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N. K. Sahoo et al.
28.8 Conclusion
In conclusion, OCT and OCTA provide detailed structural evaluation in a wide range of retinal pathologies. Their use, as part of multimodal imaging strategies, can support the diagnosis and treatment-response evaluation of many retinal conditions. In many cases, the noninvasive nature of OCT and OCTA is signicantly advantageous over dye-based angiography.
Funding Hyderabad Eye Research Foundation, Hyderabad, India.
Disclosure GC: Speaker for Zeiss, Topcon
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Microperimetry
29
KaraR.Grimes andJayChhablani
29.1 Introduction
Microperimetry, or fundus-tracked perimetry, is a visual eld test to assess central retinal func­tion. Current uses of microperimetry have been built on early developments of non-automated fundus- tracked perimetry. These devices have subsequently improved with the innovation of scanning laser ophthalmoscopy. Microperimetry allows for the measurement of xation stability and topographic characterization of visual func­tion, enabling a correlation between retinal structure and visual function. Using microperim­etry, the sensitivity threshold of any point of the retina can be matched with its clinical appear­ance in real- time. This method can therefore pro­vide insights into disease progression and severity, particularly in conditions that affect the retina. This chapter comprehensively reviews the history, technology, techniques, and clinical application of microperimetry.
K. R. Grimes (*) New York Medical College, New York, USA
J. Chhablani Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA
29.2 Brief History
ofMicroperimetry
The introduction of perimetry to the eld of oph­thalmology is credited to Albrecht von Graefe in the mid-nineteenth century, building on the revo­lutionary work of the founder of the ophthalmo­scope, Hermann von Helmholtz [1]. In 1856, these early ophthalmologists used various xa­tion points during fundus examinations to create a visual eld plot [2]. Nearly a century following these experiments, clinicians began publishing documentation of retinal sensitivity while exam­ining the fundus. Early devices permitting static fundus-tracked perimetry were reported in the late 1970s [3]. Subsequent key developments in microperimetry were made following the inven­tion of the scanning laser ophthalmoscope (SLO) by Webb, Hughes, and Pomerantzeff in 1980 [4]. The originally designed SLO used a laser to illu­minate a small area of the retina, employing a novel principle in which light was collected from one retinal point at a time [5]. This method facili­tates repeated inspection of the retina and allows the exact locus of each point to be viewed directly by the clinician to measure acuity and investigate macular disease [5].
The SLO 101 (Rodenstock Instrument GmbH, Ottobrunn-Riemerling, Germany) was the rst commercially available device supporting fundus- tracked perimetry. In the following years, Microperimeter 1 (MP-1, NIDEK, Gamagori,
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2024 T. Das, P. Satgunam (eds.), Ophthalmic Diagnostics, https://doi.org/10.1007/978-981-97-0138-4_29
387
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K. R. Grimes and J. Chhablani
Japan) was more often used for fundus-tracked perimetry. The MP-1 had real-time automated full-threshold perimetry software, allowing fun­dus perimetry in a larger, color-visualized eld. Although MP-1 was more reliable than SLO for xation analysis, limitations of poor infrared image quality and artifacts disrupting the test grid on fundus imaging spurred further developments on this instrument [6]. These technical limita­tions were addressed by the Macular Integrity Assessment System (CenterVue, Padova, Italy), which provided higher quality images and a dynamic range of 36 dB compared to earlier instruments. The Microperimeter 3 (Mp-3, NIDEK) and Compass (CenterVue) were later adaptations of previous devices that allowed for mesopic (1.27 cd/m2) and photopic (10 cd/m2) testing using liquid crystal display (LCD) and light-emitting diode (LED) projectors, respec­tively. Additionally, various research groups have developed custom-built devices for microperim­etry to answer specic research questions [7].
MP-3, the Spectral Optical Coherence Tomography (OCT) SLO (OPKO Health, Inc., Miami, FL, USA), the COMPASS, and the Macular Integrity Assessment System (MAIA).
29.3.1 Analysis ofRetinal Sensitivity
The principal feature of microperimetry is the abil­ity to present stimuli on a liquid crystal display background at specic locations in the retina, which allows for continuous visualization (Fig.29.1a and b) of the retina [8]. Retinal sensitiv- ity is measured as the minimal light intensity per­ceived by the patient when the retina is stimulated by spots of light in specic areas. Each examina­tion can differ with variable numbers of stimuli and different elds of vision. In microperimetry, the stimuli luminance is measured in apostilbs (asb), which is an absolute unit of luminance equal to
0.3183cd/m2. The maximum intensity emitted by the fundus-tracking perimeter is then used to create the relative decibel (dB) scale (Fig.29.1c).
29.3 Technology
29.3.2 Decibel Scale, Weber’s Law,
The development of commercially available microperimeters over the past 50years has been largely based on standard automated perimetry and has led to the widespread use of fundus­tracked perimetry. Yet, some factors of fundus­tracking are unique to microperimetry and vary depending on the instrument. Currently, devices used for microperimetry include the MP-1 and
abc
Fig. 29.1 Standard output given by the MAIA micrope­rimeter for a healthy subject. (a) Point threshold values overlaid onto a fundus image. (b) Heatmap output using a radial interpolation with point threshold values. (c)
Weber’s law, Fechner’s law, and the decibel scale are used to determine stimulus brightness in microperimetry [7]. Weber’s law describes the relationship between the smallest change in the intensity of the light stimulus (I) and the initial stimulus intensity (I). Based on the assumptions
Histogram of point threshold values and a mean sensitiv­ity value for all points. (Reprinted with permission from Josan etal. [8] Copyright 2021, Association for Research in Vision and Ophthalmology)
Fechner’s Law
constant
I
I
I
I
29 Microperimetry
Table 29.1 Commercially available microperimetry devices
Device
MP-1 2004; Nidek 1.27cd/m2128cd/m20–20dB Goldmann I,
OCT-SLO 2006; Optos 10cd/m2125cd/m20–20dB Goldmann III 4mm 29.7° 8Hz MAIA 2015;
MP-3 2015; Nidek
COMPASS 2016;
Year; manufacturer
CenterVue
co.,
CenterVue
Background luminance
1.27cd/m21000 asb 0–36dB Goldmann III 2.5mm 36° 25Hz
31.4 asb 10,000 asb 0–34dB Goldmann
31.4 asb 10,000 asb 0–25dB Goldmann III 3mm 60° 25Hz
Maximum stimulus luminance
Threshold range Stimuli Size
II, III, IV eV
I-V
Minimum pupil size
4mm 22.5° 25Hz
4mm 40° 430Hz
Visual eld
Tracking frequency
389
of Weber’s law, Fechner’s law describes the pro­portional relationship between subjective sensa­tion (S) and the logarithm of stimulus intensity. In this equation, the maximal luminance of an instrument (I luminance (I=I
) is proportional to the differential
max
threshold
I
Background
) [7].
Weber’s Law
K
=
()
Fechner’s Law
S
()
=
in dB x10 log
max
Data are interpreted according to Weber’s and Fechner’s laws to determine the stimulus bright­ness in decibels (dB). Zero dB is dened as the brightest stimulus that can be produced. Each 1dB increment corresponds to an attenuation of the luminance in the stimulus by a factor of 1.26, while 3dB corresponds to a two-fold attenuation of luminance, and 10 dB corresponds to a ten­fold attenuation as described by Pfau etal. (2021) [7]. In the most widely used commercially avail­able instruments, the stimuli can be presented over a dynamic range of 0–20dB with a scotopic background luminance of <0.03cd/m2, mesopic background luminance of 1.27cd/m2, or photopic background luminance of 10cd/m2. The decibel scale is not standardized because maximal lumi­nance can vary between instruments (Table29.1). Additionally, some microperimeters, such as the MAIA, color-code the decibel scale for interpre­tation, with “green” representing normal, “red” representing abnormal, and “black” representing a scotoma (Fig.29.1c).
Various stimulus patterns are used to test the central visual eld. The fundus image is viewed and tracked using an infrared fundus camera or an infrared SLO throughout perimetric testing. Concurrently, data from the visual eld is mapped directly to the fundus image (Fig. 29.1a). The minimal retinal sensitivity over a certain area is then measured by projecting the light stimuli over a specied spot several times at different intensities. Stimuli vary in luminous intensity and size, with the Goldman size III (0.43° and
4.0 mm2 area) being the most used size (Table 29.1). The Goldman size IV stimulus (1.72 and 64 mm2 area) is larger and is more often tested in people with low vision or in scoto­pic conditions in healthy eyes.
29.4 Technique
Microperimetry measures the sensitivity of the macula and allows examiners to perceive changes as a diagnostic tool. Although this process is automatic, the technician can have a substantial impact on the outcome of the examination. The following section will discuss common practices to obtain the best results using microperimetry.
29.4.1 Adaptation oftheRetina
andPupil Dilation
Before beginning microperimetry, it is essen­tial to allow the retina to adapt to the changing light conditions. For mesopic (or twilight) test­ing, 10minutes of adaptation is sufcient after
390
K. R. Grimes and J. Chhablani
exposure to a bright stimulus, such as fundus imaging [9]. Contrastingly, adaptation to mesopic lighting is not required following exposure to ambient lighting [10]. Studies have shown that mesopic microperimetry perfor­mance does not improve with increasing adap­tation time beyond 20min [10]. Microperimetry in scotopic (or dim-light) conditions requires at least 20min of dark adaptation, particularly for patients with retinal diseases [11]. Additional time (30–40minutes) is suggested for older adults and/or those with Bruch’s membrane damage [12].
The minimum pupil size needed for adequate testing varies depending on the machine used. Dilation requirements vary from ~2.5 mm to ~6mm, depending on the instrument (Table29.1) [13]. The state of the eye must remain consistent across examinations, irrespective of whether the eye is dilated or undilated. No further preparation of the eye is required.
29.4.2 Evaluation, Instruction,
andDuration ofTesting
During the evaluation, each eye is tested inde­pendently by covering one eye rst, then the other. A customized stimulus grid may be designed to evaluate a specic number of points located at varying degrees from xation. The patient must actively collaborate with the pro­vider during the examination by pressing a but­ton each time a light stimulus is perceived in various positions on a screen. Some devices pro­vide auditory feedback if the patient’s eyes move out of alignment. Regardless of this feed­back, the technician should continue to optimize alignment throughout the examination. This also applies to adjusting the plane of focus. Although many devices will auto-focus, auto­align, and have automatic grid placement, man­ual input is necessary to ensure the optimal focus and alignment are achieved at the most accurate sensitivity.
The total duration of evaluation (for both eyes) is approximately 25minutes. If consecutive tests are being performed, a few minutes of rest
between the tests may be benecial to the patient to minimize the effect of fatigue. Additionally, the accuracy of microperimetry can be improved if the patient receives adequate instruction and practice.
29.4.3 Fixation Testing
Microperimetry devices use xation testing to measure the ability of the eye to xate on the preferred retinal locus (PRL). In patients who lose central xation automatically, the next pre­ferred spot is known as the PRL.The provider can instruct the patients to nd the PRL quickly (e.g., using ashcards) once the scotoma loca­tion, position, and size relative to the PRL have been identied. Providers can then estimate xation stability at the PRL, which can direct intervention to improve functional vision. Using xation testing, the precision of eye xa­tion on a target can be evaluated, and xation can be measured at a location up to 25 times per second [14]. During testing, landmarks in the retina are tracked and then plotted as xation points over an image of the fundus, revealing the portion of the retina used to see the stimulus (Fig.29.2) [15].
29.4.4 Photopic, Scotopic, andMesopic Conditions
The relative contributions of rods and cones to vision vary across changing light intensities, with most vision being mediated by the cone (phot­opic) system and the rod (scotopic) system con­tributing to the low-light vision. However, rods comprise nearly 95% of retinal photoreceptors and cones comprise less than 5%. The properties of rods and cones are isolated in microperimetry by the selection of background luminance. Conventional microperimetry is typically per­formed under mesopic or twilight conditions in a dim but not completely dark room. The rod ver­sus cone function can be evaluated under phot­opic, scotopic, or mesopic conditions by selecting the background luminance.
56
y (degrees)
a
c
29 Microperimetry
391
7.5
5.0
2.5
0.0
–2.5
12 15
x (degrees)
18 21
6 5 4 3 2
distance [°]
1
1234
Fixation Graph
time [minutes]
b
Fig. 29.2 Fixation in a healthy subject. (a) Custom 181- point grid pattern with 0.5° spacing. (b) Three consecutive examinations for an example participant: left, middle, and right with xation on the target, xation off the target, and repeat xation on the target, respectively. (c) Time-series
29.4.5 Follow-Up
Follow-up testing can be performed on the same area of the retina using the same parameters as previous tests. By re-measuring the same anatom­ical locations, changes in sensitivity and xation
xation graph detailing eye position throughout testing. (Reprinted with permission from Josan et al. [15] Copyright 2023, Association for Research in Vision and Ophthalmology)
allow researchers to evaluate disease progression and/or assessment of treatment outcomes. It is important to remember that comparing xation stability between machines is unreliable due to inherent differences in stimulus/background con­trasts and tracking frequency (Table29.1).
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29.5 Clinical Application andInterpretation
Microperimetry is the technique of choice to assess residual visual function. It has been used to study macular degenerative diseases, including age-related macular degeneration, diabetic macu­lar edema, hereditary retinal dystrophies, and macular dystrophies. This tool is also benecial for the visual rehabilitation of people with low vision, as its software can be used to train eccen­tric xation and stimulate a new preferred point of view [16]. Additionally, microperimetry can quantitatively examine the retina and allow early surgical treatment of macular diseases, such as retinal detachment and epiretinal membrane. In this section, we provide an overview of the clini­cal application of microperimetry in completed clinical studies and trials.
29.5.1 Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is caused by damage to the macula. Globally, it is the leading cause of blindness in adults over 50 [17]. This disease is categorized into neovascular (wet) and non-neovascular (dry) AMD, with the former referring to the late stage of the disease. The current rst-line treatment for neovascular AMD (nAMD) is anti-vascular endothelial growth factor (anti-VEGF) injections. Although OCT has been used to locate uid in the macula and direct treatment, [18] this technique does not provide information about the retinal function. Microperimetry is a diagnostic technique that can be used to evaluate the function of the retina in people with AMD.
29.5.1.1 Neovascular Age-Related
Macular Degeneration
This progressive retinal degenerative disease is characterized by neovascularization of the cho­roid [19]. The progression of the disease is slow and may not be associated with a loss of vision [20]. Available evidence suggests that an impor­tant predictor for visual outcomes in nAMD fol-
lowing treatment with anti-VEGF is the interval between symptom onset and the initiation of treatment [21]. By identifying early changes in the retina, such as uid in the intraretinal and/or subretinal space, treatments can be initiated ear­lier, improving the patient’s long-term visual out­comes. Microperimetry studies have evaluated improvements in retinal sensitivity and changes in scotoma size following anti-VEGF treatment [22].
An early loss in macular function can be detected by microperimetry before the devel­opment of signicant visual impairment and has been reported as a predictor of the progres­sion of AMD to the advanced neovascular stage [23]. Other studies have used microperimetry to detect changes in retinal sensitivity in asymptomatic AMD and have measured a sta­tistically signicant improvement in retinal sensitivity within treatment-naïve cohorts [20,
22]. These ndings, and those reported in anti-
VEGF studies, may be subjective because there is a learning curve with microperimetry in which retinal sensitivity can improve with repeat testing [24].
Larger studies, such as the Laser Intervention in Early Stages of AMD (LEAD) study, used microperimetry to detect the onset of nAMD [25]. Although microperimetry was the best method to detect nAMD in this study, further ndings revealed no signicant difference between microperimetry and best corrected visual acuity in detecting the onset of nAMD due to low sensitivity ranges (between 11% and 35%) [25]. Other studies found that scotopic sensitivity is a better functional indicator for evaluating early and intermediate AMD progres­sion than mesopic sensitivity [26]. Although sco­topic microperimetry takes longer and requires prior dark adaptation, this method is more sensi­tive in detecting and differentiating changes in rod and cone cells [26]. Conversely, mesopic microperimetry was better than scotopic perim­etry in predicting AMD progression through morphological changes [27]. Both scotopic and mesopic testing were more sensitive to changes during early AMD than intermediate or advanced AMD [27].
29 Microperimetry
393
Larger longitudinal studies are needed to con­tinue tracking the progression of AMD using microperimetry. Although it is a useful tool in evaluating changes in the early stages of AMD, the ability to detect such changes using micrope­rimetry can be improved by using patient-tailored perimetry patterns that allow for an increased density of test points [7, 12].
29.5.1.2 Non-Neovascular Age-
Related Macular Degeneration andGeographic Atrophy
Microperimetry has frequently been used as an alternative to best corrected visual acuity (BCVA) to measure the foci of geographic atrophy (GA) (Fig. 29.3). These foci often present as foveal­sparing scotomas in non- neovascular AMD [12]. Multiple studies have used this technique to determine the number of scotomatous loci and the mean sensitivity of the macula as an alterna­tive to BCVA [28]. One of the rst known studies assessing macular function using microperimetry examined the eye following lutein supplementa­tion in patients with non-neovascular AMD [29]. Microperimetry measurements demonstrated a tendency toward improvement in macular func­tion although the effect did not reach statistical signicance [29]. Other assessments of retinal sensitivity using microperimetry are subthresh­old laser treatment for GA secondary to AMD, [30] retinal sensitivity at different stages of AMD [31], and following administration of medica­tions such as elamipretide [32].
29.5.2 Diabetic Retinopathy
andDiabetic Macular Edema
raphy, contrast sensitivity, low- luminance visual acuity, and microperimetry [34]. Eyes with DR or diabetic macular edema (DME) can have normal visual acuity despite reduced retinal sensitivity, suggesting that changes in sensitivity may pre­cede reductions in visual acuity (Fig.29.4) [35].
Functional testing of macular sensitivity using microperimetry can assess disease severity and response to therapy by quantifying functional loss due to extrafoveal macular edema or isch­emic diabetic maculopathy. Studies using micro­perimetry have demonstrated that patients with DR have signicant loss of retinal sensitivity as compared to healthy individuals (p<0.001); the decrease in sensitivity is more apparent with increasing severity of DR. [36] The decline in retinal sensitivity has been correlated with the decreased thickness of the nerve ber layer, [37] the photoreceptor layer measured by OCT, [37] and the severity of neuropathy [38]. However, other studies have found only a weak association between the structural and functional decits in early-stage DR, suggesting that other mecha­nisms, in addition to retinal thinning, may under­lie the functional defects [39].
Most microperimetry studies for DR and dia­betic maculopathy are done with pre-established patterns that study 20° of central vision. Other studies created a customized grid that was super­imposed with OCT-A. Although this method offers point-to-point structural and functional correlations for a detailed evaluation, the ndings have been inconsistent; this may be due to differ­ences in the test populations and the instruments used [40]. Microperimetry can also detect decreased retinal sensitivity in patients without macular edema, without DR, and in pre-diabetics.
The long-term effects of diabetes mellitus can lead to diabetic retinopathy (DR), causing dam­age to the retina and, potentially, blindness [33]. Diabetes is associated with asymptomatic vascu­lar damage that can progress before clinical signs appear. Proposed tests to detect early functional and structural abnormalities in DR include optical coherence tomography (OCT) and OCT­angiography (OCT-A), multifocal electroretinog-
29.5.3 Stargardt’s Disease
Stargardt’s disease type 1 (STGD1) is the most common cause of juvenile macular dystrophy caused by biallelic mutations in the ABCA4 gene. An early diagnosis may be established using multimodal imaging, but patients can be easily misdiagnosed and subjected to multiple tests and
394
a
b
Manual registration
MP-3 color fundus
K. R. Grimes and J. Chhablani
SLO
Fovea center
MP grid alignment
MP grid positions
Manual keypoints
Fig. 29.3 Aligning microperimetry with scanning laser ophthalmoscopy (SLO) image to measure retinal sensitivity in in dry AMD. (a) User-selected key points in the color fun­dus photograph (CFP) and at the same anatomic location in the SLO (red crosses) to align CFP with SLO. (b) Fovea cen-
therapies. Typical disease progression spares the peri-capillary and foveal regions and presents with bilateral central vision loss with variable degrees of macular atrophy. As such, BCVA is
ter position and scaling of the grid were manually set such that microperimetry measurement locations matched with CFP (left). Final locations are presented on SLO to the user for validation (right). (Reprinted with permission from Reiter etal. [31] Copyright 2023, Springer Nature)
insufcient in quantifying the functional loss over time. The visual function outcomes generated by microperimetry have been used in Stargardt’s disease treatment trials, specically to