REVIEW

CURRENT OPINION Introduction to microperimetry and its use in analysis of geographic atrophy in age-related

Mostafa Hanout, Nicholas Horan, and Diana V. Do

Purpose of review This article discusses recent advances in the fundus-guided perimetry (microperimetry) and its utilization in evaluation and monitoring of patients with geographic atrophy. Recent findings Although best-corrected visual acuity has been gold standard in clinical practice for decades, it does not provide an entire assessment of visual function that determines daily activity and quality of life of a patient. Furthermore, psychophysical tests, including low-luminance visual acuity, reading speed, and contrast sensitivity, cannot be used to quantify retinal sensitivity or detect pattern of retinal dysfunction. Microperimetry provides a true evaluation of visual function by offering fundus-controlled testing through eye-tracking technology that allows for structural and functional correlation and test–retest reliability for the same test point. Furthermore, it enables precise assessment of location and stability of fixation. Recent research has shown microperimetry to be more representative of the macular function in macular diseases. Summary Microperimetry is currently the clinical investigation of choice to assess residual visual functions and functional vision in macular degenerative diseases, especially geographic atrophy. There is an increasing popularity to employ microperimetry in clinical trials investigating new treatments for geographic atrophy, as well as other macular degenerative diseases, as a reliable functional outcome measure. Keywords fixation, geographic atrophy, microperimetry, preferred retinal locus, retinal sensitivity

INTRODUCTION low-luminance visual acuity among others. How- The advances in retinal imaging technologies ever, none of these testing parameters has proved have revolutionized contemporary diagnostic in ability to quantify retinal sensitivity or detect and enabled early detection along pattern of retinal dysfunction [2–4]. For many years, with documentation of treatment results of retinal conventional static perimetry has been established diseases. Precise clinical evaluation of retinal, as an essential clinical tool for quantification of especially macular involving, diseases necessitates visual field and retinal threshold especially in glau- correlating both the morphological and the func- coma and neuro-ophthalmological disorders. None- tional aspects. The latter is more self-appreciated by theless, it is often inadequate for accurate evaluation patients, as major visual tasks determining the qual- of macular function, especially with troublesome ity of life of patient grossly depend on it [1]. For eccentric or unsteady fixation, or both [1,5,6]. decades, best-corrected visual acuity has been the gold standard in clinical practice; however, it does not represent an entire assessment of macular func- Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, tion. There are several puzzling presentations by Omaha, Nebraska, USA patients whose visual function is inconsistent with Correspondence to Diana V. Do, MD, Stanley M. Truhlsen Eye Institute, visual acuity such as patients with paracentral mac- University of Nebraska Medical Center, 985540 Nebraska Medical ular lesions sparing the foveal center. Several psy- Center, Omaha, NE 68198-5540, USA. Tel: +1 402 559 4276; chophysical tests have been utilized, in addition to fax: +1 402 559 5514; e-mail: [email protected] visual acuity, to evaluate macular function such as Curr Opin Ophthalmol 2015, 26:149–156 Amsler grid, contrast sensitivity, reading speed, and DOI:10.1097/ICU.0000000000000153

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fundus observation during examination [9]. The KEY POINTS main challenge was that the bright light necessary Best-corrected visual acuity, psychophysical tests, and for adequate retinal illumination will interfere with conventional perimetry, albeit useful, do not fulfill the functional testing. With the advent of scanning desired comprehensive assessment of macular function laser ophthalmoscope (SLO), the infrared light in macular degenerative diseases. source permitted simultaneous observation of the fundus during examination and led to introduction Residual visual function has more impact on the patient daily activity and quality of life. of the first microperimeter (SLO 101, Rodenstock, Ottobrunn, Germany) in the year 1982 [9,10]. Microperimetry is currently the clinical investigation of Shortcomings of this device included semiauto- choice to assess residual visual functions and functional mated stimulus presentation and lack of eye tracker vision in macular degenerative diseases, especially to compensate for ocular movements; the device is geographic atrophy. no longer available in the market. These limitations Microperimetry offers fundus-controlled testing of retinal have been overcome by Nidek MP-1 (Nidek Tech- sensitivity through eye-tracking technology that allows nologies, Padova, Italy) that was introduced to the for structural and functional correlation and test–retest market in 2003 as the first fundus perimeter with eye reliability for the same test point. Furthermore, it tracker that compensates for eye movements based enables precise assessment of location and stability of fixation. on an initial frame. With these new features in Nidek MP-1, exact correlation between retinal dis- Recent trends may call for incorporating microperimetry order and functional defects was rendered possible as a standard functional outcome measure in clinical even in eyes with poor or unstable fixation trials of geographic atrophy. [11,12&,13,14]. Thereafter, in 2006, a more recent Spectral OCT/SLO microperimeter was introduced to the market by OPKO/OTI (OPKO Instrumenta- More recently, microperimetry has effectively tion, Miami, Florida, USA) that incorporated spec- provided fundus-correlated functional testing, tral optical coherence tomography (OCT) with test–retest reliability for the same test point, precise microperimetry, offering an additional advantage assessment of the location and stability of fixation, of correlating retinal dysfunction with the corre- and compensation for ocular movements. By incor- sponding ultrastructural finding as shown by porating these features, microperimetry has become OCT. The technology was later transferred to Optos the clinical investigation of choice to assess residual Inc., and the device was named Optos OCT/SLO visual functions and functional vision in macular (Optos, Dunfermline, Scotland, UK). Optos OCT/ diseases [7,8]. SLO is the only US Food and Drug Adminis- This article covers basic concepts and recent tration-approved microperimeter; it received advances in microperimetry, common market- 510(k) clearance in 2013 [3,15–18]. Macular Integ- available microperimeters, and the steadily growing rity Assessment (MAIA; CenterVue, Padova, Italy) role of microperimetry in clinical evaluation and was the latest instrument to reach the market in monitoring of macular diseases, particularly, geo- 2009, garnished with high-frequency eye tracker graphic atrophy. Latest research observations repor- and a line confocal SLO [6,7]. Table 1 summarizes ted during the review period are also summarized. key differences between the three commercially available microperimeters. EVOLUTION OF MICROPERIMETRY According to many experts in the field, ‘micro- CLINICAL APPLICATIONS OF perimetry’ is not the most accurate naming for this MICROPERIMETRY ocular imaging technology, given the currently used Indeed, microperimetry surpasses conventional peri- examination parameters of stimulus size ranging metry in several aspects in evaluation of retinal sen- from Goldman I to V, and examination field sitivity in macular diseases [19]. One fundamental of up to 158–208 from the foveal center. Rather, advantage of microperimetry is the real-time tracking ‘fundus-correlated perimetry’ or ‘fundus-guided of the fundus throughout perimetric testing. This perimetry’ are considered more accurate names. allows perimetric examination of patients with For sake of simplicity, we used the term ‘micro- eccentric or unstable fixation. The ability of regis- perimetry’ throughout the article [5,6]. The need tration of macular sensitivity results on digital fundus to achieve correlation between clinically apparent photograph allows for functional and structural retinal disorder and functional testing urged the correlation [6]. Furthermore, in conventional peri- demand to design a perimetry device that enables metry, the stimulus is projected on a screen in front

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Table 1. Summary of commercially available microperimeters

Nidek MP-1 Optos OCT/SLO MAIA

Manufacturer Nidek Technologies, Optos, Dunfermline, CenterVue, Padova, Italy Padova, Italy Scotland, UK Year of arrival to the market 2003 2006 2009 Features of incorporated fundus imaging Infrared and digital color SLO black and white SLO black and white

Microperimetric examination parameters Size of the of the microperimetry testing field 458 29.78 368 Fixation assessment Eye-tracking technology SLO High-frequency eye tracker Background luminance 1.27 cd/m2 10 cd/m2 1.27 cd/m2 Highest stimulus intensity 128 cd/m2 125 cd/m2 318 cd/m2 Dynamic range of stimulus attenuation 0–20 dB 0–20 dB 0–36 dB Coregistration of retinal sensitivity map Automatic or Manual Automatic with simultaneous Automatic coregistration on the fundus image Options SLO and OCT Advantages and unique features Continuous fundus Combined OCT for structural High-resolution fundus imaging autofocus and functional correlation 1024 1024 Biofeedback training Biofeedback training Automatic retest Available Available Available

MAIA, Macular Integrity Assessment; OCT, optical coherence tomography; SLO, scanning laser ophthalmoscope. of the patient’s eye, whereas in microperimetry, the doubt that this innovative imaging modality, stimulus is directly projected on the predefined microperimetry, has significantly increased our retinal points helped with the eye-tracking techno- knowledge and understanding of many macular logy. This is another key advantage that allows for disorders. For instance, microperimetry revealed accurate test–retest of the same point in microperim- the presence of dense over macular holes etry with a shift range of about 0.538. On the other [37] and over macular areas where there is loss of hand, sensitivity of a given point in conventional integrity in the inner segment/outer segment layer perimetry represents, in fact, the average of an area of [15]. Similarly, detecting the shift of preferred about 58 [8]. retinal locus (PRL) from the foveal center to the The development of multiple commercially intact retina superior to central scotomas in macular available microperimeters, such as Nidek MP-1, holes or paracentral scotomas in number of other Optos OCT/SLO, and MAIA, has led to widespread macular dystrophies would have not been possible use of microperimetry and allowed thorough evalu- without microperimetry [5]. ation of the device in clinical studies. Since late 80th In general, clinicians and researchers should be of the last Century, microperimetry has been inves- familiar with the features of different commercially tigated in enormous number of clinical studies. It available microperimeters so that they can select the was shown to play a great role in diagnosis and version that services their purposes. For instance, follow-up of myriad of retinal and macular disorders Optos OCT/SLO may be the best choice for retina including age-related macular degeneration (AMD) specialists practicing medical and surgical retina as [20,21], geographic atrophy [22,23,24&,25,26], cho- it combines OCT with microperimetry (Fig. 1). On roidal neovascularization [27], diabetic retinopathy the other hand, those who practice low vision reha- [15–17,28], uveitic macular edema [29–31], central bilitation for patients with macular degenerative serous chorioretinopathy [32], and macular dystro- diseases such as geographic atrophy will benefit phies such as Stargardt’s disease [33] and North from the biofeedback training module in Nidek Carolina dystrophy [34]. Moreover, it has been MP-1 and MAIA. instrumental in evaluating treatment results of sev- eral pharmacological , as well as laser and surgical procedures. Examples include intravitreal ROLE OF MICROPERIMETRY IN ANALYSIS antivascular endothelial growth factor for treating OF GEOGRAPHIC ATROPHY neovascular AMD [35], retinal laser photocoagula- The term ‘geographic atrophy’ was devised by the tion for diabetic macular edema [36], and pars plana pioneer J. Donald M. Gass in 70th of the last century vitrectomy for macular holes [37,38]. There is no who first used it to describe discrete single or

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FIGURE 1. Combination of functional assessment using microperimetry and morphological assessment using OCT are combined in the Optos OCT/SLO Microperimeter (Optos, Dunfermline, Scotland, UK). The retinal sensitivity grid is imposed on the fundus image. The horizontal (blue line) and the vertical (green line) OCT scans crosses at one point that shows an absolute (0 dB). This enables precise structural and functional evaluation of the exact location in the fundus. In the bottom right corner of the image, the retinal sensitivity map is shown imposed on the SLO fundus image, with absolute scotoma over the area of geographic atrophy. On the right side of the same retinal sensitivity map, the fixation assessment shows stable central fixation with 92% of the fixation points lying within the central 28 circle. The image was acquired by the authors at the Diagnostic Center at the Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA. OCT, optical coherence tomography; SLO, scanning laser ophthalmoscope. multiple coalescent areas of loss of the retinal autofluorescence, and optical coherence tomo- pigment epithelium in patients with macular drusen graphy [26,44,45]. Examination of the functional [39]. Geographic atrophy is the hallmark clinical loss associated with increase in geographic atrophy finding of the advanced form of nonexudative area may help toward more comprehensive under- AMD and is acknowledged to account for 20% of standing of the disease process. Best-corrected visual the legal blindness attributed to AMD in North Amer- acuity does not correlate reliably with geographic ica [40]. Characteristically, loss of photoreceptor atrophy progression and does not reflect the actual layer, retinal pigment epithelium, and choriocapilla- visual disability. Patients with geographic atrophy ries in geographic atrophy starts parafoveally leading have shown reduction in low-luminance visual to parafoveal scotomas and dysfunction of rods and acuity, contrast sensitivity, and reading speed in cones interfering with the daily activities of the previous studies [46,47]. However, the temporal patient such as reading and driving. Eventually, geo- changes in these measurements and its correlation graphic atrophy progresses to the fovea leading to with anatomic change have never been fully inves- profound effect on central visual acuity [41,42]. At tigated. present, there is no known effective treatment that With its ability to produce precise and repeat- can reverse the detrimental effects of geographic able mapped measurements of retinal sensitivities, atrophy or halt its progression [43]. The gradual microperimetry may represent the optimal poten- time-dependent change in the area of geographic tial imaging modality that may close the loop atrophy lesion(s) is a key feature that has been closely between anatomic and functional evaluation in geo- studied using wide variety of imaging modalities graphic atrophy, specifically, and macular degener- including digital fundus photography, fundus ative disorders, in general. At present, the role of

152 www.co-ophthalmology.com Volume 26 Number 3 May 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. Introduction to microperimetry and its role in analysis of geographic atrophy Hanout et al. microperimetry in degenerative macular disease assumes foveal function. Early in the adaptation with geographic atrophy is being heavily process, multiple loci in the retina may be recruited researched. There are numerous clinical trials and become preferred over all other retinal areas for exploring different treatment modalities for macu- the higher visual tasks. In addition, those loci show lar degeneration, and microperimetry imaging has greater potential to improve in functionality with become a mainstay in monitoring the disease prog- training, become more repeatedly aligned with ress. Microperimetry has been recently utilized in a visual targets, and become used as oculomotor refer- phase I trial looking at autologous bone marrow ence. Such retinal areas are referred to as PRLs cells in the restoration of retinal tissue [48]. It was [53,54]. Later in the adaptation process, usually a also employed in another phase I/II trial investi- single PRL takes over eccentric visual function and gating the effects of intravitreal sirolimus in geo- becomes the only functional retinal locus with well graphic atrophy [49]. Furthermore, a phase I trial established location in the retina [53]. also used microperimetry to evaluate safety of intra- Before the advent of the SLO, PRL was crudely ocular delivery of ciliary neurotrophic factor for identified by clinical observation. Microperimeters macular telangiectasia type 2 [50]. These studies offer optimal instrumentation to detect the precise are far from the only ones, but they portray the topographic location of the PRL and its orientation wide variety of studies investigating new treatments from the old fovea. The PRL appears on microperim- for macular diseases, all incorporate the use of etry as a circumscribed area in the retina covered microperimetry to monitor treatment effectiveness. with fixation points [52]. The orientation of the PRL from the old fovea can be expressed and docu- mented in degrees of eccentricity, which is essential ASSESSMENT OF MACULAR SENSITIVITY for research studies and disease monitoring in IN GEOGRAPHIC ATROPHY clinical setting [8]. A decline in macular sensitivity and increase in macular scotoma has been observed in clinical stud- ies of geographic atrophy. In a study that followed FIXATION STABILITY nine patients with bilateral geographic atrophy for The second crucial component of the natural adap- 24 months to evaluate the change in retinal sensi- tation process that follows irreversible central vision tivity, a general trend of decreasing retinal sensi- loss in geographic atrophy encompasses improving tivity was observed in the overall tested area, the fixation stability in the new PRL to achieve including areas outside the geographic atrophy better visual function. This process is modulated lesion. Furthermore, all eyes demonstrated an over- through the oculomotor function [8]. Fixation all increase in the number of points with absolute stability, may also be referred to as fixation quality, scotoma during the follow-up period [23]. is defined as the ability of the eye to maintain In another study, microperimetry was used to fixation in the PRL. Fixation would be considered examine retinal sensitivity in areas with nascent stable if 75% or more of fixation points fall within 28 geographic atrophy compared with nonatrophic diameter circle; relatively unstable if less 75% are areas in 24 eyes with intermediate AMD. Areas of inside the 28 diameter circle but more than 75% fall nascent geographic atrophy showed worse retinal inside the 48 diameter circle; and unstable if less sensitivity compared with nonatrophic areas, but than 75% of the fixation points are inside the 48 better retinal sensitivity compared with areas of diameter circle [27]. Fixation stability can also be drusen-associated atrophy as detected on spectral assessed by measuring the area covered by the domain OCT [24&]. fixation points in square degrees, referred to as the bicurve ellipse area (BCEA) (Fig. 2), which can be accurately estimated using microperimetry. EXTRAFOVEAL FIXATION AND BCEA is calculated from the minor and major axes PREFERRED RETINAL LOCUS of an ellipse area covering fixational eye move- Geographic atrophy will eventually result in retinal ments, accounting for 2 standard deviations (SDs) damage and irreversible loss of central vision. Con- of recorded eye movements. A recent study showed sequently, several functional adaptation strategies the mean BCEA to be 0.05382 (SD ¼ 0.022) in normal will develop to compensate for the resultant visual eyes and 6.7682 (SD ¼ 8.36; range, 0.21–31.858)in disability and enhance the residual functional eyes with AMD, respectively [55]. vision [51]. A key adaptive mechanism is to develop In a recent study that followed patients with an eccentric retinal area with preserved visual func- geographic atrophy for 24 months using of micro- tion, and is physically close to, commonly at the perimetry, decreases in mean fixation quality were superior border of [52], the lost fovea so that it observed for both measures using the 28 and 48

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FIGURE 2. Results of microperimetric examination of the left eye of a patient with geographic atrophy using Nidek MP-1 Microperimeter (Nidek Technologies, Padova, Italy). Retinal sensitivity map shows several points with absolute scotoma over the geographic atrophy area. The BCEA is enlarged measuring 4.1 degrees square (4.182). Normal BCEA is reported to be 0.05382 (SD ¼ 0.02282). Fixation is labeled as ‘relatively unstable’, as shown in the panel on the top left corner, with only 57% of the fixation points within the central 28 circle, but with 92% of the fixation points within the central 48 circle. Testing parameters were: stimulus size ¼ Goldmann III, duration ¼ 200 ms, and strategy ¼ 4-2, pattern ¼ 10-2 68 points. The image was acquired by the authors at the Diagnostic Center at the Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, Nebraska, USA. BCEA, bicurve ellipse area; SD, standard deviation. circles over the study duration with the mean per- AMD, and there are multiple psychophysical factors centage of fixation positions located within the 28 affecting variability in clinical trials being per- circle decreasing by 11.9% per year, and that located formed currently. Learning effect commonly takes within the 48circle decreasing by 11.7% per year place between the first and second test. Regardless of [23]. In addition, at 24 months, 16.6% of eyes the condition of the individual patient, it has fre- labeled to have ‘stable fixation’ at baseline pro- quently been shown that the patient will show gressed to ‘relatively unstable’, and 60% of eyes perceived improvement upon repeated examination labeled ‘relatively unstable’ at baseline progressed [56&&]. It has been recommended to automatically to ‘unstable’. None of the enrolled eyes evaluated discount the first test and to count the repeated one in the study demonstrated an improvement in fix- as baseline to combat this effect. Other aspects of ation stability throughout the 24-months follow-up study design need to be accounted for, such as period [23]. adaptation when performing examinations on one eye immediately after the other, experience of the operator of the machine, and timing between tests RELIABILITY OF MICROPERIMETRY [56&&]. RETEST IN GEOGRAPHIC ATROPHY There are different parameters for the measure- Test–retest reliability has been an area of discussion ments of microperimetry including macular mean when looking at the clinical implications of micro- sensitivity, macular mean deviation, and point- perimetry in patients with geographic atrophy in wise sensitivity [57]. Mean sensitivity and mean

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