Effectiveness of anti-VEGF treatment in wet Age-related Macular Degeneration; an evaluation of silent reading performance with eye movement analysis

doi:10.21203/rs.3.rs-1974887/v1

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Effectiveness of anti-VEGF treatment in wet Age-related Macular Degeneration; an evaluation of silent reading performance with eye movement analysis

https://doi.org/10.21203/rs.3.rs-1974887/v1

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Purpose: To evaluate silent reading performance by means of eye fixation analysis before and after anti-VEGF treatment in wet AMD (wAMD) patients.

Methods: Twenty wAMD patients who underwent anti-VEGF treatment, in one eye, served as the AMD group. Twenty adults without ocular pathology, served as the control group. Central Retinal Thickness (CRT) and near visual acuity (VA) were assessed at baseline and after 3-4 months following their first visit. Reading performance was evaluated using short passages of 0.4 logMAR print size at 40 cm distance. Eye movements were recorded using a video eyetracker. Data analysis included computation of reading speed, fixation duration, number of fixations, and percentage of regressions.

Results: In the AMD group, silent reading speed in the treated eye correlated well with CRT reduction and improved significantly by an average of 15.9±28.5 wpm (p=0.041). This improvement was accompanied by an average reduction of 0.24±0.38 in fixations per word (p=0.023). The corresponding improvement in monocular VA was not statistically significant, as was the case with other eye fixation parameters.

Conclusion: VA tests may underestimate the potential therapeutic effects following anti-VEGF treatment. Evaluating silent reading performance and eye fixation parameters may better characterize the effectiveness of therapeutic approaches in wAMD patients.

retina

AMD

reading

functional vision

eye movements

Age-related Macular Degeneration (AMD) is one of the most common causes of blindness in developed countries¹. AMD is a disease often ending up with significantly reduced vision, requiring visual rehabilitation², although treatment based on anti-VEGF factors has improved the natural outcome of the disease^3,4.

Since many activities of daily living rely on reading, it is not surprising that reading difficulty is a primary reason among individuals to seek referral to a low vision clinic⁵ and a strong predictor of vision-related quality of life⁶. However, reading performance tests are not routinely used in clinical practice, which mainly relies on visual acuity (VA) measures, despite being a relatively poor predictor of functional vision impairment^7,8, especially when early functional deficits in AMD are under investigation⁹. On the other hand, it is crucial to determine whether any changes in reading performance can predict clinical and physiological changes, thus standardised reading tests are of importance¹⁰.

Although reading impairment in AMD patients is likely multi-factorial^11,12, efficient reading is hampered due to the presence of retinal scotomas centrally, even compared to other low vision patients^5,13,14. As a result, AMD patients tend to change their fixation to the near retinal periphery, a process known as eccentric viewing^15,16. When using peripheral retina, reading becomes very difficult or even impossible and does not seem to depend on patient VA or contrast sensitivity¹⁷. Difficulty in reading correlates with shorter saccades and higher percentage of regressions, especially at low luminance levels¹⁸.

The primary aim of the present study was to evaluate reading performance in patients with wet AMD (wAMD) who received anti-VEGF treatment, under real-world clinical conditions, namely normal silent passage reading speed with the concurrent recording of eye fixation parameters. Comparison data was obtained from a group of adults without ocular pathology. A secondary aim was to assess the extent to which improvement in reading behavior is determined by anatomical treatment-related changes (i.e., reduction in central retinal thickness (CRT), changes in conventional treatment outcomes (i.e., monocular visual acuity), and changes in oculomotor behavior.

Participants

Twenty wAMD patients, native Greek speakers, who were scheduled to undergo anti-VEGF treatment in the Ophthalmology Department of the University Hospital of Heraklion were recruited. Exclusion criteria included: any other ocular disease or systemic pathology, spectacle-corrected VA for far and near in each eye worse than 0.40 logMAR in AMD patients and worse than 0.20 logMAR in controls, clinically significant abnormal phorias, any history of refractive or other ocular surgery (cataract surgery was allowed if both eyes had been treated) and any neurological and psychiatric disorder which could affect reading performance.

Data from four patients were excluded from further analyses, due to deterioration of the disease to the extent that prevented them from reading the printed passage on the follow-up visit (n = 3) and presence of retinal Pigment Epithelial Detachment (PED) in one patient, associated with a dramatic increase in CRT of 333 nm, measured using Ocular Coherence Tomography (OCT). The final data set of the “AMD group” comprised of 16 patients (10 women) aged 71 years (SD = 8, range: 52 to 80 years) who had attained an average of 9 (SD = 5) years of formal education. The sample included newly diagnosed (N = 9) and patients with wAMD under anti-VEGF treatment in PRN (when needed) protocol that had been relapsed (N = 7). We considered a patient to have relapsed when he / she presented with a deterioration in OCT, indexed by increased central macular thickness (CMT) or increase of intra-retinal fluid (IRF) or increase of sub-retinal fluid (SRF) alone, or in any combination along with VA deterioration (as long as VA is equal or better than 0.4 logMAR). Relapsed patients repeated the entire treatment protocol consisting of at least 3 monthly injections and PRN afterwards. None of the patients discontinued the medication and no adverse drug reaction was observed.

Twenty participants without ocular pathology (8 women) aged 65 years (SD = 6, range: 56 to 75 years) who had attained an average of 12 (SD = 4) years of formal education served as controls. Controls were older than patients by 6 years on average (CI from 1 to 10, p = 0.01) and had attained slightly higher education level (p = 0.08). In addition, the two groups were initially compared on standardized tests of word and pseudoword reading efficiency (assessment is described in detail in ¹⁹). They displayed comparable age- and education-adjusted word (p = 0.1) and pseudoword (p = 0.4) reading efficiency. Age- and education-adjusted z scores are reported in Table 1.

Table 1

CRT, near visual acuity and reading performance across visits and average differences for the two groups.
	AMD patients				Control group
	Before treatment	After Treatment	Median Difference (95% CI)	P value	Visit 1	Visit 2	Median Difference (95% CI)	P value
CRT (µm)	325 (61)	284 (63)	-41 (-66 to -16)*	0.004	285 (25)	--	--	--
Near VA (B)¹	0.25 (0.16)	0.22 (0.15)	-0.04 (-0.10 to 0.02)	0.2	0.02 (0.06)	0.02 (0.09)	0.00 (-0.04 to 0.03)	0.9
Near VA (M)¹	0.33 (0.13)	0.29 (0.16)	-0.04 (-0.11 to 0.04)	0.2	0.09 (0.08)	0.10 (0.08)	0.01 (-0.02 to 0.05)	0.4
Passage Reading
Reading speed (B)²	104.1 (52.7)	108.3 (40.2)	4.2 (-19.2 to 27.7)	0.7	193.7 (46.7)	199.7 (57.6)	6.1 (-8.2 to 20.4)	0.4
Reading speed (M)²	69.4 (32.9)	85.3 (33.5)	15.9 (0.7 to 31.1)*	0.041	182.5 (47.9)	184.3 (55.0)	1.8 (-11.1 to 14.6)	0.8
Fixation Duration (B)³	318 (56)	318 (51)	0 (-26 to 26)	1.0	238 (38)	233 (40)	-6 (-15 to 3)	0.2
Fixation Duration (M)³	377 (94)	362 (80)	-15 (-50 to 19)	0.4	252 (46)	254 (48)	2 (-7 to 12)	0.6
Fixations per Word (B)⁴	1.32 (0.39)	1.29 (0.39)	-0.03 (-0.22 to 0.15)	0.7	0.93 (0.22)	0.92 (0.24)	-0.02 (-0.06 to 0.03)	0.5
Fixations per Word (M)⁴	1.70 (0.51)	1.46 (0.44)	-0.24 (-0.45 to -0.04)*	0.023	0.97 (0.25)	1.00 (0.27)	0.02 (-0.05 to 0.09)	0.5
Regressions (B)⁵	17.9 (6.2)	17.8 (6.3)	-0.1 (-2.1 to 1.9)	0.9	15.1 (5.8)	14.2 (5.8)	-1.0 (-2.3 to 0.4)	0.1
Regressions (M)⁵	18.8 (7.2)	17.0 (7.9)	-1.8 (-4.7 to 1.0)	0.2	13.5 (6.0)	13.2 (4.8)	-0.3 (-2.3 to 1.7)	0.7
Ex-Gaussian µ (B)⁶	221 (41)	228 (37)	-7 (-27 to 13)	0.5	176 (37)	170 (37)	-7 (-16.7 to 3.7)	0.2
Ex-Gaussian µ (M)⁶	252 (87)	243 (58)	-9 (-40 to 23)	0.6	187 (49)	186 (49)	-1 (-10.0 to 8.6)	0.9
Ex-Gaussian τ (B)⁷	122 (42)	130 (43)	-8 (-31 to 15)	0.5	73 (24)	79 (29)	6 (-3.7 to 15.7)	0.2
Ex-Gaussian τ (M)⁷	147 (63)	152 (60)	-5 (-23 to 12)	0.5	75 (35)	82 (42)	7 (-0.5 to 14.3)	0.07
Word-level reading fluency
Words (z score)⁸	0.10 (1.1)	--	--	--	0.20 (1.0)	--	--	--
Words/min	90.7 (12.3)	--	--	--	108.6 (13.2)	--	--	--
Pseudowords (z score)⁸	-0.21 (1.3)	--	--	--	-0.05 (0.9)	--	--	--
Pseudowords/min	42.9 (12.2)	--	--	--	52.1 (11.2)	--	--	--
Abbreviations; B: Binocular, M: Monocular. ¹In logMAR; 2 In words per minute; ³In ms; ⁴Average number of fixations per word; ⁵Percentage of regressions in total number of saccades; ^6–7In ms, ⁸Age- and education-adjusted z scores based on population norms (binocular reading).
^*Statistically significant change (p < 0.05)

Written consent was obtained from all participants after they received a written explanation of the nature of the study. The study was conducted in adherence to the tenets of the Declaration of Helsinki according to a research protocol approved by the Research Board of the University Hospital of Heraklion.

Visual acuity

VA for near was measured using the European-wide standardized logMAR charts²⁰. All subjects were asked to identify each letter starting from the upper left corner until they reach a row in which they could not correctly identify more than one letter. VA (in logMAR) was derived from the calculation of correctly identified letters.

Reading performance

Silent reading performance was evaluated with three reading cards each displaying a passage of approximately 140 words each. The cards were developed to assess reading behavior in Greek and had similar average word frequency and word length. A different card was used for each condition (left/right eye and binocular) in a counterbalanced order across participants to prevent any learning effects. A standard print size of 0.4 logMAR (1.0 M at 40 cm) was used. Participants were instructed to read the text silently at a comfortable pace to understand the meaning of the passages and answer five simple multiple-choice questions.

Eye movements from both eyes were recorded simultaneously during passage reading, at a sampling rate of 500Hz, using video oculography (Eye-Link II, SR Research Ltd). All measurements were performed with subjects seated on a chair with their head stabilized by means of a chin rest to minimize head movements.

Procedure

Patients with AMD were measured on two different visits using identical procedures: the first visit took place immediately after diagnosis and before any therapeutic intervention for the naive patients and before initiation of therapy for relapse for the remaining patients. The second visit took place three to four months following the first visit, after they had completed their scheduled standard anti-VEFG treatment of three intravitreal ranibizumab injections (Lucentis, Novartis Pharma AG, Basel, Switzerland). Participants in the control group were assessed using identical material and procedures on two occasions three to four months apart. On each visit all participants had an OCT (Spectralis, Heidelberg Engineering, Germany) and Best Corrected Visual Acuity (BCVA) evaluation monocularly and binocularly, while they were administered the reading efficiency tests prior to the passage reading session. CRT was measured in the central 1 mm of the retina. VA and reading recordings took place at a 40 cm distance in a well-lit room (chart background luminance was about 55 cd/m²; illuminance at cornea was about 60 lux) with participants’ best refractive correction for near.

Data analysis

Reading performance was assessed with silent reading speed and with a set of eye-movement based parameters during passage reading: number of fixations, fixation duration, forward saccadic length and percentage of regressions. Reading speed (in words/minute, wpm) was calculated from the number of words read from the passage divided by total reading time.

Fixations with duration between 75 and 1000 ms were analyzed; the median fixation duration for each participant was calculated. Analysis of the number of fixations during reading was based on mean number of fixations per word. Fixation duration and number of fixations per word refer only to the forward fixations.

In addition, frequency distributions of forward fixation durations were fitted with an ex-Gaussian distribution, a convolution of a normal and exponential distribution. Ex-Gaussian analysis uses three parameters: location (mean, µ) and standard deviation (σ) of the Gaussian (normal) distribution, and τ, which reflects the mean and the standard deviation of the exponential component²¹.

Associations between measurements were assessed through Pearson correlation coefficients and evaluated at p < 0.05. Changes on the dependent variables between visits in each group were assessed through paired-sample t-tests. Ninety-five per cent confidence intervals were also calculated. All analyses were performed using SPSS v27.

Change in Central Retinal Thickness and Visual Acuity

Effectiveness of 3-month anti-VEGF treatment was anatomically indicated by a statistically significant reduction in CRT by 41 ± 47 µm (95% CI from 16 to 66 µm, p = 0.004). Although the reduction in CRT following treatment correlated well with the change in VA (r=-0.71, p = 0.003), the improvement in near monocular and binocular VA was minimal and not statistically significant. VA improvement was found to be on average 0.04 logMAR in both monocular (95% CI from − 0.03 to 0.12, p = 0.248) and binocular viewing conditions (95% CI from − 0.02 to 0.10, p = 0.148; see Τable 1).

Similarly, for the control group, near VA did not exhibit any changes between the two visits as measured binocularly (95% CI from − 0.03 to 0.04, p = 0.929) and monocularly for the RE (95% CI from − 0.05 to 0.02, p = 0.446). Figure 1 plots monocular visual acuity in AMD and control groups on both visits.

Reading speed and eye fixation parameters

Control group. No differences were found in passage reading speed between the two visits, in both monocular (95% CI from − 11.1 to 14.6, p = 0.8) and binocular viewing conditions (95% CI from − 8.2 to 8, p = 0.4). In addition, no statistically significant difference was found in any eye fixation parameter in either binocular or monocular testing (see Table 1), suggesting minimal learning effects.

wAMD Group: Reading speed. Improvement in passage reading speed was observed in 11/16 of patients which was accompanied by improvement in visual acuity in 8/11 patients (VA improved in one additional patient without concomitant improvement in reading speed). On average, passage reading speed improved from 69.4 to 85.3 wpm, i.e. by an average of 15.9 ± 28.5 wpm (95% CI from 0.7 to 31.1 wpm, p = 0.041). Reading speed in binocular viewing did not change significantly between the two visits (see Table 1).

wAMD Group: Fixation parameters. There was a significant reduction in the number of fixations per word, averaging 0.24 ± 0.38 fixations (95% CI from 0.04 to 0.45, p = 0.023; see Fig. 2), which was strongly correlated with the concurrent reduction in CRT (r = 0.71, p = 0.003). Changes in the other eye fixation parameters with treatment were in the expected direction, but did not reach significance: fixation duration decreased by 15 ± 66 ms (p = 0.359), percentage of regressions by 1.8 ± 5.4% (p = 0.189), and ex-Gaussian parameters µ and τ by 9 ± 58 ms (p = 0.571) and 5 ± 42 ms (p = 0.528), respectively.

Correlates of improvement in passage reading speed (treated eye). As expected, improvement in monocular reading speed was closely associated with the concurrent reduction in CRT (r=-0.68, p = 0.004). Although near VA did not improve with treatment on a group basis, it was closely associated with the degree of improvement in monocular passage reading speed (r = 0.70, p = 0.003) (see Fig. 3).

Regarding eye movement parameters, treatment-related changes in the number of fixations (r=-0.67, p = 0.006), average fixation duration (r=-0.65, p = 0.006), percentage of regressions (r=-0.52, p = 0.041) and ex-Gaussian parameter µ (r=-0.66, p = 0.005) were all significantly associated with the degree of improvement in monocular passage reading speed (see Fig. 4).

To further assess the joint contribution of change in monocular VA and in eye fixation parameters to the improvement in passage reading we computed two complementary hierarchical, linear multiple regression models. Monocular VA was always entered in the first step. Due to collinearity concerns, fixation duration, percentage of regressions and parameter µ were not entered together in the same regression model. Model 1 included change in fixation duration, number of fixations per word, and percentage of regressions entered together in the second step. In Model 2, number of fixations per word and the ex-Gaussian parameter µ were entered together in the second step.

Both models were significant (p < 0.001) with the predictor variables accounting for 85 and 79% of the variance in reading speed improvement. Model 1 revealed that reductions in fixation duration (B=-0.21, SE = 0.06, p = 0.006) and in the number of fixations per word (B=-30.92, SE = 11.03, p = 0.017) were significant predictors of improvement in reading speed even after controlling for the observed change in VA. Model 2 revealed that in addition to the reduction in the number of fixations, a reduction in the parameter µ significantly and independently predicted improvement in reading speed (B=-0.23, SE = 0.06, p = 0.002), even after controlling for the change in VA. The total amount of variance accounted for by eye movement parameters beyond that contributed by VA was 40% in Model 1 and 35% in Model 2. Finally, to facilitate comparisons with previous studies we performed supplementary analyses by excluding VA as a predictor of reading speed. These models indicated that eye fixation parameters alone can account for as much as 76% of the variance in the degree of improvement in reading speed.

Correlates of CRT changes. To quantify the extent of therapeutic effects on retinal physiology and more specifically on the change in CRT, as predicted by the improvement in monocular VA and by the eye fixation patterns, we computed a complementary hierarchical, linear multiple regression model. Monocular VA was entered in the first step. Due to collinearity concerns, fixation duration, percentage of regressions and parameter µ were not entered together in the same regression model. The model included change in number of fixations per word, entered in the second step, and change in fixation duration in the third step.

Change in VA accounted for 50% of the variance in CRT improvement. When change in the number of fixations was added, the model accounted for 67% of the variance in CRT improvement. On the other hand, when fixation duration or percentage of regressions with parameter µ were added in the model, no statistically significant change in R Square was observed. Final model, which included only changes in VA and in the number of fixations, was highly significant (R Square = 0.668, p = 0.001). Moreover, reduction in the number of fixations (B = 55.92, SE = 22.30, p = 0.026) was a significant predictor of CRT improvement, even after controlling for the observed change in VA. Finally, we performed supplementary analyses by excluding VA as a predictor of CRT. The model indicated that the number of fixations alone can account for as much as 46% of the variance in CRT improvement.

The main aim of the study was to assess the therapeutic effects of anti-VEGF treatment in wAMD patients, which significantly reduced CRT in the treated eye, by evaluating reading performance under real-world clinical conditions. This was achieved by measuring silent passage reading by means of eye movement / fixation analysis using a high-resolution video eye tracker.

Following anti-VEGF treatment, monocular silent passage reading speed increased statistically significantly, from 69.4 to 85.3 wpm, while a concurrent significant improvement in the average number of forward fixations (0.24 ± 0.38) was also observed. No significant treatment-related differences were found for other fixation parameters, i.e. fixation duration, ex-Gaussian parameters µ and τ of the fixation duration frequency distributions and regressions. The improvement both in reading speed and in the number of fixations was strongly correlated with the reduction in CRT following treatment. Improvement in monocular passage reading speed of the treated eye was also related to the improvement in near monocular VA. However, the average change in VA observed in the present study was minimal and this may be due to the relatively small reduction in CRT (95% CI: 16 to 66 µm). Previous studies reported notable improvement in near VA^4,22−24 accompanying larger reductions in CRT (e.g., ranging from 150 to 175 µm)⁴.

The second aim of the present study was to account for the observed improvement in monocular passage reading speed. Hierarchical multiple regression models highlighted treatment-related changes in three eye movement parameters as significant predictors of the degree of improvement in reading speed, even after controlling for near VA: average number of fixations per word, average fixation duration and ex gaussian parameter µ. It should be noted, however, that among these measures only the average number of fixations was statistically significantly reduced following treatment. Taken together these results suggest that improvement in reading speed reflected primarily a concomitant reduction in the number of fixations performed. The strong correlation found between silent reading speed and the number of fixations could be explained by a visual span expansion, which usually accompanies CRT shrinkage and is known to have a significant effect on reading performance in patients with maculopathy^25,26.

The total effect of eye movement parameters on the change in treatment-related monocular passage reading speed in AMD patients was in the order of 76%. In a different setting (readers with simulated scotomas), the number of saccades and fixation duration accounted for as much as 94% of the total variance of reading speed²⁷. While the debate on the relative importance of the number of saccades is ongoing, the majority of previous studies agree with current results by identifying forward saccade size, which is highly correlated with reduced fixations, as the best predictor of reading speed¹⁸. On the other hand, the role of fixation duration on predicting reading speed changes in AMD patients is not so clear. A negative association has been reported by Calabrese et al. in patients with AMD and Stargardt’s disease²⁸, while others failed to show a significant association^17,18,29.

In interpreting these discrepancies, one should consider important methodological differences among studies, as for example in the type of texts^10,12 and the reading mode, ie. silent vs reading aloud^30,31. In the present study reading speed was assessed during silent passage reading of continuous paragraphs instead of single sentences, at a comfortable pace, to simulate real-life reading conditions, while in most clinical studies participants were asked to read the texts out loud and as fast as they can. It is well known that parafoveal information contributes to faster silent reading speed through a reduction in both the duration and number of fixations, while reading slows down when parafoveal information is masked³². Although the lack of parafoveal information slows down reading speed in both oral and silent reading, the effects of parafoveal information are larger in silent than in oral reading, especially for faster readers³¹. Moreover, among glaucoma patients with bilateral VF loss, the greatest impact is present during silent reading than oral reading, over prolonged durations³⁰, and this association was independent of visual acuity.

Regarding VA, current results are in agreement with previous studies, hinting that VA assessment is not sufficient to evaluate functional visual rehabilitation in low vision patients^17,33. Our hierarchical linear multiple regression model revealed that change in VA accounted for 50% of the variance in CRT improvement and that, when change in the number of fixations is added, then the model can account for 67% of this variance. The joint contribution of VA and the number of fixations may reflect both foveal and parafoveal visual processing, which are known to be affected in AMD¹¹.

In interpreting the present results, several limitations need to be considered. First, the relatively small size of the patient group may have restricted statistical power to detect more subtle changes in VA and other eye fixation parameters. Second, CRT and VA may not be the optimal indicators of the degree of retinal and functional impairment (i.e., foveal vision) of the affected eye, respectively. However, in some patients the retinal fluid is detected in parafovea and as a result, neither CRT nor VA are severely affected. Microperimetry³⁴ and functional tests which consider the AMD patients’ slow information transfer rate²⁵, may provide complementary indices of macular visual function and progression of the disease. Finally, functional reading was not assessed using formally standardized passages, such as IReST, which are now available in Greek³⁵.

In this study, we show that VA underestimates the improvement in functional vision after anti-VEGF treatment. In addition, an appropriate eye-movement analysis in reading tasks with standardized texts may provide crucial information regarding the progress of eye diseases, especially maculopathies. Using this method in combination with other tests, may help eyecare specialists better evaluate functional vision and obtain useful information regarding parafoveal visual processing.

Grant Support

The study was funded with an Investigator Initiated Trial (IIT) by Novartis AG.

Acknowledgements

The study was funded by Investigator Initiated Trial (IIT) by Novartis AG. We thank participating investigator Michalis Agiorgiotakis, LOV, School of Medicine, University of Crete, for his contribution in data analysis.

Author Contributions

EK and SP had full access to all study data and take responsibility for its integrity and the accuracy of its analysis.

Study Concept and design: SP and MKT.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: EK and SP.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: EK, SP and PS.

Obtained funding: MKT and SP.

Administrative, technical, or material support: SP, EK and MKT.

Supervision: SP, PS and MKT.

Statements and Declarations

All authors report neither financial nor non-financial interest.

Data availability statement

Raw data were generated at School of Medicine, University of Crete. Derived data supporting the findings of this study are available from the corresponding author (SP) on request.

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No competing interests reported.

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Effectiveness of anti-VEGF treatment in wet Age-related Macular Degeneration; an evaluation of silent reading performance with eye movement analysis

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Abstract

Figures

Introduction

Materials And Methods

Participants

Visual acuity

Reading performance

Procedure

Data analysis

Results

Change in Central Retinal Thickness and Visual Acuity

Reading speed and eye fixation parameters

Discussion

Declarations

References

Additional Declarations

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