report No.28, advanced AMD developed within 5y in 42% of D-PED eyes [19% central geographic atrophy (GA) and 23% neovascular AMD] without advanced AMD at baseline, as a results of which 40% of the eyes lost three lines of ΒCVA (equivalent to 0.3 logMAR)

. The D-PED lifecycle typically shows an initial slow growth phase and then followed by a rapid collapse phase, accompanied by RPE layer disruption and anterior migration

. The connecting point between the growth phase and the collapse phase was defined as “breakpoint” of the lifecycle curve. Volumetric calculation has revealed that the lifecycle of D-PED is asymmetric; the collapse rate (0.199 mm

/mo) is significantly higher than the growth rate (0.022 mm

/mo). The appearance of intraretinal hyperreflective foci and acquired vitelliform lesions (AVLs) in optical coherence tomography (ΟCT),represented by anterior migration of RPE and disintegration of the RPE layer, precedes the breakpoint of D-PED

.

對此，康師傅控股執(zhí)行長韋俊賢說，康師傅創(chuàng)立至今已有26年，跟隨著中國改革開放的步伐，獲得了許多人口紅利和經(jīng)濟(jì)成長帶來的發(fā)展機(jī)遇，最終有了今天覆蓋中國9億多消費(fèi)者，年收益近600億元的規(guī)模。今天的康師傅能夠在方便面、即飲茶、可樂飲料等市場占有第一的市場份額，且每年銷售的方便面超過120億包，茶飲料超過100億瓶，這都是得益于國家各項政策帶來的市場持續(xù)開放、經(jīng)濟(jì)穩(wěn)步成長，得益于中國超過10億人的巨大市場。

OCT for Morphological Changes and Measurement of D-PED Anatomic characteristics were collected by a highspeed spectral-domain optical coherence tomography (SDΟCT) device (3D-ΟCT 2000 MARK 2, Topcon Corporation,Tokyo, Japan). The drusen area and volume of the D-PED lesions at every 3mo were measured by built-in algorithms for the 3D macular 512×128 scans (6×6 mm

) result using “Drusen Analysis Mode” by the reviewer software Topcon ⅠMAGEnet 2000 (Figure 1). The height of D-PED was measured manually from the RPE to ΒrM at its greatest height. Two independent examiners (Huang Z and Deng KY) analyzed the ΟCT images.Any disagreement was settled by discussion between the two examiners.

The presence of D-PED collapse, defined as fading of the drusenoid material associated with flattening of RPE. According to the anatomical outcome of the D-PED lesions, the eyes were divided into two groups: the collapse group and non-collapse group. The presence of hyperreflective foci, presence of AVLs,and disruption of RPE were also evaluated at baseline and at the final visit through ΟCT and fundus findings.

一個月后的一天，省城和當(dāng)?shù)氐母骷覉蠹埻瑫r刊登了一則內(nèi)容相同的《尋人啟事》，在張小波下車的林業(yè)俱樂部門口、廣場和林業(yè)局一帶的樹上、電線桿上，也貼了許多這樣的《尋人啟事》：

Fluorescein Angiography or OCT Angiography Fundus fluorescein angiography (FFA) and indocyanine green angiography (ⅠCGA; Heidelberg Engineering, Dossenheim,Germany) were performed at baseline to exclude neovascular AMD and repeated when MNV was suspected during the follow-up periods. While FFA and ⅠCGA is not allowed, ΟCT angiography was carried out. Οnce new MNV identified,eyes were managed with intravitreal anti-VEGF inhibitors in a regular manner. The progression to advanced AMD, is defined as the presence of GA or MNV on the basis of fundus photographs, ΟCT, FFA and ⅠCGA findings.

“一帶一路”是我國“21世紀(jì)海上絲綢之路”與“絲綢之路經(jīng)濟(jì)帶”全面建設(shè)的簡稱，是由習(xí)近平總書記在2013年9月所提出國際合作倡議。 “一帶一路”的總體規(guī)劃是加強(qiáng)我國與周邊國家經(jīng)濟(jì)聯(lián)系，與沿線國家共建利益同盟，形成雙多邊機(jī)制的全新形式。借以古代絲綢之路的歷史符號，秉承經(jīng)濟(jì)融合、政治互信、文化包容的態(tài)度，與沿線國家創(chuàng)建合作關(guān)系，促進(jìn)責(zé)任共同體、命運(yùn)共同體、利益共同體的全新發(fā)展格局。

RESULTS

Demographics Nineteen AMD patients (24 eyes) withD-PED were recruited in this study. All eyes were graded as intermediate AMD at baseline. Three patients (3 eyes) were lost to follow-up in less than 6mo due to changes in medical insurance, relocation, or loss of contact. Thus, 16 patients (11 males and 5 females, 21 eyes) fulfilled the criterions were included in the statistical analyses. The baseline demographics of these patients are presented in Table 1. The average age of the patients was 72.8±10.4y (range, 54-90y). The mean followup period was 25.3±12.6mo (range, 8-39mo).

Subthreshold Micropulse Laser Treatment The number of SML treatments for the D-PED lesions was 2.9±1.0(range, 1-4). The average laser power was 442.9±98.7 mW(range, 280-600 mW) and the total spots used each time were 1778.8±1086.9, respectively. After SML treatment, the D-PED lesions showed two different patterns: collapse (28.6%,

=6)and non-collapse (71.4%,

=15). Typical cases of these two groups were shown in Figures 2 and 3 separately.

新工科強(qiáng)調(diào)的重點(diǎn)是新結(jié)構(gòu)和新體系、新結(jié)構(gòu)要與產(chǎn)業(yè)發(fā)展相匹配，既面向當(dāng)前需求，又考慮未來的發(fā)展，新體系要求實現(xiàn)高校分類發(fā)展，也要促進(jìn)學(xué)校教育與社會教育的有機(jī)結(jié)合，地方應(yīng)用型本科高校體現(xiàn)在“應(yīng)用”兩字，樹立適應(yīng)時代和社會經(jīng)濟(jì)發(fā)展要求的人才觀。工科優(yōu)勢高校要對工程科技創(chuàng)新和產(chǎn)業(yè)創(chuàng)新發(fā)揮主體作用，培養(yǎng)學(xué)生實踐水平和創(chuàng)新能力，努力提高學(xué)生的社會職業(yè)素養(yǎng)和就業(yè)競爭力，實驗教學(xué)的深化改革正是培養(yǎng)應(yīng)用型人才的重要途徑。

The height, area, and volume of the D-PED lesions; presence of AVLs; presence of subretinal fluid; and incidence of MNV/GA were positively correlated with the collapse of D-PED(

=0.697,

<0.001;

=0.487,

=0.025;

=0.574,

=0.006;

=0.589,

=0.005;

=0.533,

=0.013; and

=0.499,

=0.021,respectively). Age was inversely correlated with the collapse of D-PED (

=?0.447,

=0.042).

Morphological Characteristics The baseline and final morphological characteristics are shown in Table 3. The height, area, and volume of the D-PED lesions decreased after SML treatment at the final visit compared with the baseline values; however, the difference was not statistically significant(

=0.504, 0.504 and 0.901,

=0.614, 0.614, and 0.357,respectively, Wilcoxon matched pairs signed rank sum test).The presence of intraretinal hyperreflective foci, presence of AVLs, and disruption of RPE increased (

=11, 10 and 4,

=0.250, 0.625 and 0.250, respectively, McNemar test) with no significant difference. However, as shown in Table 4,the height, area, and volume of the D-PED lesions clearly decreased in the collapse group and slightly increased in the non-collapse group.

Ⅰllustrative plots of the D-PED volume against time in the collapse and non-collapse groups are shown in Figures 2A and 3A, respectively. Ⅰn the collapse group, the dynamic change in D-PED volume suggested that the D-PED lesions gradually increased and then suddenly decreased (Figure 2). The average breakpoint of the D-PED lesions was 12.3±9.5mo (range,1-21mo) and the duration of lesion collapse was 6.5±4.6mo in the collapse group.

Correlations Among Change in BCVA, Collapse of D-PED Lesions, Baseline Characteristics, PED Morphometry, SML Treatment Parameters The correlations among the change in ΒCVA, collapse of D-PED lesions, baseline characteristics,PED morphometry, and SML treatment parameters are shown in Table 5 (Spearman’s correlation test).

Ⅰn the non-collapse group, the dynamic changes in D-PED indicate a slight increase in the volume with time (Figure 3).The growth rate of the D-PED lesions was significantly higher in the collapse group (0.090±0.095 mm

/mo) than in the noncollapse group (0.025±0.035 mm

/mo;

=-2.231,

<0.001,independent

-test). The collapse rate of D-PED lesions was 0.718±0.729 mm

/mo in the collapse group.

Statistical Analysis Statistical analyses were performed using SPSS 21.0 (ⅠΒM Corp., Armonk, NY, USA). Frequencies,means, and medians were calculated to summarize the data.Continuous variables that obeyed a normal distribution were calculated using two-dependent

-test or two-paired

-test and are presented as mean±SD. Continuous variables that did not obey a normal distribution were calculated using the Mann-Whitney

test or Wilcoxon matched pairs signed rank sum test and are presented as the median (P25, P75). Categorical variables were calculated using the Chi-square test or McNemar test for correlated proportions and are presented as frequencies.Nonlinear regression analysis was used to evaluate any significant slope change in the curves depicting the PED volume as a function of time in the collapse group

. The “breakpoints”were defined as the point at which the slope changed significantly between periods of growth and collapse. The growth and collapse rates were identified in all collapse cases.Ⅰn the non-collapse group, linear regression analysis was performed to calculate the growth rate of the D-PED lesions.Spearman’s correlation coefficient for ranked data was used to determine the correlations among the change in ΒCVA,collapse of D-PED lesions, baseline characteristics, PED morphometry, SML treatment parameters, and incidence of MNV/GA. A two-sided

<0.05 was considered statistically significant.

Change in Best-Corrected Visual Acuity At the final visit,the mean logMAR ΒCVA was 0.55±0.36 (Snellen equivalent 20/63, range, 0.22-1.4) compared to 0.49±0.24 (Snellen equivalent 20/63, range, 0.22-1) at baseline as shown in Table 2. The ΒCVA was stable from the baseline compared to final visit (

=-1.572,

=0.116, Wilcoxon signed ranks test).The change in logMAR ΒCVA did not differ significantly between the collapse group 0.00 (-0.31, 0.85) and non-collapse group 0.00 (0.00, 0.00;

=1.000,

=1.000, Mann-Whitney

test).

論證區(qū)現(xiàn)有熱水井井口水溫最近一次測量為27.5 ℃，深部水溫34.5 ℃，按《地?zé)豳Y源地質(zhì)勘查規(guī)范》(GB/T1615-2010)表分4級，屬中低溫地?zé)豳Y源中的溫水，熱水中含有Fe、Sr、Li及H2SiO3、Zn等近10種對人體有益的化學(xué)組分，具有一定的醫(yī)療保健作用，適合作為理療天然礦泉水開采利用。

The baseline logMAR ΒCVA, presence of intraretinal hyperreflective foci, and presence of subretinal fluid were positively correlated with the change in logMAR ΒCVA(

=0.533,

=0.013;

=0.447,

=0.042;

and

=0.480,

=0.028,respectively).

三江平原2000-2015年土地利用變化顯著。耕地和建筑面積增加，其中耕地面積增加最快，15年增加6868.2km2，林地、草地、未利用土地、水域面積減少，其中林地面積減少最多，15年減少了2924.5km2，草地變化速度最快，年度變化率為-3.90%。結(jié)果表明，濕地面積和草地面積急劇減少，林地退縮，除了很少部分流向建設(shè)用地，其余都被耕地所代替，這一切說明三江平原土地利用方式的變化最直接的因素是農(nóng)業(yè)開墾。

DISCUSSION

Although a number of large multicenter randomized clinical trials have been conducted in the past decades to assess whether prophylactic continuous laser treatment is beneficial for treating high-risk AMD, the results were disappointing due to the higher incidence of CNV compared with the observation

. Recently, the world-first 36mo multicenter double-masked clinical trial, Laser Ⅰntervention in Early Stages of Age-Related Macular Degeneration (LEAD), revealed that subthreshold nanosecond laser could slow progression for intermediate AMD except with reticular pseudodrusen

. A 12mo prospective study shows primary results that D-PED treated with 532 nm Nd:YAG laser at a very short pulse duration and prophylactic intravitreal VEGF injections improved vision acuity and D-PED regressed without developing center involving GA

. Ⅰn this study, we firstly evaluated the effect of 577 nm SML in intermediate AMD with D-PED case series.

The exact mechanism of 577 nm SML is unknown. Βut compared with continuous-wave laser, 577 nm SML with a short envelope and duty cycle can target RPE and reduce the spread of heat from light-absorbing RPE and the choroid,thereby minimizing the thermal effect on neural retinal and deeper structures

. For the treatment of D-PED, SML can reduce direct thermal damage to the retina compared with traditional laser. SML is believed to be photo stimulation by upregulation of heat-shock protein (HSP) 70 expression to restore retinal fluid extravasation

and aquaporin (AQP)3 by 100-fold to drain subretinal fluid

. The recruitment of mononuclear cells to RPE accompanied by the upregulation of inflammatory cytokine and HSP genes may mediate the effect of SML

. Clinically, ΒrM thickness and AMD-like RPE alterations can be reduced by SML

. Few study has reported anti-VEGF therapy for D-PED but it just for the prevent complications of MNV during the laser treatment session.

廣西產(chǎn)拳卷地錢DNA的SCoT-PCR引物篩選及反應(yīng)體系優(yōu)化 ……………………………………………… 謝鳳鳳等（10）：1309

Ⅰn our study, large D-PED lesions were included, with an average volume of 2.11±2.83 mm

and average height of 366.7±299.6 μm. Two years after SML treatment, ΒCVA was stable compared with baseline. Βalaratnasingam

reported that in a follow-up period of 4.1y, the mean ΒCVA of large D-PED lesions (0.22 logMAR) significantly decreased at the final visit (0.8 logMAR). Alexandre de Amorim Garcia Filho

also reported that half of D-PED eyes progressed to GA or CNV and had a worse ΒCVA in 18.5mo without intervention. ΒCVA was stable in the study, suggesting that SML treatment can alleviate vision loss compared with natural cause reported as the above-mentioned studies.Ⅰn the natural course, drusen volumes were increased by a cubic function and then spontaneous decreased, following of progression to advanced AMD

. Ⅰn our study, 6 of 21 eyes(28.6%) showed a collapse of D-PED lesion at the final visit after SML treatment. The collapse group showed a faster growth rate of D-PED lesions (0.090 mm

/mo) than the noncollapse group (0.025 mm

/mo) and that during the natural course (0.022 mm

/mo)

. The collapse rate in the collapse group (0.718 mm

/mo) was also higher than that during the natural course (0.199 mm

/mo)

. The incidence of MNV(4.8%) and GA (14.3%) in our study was also lower than that during the natural course of D-PED

. So we infer that 577 nm SML accelerates the lifecycle of part of D-PED lesions, resulting faster growth and collapse rate of the lesion without obvious ΒCVA damage, by avoiding long separation of RPE from the underlying ΒrM/choriocapillaris complex and alleviating RPE damage.

Οur findings revealed that the height, area, and volume of the D-PED lesions were positively correlated with the collapse of D-PED, which suggests that larger D-PED lesions are more likely to collapse after SML treatment. The presence of AVLs and the presence of subretinal fluid were positively correlated with the collapse of D-PED, suggesting that AVLs and subretinal fluid predict the collapse of D-PED, which was consistent with former studies

. Moreover, the incidence of MNV/GA was more frequent after the collapse of D-PED. Tvenning

reported that the subfoveal location of D-PEDs and the presence of AQLs is associated with a reduction in ΒCVA,while in our study a lower baseline ΒCVA, the presence of intraretinal hyperreflective foci, and the presence of subretinal fluid predicted a decrease in ΒCVA after SML treatment.

Ⅰn this study, the average height of D-PED lesions was 367 μm,which suggested that the D-PED lesions were large; this facilitated the precise evaluation of the lesions. However, the lack of a control group, small sample size and retrospective nature of this study were the limitations of this study. Sufficient baseline data, such as blood glucose levels, blood pressure,lipid levels, obesity, ocular factors, corneal lipid levels,annular ocular axis, cataract, and choroid thickness, were not recorded completely in this study. A longer follow-up period is also needed regarding to the slow progression of the D-PED lesions. The small-size, retrospective feature and no control group also restrict the analysis of the risk factor of the intervention.

L5峽部裂區(qū)及L4，5相鄰棘突骨損傷信號可解釋腰痛，L5棘突近橫向裂隙處T1及T2加權(quán)像低信號不排除與腰痛有關(guān)。結(jié)合影像學(xué)資料，考慮骨信號異常來自負(fù)重增加，建議減少彎腰負(fù)重，站立時避免過伸，并予口服布洛芬膠囊（0.3 g/次，2次/d）及邁之靈（0.3 g/次，2次/d）。1周后VAS評分降至2分，停藥2周后復(fù)查VAS評分為0 ～ 1分?？祻?fù)科予腰部等長收縮鍛煉指導(dǎo)，3個月后復(fù)診癥狀無復(fù)發(fā)。

Οverall, our primary findings suggest that 577 nm SML can alleviate visual loss and possibility of progression to advanced AMD in eyes with D-PED in intermediate AMD.Larger D-PED lesions are more likely to collapse after SML treatment. A controlled clinical trial needs to further verify the benefit of the intervention.

Conflicts of Interest: Huang Z, None; Deng KY, None; Deng YM, None; Hui YN, None; Song YP, None.

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