Retinal thickness in children with anisohypermetropic ...

Downloaded from http://bjo.bmj.com/ on February 14, 2015 - Published by group.bmj.com

BJO Online First, published on February 13, 2015 as 10.1136/bjophthalmol-2014-305685 Clinical science

Retinal thickness in children with anisohypermetropic amblyopia Tomo Nishi, Tetsuo Ueda, Taiji Hasegawa, Kimie Miyata, Nahoko Ogata Department of Ophthalmology, Nara Medical University, Kashihara, Nara, Japan Correspondence to Dr Tomo Nishi, Department of Ophthalmology, Nara Medical University, 840 Shijo cho Kashihara, Kashihara, Nara 634-8522, Japan; [email protected] Received 16 June 2014 Revised 19 December 2014 Accepted 16 January 2015

ABSTRACT Purpose To determine the thickness of the fovea in eyes of children with anisohypermetropic amblyopia, their fellow eyes and eyes of age-matched controls. Additionally, to assess the effects of optical treatment on the foveal thickness in eyes with anisohypermetropic amblyopia. Materials and methods Twenty-one patients (6.0 ±2.3 years, mean±SD) with anisohypermetropic amblyopia and 25 age-matched controls (5.6±1.9 years) were studied. Spectral-domain optical coherence tomography (SD-OCT) was used to obtain OCT images. The foveal thickness and the thickness of the outer nuclear layer (ONL), photoreceptor inner segment (IS) layer and outer segment (OS) layer were measured by the embedded OCT software. Results The length of the OS was significantly greater in the fellow eyes (48.0±6.6 mm) than in the amblyopic eyes (42.4±4.6 mm, p=0.03). One year after the optical treatment of the anisohypermetropia, the best-corrected visual acuity (BCVA) improved and the length of the OS was significantly increased ( p=0.0001). After optical treatment, there was no more significant difference in the OS length between the amblyopic eyes and the fellow eyes ( p=0.95). The change of BCVA was significantly correlated with the change of the length of the OS 1 year after the treatment (r=0.52; p=0.0004). Conclusions Anisohypermetropic amblyopic eyes have qualitative and quantitative differences in the retinal microstructures of the fovea from normal eyes. An increase in the OS length was detected in the amblyopic eyes after the optical treatment. A significant correlation was found between the increased OS length and better BCVA. Trial registration number The trial registration number of the internal review board of Nara Medical University was 774.

INTRODUCTION

To cite: Nishi T, Ueda T, Hasegawa T, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-305685

Amblyopia is a developmental disorder of the visual system that is characterised by reduced visual acuity in the absence of ophthalmoscopically visible pathological changes.1 It can be caused by a deprivation of clear vision during the period of neural plasticity early in life,2 3 and experimental evidence has shown that amblyopia is associated with developmental abnormalities in the visual cortex.4–6 In humans with strabismic amblyopia, the lateral geniculate nucleus has been found to be anatomically abnormal.7 However, careful examinations of the microstructures of the photoreceptors of amblyopic eyes by optical coherence tomography (OCT) have shown that the bulge of the foveal ellipsoidal zone (EZ), earlier called the photoreceptor inner and outer

segment (IS/OS) line, was absent more frequently in amblyopic eyes than in normal eyes.8 This indicated a possible abnormal development of the photoreceptors in amblyopic eyes. There are also subtle changes in the outer nuclear layer (ONL) of the fovea of amblyopic eyes suggesting possible alterations of the photoreceptors.9 However, there is no consensus about the microstructure of the retina of amblyopic eyes. Thus, the purpose of this study was to determine the foveal thickness in eyes of children with anisohypermetropic amblyopia, and to compare the findings with that of the fellow eyes and with eyes of agematched controls. To accomplish these objectives, we performed SD-OCT on children with anisohypermetropic amblyopia and compared the findings in the amblyopic eyes with that of the fellow eyes and control eyes. We also investigated the changes in the retinal thickness before and after optical treatment of eyes with anisohypermetropic amblyopia.

PATIENTS AND METHODS Patients and controls This was a cross-sectional comparative, interventional study conducted at the Nara Medical University between April 2012 and October 2013. The protocol for this study conformed to the tenets of the Declaration of Helsinki and was approved by the internal review board of Nara Medical University. An informed consent was obtained from all the patients or parents to perform the original measurements and to review their medical records. An eye was classified as being amblyopic when the best-corrected visual acuity (BCVA) was worse than 20/30 in one eye and was at least 2 Snellen lines worse than that of the fellow eye. Anisometropia was defined as being present when the difference in the refractive error (spherical equivalent) between the two eyes was >2 dioptres (D). We used the same examination procedures on the amblyopic eyes, the fellow eyes of amblyopic patients and the right eyes of the controls. The axial length and visual acuity in 18 of the eyes of the amblyopic patients and 20 of the eyes of the control patients have been reported.10 All of the patients and controls had comprehensive eye examinations including slit-lamp biomicroscopy, extraocular motility assessments, subjective cycloplegic refractions (1% cyclopentlate and 2.5% phenylephrine), dilated funduscopy and SD-OCT recordings. Patients with organic eye diseases, history of intraocular surgery, laser treatment, cataract, glaucoma, premature infants or any retinal disorders were excluded. The control group was composed of children whose BCVA was equal to or better than 20/20. Children with myopia greater than –1.00 D

Nishi T, et al. Br J Ophthalmol 2015;0:1–5. doi:10.1136/bjophthalmol-2014-305685

Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence.

1


Clinical science were excluded. Additionally, two children who could not cooperate for the OCT examinations were excluded. Visual acuity was measured with a standard Snellen chart, and the decimal visual acuity was converted to the logarithm of the minimal angle of resolution (logMAR) units for the statistical analyses. The axial length of the eye was measured with the IOL Master (Carl Zeiss Meditec, Dublin, California, USA).

Optical treatment Full correction spectacles were prescribed at the first visit based on cycloplegic (topical 1% cyclopentlate and 2.5% phenylephrine) retinoscopy. One year (±1 month) after the beginning of the optical treatment, the patients had ophthalmic examinations as performed at the first visit. The effects of the optical treatment on the anisohypermetropic amblyopic eyes were evaluated by the BCVA, axial length and OCT findings. All subjects were measured by the same examiner who was masked to whether the patient was amblyopic or otherwise.

Optical coherence tomography The central foveal thickness and the thicknesses of the ONL, photoreceptor IS layer and photoreceptor OS layer were measured by Spectralis spectral-domain OCT (SD-OCT; Heidelberg Engineering, Heidelberg, Germany) in all patients and controls. The Spectralis TruTrack Active Eye Tracking System was used to examine the eyes, and this system was especially useful for children who had difficulty in maintaining fixation. We used the high-speed mode to record the images. We identified the fovea to be at the centre of the vessel-free area during the recordings of the images. In the OCT images, the fovea was defined as the area where the inner retinal layers (the nerve fibre layer, ganglion cell layer, inner plexiform layer and inner nuclear layer) were absent. The second examination was performed after 1 year, and the OCT system was set to the ‘follow-up mode’. This allowed an automatic imaging of the same retinal position. The retinal thicknesses were measured by two independent experienced observers who were masked to the diagnosis and other clinical information. They measured the retinal thickness manually with the embedded OCT software, and one pixel was equivalent to 10.77 mm. The ONL thickness was the distance between the outer border of the inner limiting membrane and the external limiting membrane (ELM) at the fovea. The photoreceptor IS length was measured as the distance between the ELM and the outer border of the highly reflective line representing the EZ at the central fovea. The photoreceptor OS length was measured as the distance between the outer border of EZ and the inner border of the retinal pigment epithelium (RPE) at the centre of the fovea (figure 1). We selected the best centred temporal scanned image of the fovea to evaluate the OCT images. The final thickness was calculated as the arithmetic means of the two observers. The interobserver reproducibility was evaluated using intraclass correlation coefficients (ICC).

the correlation between the change of the visual acuity and the change of the retinal thickness of the amblyopic eyes, its fellow and control eyes was determined by Pearson’s correlation coefficient. A p0.05, ANCOVA). The mean thicknesses of the ONL, IS and OS were 86.1±11.1 mm, 49.6±10.0 mm and 42.4±4.6 mm, respectively, in the amblyopic eyes. The mean thicknesses of the same layers for the fellow eyes were 83.2±13.1 mm, 43.8±9.9 mm and 48.0±6.6 mm, respectively, and the mean thicknesses of the same layers in the control eyes were 90.8±11.5 mm, 47.4±5.8 mm and 46.5 ±3.0 mm, respectively. There were no significant differences in the foveal retinal thickness and the thicknesses of the ONL and

2


Statistical analyses


Clinical science Figure 1 Thickness of the outer nuclear layer (ONL) at the fovea is the distance between the outer border of the inner limiting membrane and the external limiting membrane (ELM) at the fovea. The thickness of the inner segment (IS) layer is the distance between the ELM and the outer border of the ellipsoidal zone (EZ). The thickness of the outer segment (OS) layer is the distance between the outer borders of the EZ and retinal pigment epithelium (RPE).

IS layers between amblyopic, fellow and control eyes. The length of the OS was significantly greater in the fellow eyes than in the amblyopic eyes ( p=0.03, ANCOVA). After ANCOVA, the differences between the amblyopic and its fellow eye, amblyopic and control eyes, were examined by Bonferroni test (table 1).

Effects of optical treatment One year after optical treatment for anisohypermetropia in the amblyopic eyes, the BCVA improved significantly from 0.35 ±0.17 logMAR units to 0.03±0.1 logMAR units ( p=0.0001, paired t test). The mean axial length changed from 21.45±0.77 to 21.61±0.87 mm which was not significant ( p>0.05, paired t test; table 2). In the fellow eyes, the mean axial length was 22.01±0.84 mm before and 22.04±0.94 mm after the correction. The change was not significant ( p>0.05, paired t test; table 2). The mean foveal, ONL and IS thicknesses of the amblyopic eyes changed from 224.5±23.6 to 216.7±17.1 mm, 86.1

±11.1 mm to 83.8±13.2 mm and 49.6±10.0 to 48.2±8.0 mm, respectively, after the treatment. The changes were not significant ( p>0.05, ANCOVA; table 2). However, the mean OS length increased significantly from 42.4±4.6 mm to 49.0 ±3.9 mm in the amblyopic eyes ( p=0.0001, ANCOVA; table 2). For the fellow eyes, the mean thicknesses of the same layers after the optical treatment were 79.3±8.5 mm, 43.9±8.5 mm, 49.1±5.3 mm, respectively. There was no more significant difference in the OS length between the amblyopic eyes and fellow eyes (p=0.95, ANCOVA). The change of BCVA was significantly correlated to the change of the thickness of OS layer (r=0.52; p=0.0004, Pearson test).

DISCUSSION There have been only a limited number of publications on the retinal thickness in children with anisohypermetropic amblyopia, and there is no consensus about whether the amblyopic

Table 1 Demographics of patients and controls

Age (years) Visual acuity (logMAR) Spherical equivalent (dioptre) Axial length (mm) Foveal retinal thickness (μm) ONL thickness (μm) IS thickness (μm) OS thickness (μm)

Amblyopic eyes (n=21)

Fellow eyes (n=21)

Control eyes (n=25)

p Value Amblyopic vs fellow vs control

p Value Amblyopic vs fellow

p Value Amblyopic vs control

p Value Fellow vs control

6.0±2.3 0.35±0.17 +4.01±1.90 21.45±0.77 224.5±23.6 86.1±11.1 49.6±10.0 42.4±4.6

6.0±2.3 −0.01±0.06 +1.73±1.50 22.01±0.84 220.0±16.9 83.2±13.1 43.8±9.9 48.0±6.6

5.6±1.9 −0.03±0.05 +1.64±1.85 21.83±1.12 229.1±25.2 90.8±11.5 47.4±5.8 46.5±3.0

0.10 0.0001 0.0001 0.14 0.56 0.39 0.28 0.03

1.0 0.0001 0.0001 0.17 1.0 1.0 0.33 0.03

0.19 0.0001 0.0001 0.44 1.0 1.0 1.0 0.08

0.19 0.23 1.0 0.44 0.87 0.53 1.0 0.08

IS, inner segment; logMAR, logarithm of the minimal angle of resolution; ONL, outer nuclear layer; OS, outer segment.


3


Clinical science

Figure 3 Optical coherence tomographic images of the fellow eye before optical correction (left) and after optical correction (right). The outer segment (OS) length changes from 52 mm to 53 mm. The black arrow indicates the OS.

suggested that a retinal thickening at the fovea occurred after the onset of amblyopia, and optical treatments induced a thinning of the retina. Yen et al17 reported that a thinning of the fovea occurred after the optical treatment of eyes with hyperopic amblyopia, but the degree of thinning was not correlated with visual improvement. This may be a process of normal development. Increasing evidences have shown that the retina is still developing throughout childhood.9 It should be noted that a significant increase of the OS length was found after the optical treatment in anisohypermetropic amblyopic eyes. The lengthening of the OS was significantly and positively correlated with the improvement of the BCVA. The photopigments are present in very high concentrations within the membranes of the photoreceptor OS discs. Vajzovic et al18 reported changes in the retina up to 5 years of age, especially the cone packing and changes in the OS layer. The foveal pit changes and resembles that of adults in 2–5 years. These changes are accompanied by a marked thickening of the ONL at the fovea which is due to cone packing and increased axon layer thickness. The length of the IS and OS increase, especially in the fovea, and become longer than the peripheral cones. We studied children from 3 to 11 years of age. At these ages, the retina is still developing as a normal course of development.9 Hendrickson, from a histological study of the retinas of adults and newborn babies, predicted that the human foveal cone density increased until around 5–8 years of age.19 An earlier study showed that a reduced number of discs reduced the magnitude of the outflow signal from the photoreceptors proportionately.20 The discs in the OSs of the photoreceptors are constantly being renewed. New discs are added at the base of the OS, while at the same time old discs are phagocytosed by the RPE.21 Therefore, the length of OS is expected to affect the function of photoreceptors, and a lengthening of the OS was seen as the visual acuity improved. We found that the visual improvement was positively correlated with the increase in the OS length. The elongation of the OS would affect the sensitivity and maturity of the retina. This is the first report showing that the OS length of amblyopic eyes changed before and after optical treatment. There are some limitations in this study. We investigated only a small number of anisohypermetropic amblyopic eyes and controls. Additionally, all of the patients were Japanese. This is important, because recent studies showed that differences in the foveal structure might be associated with ethnic differences.16 22 Thus, further studies including a larger number of subjects of different ethnicities will be necessary to confirm our findings. Additionally, the retinal thickness was determined manually because there is no commercially available automated software to make these measurements. Szeigeti et al9 used the custombuilt OCT retinal image analysis (OCTRIMA) software to measure the retinal thickness, and Ooto et al13 measured the retinal thickness manually by two independent ophthalmologists just as we did. If segmentation errors occurred in measuring the retinal thickness by the software, manual correction of the boundary detection is needed.23 Thus, we measured the retinal thickness manually at the fovea in the summated images. In conclusion, amblyopic eyes have quantitative differences in the retinal microstructures of the fovea compared with that of the fellow and control normal eyes. Optical treatments resulted in an improvement of the visual acuity and also a lengthening of the OS in anisohypermetropic amblyopic eyes. A significant correlation was found between the increased OS length and better BCVA.

4


Figure 2 Optical coherence tomographic images of an anisohypermetropic eye before optical correction (left) and after optical correction (right). The outer segment (OS) length in the amblyopic eye increases from 40 mm to 51 mm. The black arrow indicates the OS. fovea is structurally abnormal. In an earlier study, we found that the subfoveal choroid of amblyopic eyes was thicker than that of control and fellow eyes.10 Huynh et al11 reported that the fovea of hyperopic amblyopic eyes of children was thicker than that of normal eyes. However, in our study, the differences in the foveal thickness between amblyopic eyes, fellow eyes and control eyes were not significant. Park and Oh12 found that the thickness of the ONL was 101.22±10.90 mm, and the thickness of OS layer was 39.5±4.2 mm in full-term children of average age 6.2±1.4 years. In our patients, the thickness of the ONL was 90.8±11.5 mm in the controls and 86.1±11.1 mm in the amblyopic eyes, and the OS length was 46.5±3.0 mm in the controls and 42.4±4.6 mm in the amblyopic eyes. However, the length of the OS was similar to that of Ooto’s report of 56±6 mm in healthy eyes of Japanese adults.13 Previous histological studies of human retina showed an OS length of 25–63 mm at the fovea.14 Srinivasan et al15 used OCT and showed that a mean OS length in the fovea of healthy adults was 40.6 mm. Thus, in our patients, the ONL was slightly thinner, and OS lengths were slightly longer than that of Park and Oh12 These differences may be due to differences in the ethnicity and age of the patients. We found that the foveal thickness decreased after the optical treatment, but the decrease was not significant. Huynh et al16


Clinical science Table 2 Data of amblyopic eyes before and after treatment Amblyopic eyes

Visual acuity (logMAR) Spherical equivalent (dioptre) Axial length (mm) Foveal retinal thickness (μm) ONL thickness (μm) IS thickness (μm) OS thickness (μm)

Fellow eyes

Before treatment (n=21)

After treatment

p Value

Before treatment (n=21)

After treatment

p Value

0.35±0.17 +4.01±1.90 21.45±0.77 224.5±23.6 86.1±11.1 49.6±10.0 42.4±4.6

0.03±0.1 +4.04±1.90 21.61±0.87 216.7±17.1 83.8±13.2 48.2±8.0 49.0±3.9

0.0001 0.97 0.52 0.52 0.95 0.72 0.0001

−0.01±0.06 +1.73±1.50 22.01±0.84 220.0±16.9 83.2±13.1 43.8±9.9 48.0±6.6

−0.01±0.07 +1.48±1.47 22.04±0.94 215.0±14.5 79.3±8.5 43.9±8.5 49.1±5.3

0.93 0.61 0.90 0.49 0.33 0.76 0.59

IS, inner segment; logMAR, logarithm of the minimal angle of resolution; ONL, outer nuclear layer; OS, outer segment.

Competing interests None.

12

Ethics approval The Internal Review Board of Nara Medical University. Provenance and peer review Not commissioned; externally peer reviewed.

13

REFERENCES

14

1 2 3 4 5 6 7 8 9

10

11

Holmes JM, Clarke MP. Amblyopia. Lancet 2006;367:1343–51. Stewart CE, Fielder AR, Stephens DA, et al. Treatment of unilateral amblyopia: factors influencing visual outcome. Invest Ophthalmol Vis Sci 2005;46:3152–60. Ohlsson J. Defining amblyopia: the need for a joint classification. Strabismus 2004;13:15–20. Von Noorden GK, Crawford ML, Levacy RA. The lateral geniculate nucleus in human anisometropic amblyopia. Invest Ophthalmol Vis Sci 1983;24:788–90. Hess RF, Thompson B, Gole G, et al. Deficient responses from the lateral geniculate nucleus in humans with amblyopia. Eur J Neurosci 2009;29:1064–70. Pineles SL, Demer JL. Bilateral abnormalities of optic nerve size and eye shape in unilateral amblyopia. Am J Ophthalmol 2009;148:551–7. Barnes GR, Li X, Thompson B, et al. Decreased gray matter concentration in the lateral geniculate nuclei in human amblyopes. Invest Ophthalmol Vis Sci 2010;51:1432–8. Al-Hadded CE. Macular ultrastructural features in amblyopia using high-definition optical coherence tomography. Br J Ophthalmol 2013;97:318–22. Szigeti A, Tatrai E, Szamosi A, et al. A morphological study of retinal changes in unilateral amblyopia using optical coherence tomography image segmentation. PLoS ONE 2014;9:e88363. Nishi T, Ueda T, Hasegawa T, et al. Choroidal thickness in children with anisohypermetropic amblyopia. Br J Ophthalmol 2014; 98:228–32. Huynh SC, Samaarawickrama C, Wang XY, et al. Unilateral amblyopia: an optical coherence tomography study. JAAPOS 2009;13:148–50.


15

16

17 18

19 20 21 22 23

Park KA, Oh SY. Analysis of spectral domain optical coherence tomography in preterm children: retinal layer thickness and choroidal thickness profiles. Invest Ophthalmol Vis Sci 2012;53:7201–7. Ooto S, Tsujikawa A, Mori S, et al. Thickness of photoreceptor layers in polypoidal choroidal vasculopathy and central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol 2010;248:1077–86. Yuodelis C, Hendrickson A. A qualitative and quantitative analysis of the human fovea during development. Vision Res 1986;26:847–55. Srinivasan VJ, Monson BK, Wojtkowski M, et al. Characterization of outer retinal morphology with high-speed, ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci 2008;49:1571–9. Huynh SC, Samarawickrama C, Wang XY, et al. Macular and nerve fiber layer thickness in amblyopia: the Sydney Childhood Eye Study. Ophthalmology 2009;116:1604–9. Yen MY, Ceng CY, Wang AG. Retinal nerve fiber layer thickness in unilateral amblyopia. Invest Ohthalmol Vis Sci 2004;45:2224–30. Vajzovic L, Hendrickson AE, O’Connell RV, et al. Maturation of the human fovea: correlation of spectral-domain optical coherence tomography findings with histology. Am J Ophthalmol 2012;154:779–89. Hendrickson AE. Primate foveal development: a microcosm of current questions in neurobiology. Invest Ohthalmol Vis Sci 1994;35:3129–33. Haeri M, Knox BE, Ahmadi A. Modeling the flexural rigidity of rod photoreceptors. Byophysical J 2013;104:300–12. Kim JY, Zhao H, Martinez J, et al. Noncanonical autophagy promotes the visual cycle. Cell 2013;154:365–76. El-Dairi MA, Asrani SG, Enyedi LB, et al. Optical coherence tomography in the eyes of normal children. Arch Ophthalmol 2009;127:50–8. Patel PJ, Chen FK, Cruz L, et al. Segmentation error in stratus optical coherence tomography for neovascular age-related macular degeneration. Invest Ohthalmol Vis Sci 2009;50:399–404.

5


Retinal thickness in children with anisohypermetropic amblyopia Tomo Nishi, Tetsuo Ueda, Taiji Hasegawa, Kimie Miyata and Nahoko Ogata Br J Ophthalmol published online February 13, 2015

Updated information and services can be found at: http://bjo.bmj.com/content/early/2015/02/13/bjophthalmol-2014-30568 5

These include:

References

This article cites 23 articles, 7 of which you can access for free at: http://bjo.bmj.com/content/early/2015/02/13/bjophthalmol-2014-30568 5#BIBL

Email alerting service

Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.

Topic Collections

Articles on similar topics can be found in the following collections Neurology (1232) Vision (581)

Notes

To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/