You are here

Article Text

Article menu

Download PDFPDF

Clinical science
Original article
Impact of early and late age-related macular degeneration on vision-specific functioning
  1. Ecosse L Lamoureux1,2,
  2. Paul Mitchell3,
  3. Gwyn Rees1,
  4. Gemmy Cheung2,
  5. Ian Yeo2,
  6. Shu Yen Lee2,
  7. Erica Liu2,
  8. Tien Y Wong1,2,4
  1. 1Centre for Eye Research Australia, the Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Australia
  2. 2Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
  3. 3Centre for Vision Research (Westmead Millennium Institute), University of Sydney, Sydney, Australia
  4. 4Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  1. Correspondence to Professor Ecosse Lamoureux, University of Melbourne, 32 Gisborne Street, East Melbourne, Victoria 3002, Australia; ecosse{at}unimelb.edu.au

Abstract

Aim To assess the impact of early and late age-related macular degeneration (AMD) on vision-specific functioning in Singapore Malays.

Methods AMD was assessed from fundus photographs. The following endpoints were considered for (a) AMD: no AMD, early AMD, and late AMD; (b) drusen: absence and presence; and (c) retinal pigment epithelium (RPE) abnormality: absence and presence. Vision functioning was assessed using the modified VF-11 scale validated using the Rasch analysis. The overall functioning score was used as the main outcome measure.

Results Retinal photographs and vision functioning data were available only for 3252 participants. After age standardisation, the prevalence of early AMD was 3.5% and late AMD 0.34%. In multivariate models, after adjusting for age, gender, education, level of income, smoking status, ocular condition and hypertension, only late AMD was independently associated with poorer vision functioning when compared with no AMD or early AMD (β (β regression coefficient)=−6.4 (CI −11.7 to −2.1; p=0.01)). Early AMD or its principal components, drusen or RPE abnormality, were not independently associated with vision functioning (p>0.05). In adjusted multinomial logistic regression models, people with late AMD were twice as likely (OR=2.23; 95% CI 1.16 to 7.11) to have low overall functioning than those without AMD.

Conclusions Late AMD has a significant impact on visual functioning, but early AMD, drusen and RPE changes have no impact. These data highlight the importance of preventive public health strategies targeting patients with early AMD signs in order to prevent progression to late AMD when visual function is compromised.

  • Age-related macular degeneration
  • vision-specific functioning
  • drusen and RPE
  • macula
  • degeneration

https://doi.org/10.1136/bjo.2010.185207

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    It has been conservatively estimated that 14 million persons are blind or visually impaired from age-related macular degeneration (AMD).1 People with late stages of disease (neovascular AMD or geographic atrophy) lose their central vision, which can impact on daily living activities that require fine vision such as reading and watching television.2 However, it is less clear if earlier stages of AMD, characterised by drusen and retinal pigment epithelium (RPE) changes, have a significant impact on visual functioning, although studies suggest some visual impairment may occur with early AMD.3

    AMD-related vision impairment impacts on mobility, difficulty in maintaining independent living tasks, such as shopping, managing finances, preparing meals and undertaking light housework, and has also been associated with depression.4 5 AMD-induced restriction of participation in daily living activities frequently leads to a compromised vision-specific quality of life.5 However, most of our knowledge to date about the impact of AMD has come from clinic-based samples6–9 with no population-based data available.

    In this paper, we report on the impact of early and late AMD on vision-specific functioning using population-based data from the Singapore Malay Eye Study (SiMES).

    Methods

    SiMES was a population-based cross-sectional study of Singaporean Malays undertaken to determine the prevalence and impact of visual loss and major eye diseases.10–12 The methodology from this study is reported elsewhere.13 14 Briefly, of the 4168 eligible participants from the sampling frame, 3280 (78.7%) participated. The study was conducted in accordance with the Declaration of Helsinki, and ethics approval was obtained from the Singapore Eye Research Institute Institutional Review Board.

    Fundus imaging

    All participants had their fundus imaged using a digital retinal camera (Canon CR-DGi with digital 10D SLR camera backing, Canon, Tokyo) following pharmacological pupil dilation. Colour photographs of Early Treatment for Diabetic Retinopathy Study (ETDRS) standard field 1 (centred on the optic disc) and ETDRS standard field 2 (centred on the fovea) were taken for each eye.15 Of 3280 participants, 3265 (99.5%) had fundus photographs with sufficient quality for grading of AMD signs. The photographs were graded for the presence or absence of AMD signs at the University of Sydney Centre for Vision Research, using the modified Wisconsin Age-related maculopathy grading system.13

    Definitions of AMD

    Drusen type was classified according to the size and sharpness of the lesion edges, and drusen were classified as hard or soft. The latter category was further subdivided into distinct and indistinct soft drusen. RPE abnormalities were graded as either hypo- or hyperpigmentation.3 In this analysis, drusen was defined as present if either hard or soft drusen were present. RPE abnormality was defined as present if either hypo- or hyperpigmentation of the RPE was detected. Early AMD was defined as ‘either soft indistinct or reticular drusen’ or ‘both soft, distinct drusen plus RPE abnormalities’ following the definition used in the Blue Mountains Eye Study.16 Late AMD was defined as the presence of either neovascular AMD or geographic atrophy.3 15 Participants were categorised by the worse eye into three mutually exclusive categories: no AMD, early AMD and late AMD.

    Vision-specific functioning

    The vision-specific functioning scale (VF-11) used in this study has been comprehensively described elsewhere.17 Briefly, 11 questions about different aspects of visual function were used to assess the level of difficulty in performing daily activities (box 1), including both near and distance activity. Items 1 to 9 used a numeric scale ranging from 0 (no difficulty) to 4 (unable to perform activity). For items 10 and 11 on driving, there were three response options (1=no difficulty; 2=a little difficulty; 3=great difficulty). Trained research assistants conducted face-to-face interviews in Malay and/or English. With the participant's consent, randomly selected interviews were recorded for periodic review by the investigators for quality control purposes.

    Box 1

    Items of the modified VF-11 items used in the study

    1. Difficulty in reading small print in the telephone book, even with glasses?

    2. Difficulty in reading newspaper size print, even with glasses?

    3. Difficulty in recognising friends when you meet them while shopping, even with glasses?

    4. Difficulty seeing stairs, even with glasses?

    5. Difficulty in reading street signs or shop signs, even with glasses?

    6. Difficulty in filling out Toto forms, even with glasses?

    7. Difficulty in playing games—chess or cards, even with glasses?

    8. Difficulty in cooking, even with glasses?

    9. Difficulty in watching television, even with glasses?

    10. Difficulty in driving during the day because of vision?

    11. Difficulty in driving at night-time because of vision?

    Items 1–9 had five response options (0=no difficulty; 1=a little difficulty; 2=moderate difficulty; 3=a great deal of difficulty; 4=unable to perform activity).

    Items 10 and 11 had three response options (1=no difficulty; 2=a little difficulty; 3=a great deal of difficulty).

    Vision and other assessments

    Participants underwent a comprehensive eye examination that included visual acuity testing and a detailed clinical anterior and posterior segment slit-lamp examination. Visual acuity was measured for each eye using a logarithm of the minimum angle of resolution (logMAR) vision chart (Lighthouse International, New York) read at 4 m. For each eye, the participant's presenting visual acuity (PVA), was ascertained with the participant wearing their ‘walk-in’ optical correction if applicable. PVA in the better eye was the better presenting distance vision of the right and left eyes. Best corrected VA, in which refractive error was corrected by certified study optometrists, was also obtained.

    Weight and height were measured using standardised procedures. Socio-economic measures, lifestyle risk factors, medication use and self-reported history of systemic diseases were elicited from the interview. Non-fasting venous blood samples were drawn and analysed for serum lipid levels, glycosylated haemoglobin, serum creatinine and glucose. The definition of other main eye conditions has been comprehensively described elsewhere.16 18

    Statistical analyses

    We used the Rasch analysis to determine whether the overall VF-11 score was valid and reliable, and possessed measurement characteristics.19 20 We used RUMM2020 software (RUMM 2020. Perth: RUMM Laboratory, 2003) and the Andrich rating scale to determine whether the VF-11 data fitted the Rasch model.21 One rating scale was used for the nine items with a five-response scale and another with the two driving items with three response options. In psychometric terms, the Rasch measurement model, also known as the Rasch analysis, is a mathematical description of the way in which respondents interact with test items in order to produce linear measurement. The Rasch analysis states that the probability that an individual would choose a response on a particular item depends on both the person's ability and item difficulty. Thus, the Rasch analysis is taken as a criterion for the structure of the responses that should be met rather than a simple statistical description of responses.19 The resulting response scale calibrations and person scores are expressed as the log of the odds units, or Logits, positioned along a hierarchical scale. Once the VF-11 data fit the Rasch model, estimates of measures on a interval scaling are provided.19 To aid interpretability, the overall score was converted from the Rasch logit range to a scale from 0 to 100, where a high score indicates a high level of visual functioning.

    Descriptive statistical analyses were performed to characterise participants' sociodemographic and clinical data using SPSS statistical software (Version 17.0). The overall vision functioning score linearly estimated using the Rasch analysis was fitted to linear regression models and used t-based 95% CIs for the regression coefficients. The models were adjusted for age, gender, monthly income, education, self-reported stroke, hypertension and diabetes. Independent significant predictors were considered to be clinically meaningful if their β coefficients were approximately 1/2 the SD of the mean. This is generally considered a useful estimate of a clinically meaningful difference.22

    Results

    Retinal photographs and VF-11 scores were available for 3252 participants whose clinical and sociodemographic data are presented in table 1. Early and late AMD were present in 159 (4.9%) and 23 (0.71%) participants, respectively. After age standardisation, early AMD prevalence in Malay persons aged 40-80 years was estimated to be 3.5% (95% CI 2.9% to 4.1%) and late AMD was 0.34% (95% CI 0.20% to 0.49%). Drusen and RPE abnormalities were found in 449 (13.8%) and 405 (12.0%) of our sample, respectively. In univariate analyses, those with early or late AMD were older, were less educated, had lower income, had a poorer presenting distance vision, and were more likely to be male, smokers (current or past) and hypertensive compared with those without AMD (p<0.05, table 1).

    View this table:
    Table 1

    Sociodemographic and clinical characteristics stratified by severity of age-related macular degeneration (AMD)

    The psychometric validation of the VF-11 in this population has been described extensively elsewhere.17 As the original VF-11 scoring system allocates high scores for those with high levels of visual disability, we reversed the scoring to provide high values for those who had more visual ability or had less difficulty. Therefore items were recoded as follows: 4, no difficulty; 3, little difficulty; 2, moderate difficulty; 1, a great deal of difficulty; and 0, unable to perform activity. The two driving items of the questionnaire showed a misfit and were subsequently removed as previously described. The remaining nine items showed unidimensionality confirming that the instrument measures the one underlying trait (vision-specific functioning) it purports to measure. Most participants had substantial vision functioning with 80.2% of the sample recoding overall VF-11 scores ≥80 (range 0–100). This was expected, as 88.6% of the sample had normal visual acuity in both eyes (logMAR≤0.3). The mean±SD overall vision functioning score was 89.2±13.2. Considering the 13.2 SD of the mean overall score, significant predictors were considered to be also clinically significant if the CIs limits of their β coefficients were either >6.6 or <6.6.22

    People with no or early AMD had a significantly better vision functioning than those with late AMD (p<0.05, table 2). No significant difference, however, was found between persons without AMD and those with early AMD (p>0.05). We found no significant difference in VF-11 scores between persons with and without drusen (89.25 (SD13.07) vs 89.42 (SD12.82); p=0.78) and in persons with and without RPE abnormalities (89.23 (SD12.91) vs 89.54 (SD13.34); p=0.65).

    View this table:
    Table 2

    Vision functioning scores stratified by severity of age-related macular degeneration (AMD), drusen and retinal pigment epithelium abnormalities

    In multivariate models, only late AMD was independently associated with poorer vision functioning compared with persons with none or early AMD (β [β regression coefficient]=−6.4 (CI −11.7 to −2.1; p=0.01; table 3)). The finding was similar comparing persons with late AMD with those with none and early AMD combined (table 3). The independent and statistically significant associations of late AMD with vision functioning, however, was not considered clinically meaningful, as the CI limits were within −6.6 and 6.6.

    View this table:
    Table 3

    Differences in the overall visual functioning score by severity of age-related macular degeneration (AMD) in linear regression models

    We divided the overall vision-specific function score into tertiles representing low (lower tertile: 0.0–83.7), moderate (intermediate tertile: >83.7–99.7) and high vision-functioning levels (higher tertile >99.7). In multinomial logistic regression models (adjusting for age, gender, education, income, smoking status, ocular conditions other than AMD and hypertension) with the high function group as a reference, persons with late AMD were more than twice as likely (OR=2.23; 95% CI 1.16 to 7.11) to have low overall functioning than those without AMD.

    In order to determine whether vision impairment primarily contributed to poorer functioning for persons with AMD, PVA in the better eye was included in the regression models. This considerably attenuated the effect of AMD on the overall vision functioning score. Although the associations were in the same direction, they were not statistically significant, either for early AMD (β=−0.45, CI −2.4 to 1.5) or for late AMD (β=−0.55, CI −5.8 to 4.7, table 3). A similar finding was obtained using best corrected vision.

    Discussion

    To date, there have been no studies reporting the impact of AMD on vision functioning from population-based samples. In this study, we showed that late AMD was independently associated with poorer functioning in those with than without late AMD or individuals with only early AMD signs. People with late AMD were twice as likely to have low levels of vision-specific functioning, than those without AMD. Importantly, there were no significant differences in vision functioning between those with no AMD signs and those with signs of early AMD. This suggests that early AMD has a relatively minimal impact on daily living activities and that efforts should be made to prevent progression from early to late AMD, at which stage the impact is substantial. Conversely, it could also be hypothesised that interventions and treatments likely to shift patients on the AMD spectrum towards early forms of the condition should also contribute to improvements in vision-specific functioning.

    Our finding of a significant difference between patients with early and late AMD on vision-specific functioning is similar to that reported by Mangione and colleagues using a clinic-based sample.23 In 201 patients principally assembled to identify risk factors for the progression of AMD, there were significant differences on overall Activities of Daily Vision Scale24 scores when comparing patients with mild versus severe AMD. This was also found for the MacDQoL, an individualised measure of the impact of AMD on quality of life, in 156 AMD patients.25 However, there was no comparison provided with non-AMD patients in either study. It therefore appears that in either clinic-based or population-based samples, severe or late AMD has a major impact on participation in daily living activities when compared with mild or early AMD.

    We found that late AMD was not independently associated with vision functioning when presenting distance vision was introduced into the model; this is not surprising. In previous work with this population, we also found an independent significant association between visual functioning and signs of diabetic retinopathy, macular oedema, clinically significant macular oedema and uncorrected myopia.13 However, as in this paper, these independent associations were no longer evident when presenting vision was included in the models. As shown in box 1, there was a systematic relationship between PVA (either in the better or worse eyes) and AMD severity. These findings confirm the impact of AMD on distance vision which in turn precludes participation in daily vision-dependent activities such as reading, watching TV and recognising faces.

    To our knowledge, previous studies have not investigated the impact of drusen and RPE abnormalities on vision-specific daily functioning. While it has been shown that the development of drusen increases with age, we report no association between both drusen and RPE abnormality and vision-specific functioning. However, further analyses showed that PVA in the better eye in persons with and without drusen (0.20 vs 0.25 logMAR) and in those with and without RPE abnormalities (0.20 vs 0.21 logMAR) were similar: all four groups had normal vision (≤0.3 logMAR). Considering that visual disability due to vision impairment is the principal contributor to poor functioning, our finding of a non-association is expected. However, future studies with large samples are needed to confirm our findings.

    Strengths of this study are its population-based design, ability to adjust for a range of risk factors and the use of Rasch analysis. Conversely, a limitation of this study is the relatively small number of cases with early and late AMD signs. While small sample sizes were anticipated in our population-based study, our findings will need confirmation in studies with larger sample sizes. Similarly, with a mean presenting VA of 0.2 logMAR, our finding that the scale is suboptimally targeted to this population was predictable. Regardless, the poor targeting is a potential limitation of the study, as it indicates that the instrument may not include the content required to fully assess the impact of AMD in this population, particularly for those with early AMD. Future investigations are therefore needed to determine if the inclusion of items of greater difficulty improves the targeting of the early AMD patients in this population.

    In conclusion, our study documents that late-stage AMD is associated with substantially poorer vision-specific functioning when compared with early AMD or no AMD in a population-based setting. Our study re-emphasises efforts to prevent progression of early to the late stages of this condition, where the impact is clearly substantial. Interventions targeting persons with early AMD signs (eg, dietary modifications, smoking cessation) could help to reduce progression to late AMD, and could also minimise the impact on daily life.

    References

    1. ↵
      1. Gehrs KM,
      2. Anderson DH,
      3. Johnson LV,
      4. et al
      . Age-related macular degeneration—emerging pathogenetic and therapeutic concepts. Ann Med 2006;38:450–71.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      1. Hassell JB,
      2. Lamoureux EL,
      3. Keeffe JE
      . Impact of age related macular degeneration on quality of life. Br J Ophthalmol 2006;90:593–6.
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Kawasaki R,
      2. Wang JJ,
      3. Aung T,
      4. et al
      . Prevalence of age-related macular degeneration in a Malay population: the Singapore Malay Eye Study. Ophthalmology 2008;115:1735–41.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. Rovner BW,
      2. Casten RJ,
      3. Tasman WS
      . Effect of depression on vision function in age-related macular degeneration. Arch Ophthalmol 2002;120:1041–4.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      1. Lamoureux EL,
      2. Pallant JF,
      3. Pesudovs K,
      4. et al
      . Assessing participation in daily living and the effectiveness of rehabiliation in age related macular degeneration patients using the impact of vision impairment scale. Ophthalmic Epidemiol 2008;15:105–13.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      1. Lamoureux E,
      2. Pallant J,
      3. Pesudovs K,
      4. et al
      . Assessing participation in daily living and the effectiveness of rehabilitation in age related macular degeneration patients using the impact of vision impairment scale. Ophthalmic Epidemiol 2008; 15:105–13.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      1. Cahill MT,
      2. Banks AD,
      3. Stinnett SS,
      4. et al
      . Vision-related quality of life in patients with bilateral severe age-related macular degeneration. Ophthalmology 2005;112:152–8.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Mangione CMGP,
      2. Lowe G,
      3. Orav EJ,
      4. et al
      . Influence of age-related maculopathy on visual functioning and health-related quality of life. Am J Ophthalmol 1999;128:45–53.
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Williams RABB,
      2. Thomas RG,
      3. Kaplan RM,
      4. et al
      . The psychosocial impact of macular degeneration. Arch Ophthalmol 1998;116:514–20.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      1. Foong AW,
      2. Saw SM,
      3. Loo JL,
      4. et al
      . Rationale and methodology for a population-based study of eye diseases in Malay people: The Singapore Malay eye study (SiMES). Ophthalmic Epidemiol 2007;14:25–35.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Lamoureux EL,
      2. Chong E,
      3. Wang JJ,
      4. et al
      . Visual impairment, causes of vision loss, and falls: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci 2008;49:528–33.
      OpenUrlAbstract/FREE Full Text
    12. ↵
      1. Wong TY,
      2. Chong EW,
      3. Wong WL,
      4. et al
      . Prevalence and causes of low vision and blindness in an urban malay population: the Singapore Malay Eye Study. Arch Ophthalmol 2008;126:1091–9.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Lamoureux EL,
      2. Saw SM,
      3. Thumboo J,
      4. et al
      . The impact of corrected and uncorrected refractive error on visual functioning: the Singapore Malay Eye Study. Invest Ophthalmol Vis Sci 2009;50:2614–20.
      OpenUrlAbstract/FREE Full Text
    14. ↵
      1. Lamoureux EL,
      2. Chong EW,
      3. Thumboo J,
      4. et al
      . Vision impairment, ocular conditions, and vision-specific function: the Singapore Malay Eye Study. Ophthalmology 2008;115:1973–81.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Mitchell P,
      2. Smith W,
      3. Attebo K,
      4. et al
      . Prevalence of age-related maculopathy in Australia. The Blue Mountains Eye Study. Ophthalmology 1995;102:1450–60.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Foster PJ,
      2. Buhrmann R,
      3. Quigley HA,
      4. et al
      . The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;86:238–42.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Lamoureux EL,
      2. Pesudovs K,
      3. Thumboo J,
      4. et al
      . An evaluation of the reliability and validity of the visual functioning questionnaire (VF-11) using Rasch analysis in an Asian population. Invest Ophthalmol Vis Sci 2009;50:2607–13.
      OpenUrlAbstract/FREE Full Text
    18. ↵
      1. Anonymous
      . Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98(5 Suppl):786–806.
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Pesudovs K
      . Patient-centred measurement in ophthalmology—a paradigm shift. BMC Ophthalmol 2006;6:25.
      OpenUrlCrossRefPubMed
    20. ↵
      1. Garamendi E,
      2. Pesudovs K,
      3. Stevens MJ,
      4. et al
      . The Refractive Status and Vision Profile: evaluation of psychometric properties and comparison of Rasch and summated Likert-scaling. Vision Res 2006;46:1375–83.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Andrich D
      . Rating formulation for ordered response categories. Psychometrika 1978;43:561–73.
      OpenUrlCrossRefWeb of Science
    22. ↵
      1. Sloan JA
      . Assessing the minimally clinically significant difference: scientific considerations, challenges and solutions. COPD 2005;2:57–62.
      OpenUrlPubMed
    23. ↵
      1. Mangione CM,
      2. Gutierrez PR,
      3. Lowe G,
      4. et al
      . Influence of age-related maculopathy on visual functioning and health-related quality of life. Am J Ophthalmol 1999;128:45–53.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Mangione CM,
      2. Phillips RS,
      3. Seddon JM,
      4. et al
      . Development of the ‘Activities of Daily Vision Scale.’ A measure of visual functional status. Med Care 1992;30:1111–26.
      OpenUrlPubMedWeb of Science
    25. ↵
      1. Mitchell J,
      2. Wolffsohn JS,
      3. Woodcock A,
      4. et al
      . Psychometric evaluation of the MacDQoL individualised measure of the impact of macular degeneration on quality of life. Health Qual Life Outcomes 2005;3:25.
      OpenUrlCrossRefPubMed
    View Abstract

    Footnotes

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval Ethics approval was provided by the Singapore Eye Research Institute Institutional Review Board.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    Linked Articles

    • At a glance
      Highlights from this issue
      Harminder S Dua Arun D Singh
      British Journal of Ophthalmology 2011; 95 i-i Published Online First: 19 Apr 2011. doi: 10.1136/bjophthalmol-2011-300199