Distance and near vision changes after intravitreal anti-vascular endothelial growth factor injection in eyes with center-involving diabetic macular edema

Abstract

Purpose:

To elucidate distance and near vision changes after intravitreal injections in center-involving diabetic macular edema (CIDME) in phakic and pseudophakic groups.

Methods:

A retrospective study was done on 148 eyes (72 phakic and 76 pseudophakic) with center-involving DME. All eyes were treated with intravitreal anti-vascular endothelial growth factor (VEGF) injection. All patients underwent distance best-corrected visual acuity (BCVA) testing, near BCVA testing, dilated fundus examination, and optical coherence tomography (OCT) at baseline and follow-up visits. Eyes that could not improve after the first injection were given 2^nd, 3^rd, and more injections in the subsequent visits.

Results:

On follow-up, post injections in the phakic group (n = 72), there were 65 eyes (90.3%) with stable/improved near vision and 59 eyes (81.9%) with stable/improved distance vision, whereas in the pseudophakic group (n = 76), 63 eyes (82.9%) and 60 eyes (78.9%), respectively. Both in phakic and pseudophakic eyes, 7.7%–13% of the cohort showed only near vision improvement.

Conclusion:

In DME, besides the changes in distance vision, there are also changes in near vision. These changes should be taken into account while determining the response to anti-VEGF in DME treatment.

The standard of care in the management of CIDME is repeated intravitreal anti-VEGF agents.[1-3] Based on several clinical trials (RISE, RIDE, RESOLVE), the assessment of improvement, stabilization, or deterioration of macular edema is made by assessing and comparing distance visual acuity and macular thickness measurements by optical coherence tomography (OCT).[4-6] The decision to continue the treatment or to stop is also based on these criteria.

Near vision in general and reading, in particular, is of great importance and interest to working-age group people; they often indicate reading difficulties as the initial symptom of DME.[7,8] The reason seems to be retinal fluid spaces, which distort or damage the photoreceptors. Unlike distance vision tests, near vision reading tests require a much larger retinal area than letter recognition tests. Thus, it gives us a better idea of the involvement of the perifoveal area.[9] In addition, reading (not letter recognition) is the macular function that most patients consider as their primary objective. Overall, the molecular mechanisms of improvement of near vision after anti-VEGF therapy in DME are thought to involve the inhibition of VEGF, reduction of inflammation and oxidative stress in the retina, thus reducing the leakage and fluid accumulation in the macula, ultimately leading to a reduction in macular edema and improvement in near vision.[10] However, none of the clinical trials using anti-VEGF for DME correlated the near vision and distance vision changes after intravitreal injection in center-involving DME, especially in both phakic and pseudophakic groups.

This study aims to elucidate distance vision and near vision changes (improvement, stabilization, and worsening) and the factors affecting them after intravitreal injection in center-involving DME in phakic and pseudophakic groups.

Methods

A retrospective chart review in two years duration was done, in which 148 eyes were given intravitreal anti-VEGF injection for center-involving DME in a tertiary eye care center in South India. Among them, 72 eyes with natural crystalline lens (i.e., phakic eye group) and 76 eyes with a posterior chamber intraocular lens (PCIOL) (i.e., pseudophakic eye group) were included in this study. The diagnosis of CIDME was done as per the previous literature.[11] Eyes with a previous history of laser photo-coagulation, intravitreal triamcinolone acetonide administration, or any vitreoretinal surgery were excluded from the study. Eyes with a history of cataract surgery during the study period were excluded from the analysis. The study was approved by the organization's Institutional Review Board, and the Tenets of the Declaration of Helsinki were strictly abided by.

A detailed chart review was done, and baseline characteristics such as age, sex, duration of diabetes, distance best-corrected visual acuity (BCVA), near best-corrected visual acuity, refractive error, intraocular pressure, and central retinal thickness were noted. Monocular distance and near visual acuity were measured by nine trained optometrists with an experience of at least five years, including two optometrists who were certificated to measure best-corrected visual acuity by The Emmes Corporation USA, for clinical trials. The chart illumination and ambient illumination were the same in the rooms where the recording of visual function was carried out.

Distance best-corrected visual acuity measurement was done using internally illuminated Snellen's light-emitting diode (LED) vision chart (Appa LED Vision Chart-20; Appasamy Associates) with a luminance of 120 cd/m². The chart was projected from a distance of 6 meters, and the patient was advised to read the largest target in Snellen's to the smallest possible optotype. The distance best-corrected visual acuity was noted in Snellen's notation and later converted into log minimal angle of resolution (log MAR) value for analysis purposes. Near best-corrected visual acuity, measurement was done uniformly using continuous text N notation near vision chart (RL Hansraj) at a working distance of 20–25 cm with an external illumination ranging between 700 and 730 lux. The near best-corrected visual acuity was noted in N notation and converted into M notation for analysis purposes.

The spherical equivalent value of refraction was considered as a measure of refractive error. Cataract was graded clinically using a 4-point grading system modified from lens opacities classification system (LOCS III), which consists of six slit-lamp images for grading nuclear color (NC) and nuclear opalescence (NO), five retro illumination images for grading cortical cataract (CC), and five retro illumination images for grading posterior subcapsular (PSC) cataract.[12] If the patient can accommodate and does not have a considerable amount of cataract, distance visual acuity is an excellent guide to near visual acuity.[13] Hence, considerable amount of cataracts (more than NS2, CC2, and any stage of PSC) were excluded from the phakic group of the study.

Retinal thickness measurements were done using Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA), following pupil dilation with 1% tropicamide. The thickness of the retina was calculated automatically using inbuilt topographic mapping software [Early Treatment Diabetic Retinopathy Study (ETDRS) thickness mapping]. A retinal map was acquired using the 3D scan protocol with 50 B-scans and 1,000 A-scans per B-scan. Central subfield thickness (CSFT) was noted. The temporal, superior, inferior, and nasal subfield thicknesses were noted at 3- and 6-mm radii.

Vision assessment for distance and near along with central retinal thickness analysis was done at the primary visit and in subsequent follow-ups. Ranibizumab and bevacizumab were the anti-VEGF agents used. Pro re nata (PRN) regimen was adopted for anti-VEGF injection without the initial three monthly loading doses. Anti-VEGF injections were administered if needed in subsequent monthly follow-ups. The decision to re-inject or observe was based on the improvement in distance vision, near vision, and reduction in central retinal thickness (CRT). The BCVA of 6/9 or 6/6, N6 was set as the endpoint. Eyes that could not meet this endpoint were re-injected in subsequent monthly follow-ups and studied in separate groups.

Statistical analysis

Clinical data was entered in Microsoft Excel 2016 and was analyzed using Statistical Package for the Social Sciences Software (SPSS for Windows, ver. 20.0). A P value less than 0.05 [Confidence interval (CI) 95%] was considered statistically significant. The Chi-square test was used for comparing categorical data. Independent t-test or its non-parametric equivalent Mann–Whitney U test for two independent groups and Kruskal–Wallis test for more than two independent groups were used.

Results

Table 1 shows the baseline characteristics of the study groups, which include 72 eyes in the phakic group and 76 eyes in the pseudophakic group with central-involving macular edema. The number of eyes that received intravitreal injection of ranibizumab was 6 and 14, respectively, in each group, and those which received intravitreal injection bevacizumab was 66 and 62, respectively. The mean baseline BCVA in the phakic group for distance was 0.68 ± 0.44 log MAR (6/24 Snellen equivalent) and for near was 1.92 ± 1.35 M notation (corresponds to N18 in N notation). Similarly, in the pseudophakic group, for distance it was 0.68 ± 0.53 log MAR (6/24 Snellen equivalent) and for near 1.76 ± 1.32 M notation (corresponds to N18 in N notation). On further analysis, none of the patients had MFIOLs among the pseudophakic group, none of the eyes have undergone corneal refractive surgeries, and none of them were using pharmacological drops for correction of the presbyopia.

Table 1.

Baseline characteristics of patients who underwent intravitreal anti-VEGF for DME in phakic and pseudophakic groups

Parameters	Phakic (n=72)	Pseudophakic (n=76)	P
Mean age (range), years	57.6 (37-74)	63.88 (50-78)	0
Male	46 (63.9%)	53 (69.7%)	0.482
Female	26 (36.1%)	23 (30.3%)	0.668
Eyes which undergone bevacizumab injection	66 (91.7%)	62 (81.6%)	0.724
Eyes which undergone ranibizumab injection	6 (8.3%)	14 (18.4%)	0.074
Eyes which received 1 injection	72 (100%)	76 (100%)	1
Eyes which received 2 injections	37 (51.4%)	47 (61.8%)	0.275
Eyes which received 3 injections	13 (18.1%)	23 (30.3%)	0.096
Eyes which received >3 injections	5 (6.9%)	16 (21.1%)	0.016*
Eyes which were N6 at baseline	20 (27.8%)	29 (38.2%)	0.199
Eyes which were 6/6 at baseline	5 (6.9%)	3 (3.9%)	0.480
Average distant vision at baseline Mean±SD† logMAR‡ (Snellen’s)	0.68±0.44 (6/24)	0.68±0.53 (6/24)	0.343
Average near vision at baseline Mean±SD† M notation (N notation)	1.92±1.35 M (N18)	1.76±1.32 M (N18)	0.298
Average spherical equivalent at baseline	0.59 DS§	-0.14 DS§	0
Average central foveal thickness (range), μm||	525.37 (106 – 987)	500 (174–987)	0.015*

*P<0.05; ^†Standard deviation; ^‡logMAR- logarithm of minimum angle of resolution; ^§DS- Dioptric sphere; ^||μm- microns

Table 2 shows the proportion of distance and near vision changes after intravitreal anti-VEGF injections in both phakic and pseudophakic groups. The number of eyes showing stability or improvement in near vision is higher compared to the distance vision in both phakic and pseudophakic groups. At one-month follow-up after all injections, 90.3% showed stable or improved near vision, and 81.9% showed stable or improved distance vision in the phakic group (n = 72). In the pseudophakic group (n = 76), 82.9% showed stable or improved near vision, and 78.9% showed stable or improved distance vision. Similar trends, where the number of eyes showing stability or improvement in near vision being higher or almost equal compared to the distance vision, were noted following each injection after first, second, third, and more than three injections in both the groups, though not statistically significant. This table also shows that, for both near and distance vision, the number of eyes showing stable or improved vision is higher in the phakic group as compared to the pseudophakic group after all injections.

Table 2.

Comparison of near vision and distance vision after intravitreal injections in center involving DME in both phakic and pseudophakic groups

Vision changes from baseline to follow-up after intravitreal injections Total No. of eyes receiving injections	Phakic			Pseudophakic
	Distance vision	Near vision	P	Distance vision	Near vision	P
	n=72			n=76
Eyes with stable or improved vision (%)	59 (81.9)	65 (90.3)	0.590	60 (78.9)	63 (82.9)	0.787
Eyes with decreased vision (%)	13 (18.1)	7 (9.7)	0.180	16 (21.1)	13 (17.1)	0.577
Eyes received 1 injection	n=72			n=76
Eyes with stable or improved vision (%)	58 (80.6)	62 (86.1)	0.715	66 (86.8)	65 (85.5)	0.930
Eyes with decreased vision (%)	14 (19.4)	10 (13.9)	0.414	10 (13.2)	11 (14.5)	0.827
Eyes received 2 injections	n=37			n=47
Eyes with stable or improved vision (%)	32 (86.5)	34 (91.9)	0.806	35 (74.5)	40 (85.1)	0.564
Eyes with decreased vision (%)	5 (13.5)	3 (8.1)	0.480	12 (25.5)	7 (14.9)	0.251
Eyes received 3 injections	n=13			n=23
Eyes with stable or improved vision (%)	11 (84.6)	11 (84.6)	1	18 (78.3)	20 (87)	0.746
Eyes with decreased vision (%)	2 (15.4)	2 (15.4)	1	5 (21.7)	3 (13)	0.480
Eyes received >3 injections	n=5			n=16
Eyes with stable or improved vision (%)	5 (100)	5 (100)	1	11 (68.8)	12 (75)	0.835
Eyes with decreased vision (%)	0	0	-	5 (31.3)	4 (25)	0.739

*P<0.05

Table 3 illustrates the comparison of variables between the phakic and pseudophakic groups that might affect the changes in distance and near vision. On comparing the groups, there was statistically no significant difference among the following factors: age, gender, duration of diabetes, spherical equivalent, central retinal thickness, and intraocular pressure.

Table 3.

Comparison of variables affecting changes in distance and near vision after anti-VEGF injections, between phakic and pseudophakic groups

Baseline Characteristics	Improved Near vision			Decreased Near vision
	Phakic eyes, Median (Ql, Q3)*	Pseudophakic eyes, Median (Q1, Q3)*	P	Phakic eyes, Median (Ql, Q3)*	Pseudophakic eyes, Median (Q1, Q3)*	P
Age
Group 1 <50 years	2.25 (1.0, 3.37)
Group 2 50-60 years	0.75 (0.50, 1.50)	1.87 (0.50, 2.81)	0.351	-2.25	-0.87 (-2.00, -0.25)	0.34
Group 3 >60 years	0.37 (0.25, 1.25)	0.75 (0.50, 2.56)	0.16	-0.50 (-1.12, -0.25)	-0.50 (-1.00, -0.25)	1
Gender
Group 1 Male	0.75 (0.50, 1.68)	0.75 (0.50, 2.81)	0.432	-0.75	-0.87 (-1.68, -0.25)	0.858
Group 2 Female	0.75 (0.25, 2.25)	0.75 (0.25, 2.56)	1	-0.62 (-3.0, -0.31)	-0.25	0.186
Duration of Diabetes
Group 1 <5 years	0.37 (0.25, 2.37)	0.25 (-)	1		-1.00
Group 2 5-10 years	1.5 (0.75, 2.25)	1.87 (0.56, 3.0)	0.936	-1.12	-0.75 (-1.5, -0.25)	0.355
Group 3 >10 years	0.50 (0.37, 1.25)	0.75 (0.50, 2.62)	0.18	-0.50 (-2.25, -0.25)	-0.25 (-1.25, -0.25)	0.521
Spherical Equivalent
Group 1 >+0.75DS†	0.50 (0.25, 1.25)	2.25 (-)	0.188	-0.62 (-1.31,-0.31)	-0.62	0.803
Group 2 +0.75DS to -0.75DS†	1.00 (0.75, 2.25)	0.75 (0.50, 3.0)	0.53	-0.75	-0.75 (-1.50, -0.25)	0.633
Group 3 >-0.75DS†	0.87 (-)	0.75 (0.37, 2.62)	0.839		-0.25 (-1.75, -0.25)
Central retinal Thickness
Group 1 <500 microns	0.75 (0.50, 1.50)	1.50 (0.37, 3.0)	0.329	-0.37	-0.25 (-1.0, -0.25)	0.256
Group 2 500-700 microns	1.50 (0.25, 2.25)	0.75 (0.50, 0.75)	0.223	-1.12 (-3.18,-0.37)	-1.00	0.634
Group 3 >700 microns	0.50 (0.50, 1.5)	1.87 (-)	0.213	-0.75 (-)
IOP
Group 1 <12 mmHg‡	0.50 (0.43, 2.25)	0.50 (-)	1		-0.75
Group 2 12-17 mmHg‡	0.75 (0.50, 1.50)	0.75 (0.50, 3.0)	0.948	-0.75 (-1.50, -0.25)	-0.75 (-1.68, -0.25)	0.754
Group 3 >17 mmHg‡	0.37 (0.25, 1.81)	0.75 (-)	0.329		-0.25
Baseline Characteristics	Improved Distance vision			Decreased Distance vision
	Phakic eyes, Median (Q1, Q3)*	Pseudophakic eyes, Median (Q1, Q3)*	P	Phakic eyes, Median (Ql, Q3)*	Pseudophakic eyes, Median (Ql, Q3)*	P
Age
Group 1 <50 years	0.59 (0.44. 0.90)			-0.20
Group 2 50-60 years	0.30 (0.10,0.40)	0.19 (0.13, 0.39)	0.814	-0.10 (-0.50,-0.05)	-0.54	0.462
Group 3 >60 years	0.20 (0.10,0.37)	0.24 (0.12,0.43)	0.365	-0.30 (-0.80,-0.10)	-0.18 (-0.40, -0.12)	0.071
Gender
Group 1 Male	0.35 (0.10,0.53)	0.18 (0.12,0.42)	0.578	-0.20 (-0.30, -0.05)	-0.30 (-0.41, -0.12)	0.738
Group 2 Female	0.25 (0.10,0.40)	0.22 (0.10,0.42)	0.324	-0.20 (-0.92, -0.10)	-0.12	0.285
Duration of Diabetes
Group 1 <5 years	0.30 (0.20, 0.70)	0.15 (0.07, 0.42)	0.273	-0.20	-0.42	1
Group 2 5-10 years	0.40 (0.22, 0.46)	0.30 (0.15, 0.47)	0.695	-0.30 (-0.30,-0.15)	-0.18 (-0.54, -0.12)	0.317
Group 3 >10 years	0.20 (0.10,0.40)	0.18 (0.12,0.42)	0.827	-0.15 (-1.17, -0.02)	-0.18 (-0.40, -0.11)	0.04
Spherical Equivalent
Group 1 >+0.75DS†	0.20 (0.10,0.30)	0.18 (-)	0.796	-0.20 (-1.21,-0.10)	-0.30	0.48
Group 2 +0.75DS to -0.75DS†	0.40 (0.20, 0.58)	0.26 (0.12,0.42)	0.566	-0.20 (-0.30, -0.10)	-0.18 (-0.40, -0.11)	0.602
Group 3 >-0.75DS†	0.1 (-)	0.12 (0.12,0.48)	0.705		-0.21 (-0.43, -0.12)
Central retinal Thickness
Group 1 <500 microns	0.30 (0.20, 0.40)	0.18 (0.12,0.43)	0.317	-0.20 (-0.30, -0.10)	-0.15 (-0.40, -0.11)	1
Group 2 500-700 microns	0.20 (0.10,0.60)	0.30 (0.12,0.41)	0.325	-0.55 (-1.34, -0.07)	-0.29 (-0.68, -0.13)	0.405
Group 3 >700 microns	0.40 (0.10,0.60)	0.44 (0.23,1.03)	0.903	-0.10	-0.29	0.414
IOP
Group 1 <12 mmHg‡	0.40 (0.15, 0.40)	0.46 (-)	0.114		-0.10	1
Group 2 12-17 mmHg‡	0.30 (0.10,0.42)	0.21 (0.12,0.41)	0.902	-0.25 (-0.30, -0.10)	-0.24 (-0.40, -0.12)	0.457
Group 3 >17 mmHg‡	0.40 (-)	0.15 (0.10,0.36)	0.447	-0.81	-0.18	0.48

*Q1,Q3 – Quartile1, Quartile3; ^†DS- Dioptric sphere; ^‡mmHG – millimeters of mercury

Fig. 1a and b show the trends in vision change, i.e., improvement, stabilization, and reduction in near and distance visions after each intravitreal injection in phakic and pseudophakic groups, respectively. In the phakic group [Fig. 1a], some eyes showed only improvement in near vision with no improvement in distance vision (11.1%, 10.8%, 7.7% and nil, after first, second, and third injections and more than three injections, respectively). Likewise, some eyes showed only distance vision improvement with no near vision improvement (16.7%, 16.2%, 15.4%, and 20% after first, second, third, and more than three injections, respectively). In the pseudophakic group [Fig. 1b], some eyes showed only improvement in near vision with no improvement in distance vision (7.9%, 4.2%, 13%, and 6.3% after first, second, third, and more than three injections, respectively). Likewise, some eyes showed only distance vision improvement with no near vision improvement (28.9%, 23.4%, 13%, and 6.3% after first, second, third, and more than three injections, respectively).

Figure 1.

Trends in vision change after each injection in (a) phakic group and (b) pseudophakic group

Fig. 2a and b show the percentage of eyes with near vision N6 and distance vision better than 6/9 at baseline and after subsequent injections for phakic and pseudophakic groups, respectively.

Figure 2.

Comparison of distance and near vision in (a) phakic and (b) pseudophakic group

Discussion

Visual acuity changes after the anti-VEGF injection have been a topic of frequent discussion in the recent past. There is still a significant amount of information to be gathered in the field of current management of DME, changes in near vision being one of them. Several studies have been done, and most of them have evaluated and reported improvement in distance vision only.[14-17] Based on these studies, injection regimens have been designed and remodeled, but there are only pieces of evidence available to suggest near vision improvement following anti-VEGF injections.[18] To our best knowledge, the study of such a kind has never been done before. It exhaustively covers both the aspects of vision change, distance, and near with relation to the lens status (i.e., for phakic and pseudophakic eyes).

To assess the near vision function, National Eye Institute Visual Functioning Questionnaire 25 (NEI VFQ-25) has been used by most of the authors. It is a validated condition-specific instrument that provides a patient-reported measure of visual function, which also includes near vision function.[18] Cusick et al.[18] studied the correlation between NEI VFQ-25 near and distance subscale scores with central visual function tests (best-corrected visual acuity, contrast sensitivity, and central visual fields) and found statistically significant relationships between NEI VFQ-25 near activities subscale scores and central visual function.

The concept of NEI VFQ-25 has been used for the qualitative analysis of the outcomes after anti-VEGF injections in RESTORE, RESTORE Extension study, RISE, and RIDE study.[14-17] In RESTORE study, the near activity scores improved by 9.0 (ranibizumab vs. laser, 5.0 to 13.0; P = 0.01) and 9.1 (ranibizumab plus laser vs. laser, 5.6 to 12.6; P = 0.006) compared with 1.1 (−3.0 to 5.2) for the laser group. Whereas distance activity scores improved by 5.3 (ranibizumab vs. laser, 1.8 to 8.9; P = 0.04) and 5.6 (ranibizumab plus laser vs. laser, 2.3 to 9.0; P = 0.03) compared with 0.4 (−3.1 to 3.8) for the laser group.[16]

Rayner et al.[19] reported that, when reading text material, a visual field extending from the currently fixated word up to 15 characters to the right of fixation is required. This area is larger than the area needed for reading a single optotype assessed in distance vision testing. Furthermore, this could explain why the near vision was more severely affected compared with distance vision at baseline and improved more at the end of the study. This suggested that the near function may better represent central visual functional changes. Similar results, though not statistically significant, were found in our analysis. The vision improvements were found to be higher in the phakic group than in the pseudophakic group. The foveal thickness was higher in phakic group, so the reduction was more. This can be one reason. In the pseudophakic group as seen from our Table 1, more number of patients needed multiple injections, probably suggesting a more severe form of edema. And this also may be the reason they dint achieve that good vision. Details are explained in Fig. 3.

Figure 3.

Distribution of eyes based on activity

The association between cataract surgery and the risk of DR is currently still not well understood. Hong et al.[20] previously reported that pseudophakic eyes among patients with diabetes were 2.65 times more likely to develop DR in 12 months compared with phakic eyes. An increase in retinal thickness in pseudophakic eyes is linked to reduced visual function and is, therefore, a good indicator of poor vision in patients with DME.[21] This could be a probable reason attributing to the inferior performance of the pseudophakic group or better performance of the phakic group after anti-VEGF injection.

The limitations of our study include its retrospective design, the presence of cataracts being a limiting factor for visual changes in the phakic group, measurement of visual acuity by Snellen's chart, which has its inherent limitations owing to the design. The pupillary diameter, which affects the near vision, could not be obtained for all due to its retrospective nature. In this retrospective study, we did not consider OCT biomarkers, and detailed information on systemic factors was not available. Additionally, the use of PRN dosing led to inadequate standardization when comparing eyes for distance and near vision.

However, this study adds new information to the already published literature on vision improvement in cases of DME, the outcomes of which can serve as a guide for future research with an increase in sample size and descriptive study design.

Conclusion

Changes in distant visual acuity and OCT are typically utilized as indicators of treatment efficacy while managing DME. Our study revealed that just about 1 in 10 people will have improvements in their near vision without corresponding changes in their distance vision. When monitoring the effectiveness of anti-VEGF in the treatment of DME, we advise taking into consideration any changes in near vision.

Availability of data

The dataset generated and/or analyzed during the current study is not publicly available due to the hospital protocols, but is available from the corresponding author on reasonable request.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.