Assessment of Vitreous Structure and Visual Function after Neodymium:Yttrium–Aluminum–Garnet Laser Vitreolysis

Assessment of Vitreous Structure and Visual Function after Neodymium:YttriumeAluminumeGarnet Laser Vitreolysis Justin H. Nguyen, BA,1 Jeannie Nguyen-Cuu, BA,1 Fei Yu, PhD,2 Kenneth M. Yee, BS,1 Jonathan Mamou, PhD,3 Ronald H. Silverman, PhD, FARVO,4 Jeffrey Ketterling, PhD,3 J. Sebag, MD, FARVO1,2,5 Purpose: Neodymium:yttriumealuminumegarnet (Nd:YAG) laser treatment is performed on vitreous floaters, but studies of structural and functional effects with objective outcome measures are lacking. This study evaluated Nd:YAG laser effects by comparing participants with vitreous floaters who previously underwent laser treatment with untreated control participants and healthy persons without vitreous floaters using quantitative ultrasonography to evaluate vitreous structure and by measuring visual acuity and contrast sensitivity function to assess vision. Design: Retrospective, comparative study. Participants: One eye was enrolled for each of 132 participants: 35 control participants without vitreous floaters, 59 participants with untreated vitreous floaters, and 38 participants with vitreous floaters previously Nd:YAG-treated. Of these, 25 were dissatisfied and sought vitrectomy; 13 were satisfied with observation. Methods: The 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-39) to assess participant visual well-being, quantitative ultrasonography (QUS) to measure vitreous echodensity, and best-corrected visual acuity (BCVA) and contrast sensitivity function (CSF) to evaluate vision. Main Outcome Measures: Results of NEI-VFQ-39, QUS, BCVA, and CSF. Results: Compared with control participants without vitreous floaters, participants with untreated vitreous floaters showed worse NEI-VFQ-39 results, 57% greater vitreous echodensity, and significant (130%) CSF degradation (P < 0.001 for each). Compared with untreated eyes with vitreous floaters, Nd:YAG-treated eyes had 23% less vitreous echodensity (P < 0.001), but no differences in NEI-VFQ-39 (P ¼ 0.51), BCVA (P ¼ 0.42), and CSF (P ¼ 0.17) results. Of 38 participants with vitreous floaters who previously were treated with Nd:YAG, 25 were dissatisfied and seeking vitrectomy, whereas 13 were satisfied with observation. Participants seeking vitrectomy showed 24% greater vitreous echodensity (P ¼ 0.018) and 52% worse CSF (P ¼ 0.006). Multivariate linear regression models confirmed these findings. Conclusions: As a group, participants previously treated with Nd:YAG laser for bothersome vitreous floaters showed less dense vitreous, but similar visual function as untreated control participants with vitreous floaters. Because some treated eyes showed less dense vitreous and better visual function than those of untreated control participants, a prospective randomized study of Nd:YAG laser treatment of vitreous is warranted, using uniform laser treatment parameters and objective quantitative outcome measures. Ophthalmology 2019;-:1e10 ª 2019 by the American Academy of Ophthalmology

Vitreous floaters are visual phenomena described as dark linear structures often with nodularities, at times accompanied by glass-noodle structures. Floaters are displaced with eye or head movement, featuring a lag and, at times, a damping effect, coming to rest with oscillation. Vitreous floaters are most disturbing in bright ambient lighting (outdoors, indoor fluorescent lighting, and light-emitting diode phone and computer screens) and during ocular saccades, causing difficulty reading because of horizontal displacement of vitreous opacities that enter the optical axis.1e3 The most common causes of vitreous floaters are posterior vitreous detachment (PVD)4,5 and myopic vitreopathy,6,7 where vitreous gel liquefaction accompanied ª 2019 by the American Academy of Ophthalmology Published by Elsevier Inc.

by collagen fibril aggregation form structures within the vitreous body that scatter light and cast shadows on the retina. After PVD, the dense collagen matrix of the posterior vitreous cortex (which is no longer spherical, but rather irregular in contour) interferes with photon transmission to the retina, a phenomenon detectable by measuring ocular straylight.8 Posterior vitreous detachment has been shown to degrade contrast sensitivity function (CSF) significantly.9 With advancing age, vitreous echodensity increases even more and CSF degrades further.10 The management of patients with bothersome vitreous floaters is controversial. Although many individuals with https://doi.org/10.1016/j.ophtha.2019.06.021 ISSN 0161-6420/19

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Ophthalmology Volume -, Number -, Month 2019 vitreous floaters are not sufficiently disturbed to be considered to have a clinically significant condition, others experience substantial diminution in quality of life,11,12 likely because of degradation in CSF.5,6,9,10 In such instances, vitreous floaters are more than just a nuisance and should be considered a disease,12 most appropriately called Vision Degrading Myodesopsia. Treatment options include observation alone, neodymium:yttriumealuminumegarnet (Nd:YAG) laser vitreolysis,13e18 and pars plana vitrectomy.5,6,19e21 Although reports have been made of increased protein content, refractive index, and viscosity of vitreous after Nd:YAG laser treatment,22 no definitive clinical studies of Nd:YAG effects have been carried out, and to date, reports of efficacy are mixed. Although Tsai et al14 claimed 100% success in 15 patients, no objective measurements were performed. In 2002, Delaney et al15 found 33% efficacy with Nd:YAG laser compared with 93% efficacy with vitrectomy, but again, no objective outcome measures were made. Shah and Heier16 recently found symptomatic improvement in only half of 52 eyes undergoing Nd:YAG laser treatment of Weiss rings alone, and only by 54% compared with before treatment, raising concerns over the promulgation of this form of therapy.23 This disappointingly limited efficacy may be the result of the photodisruptor effects of Nd:YAG lasers that cannot ablate vitreous structures, and instead only transform large particles into smaller (and necessarily more numerous) structures.24,25 Indeed, previous studies report an increased number of floaters after Nd:YAG laser vitreolysis.26 Other reported complications are elevated intraocular pressure and glaucoma,27 accelerated cataract progression,28,29 posterior capsule defects requiring cataract surgery,30,31 retinal injury,32,33 retinal detachment,34 and visual field scotomata.35 Thus, it is important that efficacy be demonstrated before widespread use of Nd:YAG treatment of vitreous opacities causing floaters. This investigation was undertaken to evaluate eyes previously treated with Nd:YAG laser vitreolysis using objective quantitative measures of vitreous structure and visual function. Comparisons with control participants without vitreous floaters and control participants with vitreous floaters but without a history of Nd:YAG treatment, were performed. Given that the Nd:YAG laser treatments were performed elsewhere in the community without a uniform standardized protocol, this study provides a real-world perspective on the issue.

Methods This retrospective comparative study adhered to the tenets of the Declaration of Helsinki. All patients signed an informed consent form approved by the institutional review board of St. Joseph Hospital, Orange, California, and completed the 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-39) to assess visual well-being. No patients had a prior history of vitreoretinal pathologic features or surgery except for 2 cases of uncomplicated retinal tears treated with successful prophylactic retinopexy. Asteroid hyalosis was excluded from this study, and only 1 eye was enrolled per participant.

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Participants The study population consisted of 132 eyes in 132 individuals (82 men, 50 women; mean age  standard deviation, 5613 years). Most participants (101/132 [76.5%]) were phakic without lens opacification. The 31 pseudophakic eyes all had monofocal intraocular lenses; multifocal intraocular lenses were excluded because evidence exists that they may degrade CSF.36,37 Furthermore, an intact posterior capsule was present in only 11 participants, suggesting that this had little or no effect on the evaluation of CSF in this study. Posterior vitreous detachment was present in 89 of 132 participants (67%). Myopia, defined as a spherical equivalent of e3 diopters (D) or more, was present in 70 of 132 participants (53%). Of these 132 participants, 97 had vitreous floaters and 35 were healthy age-matched control participants who were volunteer students, staff, and patient family members. There were no differences in these 2 groups related to age (P ¼ 0.22), prevalence of myopia (P ¼ 0.41), or visual acuity (P ¼ 0.26; see Table 1). The group with vitreous floaters included more participants with pseudophakia than the control participants did (30% vs. 6%), but multivariate linear regression analyses found no influence by lens status (see below). In the 97 participants with vitreous floaters, 37 had only PVD without myopia, 11 had only myopic vitreopathy without PVD, 36 had PVD and myopic vitreopathy, and 13 eyes had no PVD or myopic vitreopathy. Understandably, PVD was more prevalent in participants with vitreous floaters than in healthy control participants (P < 0.001; Table 1), but multivariate linear regression analyses showed that this did not influence other findings (see below). Of the 97 eyes with vitreous floaters, 38 had a history of previously having undergone Nd:YAG laser vitreous treatment(s), constituting the entire group of patients evaluated at this center from 2014 through March 2019 with a history of having undergone this treatment. The remaining 59 participants with vitreous floaters were evaluated during that same period, but had no history of Nd:YAG laser vitreous treatments and were selected to be agematched control participants for the treatment group. There were no differences between these groups with respect to age (P ¼ 0.74), prevalence of myopia (P ¼ 0.41), prevalence of pseudophakia (P ¼ 0.17), or visual acuity (P ¼ 0.42; Table 1). Because these treatments were performed elsewhere, no reliable documentation is available concerning laser type, laser parameters, number of treatment sessions, or number of laser applications per treatment session. Of the 38 participants treated with Nd:YAG laser therapy before presentation, 25 were dissatisfied with the results and elected to undergo vitrectomy. Based on that choice, these participants were classified as seeking vitrectomy, whereas the remaining 13 participants who chose observation were classified as being satisfied with observation. There were no differences between the 2 groups in age (P ¼ 0.70), visual acuity (P ¼ 0.06), or prevalences of pseudophakia (P ¼ 1.00), PVD (P ¼ 0.29), or myopia (P ¼ 0.17).

Vitreous Structure Vitreous structure and the presence of PVD were evaluated by quantitative ultrasonography (QUS) using a customized 15-MHz probe (AVISO; Quantel Medical, Claremont-Ferand, France), as described previously.38 The scan orientation was horizontal through the macula. Three parameters were measured: the sum of the square of the acoustic values within the central and posterior vitreous divided by the area of measurement (energy, E), the percentage of the central and posterior vitreous filled by echogenic clusters of more than 50 pixels or 0.069 mm (P50),

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Vitreous Nd:YAG Structure and Function Effects

Table 1. Vitreous Floater Eyes Compared with Control Eyes Untreated Treated Floater Eyes Floater Eyes (n [ 59) (n [ 38) Clinical characteristics Age (yrs), mean  SD Myopia, no (%) Pseudophakia, no (%) PVD, no (%) Testing, mean  SD BCVA (logMAR) CSF (Weber index) QUS

Control Eyes (n [ 35)

5714

5613

5215

35 (59)

19 (50)

16 (46)

21 (36)

8 (21)

2 (6)

49 (83)

24 (63)

16 (46)

0.120.16

0.100.09

P Value

0.22* 0.74y 0.41z 0.41x 0.003z 0.17x <0.001z 0.032x

0.080.10

0.26* 0.42y 4.62.7 3.91.6 2.00.5 <0.001* 0.17y 872.6270.8 671.5177.5 553.9132.2 <0.001* <0.001y

NEI-VFQ-39 score Composite

78.213.1

76.511.8

87.27.7

General vision

70.114.4

68.512.1

80.211.5

Near vision

73.619.5

73.815.3

85.012.2

Distance vision

76.819.6

75.016.0

87.410.9

Driving

77.318.9

80.215.3

92.07.1

<0.001* 0.51y <0.001* 0.58y 0.003* 0.96y 0.003* 0.63y <0.001* 0.43y

BCVA ¼ best-corrected visual acuity; CSF ¼ contrast sensitivity function; logMAR ¼ logarithm of the minimum angle of resolution; NEI-VFQ39 ¼ 39-item National Eye Institute Visual Function Questionnaire; PVD ¼ posterior vitreous detachment; QUS ¼ quantitative ultrasound composite index; SD ¼ standard deviation. Comparing all groups, there were no differences in age (P ¼ 0.22) and the prevalence of myopia (P ¼ 0.41). Pseudophakia and PVD were more prevalent in eyes with vitreous floaters (P ¼ 0.003 and P < 0.001, respectively), but multivariate linear regression analyses showed that this had no influence on other findings (see text and Table 2). Visual wellbeing (NEI-VFQ-39 composite and selected subscales) was worse in those with vitreous floaters, although BCVA was similar in both groups. Vitreous echodensity (QUS) was 43% greater (P < 0.001) and CSF was 118% worse (P < 0.001) in eyes with vitreous floaters, probably accounting for dissatisfaction with vision. Although QUS was less in the neodymium:yttriumealuminumegarnet laser-treated group compared with the untreated floaters group (P < 0.001), there were no differences in BCVA (P ¼ 0.42), CSF (P ¼ 0.17), or NEI-VFQ-39 composite (P ¼ 0.51), and all NEI-VFQ-39 subscales, suggesting that as a group, Nd:YAG laser-treated eyes had structural differences in vitreous, but not better visual function. *Analysis of variance for comparisons across all 3 groups. y t-Test for comparisons between treated and untreated floaters groups. z Fisher exact test for comparisons across all 3 groups. x Fisher exact test for comparisons between treated and untreated floaters groups.

and the mean of the acoustic values divided by the area of the central and posterior measurement area (mean, M).38 A combination of these parameters was calculated as the QUS composite score: E / 2 þ (M  10) þ (P50  100). Spectraldomain OCT (Optos, Marlborough, MA) confirmed the presence of PVD whenever the posterior vitreous cortex could be visualized and ruled out the presence of vitreomaculopathy.

Table 2. Multivariate Linear Regression Comparisons of Eyes with Vitreous Floaters to Control Eyes Testing BCVA (logMAR) Untreated floaters vs. control Treated floaters vs. control Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic CSF (Weber index) Untreated floaters vs. control Treated floaters vs. control Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic QUS (composite) Untreated floaters vs. control Treated floaters vs. control Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic NEI-VFQ-39 (composite) Untreated floaters vs. control Treated floaters vs. control Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic

95% Confidence Interval

P Value

0.05

e0.01 to 0.10

0.13

0.02

e0.04 to 0.08

0.55

0.002 e0.01 e0.03

0.000e0.004 e0.07 to 0.05 e0.08 to 0.03

0.035 0.71 0.34

2.44

1.53e3.35

<0.001

1.79

0.86e2.72

<0.001

0.04 0.12

0.01e0.07 e0.84 to 1.08

0.017 0.80

e0.29

e1.17 to 0.58

0.51

309.0

216.6e401.3

<0.001

101.8

7.7e195.9

7.1 e13.9 e67.7

0.000e0.004 e111.3 to 83.5 e156.8 to 21.4

<0.001 0.78 0.14

e10.0

e15.2 to e4.9

<0.001

e11.6

e16.9 to e6.4

<0.001

Slope Estimate

0.22 e3.3 4.2

0.03e0.40 e8.7 to 2.1 e0.7 to 9.2

0.034

0.023 0.23 0.095

BCVA ¼ best-corrected visual acuity; CSF ¼ contrast sensitivity function; logMAR ¼ logarithm of the minimum angle of resolution; NEI-VFQ39 ¼ 39-item National Eye Institute Visual Function Questionnaire; PVD ¼ posterior vitreous detachment; QUS ¼ quantitative ultrasound composite index. BCVA was no different in treated and untreated patients as compared with control participants. However, CSF, QUS, and NEI-VFQ-39 score all were significantly different in treated and untreated patients with floaters compared with control participants. There was no influence of lens status or PVD on BCVA, CSF, QUS, or NEI-VFQ-39 findings.

Visual Function Best-corrected visual acuity (BCVA) was measured using standard Snellen charts expressed as the logarithm of the minimum angle of resolution. Contrast sensitivity function was measured using the Freiburg acuity contrast test (FrACT) with automated software using a light-emitting diode display monitor. The FrACT uses a large tumbling monochromatic Landolt C optotype (3.3 diameter; 20/200), where the gap of the C can have 1 of 8 orientations. At varying contrast levels and a spatial frequency of 5 cycles per degree, FrACT uses psychometric methods combined with antialiasing and dithering to provide an automated, paced, accurate measurement of CSF.39e43 All patients were dark adapted, and mesopic lighting conditions were simulated with the luminance of the light-emitting diode monitor set to maximum brightness. At least 1 m of viewing distance is recommended by the test

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Ophthalmology Volume -, Number -, Month 2019 Table 3. Comparison of Participants Previously Treated with Neodymium:YttriumeAluminumeGarnet Laser Therapy Seeking Vitrectomy with Participants Satisfied with Observation Neodymium:YttriumeAluminumeGarnet Laser Treated Seeking Vitrectomy (n ¼ 25) Clinical characteristics Age, mean  SD Myopia, no. (%) Pseudophakia, no. (%) PVD, no. (%) Testing, mean  SD BCVA (logMAR) CSF (Weber index) QUS NEI-VFQ-39 score Composite General vision Near vision Distance vision Driving

Satisfied with Observation (n ¼ 13) P Value

5515

579

0.70*

10 (40)

9 (69)

0.17y

5 (20)

3 (23)

1.00y

14 (56)

10 (77)

0.29y

0.120.09

0.060.07

0.058*

4.41.7

2.90.7

0.006*

719.6180.0

578.8135.1

0.018*

74.011.9 67.512.5 71.016.6 71.016.8 79.315.9

81.310.5 70.511.3 79.310.8 82.711.6 81.814.6

0.068* 0.48* 0.11* 0.031* 0.64*

BCVA ¼ best-corrected visual acuity; CSF ¼ contrast sensitivity function; logMAR ¼ logarithm of the minimum angle of resolution; NEI-VFQ-39 ¼ 39-item National Eye Institute Visual Function Questionnaire; PVD ¼ posterior vitreous detachment; QUS ¼ quantitative ultrasound composite index; SD ¼ standard deviation. Comparing participants seeking vitrectomy with participants satisfied with observation, there were no differences in age or the prevalence of myopia, pseudophakia, or PVD. Participants seeking vitrectomy understandably trended to worse visual well-being (P ¼ 0.068), a consideration that was probably limited by small sample sizes. Subscale analyses found that distance vision was better in treated participants who were satisfied with observation (P ¼ 0.03), whereas the remaining subscales (general vision, near vision, and driving) were not, although there was a trend for the near vision subscale (P ¼ 0.11). Although BCVA was the same between the 2 groups, there was 24% greater vitreous echodensity (QUS finding) in the group seeking vitrectomy (P ¼ 0.018), probably accounting for the observed 52% greater degradation in the CSF in these participants (P ¼ 0.006). Marginal differences for BCVA (P ¼ 0.058) are probably the result of small sample sizes. *Student t test. y Fisher exact test.

developers, so in this study, the distance was 2.9 m for each participant. Screen resolution (pixels per millimeter) was measured manually with a ruler and was calculated by the software for visual angle determination. The Weber index (%W), defined as the relationship between the brightest luminance and lowest luminance, was calculated as: %W ¼ 100%  ðmaximum luminance  minimum luminanceÞ= maximum luminance; where higher %W represents worse CSF. This testing paradigm has been used previously to evaluate the effects of PVD9 and aging vitreous,10 as well as the results of vitrectomy for bothersome vitreous floaters and degraded CSF (Vision Degrading

4

Myodesopsia)5,6 and macular pucker.44 Reproducibility of CSF using FrACT at this center was reported previously at 92% in one study,5 with a second study demonstrating repeatability of 89.2% in control participants and 94.4% in participants with vitreous floaters.6

Statistical Analyses Statistical analyses were performed using SAS software version 9.4 (SAS Institute, Inc, Cary, NC). The Fisher exact test was used to compare differences in the prevalence of pseudophakia, myopia, and PVD. Student t test was used to assess mean differences in age, degree of myopia, BCVA, CSF, QUS results, and NEI-VFQ-39 score comparisons between Nd:YAG groups, whereas the analysis of variance was used to assess mean differences among untreated eyes with vitreous floaters, treated eyes with floaters, and control participants without vitreous floaters. Multivariate linear regression modeling was performed to examine differences in BCVA, CSF, NEI-VFQ-39 score, and QUS results among the study groups after adjusting for potential confounders including age, pseudophakia, and PVD status. The outcomes of the regression models were BCVA, CSF, NEI-VFQ-39 score, and QUS results, which were continuous variables, whereas the group variable was the predictor variable.

Results Compared with healthy age-matched control participants, participants with vitreous floaters had worse overall visual well-being (NEI-VFQ-39 composite score; P < 0.001), as well as general vision (P < 0.001), near vision (P ¼ 0.003), distance vision (P ¼ 0.003), and driving (P < 0.001; Table 1). Vitreous echodensity (a QUS finding) was 43% greater (P < 0.001) and CSF was 118% worse (P < 0.0001) in all participants with vitreous floaters. These differences were even greater when comparing those with untreated vitreous floaters with control participants (57% greater QUS results and 130% worse CSF). Multivariate linear regression models showed that these differences remained after adjusting for age, pseudophakia, and PVD status (Table 2). Comparing participants with vitreous floaters who were treated previously with Nd:YAG laser with untreated participants with vitreous floaters (Table 1), vitreous echodensity (a QUS finding) was 23% less in Nd:YAG-treated participants (P < 0.001), but there were no differences in visual well-being (NEI-VFQ-39 score; P ¼ 0.51), visual acuity (BCVA; P ¼ 0.42), or CSF (P ¼ 0.17). Multivariate linear regression models showed that after controlling for age, pseudophakia, and PVD status, there was still a statistically significant difference in vitreous echodensity (P < 0.001), but no differences in NEI-VFQ-39 score (P ¼ 0.57), BCVA (P ¼ 0.3), or CSF (P ¼ 0.18). What is lacking, however, is information concerning vitreous structure and visual function in these participants before Nd:YAG laser treatments. Two subgroups of patients were treated with Nd:YAG laser: 13 patients who were satisfied with the results (satisfied with observation) and 25 patients who were dissatisfied enough to seek vitrectomy. The effects of vitrectomy surgery have been reported previously5,6,9,15,17 and are not the subject of this investigation. The NEI-VFQ-39 score was slightly (P ¼ 0.068) worse in participants who were dissatisfied with the results of laser therapy, consistent with their decision to elect surgery. The lack of statistical significance is probably the result of insufficient power or sample size for this subgroup analysis. Subscale analyses found that distance vision was worse in those seeking vitrectomy (P ¼ 0.031), whereas only near vision trended to significance

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Vitreous Nd:YAG Structure and Function Effects

Table 4. Multivariate Linear Regression Comparisons of Eyes with Floaters Treated with Neodymium:YttriumeAluminumeGarnet Laser Therapy versus Untreated Eyes with Vitreous Floaters Testing BCVA (logMAR) Nd:YAG-treated vs. untreated Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic CSF (Weber index) Nd:YAG-treated vs. untreated Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic QUS (composite) Nd:YAG-treated vs. untreated Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic NEI-VFQ-39 (composite) Nd:YAG-treated vs. untreated Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic

Slope Estimate floaters

floaters

floaters

floaters

95% Confidence Interval

P Value

e0.03 0.002 e0.03 e0.03

e0.09 to 0.03 e0.0004 to 0.005 e0.11 to 0.05 e0.09 to 0.04

0.30 0.093 0.49 0.39

e0.66 0.06 0.12 e0.45

e1.63 to 0.32 0.01e0.10 e1.22 to 1.45 e1.52 to 0.63

0.18 0.015 0.86 0.41

e305.8 to e112.7 3.7e12.6 e159.3 to 105.0 e177.5 to 35.5

e209.2 8.2 e27.1 e71.0

e7.7 to 4.2 0.02e0.51 e11.4 to 3.0 e1.7 to 9.9

e1.7 0.26 e4.2 4.1

<0.001 <0.001 0.68 0.19 0.57 0.035 0.25 0.17

BCVA ¼ best-corrected visual acuity; CSF ¼ contrast sensitivity function; logMAR ¼ logarithm of the minimum angle of resolution; Nd:YAG ¼ neodymium:yttriumealuminumegarnet; NEI-VFQ-39 ¼ 39-item National Eye Institute Visual Function Questionnaire; PVD ¼ posterior vitreous detachment; QUS ¼ quantitative ultrasound composite index. Although vitreous echodensity (QUS finding) was significantly less in treated participants with vitreous floaters (P < 0.001), visual function (BCVA and CSF) was no different in treated versus untreated participants with vitreous floaters. As a consequence, visual well-being (NEI-VFQ-39 score) also was no different in treated versus untreated participants. There was no influence of lens status or PVD on BCVA, CSF, QUS, or NEI-VFQ-39 findings.

(P ¼ 0.11), likely because of insufficient power or sample size for this subgroup analysis. Vitreous echodensity (a QUS finding) was 24% greater (P ¼ 0.018), CSF was 52% worse (P ¼ 0.006), and BCVA was only a little worse (P ¼ 0.058) in participants seeking surgery, possibly because of insufficient power or sample size for attaining statistical significance in this subgroup analysis (Table 3). Multivariate linear regression models were performed by adjusting for potential confounders including age, pseudophakia, and PVD. The results (Tables 4 and 5) confirmed that participants satisfied with observation had better NEI-VFQ-39 results (P ¼ 0.042), superior CSF (P ¼ 0.002), better BCVA (P ¼ 0.037), and less vitreous echodensity (a QUS finding; P ¼ 0.023). One participant was evaluated prospectively before and after Nd:YAG laser treatment to the vitreous. The details of that case report follow as a demonstration of how this approach can be used in future prospective studies.

Case Report A 67-year-old white man with e3.5 D of myopia previously corrected by LASIK sought treatment for bilateral bothersome floaters of 20 months’ duration, worse in the left eye, where floaters suddenly increased 5 months before presentation. Past ocular and medical histories were unremarkable. On physical examination, visual acuity was 20/25 with normal intraocular pressure. Contrast sensitivity function in the left eye was degraded to 5.04 %W (right eye ¼ 1.85 %W). On physical examination, the anterior segment showed mild lenticular opacification. Posteriorly, visual evidence was found of considerable linear and membranous opacities in the central vitreous of the left eye (Fig 1A). Ultrasonography detected PVD (Fig 2A, B), confirmed by OCT. The QUS analysis resulted in energy of 724 AU, a mean of 25.2 AU, and P50 of 1.75 AU, with

a composite QUS score of 789. The patient was advised to try coping with the symptoms before considering surgical intervention. During that time, he chose to go elsewhere and underwent Nd:YAG laser treatments of the vitreous in the left eye, performed on 4 separate occasions, but no details are available concerning the treatments. The patient subsequently returned reporting persistent bothersome vitreous floaters. The BCVA was unchanged at 20/25 and CSF remained degraded. Vitreous examination and scanning laser ophthalmoscopy (Fig 1B) demonstrated vitreous opacities. The QUS analysis quantified vitreous density at 734, very similar to the pretreatment level of 789 (Fig 2C, D).

Discussion Acceptance of Vision Degrading Myodesopsia as a disease has been hindered by the lack of objective quantitative measures with which to distinguish among mild, moderate, and severe cases. The NEI-VFQ-39 is useful in quantifying the impact on general visual well-being, but floater-specific questionnaires may be more telling.45 Sometimes, OCT can detect shadowing by posterior vitreous opacities,46 but this has never been quantified. Ocular straylight measurements may be useful,8 but this parameter is difficult to relate to patient visual function. Quantitative ultrasonography and CSF testing have been shown to provide objective measures with which to gauge disease severity in eyes with vitreous floaters.5,6,10 Using these 3 indices, this study of 38 patients who underwent Nd:YAG laser treatments before presentation found no

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Ophthalmology Volume -, Number -, Month 2019 Table 5. Multivariate Linear Regression Comparisons of Neodymium:YttriumeAluminumeGarnet Laser Therapy-Treated Participants Seeking Vitrectomy with Those Satisfied with Observation Testing BCVA (logMAR) Satisfied vs. dissatisfied Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic CSF (Weber index) Satisfied vs. dissatisfied Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic QUS (composite) Satisfied vs. dissatisfied Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic NEI-VFQ-39 (composite) Satisfied vs. dissatisfied Age (per yr) PVD: present vs. absent Pseudophakic vs. phakic

95% Confidence Interval

P Value

e0.06 0.001 0.01 0.05

e0.12 to e0.004 e0.002 to 0.003 e0.05 to 0.08 e0.02 to 0.13

0.037 0.66 0.66 0.13

e1.63 0.02 0.65 e0.58

e2.63 to e0.62 e0.03 to 0.07 e0.55 to 1.86 e1.86 to 0.69

0.002 0.017 0.80 0.51

e260.5 to e20.2 e1.9 to 9.9 e171.3 to 116.0 e197.0 to 106.9

0.023 0.18 0.70 0.55

0.3e16.1 0.03e0.80 e16.6 to 2.3 e11.3 to 8.7

0.042 0.037 0.13 0.79

Slope Estimate

e140.3 4.0 e27.6 e45.0 8.2 0.42 e7.1 e1.3

BCVA ¼ best-corrected visual acuity; CSF ¼ contrast sensitivity function; logMAR ¼ logarithm of the minimum angle of resolution; NEI-VFQ-39 ¼ 39-item National Eye Institute Visual Function Questionnaire; PVD ¼ posterior vitreous detachment; QUS ¼ quantitative ultrasound composite index. Vitreous echodensity (QUS finding) was significantly less in treated participants who were satisfied with observation as compared with those seeking vitrectomy (P ¼ 0.023). Visual well-being (NEI-VFQ-39, P ¼ 0.042) and visual function (BCVA, P ¼ 0.037; and CSF, P ¼ 0.002) similarly were better in participants satisfied with observation than those seeking vitrectomy. Lens status and PVD did not seem to influence these findings.

differences when compared with 59 untreated control participants with vitreous floaters with respect to visual wellbeing (NEI-VFQ-39 score) and visual function measured by Snellen visual acuity and CSF testing. This is quite interesting, insofar as QUS found 23% less (P < 0.001) vitreous echodensity in treated eyes compared with untreated eyes (Table 1), yet visual function was no different, accounting for no differences in overall visual well-being (NEI-VFQ-39 score) between the 2 groups. This was confirmed in subscale analyses for general vision, near vision, and driving. Because no other ocular pathologic features were present, it is presumed that there were no untoward effects or complications of Nd:YAG laser treatments. However, it should be pointed out that there may be selection bias, in that mostly patients who were dissatisfied after Nd:YAG laser treatment sought evaluation at this center and the results may be influenced by this factor. Indeed, in a small subgroup of patients who were satisfied enough with the results of Nd:YAG laser treatment to elect observation without further treatment, less vitreous echodensity, better visual acuity, and superior CSF were found compared to treated participants who were dissatisfied with the results of laser treatment and sought vitrectomy. How exactly these 2 groups compared prior to Nd:YAG laser treatment with regard to vitreous structure and how this may account for the differences in vision and happiness are currently unknown. Prospective ultrasonography in the case report of a patient who was dissatisfied with the results of Nd:YAG treatment showed a different appearance on QUS after

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Nd:YAG laser treatment than before (Figs 1 and 2), but objective measures found no quantifiable differences in echodensity after Nd:YAG laser treatment. Therefore, it is possible that in many (but perhaps not all) cases, photodisruption created by Nd:YAG laser treatment breaks down larger vitreous particles into smaller structures, altering the appearance on ultrasonography. However, because there are now more particles, the net effect is no change in overall vitreous echodensity, as was observed in the case report. This is corroborated by the observation that there was no improvement in CSF, leaving the patient dissatisfied enough to seek vitrectomy. In fact, in this study, 25 participants were sufficiently dissatisfied with Nd:YAG laser treatment effects that they sought vitrectomy to cure their Vision Degrading Myodesopsia. Future studies with ultrasonography, advanced OCT imaging, dynamic light scattering,47 or a combination thereof should be undertaken to measure average particle sizes and to calculate the number of vitreous particles in situ to clarify this matter further.48 Limitations of this study include the retrospective nature, the aforementioned selection bias, heterogeneity in the intervention group, no accurate information concerning Nd:YAG laser treatment parameters or number of treatments, and CSF measurements that were obtained only in mesopic lightning. It is well known that the impact of vitreous floaters varies from negligible to significant depending on ambient and background lighting. Thus, future studies should examine the relationship of subjective and objective findings in different lighting conditions, similar to

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Vitreous Nd:YAG Structure and Function Effects

Figure 1. A, Scanning laser ophthalmoscopy image obtained on presentation demonstrating a round vitreous opacification in the superonasal macula and a linear area of opacification nasal to the fovea. B, Scanning laser ophthalmoscopy after neodymium:yttriumealuminumegarnet treatments (4 separate sessions), vitreous opacification appears to be located in multiple smaller (compared with Fig 1A) areas centrally and inferonasally.

the use of glare testing for the evaluation of cataracts.49,50 The small sample size comparing participants satisfied with observation and participants seeking vitrectomy also is a limitation, as is the lack of information regarding Nd:YAG laser treatment parameters, making it difficult to draw definitive conclusions concerning laser treatments.

Nonetheless, the present study does provide a real-world perspective on the issue and stands as a strong call for a randomized, prospective trial with uniform Nd:YAG laser parameters, enabling scientific analysis. Furthermore, it is imperative that objective, quantitative outcome measures be used.

Figure 2. A, B, Ultrasonography obtained at presentation demonstrating vitreous echodensity in the central and posterior vitreous body. C, D, Ultrasonography obtained after neodymium:yttriumealuminumegarnet laser treatments (4 sessions) demonstrating smaller (compared with A and B) areas of vitreous echodensity, with possibly more foci of vitreous density centrally and posteriorly.

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Ophthalmology Volume -, Number -, Month 2019 In conclusion, the results of this retrospective, comparative study show that many patients who have undergone Nd:YAG laser treatment to vitreous opacities remain symptomatic and are still sufficiently bothered by floaters to seek further medical attention. Thus, this treatment is not a panacea and further research needs to be undertaken to determine if certain types of vitreous opacities are amenable to Nd:YAG laser treatment, whereas others are not responsive. Treatment parameters such as the number of laser applications, laser power settings, focusing lens type, number of treatment sessions, and other treatment aspects need to be defined. It is notable that the results of this study found some patients who have undergone Nd:YAG laser treatment are satisfied with observation. Although the status of their pretreatment vitreous structure and visual function is not known, it is possible that these improved after Nd:YAG laser treatment, indicating a need for prospective, randomized investigations using objective measures of vitreous structure and visual function in the same participants before and after Nd:YAG laser treatments of vitreous. The primary outcomes for such a study would be quantitative quality-oflife measures, quantification of vision by measuring visual acuity and CSF (or similar measurements), and quantitative ultrasonography (or other quantitative objective imaging method) to evaluate vitreous structure before and after Nd:YAG laser treatments performed with uniform laser parameters to eliminate heterogeneity in the intervention group. The size of such a study will depend on F-power testing and which outcome measures will be used. The results of the study presented herein predict that NEI-VFQ-39 testing will have only approximately a 10% difference, thus requiring a larger cohort; that QUS will have a little more than a 15% difference; and that CSF testing will show a more than 50% difference between treated and untreated participants, requiring the smallest cohort. Ideally, such studies also should compare the findings with those of patients undergoing other forms of therapy, such as limited vitrectomy5,6,20 and perhaps pharmacologic vitreolysis51e53 to identify which treatments may be most suitable for different patients.

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5. Sebag J, Yee KM, Wa CA, et al. Vitrectomy for floaters: prospective efficacy analyses and retrospective safety profile. Retina. 2014;34:1062e1068. 6. Sebag J, Yee KMP, Nguyen JH, Nguyen-Cuu J. Long-term safety and efficacy of limited vitrectomy for vision degrading vitreopathy resulting from vitreous floaters. Ophthalmol Retina. 2018;2:881e887. 7. Gale J, Ikuno Y. Myopic vitreopathy. In: Sebag J, ed. Vitreous d in Health and Disease. New York: Springer ScienceþBusiness Media; 2014:113e129. 8. Castilla-Marti M, van den Berg TJ, de Smet MD. Effect of vitreous opacities on straylight measurements. Retina. 2015;35(6):1240e1246. 9. Garcia GA, Khoshnevis M, Yee KMP, et al. Degradation of contrast sensitivity function following posterior vitreous detachment. Am J Ophthalmol. 2016;172:7e12. 10. Garcia GA, Khoshnevis M, Yee KMP, et al. The effects of aging vitreous on contrast sensitivity function. Graefes Arch Clin Exp Ophthalmol. 2018;256(5):919e925. 11. Wagle AM, Lim WY, Yap TP, et al. Utility values associated with vitreous floaters. Am J Ophthalmol. 2011;152(1):60e65. 12. Sebag J. Floaters and the quality of life. Am J Ophthalmol. 2011;152(1):3e4. 13. Gandhi JS. Nd:YAG vitreolysis as a treatment for vitreous floaters. Eye (Lond). 2003;17(1):113. 14. Tsai WF, Chen YC, Su CY. Treatment of vitreous floaters with neodymium laser. Br J Ophthalmol. 1993;77(8):485e488. 15. Delaney YM, Oyinloye A, Benjamin L. Nd:YAG vitreolysis and pars plana vitrectomy: surgical treatment for vitreous floaters. Eye (Lond). 2002;16(1):21e26. 16. Shah CP, Heier JS. Nd:YAG laser vitreolysis vs sham Nd: YAG vitreolysis for symptomatic vitreous floaters: a randomized clinical trial. JAMA Ophthalmol. 2017;135(9): 918e923. 17. Kokavec J, Wu Z, Sherwin JC, et al. Nd:YAG laser vitreolysis versus pars plana vitrectomy for vitreous floaters. Cochrane Database Syst Rev. 2017;6:CD011676. 18. Shaimova VA, Shaimov TB, Shaimov RB. Evaluation of Nd: YAG-laser vitreolysis effectiveness based on quantitative characterization of vitreous floaters. Vestn Oftalmol. 2018;134(1):56e62. 19. Sommerville DN. Vitrectomy for vitreous floaters: analysis of the benefits and risks. Curr Opin Ophthalmol. 2015;26(3): 173e176. 20. Ivanova T, Jalil A, Antoniou Y, et al. Vitrectomy for primary symptomatic vitreous opacities: an evidence-based review. Eye (Lond). 2016;30(5):645e655. 21. de Nie KF, Crama N, Tilanus MA, et al. Pars plana vitrectomy for disturbing primary vitreous floaters: clinical outcome and patient satisfaction. Graefes Arch Clin Exp Ophthalmol. 2013;251(5):1373e1382. 22. Abdelkawi SA, Abdel-Salam AM, Ghoniem DF, Ghaly SK. Vitreous humor rheology after Nd:YAG laser photo disruption. Cell Biochem Biophys. 2014;68(2):267e274. 23. Lim JI. YAG laser vitreolysisdis it as clear as it seems? JAMA Ophthalmol. 2017;135(9):924e925. 24. Sebag J. Methodological and efficacy issues in a randomized clinical trial investigating vitreous floater treatment. JAMA Ophthalmol. 2018;136(4):448. 25. Kokavec J, Ang GS, Sherwin JC. Methodological and efficacy issues in a randomized clinical trial investigating vitreous floater treatment. JAMA Ophthalmol. 2018;136(4): 447e448.

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26. Hahn P, Schneider EW, Tabandeh H, et al. Reported complications following laser vitreolysis. JAMA Ophthalmol. 2017;135(9):973e976. 27. Cowan LA, Khine KT, Chopra V, et al. Refractory open-angle glaucoma after neodymium-yttrium-aluminum-garnet laser lysis of vitreous floaters. Am J Ophthalmol. 2015;159(1): 138e143. 28. Sun IT, Lee TH, Chen CH. Rapid cataract progression after Nd:YAG vitreolysis for vitreous floaters: a case report and literature review. Case Rep Ophthalmol. 2017;8:321e325. 29. Koo EH, Haddock LJ, Bhardwaj N, Fortun JA. Cataracts induced by neodymium-yttrium-aluminium-garnet laser lysis of vitreous floaters. Br J Ophthalmol. 2017;101(6): 709e711. 30. Noristani R, Schultz T, Dick HB. Cataract formation after YAG laser vitreolysis: importance of femtosecond laser anterior capsulotomies in perforated posterior capsules. Eur J Ophthalmol. 2016;26(6):e149ee151. 31. O’Day R, Cugley D, Chen C, Fabinyi D. Bilateral posterior capsule injury after Nd:YAG laser vitreolysis: unintended consequence of floaters treatment. Clin Exp Ophthalmol. 2018;46(8):956e958. 32. Stein GE, Jung JJ, Bodine S, et al. Vitrectomy for macular hole following Nd:YAG laser injury. Taiwan J Ophthalmol. 2016;6(4):195e198. 33. Baillif S, Paoli V, Francheschetti C, Gastaud P. Retinal injury following Nd:YAG laser treatment of symptomatic vitreous floaters. J Fr Ophtalmol. 2011;34(8):589e591. 34. Benhamou N, Glacet-Bernard A, Le Mer Y, et al. Retinal detachment following YAG laser section of vitreous strands. Apropos of 3 cases. J Fr Ophtalmol. 1998;21(7):495e500. 35. Milani P, Pierro L, Pece A, et al. Retinal photoreceptor focal disruption secondary to accidental Nd:YAG laser exposure. Int Ophthalmol. 2011;31(5):409e412. 36. Montés-Micó R, España E, Bueno I, et al. Visual performance with multifocal intraocular lenses: mesopic contrast sensitivity under distance and near conditions. Ophthalmology. 2004;111(1):85e96. 37. de Silva SR, Evans JR, Kirthi V, et al. Multifocal versus monofocal intraocular lenses after cataract extraction. Cochrane Database Syst Rev. 2016;12:CD003169. 38. Mamou J, Wa CA, Yee KMP, et al. Ultrasound-based quantification of vitreous floaters correlates with contrast sensitivity and quality of life. Invest Ophthalmol Vis Sci. 2015;56(3): 1611e1617.

39. Bach M. The Freiburg visual acuity testdautomatic measurement of visual acuity. Optom Vis Sci. 1996;73(1):49e53. 40. Bach M. The Freiburg visual acuity test-variability unchanged by post-hoc re-analysis. Graefes Arch Clin Exp Ophthalmol. 2007;245(7):965e971. 41. Dennis RJ, Beer JM, Baldwin JB, et al. Using the Freiburg acuity and contrast test to measure visual performance in USAF personnel after PRK. Optom Vis Sci. 2004;81(7): 516e524. 42. Bach M. Anti-aliasing and dithering in the Freiburg visual acuity test. Spat Vis. 1997;11(1):85e89. 43. Jensen BH, Bram T, Kappelgaard P, et al. Visual function and retinal vessel diameters during hyperthermia in man. Acta Ophthalmol. 2017;95:690e696. 44. Nguyen JH, Yee KM, Sadun AA, Sebag J. Quantifying visual dysfunction and the response to surgery in macular pucker. Ophthalmology. 2016;123(7):1500e1510. 45. Nguyen-Cuu J, Nguyen E, Yee KMP, et al. Self-administered questionnaires correlate with visual function and vitreous structure in patients with vitreous floaters. Invest Ophthalmol Vis Sci. 2017;58(8):1346. 46. Schwartz SG, Flynn Jr HW, Fisher YL. “Floater scotoma” demonstrated on spectral-domain optical coherence tomography and caused by vitreous opacification. Ophthalmic Surg Lasers Imaging Retina. 2013;44(4):415e418. 47. Ansari RR, Suh KI, Dunker S, et al. Quantitative molecular characterization of bovine vitreous and lens with non-invasive dynamic light scattering. Exp Eye Res. 2001;73(6):859e866. 48. Sebag J, Sadun AA, Pierce EA. Paradigm shifts in ophthalmic diagnostics. Trans Am Ophthalmol Soc. 2016;114:WP1. 49. Epitropoulos AT, Fram NR, Masket S, et al. Evaluation of a new controlled point source led glare tester for disability glare detection in participants with and without cataracts. J Refract Surg. 2015;31(3):196e201. 50. Superstein R, Boyaner D, Overbury O. Functional complaints, visual acuity, spatial contrast sensitivity, and glare disability in preoperative and postoperative cataract patients. J Cataract Refract Surg. 1999;25(4):575e581. 51. Sebag J. Molecular biology of pharmacologic vitreolysis. Trans Am Ophthalmol Soc. 2005;103:473e494. 52. Sebag J. Pharmacologic vitreolysisdpremise and promise of the first decade. Retina. 2009;29(7):871e874. 53. Sebag J. Pharmacologic vitreolysis. In: Sebag J, ed. Vitreous d in Health and Disease. New York: Springer ScienceþBusiness Media; 2014:799e816.

Footnotes and Financial Disclosures Originally received: September 25, 2018. Final revision: June 9, 2019. Accepted: June 14, 2019. Available online: ---. 1

Financial Disclosure(s): The author(s) have made the following disclosure(s): J.M.: Patent e quantitative ultrasonography. Manuscript no. 2018-2188.

R.H.S.: Patent e quantitative ultrasonography.

VMR Institute for Vitreous Macula Retina, Huntington Beach, California.

J.K.: Patent e quantitative ultrasonography.

Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.

J.S.: Patent e quantitative ultrasonography.

2

3

Lizzi Center for Biomedical Engineering, Riverside Research, New York, New York.

4

Department of Ophthalmology, College of Physicians & Surgeons, Columbia University, New York, New York.

5

Doheny Eye Institute & Department of Ophthalmology, University of California, Los Angeles, Pasadena, California. Presented in part at: Association for Research in Vision and Ophthalmology Annual Meeting, May 2018, Honolulu, Hawaii; American Ophthalmological Society Annual Meeting, May 2018, Dana Point, California.

Supported in part by the VMR Research Foundation. The funding organization had no role in the design or conduct of this research. HUMAN SUBJECTS: Human subjects were included in this study. The human ethics committees at St. Joseph Hospital approved the study. All research adhered to the tenets of the Declaration of Helsinki. All participants provided informed consent. No animal subjects were included in this study. Author Contributions: Conception and design: Nguyen, Sebag

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Ophthalmology Volume -, Number -, Month 2019 Analysis and interpretation: Nguyen, Nguyen-Cuu, Yu, Yee, Mamou, Silverman, Ketterling, Sebag Data collection: Nguyen, Nguyen-Cuu, Yee, Sebag Obtained funding: Mamou, Silverman, Ketterling, Sebag Overall responsibility: Nguyen, Yu, Sebag Abbreviations and Acronyms: BCVA ¼ best-corrected visual acuity; CSF ¼ contrast sensitivity function; D ¼ diopter; FrACT ¼ Freiburg acuity contrast test;

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Nd:YAG ¼ neodymium:yttriumealuminumegarnet; NEI-VFQ-39 ¼ 39item National Eye Institute Visual Function Questionnaire; PVD ¼ posterior vitreous detachment; %W ¼ Weber index. Correspondence: J. Sebag, MD, FARVO, VMR Institute for Vitreous Macula Retina, 7677 Center Avenue, Suite 400, Huntington Beach, CA 92647. E-mail: jsebag@ VMRinstitute.com.