The impact of progressive visual field constriction on reading ability in an inherited retinal degeneration

Abstract

Background

Ability to read is an important factor in the quality of life. Choroideremia is an inherited retinal degeneration presenting with gradual, progressive constriction of the central visual field, providing a useful disease model to investigate the impact of visual field on reading ability.

Objective

Provide practical guidance on usefulness of measuring reading ability in patients.

Method

The Radner reading test was administered to 65 eyes with choroideremia. To quantify the residual retinal area, patients underwent microperimetry and imaging. The visual angle subtended by the largest letter read by each subject was calculated using Emsleys Model Eye.

Results

A minimum of one letter must be seen to allow the eye to read, with preservation of foveal sensitivity. The relationship between reading speed and acuity varies with visual field. Reading speed is higher in eyes with an intact fovea (P<0.001 right eye, P=0.06 left eye). Qualitative analysis of the direction of intact retina did not indicate any directional impact on measurement.

Conclusions

In order to read, an eye must have enough retinal width close to the fovea to see at least one full letter. Direction of print does not impact the ability to read, allowing results from different languages to be combined in clinical trials.

2. Introduction

Near (reading) vision has a large impact on quality of life, often being related to independence (1). Difficulties with reading remain the most common problem for presentation at a low vision clinic (2). Distance visual acuity may not predict reading ability across all visual acuities, due to the variability of reading speed across different print sizes and variability in retinal anatomy (3–5). Reading performance should therefore be considered as a separate measure from distance vision.

Reading speed can be affected by the type of vision loss, disease state and to a lesser degree, the presence of cataract (5,6). These factors can have differential impacts on reading speed versus reading acuity, making it helpful to assess these two near vision functions independently. Additionally, reading ability is thought to be impacted by the area of the visual field being used, with the central horizontal field along the reading plane (to enable tracking of the next word in a line of text) and the inferior field (to allow tracking of the next line of text) inferior field being considered the most important (6,7). This will impact on the area of the retina being used for reading as well as the visual span.(8,9) The visual field loss will restrict the number of letters that are physically visible at any one time and likely reduce the reading speed due to the loss of the visual span.

The Radner reading charts allow the measurement of both speed and acuity in a quick, systematic way. It has been validated for use in multiple languages and extensively used for several disease states (3,10,11). The Radner charts have been shown to perform well in low vision patients (5). The test consists of 28 selected short sentences in Helvetica font. The sentences are of similar difficulty and syllabilic content, based on logMAR size progression between paragraphs. The resulting logRAD score is comparable to logMAR and can be adjusted for the working distance used (3,12).

Choroideremia is an X-linked inherited retinal disease characterized by peripheral visual field loss with relative preservation of the central vision (13). This provides a great model to study reading vision as the preserved central retina including the fovea is unlikely to change the pattern of fixation eye movements. The area of functional retina can be accurately quantified by autofluorescence imaging and microperimetry, providing information about the effective visual field to allow real world understanding on the impact of reading performance (13,14). This is becoming more important since the development of phase 3 gene therapy trials for choroideremia, following the successful completion of the phase 1/2 studies (15). This information can also be applied to other inherited retinal dystrophies, particularly rod-cone dystrophies or conditions causing variable visual field defects affecting the periphery more than the center.

3. Materials and Methods

Patients were assessed for inclusion in an ongoing clinical trial, an open-label Phase 2 clinical trial of retinal gene therapy for choroideremia using an adeno-associated viral vector encoding REP1 (Clinica/Trials.gov identifier: NCT02407678, approved by NRES Committee London – West London & GTAC, reference GTAC171 and NCT01461213), conducted in accordance with the Declaration of Helsinki at the Oxford University Hospitals NHS Foundation Trust, United Kingdom. Thirty-three male patients with a genetically confirmed diagnosis of choroideremia completed monocular Radner Reading Chart^© (Precision Vision, Woodstock, IL, USA) testing with optimised refractive error in place. Time taken to read standardised ‘sentence optotypes’ of logarithmically reducing print size were measured and mean reading speed calculated in words per minute (w/min) across all the print sizes. Monocular best corrected distance visual acuity was measured following refraction, using the Early Treatment for Diabetic Retinopathy Study (ETDRS) protocol.

Subjects also underwent microperimetry testing using the MAIA (Macula Integrity Assessment) system (CenterVue SpA, Padova, Italy) after 20 minutes of dark adaptation (light level <1 lux). The 10-2 grid was used using a 4-2 staircase test algorithm. The mean sensitivity around the preferred retinal locus (PRL) was calculated from the average of the four points directly surrounding the PRL. Fixation stability was analysed using the output from the bivariate contour ellipse area indices.

Anatomical methods were used to locate the precise position of the fovea in relation to the residual retina remaining. Macula enhanced depth optical coherence tomography (EDI-OCT) and BluePeak laser fundus autofluorescence (AF) images were obtained using the Spectralis HRA+OCT system (Heidelberg Engineering GmBH, Heidelberg, Germany). Images were processed using Heidelberg Eye Explorer software (Heidelberg Engineering GmBH, Heidelberg, Germany) to first locate the foveola on the EDI-OCT, which is then precisely mapped onto the corresponding 30 degree AF image. A caliper tool was used to measure the horizontal and vertical dimensions of the AF area extending from the center of the fovea; these dimensions were subsequently broken down into their constituent nasal, temporal, superior, and inferior parts. The horizontal and vertical dimensions of AF were used to approximate the functional visual field of each subject, AF area being representative of the presumed surviving retina.(16) For those patients whose fovea fell outside their surviving retina, the caliper tool was used to measure the distance from the fovea to the closest edge of surviving retina, which was assigned a negative value. For all patients, the total area of surviving retina on the 30 degree AF image was also calculated using the draw region tool within Heidelberg Eye Explorer software (HEYEX).

The visual angle subtended by the largest Radner letter read by each subject was calculated using the principles of Emsleys Model Eye, which assumes an overall focal length of 22.22 mm (Figure 1) (17). Using HEYEX, calipers were placed on the AF image to represent the calculated the theoretical retinal image size subtended by a letter on the Radner Reading Chart read at 40cm. The resulting image was exported to Microsoft Word 2010 (Microsoft, Washington, USA) and a Radner chart letter of matching size was overlaid onto the image. The largest letter was considered in this way in order to better understand the impact of visual field loss on reading ability. All statistical analyses were conducted in StatsDirect (StatsDirect Ltd, Cambridge, UK).

Fig. 1.

The Emsleys Model Eye used to calculate the projected retinal image size. Retinal image size (L’); maximum letter height (L); distance from the principle point to the nodal point (D) = 5.55 mm + working distance of the test; distance between nodal point and the retina (D’) = 16.67 mm. L’ = D’*(L/D).

4. Results

A total of 65 eyes from 33 patients were examined. Patient characteristics are shown in Table 1. The eyes were classified into 3 groups depending on the position of the anatomical fovea relative to the remaining functional visual island based on AF imaging (14,16): (1) eyes whose fovea fell within the functional retinal island;(2) eyes whose fovea fell at the edge of their visual island; and (3) eyes whose fovea fell outside the retinal island. This was achieved by tracing out the bright border on the AF image as per the method previously reported to delineate the remaining retina. The foveal centre was marked on corresponding OCT images from the same appointment day and the markings transferred to the AF image to provide accurate localisation and allow assessment of where the fovea fell in relation to the retinal island.

Table 1.

Patient characteristics for the full cohort as well as each foveal-defined group. Data is presented as mean ± SD as all reading and imaging parameters followed a normal distribution. VA and age data are presented as median and interquartile range. VA is visual acuity; AF is fundus autofluorescence.

	Full cohort	Fovea within visual island (Fovea Group 1)	Fovea at the edge of visual island (Fovea Group 2)	Fovea outside visual area (Fovea Group 3)
N (eyes)	65	47	5	13
Age (years)	40 (19–68)	36 (19–55)	47 (42–53)	48 (31–68)
Mean Reading Speed (words/min)	114.9 ± 43.2	129.0 ± 30.2	87.0 ± 41.6	62.6 ± 52.0
Max reading speed (words/min)	153.2 ± 57.8	169.4 ± 42.4	130.7 ± 50.1	88.1 ± 77.1
Total AF foveal width (μm)		3113.9 ± 1559.2	NA	NA
Total AF foveal height (μm)		3417.2 ± 1907.4	NA	NA
Total AF area (mm2)	11.2 ± 11.0	14.0 ± 11.6	4.2 ± 1.4	3.6 ± 5.0
Reading area under the curve (words per minute/logRAD)		107.0 ± 55.1	NA	NA
Average microperimetry threshold (dB)	7.2 ± 6.8	9.2 ± 6.6	0.8 ± 1.1	1.8 ± 3.0
Mean central microperimetry sensitivity (dB)	17.2 ± 9.8	21.3 ± 7.12	2.2 ± 3.8	6.4 ± 6.0
Distance VA (logMAR)	0.2 (1.0 to - 0.1)	0.1 (0.9 to - 0.1)	0.3 (0.8 to 0.1)	0.5 (1.0 to 0.1)
Near VA (logRAD)	0.16 (1.1 to -0.11)	0.10 (1.1 to -0.11)	0.18 (0.4 to 0.01)	0.42 (1.1 to 0.1)

4.1. Reading speed across eyes

The effective size of the print on the retina is demonstrated in Figure 2 with the impact on reading described. Eyes A and B were able to read print but eye C could not see any letters so had a reading speed of 0 words per minute. The full letter needs to fall within structurally intact retina in order to allow reading, which means that smaller print is beneficial to patients with smaller visual fields. From our cohort, a minimum of one letter was required for the patient to be able to read. There were no instances with a minimum 1 letter width and no ability to read. However, each eye displayed a peak sensitivity or maximum reading speed for reading as denoted by the peak of the curve, with both smaller letters and larger letters showing reduced speed (Figure 3). The location of the peak in terms of LogRAD size varied between individuals indicating the benefit of measuring this on an individual basis (Table 2). The tests were compared for right and left eyes separately comparing group 1eyes (24 right eyes and 23 left eyes) with groups 2 and 3 eyes combined (9 right eyes and 9 left eyes) after exclusion of the eyes unable to perform the test. In the right eye the difference in mean reading speed was significant (Mann-Whitney U test P < 0.001, median difference -76 words/minute, 95% Cl with Hodges-Lehman estimator -39 to -100 words/min, n=24 and 8 respectively). The relationship was similar with left eyes approaching statistical significance (Mann-Whitney U test P = 0.06, median difference 51 words/minute, 95% Cl -3 to 97 words/min, n=23 and 7 respectively). Group 1 eyes were able to read faster than the group 2 and 3 eyes.

Fig. 2.

Demonstration of the predicted reading image size projected onto the retina as calculated by the Emsley model. Patient A was able to comfortably read LogRAD print 1.0 as shown. Patient B was able to slowly read the LogRAD 1.1 letters shown, whereas patient C was unable to read the same size as the full letter did not fit within the island.

Fig. 3.

Alteration in reading speed with letter size in a representative patient with good central vision (A) and with poor central vision (B). Reading speed appears to decrease at smaller and larger acuities than the optimal point but the shape of the curve changes across the cohort.

Table 2.

Results for each participant. The near visual acuity, maximum reading speed and the print size this was achieved at, as well as the minimum reading speed at the corresponding print size is shown to demonstrate the variability in results.

Eye	Near Visual Acuity (logRAD)	Maximum reading speed (words/min)	Print size for this measurement	Minimum reading speed (words/min)	Print size for this measurement
1	0.200	148.673	0.900	60.650	0.200
2	0.100	182.609	0.500	69.421	0.100
3	0.020	145.581	0.200	26.038	0.000
4	-0.030	140.234	0.800	32.420	0.100
5	0.115	220.472	0.600	31.461	-0.100
6	-0.075	180.645	0.800	31.461	-0.100
7	0.100	177.590	0.400	85.977	0.100
8	0.000	169.697	0.700	64.073	0.000
9	-0.085	152.450	0.600	9.251	0.000
10	0.110	209.476	0.900	62.454	0.100
11	0.100	180.258	0.200	57.338	0.100
12	0.100	169.697	1.100	23.204	0.100
13	0.210	166.667	0.800	80.614	0.300
14	0.060	177.966	0.400	33.967	0.100
15	0.100	181.818	0.900	91.304	0.200
16	0.000	205.379	0.800	28.103	0.000
17	0.110	145.833	0.800	31.111	0.100
18	0.130	166.667	0.800	38.621	0.100
19	0.110	251.497	0.500	27.741	0.000
20	-0.110	192.220	1.100	43.344	-0.200
21	0.100	129.231	0.700	54.545	0.100
22	0.315	168.675	0.900	91.803	0.400
23	0.200	150.000	0.900	47.673	0.200
24	0.215	135.484	0.700	22.642	0.200
25	0.000	170.040	0.400	103.576	0.900
26	0.400	67.851	0.700	22.783	1.100
27	0.205	145.329	0.800	37.053	0.200
28	0.305	57.931	0.800	6.925	0.300
29	0.600	54.194	0.600	40.191	1.100
30			Unable to read
31	0.300	40.580	1.000	13.440	0.400
32	0.410	33.202	0.600	9.459	0.400
33	1.100	11.748	1.200	5.512	1.100
34	0.000	176.842	0.900	48.138	0.000
35	0.100	172.840	0.600	70.529	0.100
36	0.140	98.824	0.500	40.462	0.100
37	-0.090	132.911	0.400	35.578	-0.100
38	0.010	187.500	0.500	61.584	0.000
39	-0.095	200.477	0.200	73.814	-0.100
40	0.050	190.909	0.500	36.522	0.000
41	-0.080	138.386	0.400	64.615	-0.100
42	0.015	150.268	0.200	72.351	0.000
43	0.100	213.198	0.200	123.348	0.100
44	0.035	138.614	1.000	19.503	0.000
45	0.280	121.916	0.900	29.546	0.200
46	0.100	152.450	1.000	89.172	0.100
47	0.080	174.274	0.900	35.413	0.000
48	0.105	160.305	0.800	47.511	0.100
49	0.030	163.107	0.900	22.234	0.000
50	0.080	138.614	1.100	14.508	0.000
51	0.170	181.818	1.100	28.966	0.100
52	0.210	216.495	0.600	34.105	0.100
53	-0.095	197.183	0.500	45.405	-0.200
54	0.225	133.333	0.700	39.810	0.200
55	0.200	138.614	0.400	94.595	0.200
56	0.010	94.382	1.000	21.429	0.000
57	0.000	218.750	0.400	128.440	0.100
58	0.200	150.538	1.000	33.667	0.300
59			Unable to read
60	0.300	262.500	0.600	97.674	0.300
61			Unable to read
62	0.405	280.000	1.000	103.704	0.600
63	0.100	178.723	0.400	100.000	0.100
64	0.620	51.852	0.800	12.000	0.600
65	1.100	16.406	1.300	7.113	1.100

4.2. Microperimetry

Microperimetry threshold has previously been reported as a more sensitive marker of central vision than visual acuity and we therefore felt it important to examine the relationship with reading ability (13). Microperimetry patterns were analysed in the fovea group 3 individuals to assess whether fixation pattern or the location of the seeing points were altered in those that could read versus those unable to read print. Three out of the four eyes that were unable to read had 3 or less seeing points located away from the fovea despite good fixation (Figure 4A). One patient did have a larger seeing island but it was very narrow at the fovea (Figure 4B). All eyes that were able to read showed a cluster of seeing points within the central portion of the microperimetry grid (Figure 4C). No pattern was noted between reading speed and nearest foveal edge in group 3 (Figure 4D).

Fig. 4.

(A) Example of an eye unable to read from Group 3 showing microperimetry seeing points far from the fovea. (B) Example of an eye unable to read from Group 3 showing large preserved microperimetry islands but insufficient width at the fovea. (C) Example of an eye able to read from Group 3 showing a cluster of seeing points enclosing the central visual field. (D) Reading speed of all Group 3 eyes. (E) Relationship between mean reading speed and autofluorescence area in Group 1 eyes. (F) Relationship between maximum reading speed and mean central microperimetry sensitivity in Group 1 eyes.

Group 1 eyes were investigated to assess which biological and functional factors impacted on the ability to read. Mean reading speed and AF area appear to show a weak relationship with increasing speed as the AF area increases until an area of 20mm² (Figure 4E), as were average reading speed and the sensitivity of the central 4 points on microperimetry (Figure 4F).

4.3. Direction of vision

Since reading English involves left to right scanning of text, we next investigated whether the meridian of preserved structurally retina had an impact on reading characteristics. Due to the correlation in the pattern of central loss between AF and microperimetry,(14) AF was used to approximate the functional VF of each subject, AF being representative of the structurally surviving retina, and therefore less variable. Only eyes within group 1 were used in this analysis in order to prevent confounding from changes in fixation altering the reading ability. Patients whose fovea fell outside or at the edge of their surviving retina were not included in this analysis. The random pattern in Figure 5 indicates that neither the horizontal nor vertical localisation of remaining print impacted on the reading ability.

Fig. 5.

Person plots demonstrating the relationship between reading speed and nasal-temporal and superior-inferior location of the surviving retina in relation to the fovea.

4.4. Reading speed versus acuity

The relationship between mean reading speed and maximum reading acuity was investigated using Spearman rank correlation. Data were collected on 32 right and 30 left eyes that were able to complete the reading task. A moderate negative correlation was detected using measurements taken from the right eye (p = -0.59, P = 0.0002), and a weak negative correlation was detected in the left eye measurements (p = -0.25, P = 0.09), suggesting that the right eye might have a more critical role for reading speed (Figure 6). Table 2 shows the minimum and maximum reading speeds measured for each eye measured along with the print size for this measurement. The near visual acuity is also shown. In some eyes the minimum reading speed was obtained at a print size larger than the maximum sensitivity.

Fig. 6.

Correlation between reading speed and reading acuity for right and left eyes.

5. Discussion/Conclusion

In order for an eye to be able to read, two conditions must be met. Firstly, the retina viewing the text must have adequate health and resolution for the size of text displayed. Secondly, the full letter must be seen within the visual field available. Our study considered both reading speed and reading acuity as important determinants of real-world visual function in retinal degenerations. Our data showed moderate to weak correlation between reading speed and acuity. The shape of this relationship varies in low vision, in keeping with previous work (5), and can provide a clue as to the visual field remaining as well as the real world function of the patient. This also shows the importance of looking at both reading speed and reading acuity as important factors. Our results also suggest that the right eye may have more influence on the reading speed but this may relate to eye dominance which was not measured.

Traditionally, low vision rehabilitation has focused on strategies of magnification. However, when the visual field is severely restricted in retinal diseases fewer larger letters could fit within the available functional retinal area so that larger scanning eye movements are required, slowing down reading. Our results showed that the relationship between reading speed and letter size is variable, thus magnification may not always represent the best strategy to aid reading. The ability to read requires acuity reserves, explaining the drop off in reading speed for smaller letters (18). Strategies for low vision rehabilitation should balance resolution and speed of the print being read.

For the English version of the Radner test, the mean reading speed achieved by a normal cohort was 201.53±35.88 words per minute.(11) Our choroideremia cohort rarely reached this level. When using high contrast print, it has been reported that 160 words per minute allows comfortable functional reading of print. To be able to read for a sustained period, 80 words per minute is required and 40 words per minute for spot reading such as post or labels (18). For eyes with a fovea within the visibly preserved retina (Group 1), mean reading speeds were above threshold for sustained reading and the maximum reading speed reached comfortable functional reading levels. Eyes with foveal splitting retinal degeneration (Group 2) could maintain sustained reading but struggled to reach comfortable reading speed without aids. When the fovea is outside the remaining retinal island (Group 3), the eyes could only manage spot reading speed. This is indicative of the fact that while choroideremia patients could maintain high levels of distance acuity until the end-stages of the disease, their quality of near vision is significantly reduced long before foveal involvement. This has an important lesson for optimizing the reading abilities of these patients by using the appropriate print size for maximum reading speed. Additionally, the visual span (ability to recognize multiple letters in the visual space) will be physically reduced in cases of visual field loss, explaining why the reading speed is reduced from early on.(8,9,19) The lack of a strong correlation between AF area and reading speed may indicate that the diameter of remaining vision at the fixation point may be the critical area rather than the full area available. In order to measure this accurately, fixation would need to be monitored and the complex shape of the remaining retinal islands taken into account.

Retinal gene therapy has been shown to help preserve or improve visual acuity in advanced choroideremia (15). In addition, gene replacement may also improve the retinal sensitivity over the macula, thus further benefiting reading speed. In order to preserve the quality of life, the minimum area of functional retina to be preserved will vary depending on the tasks important to the patient (1). If we make the assumption that spot reading is the minimum acceptable target for a therapeutic strategy, the minimum retinal island width to achieve this could be calculated. For instance, newspaper print is equivalent to around 0.4 logRAD (20). In order for the width of a retinal island to contain a 0.4 letter, it needs to be at least 118 μm in width. In addition maximum reading acuity can potentially be increased as central microperimetry sensitivity increases, providing additional benefits following therapeutic intervention. The eyes unable to read had lost all sensitivity in the central fovea showing the importance of preserving this area for therapeutic benefit. This is not the case in age- related macular degeneration and may reflect the more widespread nature of rod-cone dystrophies.(21)

We also assessed whether the shape of the remaining functional retinal islands correlated with reading ability. Interestingly, the direction of the preserved retina in relation to the fovea, and therefore direction of the adjacent letter visible, did not appear to have any impact on reading ability. Phase 2 and 3 trials for new therapies are often multicenter, spanning across continents. The Radner reading test is available in a number of languages, some of which have text directions different to English. This work would suggest that the direction of the text should not impact on the results, so measurements in different languages could be combined regardless of the direction of the text. This provides valuable information to guide near-vision testing in future international multi-centered clinical trials using reading ability as an outcome measure.

In conclusion, the Radner reading chart is a practical and useful test for the measurement of both reading speed and reading acuity in retinal disease. These factors present valuable outcome measures in therapeutic trials and should be analyzed in combination rather than separately. While the relationship between text size and the functional retinal area contribute to reading speed, the centration of the retinal area in relation to the fovea does appear to impact on the ability to read. Therefore, in order to be able to read, an eye must have enough retinal width close to the fovea to see the at least one full letter of the print being read. Direction of the print does not impact the ability to read, allowing tests in different languages to be combined in a clinical trial setting.