The VA-CAL Test Quantifies Improvement of Visual Acuity in Achromatopsia by Means of Short-Wave Cutoff Filter Glasses in Daily Living Conditions

Abstract

Purpose: To quantify visual performance of patients with achromatopsia at various contrast and luminance combinations typical for daily living conditions, in comparison to controls, and to measure beneficial effects of short-wavelength cutoff filter glasses used by patients with achromatopsia to reduce glare sensation.

Methods: Best-corrected visual acuity (BCVA) was tested with Landolt rings using an automated device (VA-CAL test). The visual acuity space was assessed for each participant with and without filter glasses (transmission >550 nm) at 46 contrast–luminance combinations (18%–95%; 0–10,000 cd/m²). The BCVA differences between both conditions were calculated for each combination as absolute values and relative to individual standard BCVA.

Results: Fourteen achromats (mean ± SD: 37.9 ± 17.6 years) and 14 normally sighted controls (mean ± SD: 25.2 ± 2.8 years) were included in the study. Without filter glasses, achromats’ BCVA was best at 30 cd/m² (mean ± SEM: 0.76 ± 0.046 logarithm of the minimum angle of resolution [logMAR], contrast = 89%) and worst at 10,000 cd/m² (mean ± SEM: 1.41 ± 0.08 logMAR, contrast = 18%), a deterioration up to 0.6 logMAR due to increased luminance and decreased contrast. Filter glasses improved achromats’ BCVA for almost all luminances by about 0.2 logMAR but lowered controls’ BCVA by about 0.1 logMAR.

Conclusions: The VA-CAL test provides numerical proof that short-wavelength cutoff filter glasses can help patients with achromatopsia in everyday life, avoiding the common situation of severe visual impairment at certain daily object contrasts and ambient luminances.

Translational Relevance: The VA-CAL test discovers losses of spatial resolution in the visual acuity space not seen in standardized BCVA assessment. Filter glasses improve the patients’ daily visual performance, rendering them a strongly recommended visual aid in achromatopsia.

Introduction

Achromatopsia is an inherited autosomal recessive retinal disease characterized by a loss of cone photoreceptor function caused by gene mutations,^1–5 mostly in the CNGA3 or CNGB3 gene^1–7 (up to 80% of the patients).⁴ This manifests itself in four main symptoms typical for this disease: a reduced best-corrected visual acuity (BCVA), photophobia (glare sensitivity), nystagmus, and total color blindness.^1–5 Gene replacement interventional trials in Tuebingen as well as on several more sites worldwide are aiming at developing treatment possibilities, showing so far only a slight improvement of visual acuity (VA) and contrast sensitivity.^2,8 However, to reduce photophobia, most patients use short-wavelength cutoff filter glasses or tinted contact lenses, blocking short-wave light from the visible spectrum, which is the main factor for photophobia.⁹ In this study, we examine the effects of these filter glasses on visual performance by measuring VA at different contrasts and luminances, reflecting daily viewing conditions, and comparing the VA results reached with or without wearing a filter glass. It is known that VA of patients with achromatopsia—also called “achromats” or rod monochromats—is vastly impaired with increasing luminance,^10,11 starting already at approximately 100 cd/m²,¹¹ although they report the perception of unbearable glare only at higher luminances. Thus, clinically measured VA determined at standardized conditions (ambient luminance 80–320 cd/m² with maximum optotype contrast)¹² is not representative and overestimates VA in daily life situations,¹¹ in which the ambient luminance already reaches 2000 to 8000 cd/m² on cloudy days¹³ and thus significantly exceeds the defined luminance range in the clinical VA test. Here we report a more reliable assessment of the visual performance of achromats under daily luminance and contrast conditions by means of the VA-CAL test.¹⁴ In addition, the study presents a new scoring chart for BCVA in a contrast–luminance visual acuity space, which is intended to be used for rapid assessment of visual performance in specific real-world viewing conditions, including those that can cause photophobia. We also can show that short-wavelength cutoff filter glasses are a very useful aid for patients with achromatopsia in daily life, as they prevent legal blindness occurring at contrast and luminance levels typical in daily life. 

Materials and Methods

Study Participants

14 achromats (ACHM; aged 16–67 years, mean ± SD: 37.9 ± 17.6 years) and 14 normally sighted controls (aged 21–29 years, mean ± SD: 25.2 ± 2.8 years) underwent the VA-CAL test at the Institute for Ophthalmic Research, Tuebingen, between June 2020 and March 2021. Three of the achromats had biallelic mutations in the CNGA3 gene and 11 in the CNGB3 gene. 

After signing an informed consent form, BCVA with early treatment diabetic retinopathy study (ETDRS) chart (4 m), slit-lamp examination, optical coherence tomography, and Farnsworth D-15 Color Test was done at an initial ophthalmic examination. Patients with additional eye disorders (e.g., cataracts or post–cataract surgery) were excluded from the study. Controls were healthy individuals with a monocular BCVA of ≧0.8 decimal (0.1 logarithm of the minimum angle of resolution [logMAR]) and no eye disorder. The participants could stop the test at any time. The protocol complied with the Declaration of Helsinki and was accepted by the local ethics committee of the medical faculty of the University in Tuebingen (431/2019BO2). 

Procedure

The VA-CAL setup was used to assess BCVA by presenting Landolt rings at a 1-m distance at ambient luminances (ALs) between 0 and 10,000 cd/m² with Weber contrasts of 18% to 95%.¹⁴ Ambient luminances were generated by high-power LEDs (Power Flat LED Tapes, 6000K; Solarox Holding GmbH, Dessau-Roßlau, Germany). The target background (5.7-degree light-protected projection surface) had a limited luminance range of 100 to 6800 cd/m². This means that under the 320-cd/m² condition and from the 8000-cd/m² condition, the target background had a slightly different luminance than the ambient light. For all other ambient luminances, the values were similar. VA at 95% contrast was measured only above 320 cd/m² because of technical limitations. The QUEST adaptive staircase was used for VA threshold estimation,¹⁵ starting with a Landolt ring at each condition with a visual angle of 0.03 degrees (VA of 0.4 logMAR) for normally sighted controls and a visual angle of 4.16 degrees (VA of 1.6 logMAR) for ACHM. 

VA was determined monocularly (eye with better VA or leading eye) without pupil dilation using best correction of refractive errors as ascertained in the BCVA test at 4 m (initial examination). For ACHM aged >40 years, an additional near addition of one diopter was added.¹⁶ 

The procedure did not differ from previous investigations with the VA-CAL test (Supplementary Fig. S1).¹⁴ The participants were instructed to indicate the opening direction of the isolated Landolt ring (8 alternative forced choice (AFC)) by wireless keypad as fast as possible (maximum of 10 seconds). A missing response within this time was considered incorrect. Response times (i.e., the time between stimulus presentation and pressing the button on the keypad) were additionally recorded. After completion of the procedure and a subsequent 15-minute break, a second trial was carried out with a short-wavelength cutoff filter glass (PC 550 nm; Multilens, Mölnlycke, Sweden) to check its effect on VA at 46 different contrast–luminance combinations by the same procedure as in the first run. The filter glass was positioned in front of the correcting lenses of the trial frame. 

Statistical Analysis

Statistical analysis was performed with JMP 15 (SAS Institute, Cary, NC, USA). We investigated the absolute number of normally sighted controls and patients with achromatopsia who completed the different luminance steps (Fig. 1). Descriptive statistics (mean and standard error [SEM] since we did group comparison)¹⁷ of VA logMAR were calculated for controls (n = 14, Figs. 2A, 2B, Table) and achromats (n = 14, Figs. 2C, 2D, Table). The mean VA of each tested luminance–contrast combination was compared with the mean VA reached at the standard condition according to DIN EN ISO 8596 (VA_st; AL = 320 cd/m², contrast = 95%) by calculating the VA difference in logMAR (Fig. 3). Normality was checked with the Anderson–Darling test. The results of the controls without a filter glass have already been published¹⁴ and are presented in this study for comparison with the data with a filter glass. Some achromats did not complete the test at high ambient luminances beyond the range of 3000 to 5000 cd/m², especially without filter glasses, because they could not keep their eyes open or had pain at a certain luminance (Fig. 1). 

Table.

 

Data of Normally Sighted Controls and Patients With Achromatopsia

 

Figure 1.

 

Number of participants completing the test at the various luminance levels. Lenses were added for refractive correction during the test. Two viewing conditions were examined with the VA-CAL test: without (A) and with a filter glass (B, transmission >550 nm). Controls completed all luminance levels (black bars in A, B), while some achromats had to stop the test at higher luminances without filter glass (red bars in A) because they could not keep their eyes open due to the high glare or pain. This improved during the run with filter glass (red bars in B).

A restricted maximum likelihood model was used for analyzing the effect of contrast and ambient luminance (fixed effects) on the participants’ (random effect) response times (RTs). Mean RTs for the specific contrast–luminance combinations were used for comparing the effect of the filter glass (Supplementary Table S1). Moreover, the responses were divided into correct or incorrect. 

For further analysis, 14 of the 46 contrast–luminance combinations with ALs from 30 to 5000 cd/m and contrasts of 18% to 82% were taken to construct a short version of the test, still including a BCVA condition (AL = 320 cd/m², C = 82%) in the range of the standard condition of DIN EN ISO 8596 norm (“standard VA”). 

The effect of the filter glass on VA under the specific contrast–luminance conditions was calculated by the logMAR differences between each VA measured without and with filter for each participant. Subregions of VA (regions of special interest) were defined by averaging the VA differences of the three adjacent contrast–luminance combinations. Color-coding (green = VA improvement, red = VA deterioration, gray = neither) was used for a graphic illustration that allows the outcome of the test to be quickly grasped (Fig. 4). 

Luminous transmittance of the filter glass was calculated by luminance with filter divided by luminance without filter multiplied by a factor of 100. 

Pupil diameter was measured by determining the number of pixels along the diameter of the pupil in a picture taken within adaptation phase to each luminance (ImageJ, version 1.8.0; National Institutes of Health, Bethesda, MD, USA) and converting the pixels to millimeters (1 pixel = 0.286 mm). Due to squinting and nystagmus, the pupil diameter could not be measured reliably in all ACHM (Supplementary Tables S2 and S3). 

Results

BCVA determined in the ACHM patients at the initial examination (ETDRS chart; luminance = 100 cd/m²; Weber contrast = 98%) was between 1.3 and 0.7 logMAR (mean ± SEM: 0.84 ± 0.04 logMAR). Spherical refractive errors of ACHM ranged from +10.5 to −9.75 diopters, with cylinders of up to −3.75 (for the distribution of spherical equivalent [sphere + astigmatism/2], see Supplementary Fig. S2A). Controls showed BCVA values between 0 and −0.3 logMAR (mean ± SEM: −0.19 ± 0.03 logMAR) with spherical refractive errors from +2.0 to −3.5 diopters and cylinders up to −1.75 (Supplementary Fig. S2B). 

The BCVA values (logMAR) of the controls determined with VA-CAL followed a normal distribution (P = 0.059 [with/without filter]), while that of the ACHM subjects did not (P < 0.0001 [with/without filter]). 

Table and Figure 2 describe mean VA at various luminances and contrasts. Controls showed an improvement in VA up to an AL of 3000 to 5000 cd/m² without filter glasses (Fig. 2A).¹⁴ Wearing filter glasses worsened the VA of controls in all conditions by about 0.1 logMAR (Fig. 2B). Compared to controls, the VA of ACHM patients was up to 1.5 logMAR worse, particularly at low contrasts and high luminances. Without filter glasses, ACHM reached their best VA at 30 cd/m². With increasing luminance, VA decreased by about 0.08 logMAR per 1000 cd/m² up to an AL of 3000 cd/m², followed by a steady low VA up to an AL of 8000 cd/m² and a subsequent drop of VA to a minimum AL of 10,000 cd/m² (Fig. 2C). Wearing filter glasses, ACHM improved their VA in all conditions (Fig. 2D), with the highest improvement at higher AL and lower contrasts. The maximum VA was shifted to an AL of 320 cd/m². The minimum VA again was reached at an AL of 10,000 cd/m². Lower contrast led to a reduction of VA in all luminances. 

Figure 2.

 

Mean visual acuity thresholds of healthy controls (n = 14; A, B) and achromats (ACHM; n = 14; C, D) determined at different contrasts and ambient luminances. SEM was used for error bars (A–D). VA was ascertained without filter glass (A: controls, C: ACHM) as well as with filter glass (B: controls, D: ACHM). The different contrasts are symbolized by different colors. VA at 95% contrast was measured only above 320 cd/m² because of technical limitations. Some of the ACHM stopped the test earlier, by which the mean VA for these luminances was calculated only by the values of the corresponding participants (see Fig. 1).

Figure 3 illustrates the VA differences (color-coded) to the standard VA testing condition (VA_st, AL = 320 cd/m², contrast = 95%). Without filter glasses, controls had VA values above VA_st, especially at high luminances with high contrasts (Fig. 3A). At lower contrasts, VA was worse than VA_st, reaching the maximum difference of about 0.4 logMAR at high and low luminances. The use of filter glasses only resulted in losses in the whole luminance–contrast space in relation to VA_st (Fig. 3B) in the range of two lines at medium contrasts, culminating in values greater than the 0.4 logMAR difference. ACHM (Fig. 3C) showed slightly better VA than VA_st only at luminances lower than 320 cd/m² with high contrasts. In the other conditions, VA was always worse than VA_st. With increasing luminance and additionally decreasing contrast, the VA difference to VA_st continually decreased up to six lines. Wearing the filter glass improved the VA of ACHM compared with VA_st (Fig. 3D). With filter glasses, their VA differences to VA_st were smaller than without the filter in the entire luminance–contrast space (Fig. 3D). A VA better than VA_st was achieved by ACHM at higher contrasts, now up to 3000 cd/m². At lower contrasts, the difference was between 0.1 and 0.2 logMAR. With filter, the maximum difference of 0.41 logMAR to VA_st occurred at the highest luminance and lowest contrast. There was an improvement of 0.21 logMAR in this condition compared to without filter. 

Figure 3.

 

Heatmap of averaged VA (logMAR) difference of each contrast–luminance combination to the standard VA value (VA_st, depicted with the star, AL = 320 cd/m², C = 95%) for controls (A = without filter, B = with filter) as well as ACHM (C = without filter, D = with filter). The VA_st of the respective participant group reached without filter glass (VAst controls = −0.41 logMAR, VA_st ACHM = 0.79 logMAR) was used as a reference for calculation of the difference. The differences are color-coded: orange to red = VA worse by 0.1 to 0.6 logMAR than achieved in the standard condition (VA_st); gray = slightly worse; green = better VA than VA_st.

In Figure 4, based on the extended results, we focused on the most critical conditions of daily life. The VA difference caused by the filter was calculated, showing how the filter affected the VA in defined luminance–contrast subregions (color-coded). In controls (Fig. 4A), VA was reduced by the filter glass in each subregion. The deterioration was smallest at high luminances with high contrasts and greatest at low luminances no matter if low or high contrasts. The mean VA difference (VA-CAL score) ranged from 0.06 logMAR (subregion L) to 0.14 logMAR (subregion C). In ACHM (Fig. 4B), on the other hand, VA improved in each subregion with the filter glass. The VA difference was smallest at low luminances with high contrasts and greatest at high luminances with low contrasts. The greatest VA improvement was −0.16 logMAR (subregion N), while the smallest VA improvement was −0.05 logMAR (subregion B). 

Figure 4.

 

Mean difference between the visual acuity with and without the filter glass, for controls (A) and achromats (B) summarized as VA-CAL score, representing VA under specific contrast–luminance conditions. The VA differences of each participant were calculated first and then averaged. The luminance–contrast conditions were divided in subregions, each containing specific testing points. The corresponding values were averaged by the mean VA difference of with versus without filter glass of the adjacent three testing points/conditions. The mean VA differences for the testing points (TPs) and the subregions (RSI) are presented in the tables on the right. TP 4 represents standard VA in VA-CAL short version and was not included in the calculation of the subregions (just three adjacent TPs). The star symbolizes the contrast–luminance combination on which VA is clinically assessed with the standard ETDRS chart. The mean VA differences are symbolized by different colors: gray = no/less difference with ±0.05 logMAR; green = improvement in VA caused by filter glass; red = deterioration of VA caused by filter glass. The different luminance and contrast levels are depicted as different symbols.

Response times of ACHM were highly significantly affected by AL (P < 0.0001) and by contrast (P = 0.0008), both with and without filter (P < 0.0001 for both parameters). In both viewing conditions, RTs became longer with increasing AL and decreasing contrast (Supplementary Table S1). Without filter, RTs increased over all contrast on average by 41.3 (95% confidence interval [CI], 34.9−47.8) ms per 1000 cd/m², with filter by 32.5 (95% CI, 27.2−37.9) ms. Thus, the filter glass caused an RT improvement of about 9 ms per 1000 cd/m². Values of incorrect responses were 150 ms longer on average than correct answers without filter and 250 ms with filter (Supplementary Fig. S3). 

Pupil diameter of ACHM already was 2 mm smaller than in the control group at the minimum AL of 0 cd/m². The pupil diameter of ACHM decreased with a higher luminance by about 1 mm at 320 cd/m², followed by another decline up to 5000 cd/m². With filter glasses, the mean pupil diameter was larger in both groups in all conditions, again showing a reduction with increasing luminance (Supplementary Tables S2 and S3). 

Luminous transmittance of the filter glass for the condition with 0 cd/m² ambient luminance, meaning only the presence of the target background with a luminance of 100 cd/m², was about 22%. For the condition with 3000 cd/m² ambient luminance, the luminous transmittance of the filter glass was 29%. 

Discussion

We investigated the effect of short-wavelength cutoff filter glasses on the visual acuity of achromats and healthy controls at different conditions of contrasts and ambient luminance using the VA-CAL test, which allows a more realistic, close to everyday life condition evaluation of the visual performance. With the conventional clinical determination of BCVA (e.g., using the ETDRS chart),¹⁸ measurements are only performed with a fixed luminance (80–320 cd/m²) and maximum optotype contrast,¹² covering only a very small range of conditions of daily life. Our results show that the VA of achromats continuously decreases with increasing luminance, reaching the status of moderate to severe visual impairment (0.5−1.3 logMAR).¹⁹ Compared to the achromats’ VA at the standard condition, this leads to a worsening of VA of about six lines. The clinically measured VA, therefore, is often overestimated and better than it is in patients’ daily living conditions, which was also found in previous studies.¹¹ Controls also showed a four-line drop in VA to standard condition with lowest contrast and highest luminance. In controls, glare thus seems to occur above 8000 cd/m², which reduces their visual performance. Thus, controls show a higher resistance to glare compared to achromats. VA changes take a different course when increasing the luminance to approximately 3000 cd/m², leading to an improvement in VA in controls at all contrasts, while achromats show a steady decline. 

At the level where achromats’ vision decreases with higher luminances, some patients use the term glare already at moderate luminance levels, showing first signs of squinting and lid closure, although most objective signs of glare (frequent lid closure, pain, inability to see large Landolt rings) occur only above luminance levels of 3000 to 5000 cd/m² (Fig. 1B). Loss of VA is therefore part of the disorder that does not allow proper information processing of rod signals in the retina even at luminance levels below values where photophobia prevents further testing. 

Photophobia in achromats and their generally poor VA can be explained by the inherited condition of nonfunctioning cone photoreceptors.^{1,2,4,5,20,21} According to achromats in this study, photophopia was also the reason why they wanted to stop the measurement at a certain luminance level without filter glasses. As a direct aid against sensation of glare, patients often use short-wavelength cutoff filter glasses, which filter out the glare-causing short wavelengths.⁹ Other studies showed reduced photophobia and improved VA when using tinted lenses.^22–24 Almost all achromats (12 of 14) could handle the highest glare of 10,000 cd/m² in this study with filter, whereas without the filter glass, only 5 of 14 achromats continued up to the highest levels tested. The filter glass apparently protects from subjective glare sensitivity and the associated feeling of discomfort. Another indication of increasing glare is the rising response time with higher luminances that was found in this study. This was improved by wearing the filter glass, which may lead to faster orientation in daily environments. 

Using the filter glass, the VA of achromats improved over all luminance–contrast combinations. Especially at high luminances, the mean VA of ACHM was up to 0.23 logMAR better than without wearing a filter glass. We also could confirm previous studies that described an increased contrast sensitivity in achromats when using filter glasses, which most likely also contributes to the improvement of VA.^9,22 Improvement of VA at higher luminances was also shown for other retinal diseases like retinitis pigmentosa.²⁵ Examples from everyday life illustrate how often one is confronted with such high luminances. Own measurements have shown that a Caucasian face already has 8000 cd/m² in the sun. The filter glass could thus also help in facial recognition. A white car in the sun has a luminance of 20,000 cd/m², and hence, potential glare and danger when crossing the street can be reduced with the filter glass. Moreover, road signs that reach up to 19,000 cd/m² in the sun could be better read and traffic lights, with luminances of between 2000 and 8000 cd/m²,¹³ could be better recognized, even though the problem of color vision still arises here. A filter glass can thus substantially help achromats in all kinds of everyday situations, both in visual performance and for general well-being. 

It may seem that normal sunglasses could simply be used to absorb the entire light spectrum and thus prevent saturation of the rods of achromats. Furthermore, there is some probability that neutral density filters of similar absorption for white light achieve the same effect. However, blocking short-wavelength light may have beneficial effects by avoiding chromatic aberration and straylight by activation of autofluorescence from the natural lens, induced by blue light in middle-aged and older adults. Nevertheless, the maximum sensitivity of rods is in the short-wavelength region of the visible spectrum, so a filter that passes only long-wavelength light is well suited.⁹ In addition, there are incomplete achromatopsias, in which some cone types function partially,²⁶ and it cannot be excluded that even in complete achromats, some cones still exist. Thus, these existing cones could be stimulated while reducing the light exposure of the rods.⁹ 

The filter glass used here (transmission >550 nm) is very well suited. It can be worn in any daily luminance situation without having to change it constantly, especially since, as shown in this study, it has a positive effect on achromatic VA at almost all luminances. Using individually selected filter glasses, as recommended,⁹ may have resulted in an even higher improvement of VA in some achromats. 

The VA of the normal controls improved with increasing luminance, as shown in other studies.²⁷ However, when using short-wavelength cutoff filter glasses, they showed a deterioration of VA for all conditions. This may be explained by the fact that the filter glass reduces the retinal illumination, an effect that in achromats is masked by the degree of improvement. Thus, the gain of VA in such conditions in achromats not only compensates this physiologic loss but also surpasses it by a further gain of almost two lines. 

Subregions representing specific luminance and contrast conditions can be used for assessing VA changes by interventions in clinical studies (VA-CAL scoring chart), for example, in the CNGA3 gene replacement therapy trial targeting achromatopsia.^2,8 For a short version, focusing on the most critical conditions of daily life, we chose luminances from 30 to 5000 cd/m², ensuring that patients could complete the test. The reduced range still allows the identification of typical VA performances and inferences of pathology. This will also result in a shorter total test duration of about 25 minutes per eye but still allows for an analysis of the results in different levels of abstraction (overall mean, quadrants, subregions, single contrast/luminance conditions). 

In conclusion, testing the BCVA of achromats in a range of critical contrast and ambient luminances by means of the VA-CAL test provides a reliable assessment of visual performance in daily life that is not possible with the clinical standard BCVA test alone. With increasing luminance and decreasing contrast, the VA of achromats can deteriorate by about six lines compared to the standard condition. Short-wavelength cutoff filter glasses proved to be a very useful aid for achromats, improving VA across all contrast–luminance combinations. Especially at higher luminances, the VA of achromats was up to two lines better than without filter glasses, thus avoiding the severe visual impairment that normally occurs in achromatopsia at higher luminances. 

Acknowledgments

The authors thank the Tistou & Charlotte Kerstan Foundation Vision 2000 and the Achromatopsie Selbsthilfe e.V. for their financial support; Fadi Nasser, Friederike Kortüm, Lisa Pohl, Melanie Kempf, and Saskia Ott for implementation and help with the initial examination; Sandra Wagner for helpful discussions; and PD Anne Kurtenbach for proofreading. 

Disclosure: J. Hilmers, EyeServ GmbH (C); M. Bach, None; K. Stingl, None; E. Zrenner, EyeServ GmbH (C), EyeServ GmbH (P); T. Straßer, EyeServ GmbH (C)