SURVEY OF OPHTHALMOLOGY VOLUME 54 NUMBER 2 MARCH–APRIL 2009 MAJOR REVIEW Psychophysical Function in Age-related Maculopathy Kumari Neelam, FRCS,1,2,3 John Nolan, PhD,1 Usha Chakravarthy, PhD,4 and Stephen Beatty, MD1,2 1Waterford Institute of Technology, Waterford, Republic of Ireland; 2Waterford Regional Hospital, Waterford, Republic of Ireland; 3Alexandra Hospital, National Healthcare Group, Singapore; and 4Queen’s University and Royal Victoria Hospitals, Belfast, United Kingdom Abstract. Age-related macular degeneration (AMD), the late stage of age-related maculopathy (ARM), is the leading cause of blind registration in developed countries. The visual loss in AMD occurs due to dysfunction and death of photoreceptors (rods and cones) secondary to an atrophic or a neovascular event. The psychophysical tests of vision, which depend on the functional status of the photoreceptors, may detect subtle alterations in the macula before morphological fundus changes are apparent ophthalmoscopically, and before traditional measures of visual acuity exhibit deterioration, and may be a useful tool for assessing and monitoring patients with ARM. Furthermore, worsening of these visual functions over time may reflect disease progression, and some of these, alone or in combination with other parameters, may act as a prognostic indicator for identifying eyes at risk for developing neovascular AMD. Lastly, psychophysical tests often correlate with subjective and relatively undefined symptoms in patients with early ARM, and may reflect limitation of daily activities for ARM patients. However, clinical studies investigating psychophysical function have largely been cross- sectional in nature, with small sample sizes, and lack consistency in terms of the grading and classification of ARM. This article aims to comprehensively review the literature germane to psychophysical tests in ARM, and to furnish the reader with an insight into this complex area of research. (Surv Ophthalmol 54:167--210, 2009. Ó 2009 Elsevier Inc. All rights reserved.) Key words. age-related maculopathy color vision hyperacuity perimetry psychophysical tests Spatial vision temporal function visual adaptation I. Introduction life expectancy, and the consequential demographic Age-related macular degeneration (AMD), the ad- shift toward an elderly population will have impli- cations for the socio-economic impact of this vanced stage of age-related maculopathy (ARM), is 24,235 a degenerative condition of the macula characterized disease. Furthermore, the currently available by dysfunction and death of photoreceptors second- therapeutic interventions for this condition are aimed largely at preservation of presenting visual ary to an atrophic (geographic atrophy, GA) and/or 205,320,321,334 a neovascular (choroidal neovascularization, CNV) acuity (VA), even though a significant event. Currently, AMD is the leading cause of blind proportion may achieve some visual gain with the 73,113,119 newer vascular endothelial growth factor inhibition registration in the developed world, with 125,332 CNV accounting for 80--90% of these cases.149,196 therapies. Thus, complete restoration of vision In the future, the prevalence and incidence of remains an unrealistic goal at least within the next ARM is expected to rise because of an increase in decade. Finally, the impact of ARM on the activities 167 Ó 2009 by Elsevier Inc. 0039-6257/09/$--see front matter All rights reserved. doi:10.1016/j.survophthal.2008.12.003 168 Surv Ophthalmol 54 (2) March--April 2009 NEELAM ET AL of daily living, self-care, emotional well-being and adaptation, central visual field, and colour discrim- overall quality of life are important, and are related ination, deteriorate in the early stages of ARM. to disease severity.57,88,92,179,298,354 Therefore pre- Furthermore, longitudinal studies have shown that vention, delay, or arrestation of progression to the some of these parameters, in isolation or in late manifestations of ARM, namely CNV and/or combination, may be of predictive value with respect GA, represent the best means of limiting the impact to the progression to CNV and/or GA with a good of this degenerative disorder on visual health and degree of sensitivity and specificity. quality of life in the elderly population. This article represents an evidence-based and The early stages of ARM are characterized by comprehensive review of psychophysical function in drusen and/or pigmentary changes of the retinal ARM, with particular emphasis on identifying those pigment epithelium (RPE), and herald the loss of parameters of visual function that may be of normal retinal status and, consequentially, an predictive value for disease progression. increased risk for the development of CNV and/or GA. A number of investigators have reported, in a cross-sectional fashion, various morphological II. Anatomy of the Macula changes in the fundus, which may be associated The macula lutea refers to a region of the with subsequent development of severe visual loss. posterior retina that measures approximately 5.5 The characteristics of drusen, such as large number mm in diameter, and is exquisitely specialized for and size, confluence, softness, and associated focal central and color vision.289 The macula differs from hyperpigmentation of the RPE, are associated with the rest of the retina by the presence of an an increased risk for progression to the neovascular exceptionally high density of neural elements and stage of this disease.42,43,45,128,269,300 However, the restricted blood supply.247 Furthermore, one of the overall predictive value of such morphological unique feature of the primate macula is the changes is low, possibly reflecting the high presence of xanthophylls, lutein (L) and zeaxanthin incidence of age-related fundus changes.335 In (Z), which provide its eponymous yellow color. addition, the relationship, if any, between morpho- Together, these two xanthophylls are referred to as logical and functional changes in the retina in ARM macular pigment (MP).35 remains unclear. For instance, in a recent study, the MP peaks in the central 1--2 degrees of the fovea, severity of functional deficits in short-wavelength and declines to optically negligible levels by 5--10 sensitive resolution acuity did not correlate well with degrees radial eccentricity, along with shoulders or the severity of morphological changes in ARM.25 flanking peaks around 0.7 degrees eccentricity.94 The early lesions of ARM may be associated with Furthermore, Berendschot et al in a recent study a decrease in VA of approximately two or fewer examined the spatial distribution of MP in 53 optotypes (i.e., letters) when compared with eyes normal subjects using a custom-built scanning laser without such lesions.169 This level of visual deficit is ophthalmoscope (SLO), and they observed a distinct neither clinically meaningful nor reliably detectable, ring pattern at a mean distance of 0.7 degree of the given that the test--retest variability of a logMAR fovea in approximately half of the subjects.27 chart is between one and two lines.18,257 In addition, Additionally, in a few of these subjects, the optical such a level of visual deterioration may pass density of MP was greater at the site of the ring undetected using the conventional Snellen chart, pattern, when compared with the optical density of suggesting, therefore, that VA, the standard test of this pigment at the fovea. visual function typically performed in the clinical It is important to note that, at the macula, L exists setting, is inadequate for the assessment of func- as a single stereoisomer, whereas Z subsists as two tional deficit in early ARM, and is therefore of no separate isomers, zeaxanthin (3R, 30R) and meso- prognostic value with respect to the risk for atrophic zeaxanthin (3R, 30S). Furthermore, both isomers of and/or neovascular changes. Z are present in equal concentrations at the macula; Consequently, other psychophysical tests of vision, however, only zeaxanthin (3R, 30R) is typically which reflect the functional status of the macula, derived from dietary sources.180 It is proposed that may be useful tools for assessing and monitoring a conversion mechanism exists in the retina, patients with early ARM, and may detect subtle whereby L is isomerized to meso-zeaxanthin, and alterations in the macula before morphological this observation may possibly explain the presence fundus changes are apparent ophthalmoscopically, of meso-zeaxanthin in the retina despite its absence and before traditional measures of VA exhibit in a typical diet. deterioration. Indeed, psychophysical studies have The macula may be further subdivided into four demonstrated that several parameters of visual anatomical zones, originally defined by Polyak,246 function, in particular contrast sensitivity, visual and named in relation to the fovea (fovea centralis). PSYCHOPHYSICAL FUNCTION IN ARM 169 The foveola, which is the innermost region of the ically, these cells have a restricted blood supply from macula, corresponds to the visual axis, and is the retina, and depend on the oxygen supplied by characterized by a high density of cone photorecep- the choriocapillaris.201 The blood flow within the tors, absence of retinal vasculature, and dominance choriocapillaris is controlled mainly by sympathetic of Midget pathways arising from these cones.247 It is innervation, and lacks metabolic autoregulatory important to note that short wavelength sensitive capabilities.93 In other words, the choroidal blood cones, rods, ganglion