Dataset On Macular Microperimetry Of Healthy Subjects Biology Essay

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Normative dataset identifying properties of the macula of healthy subjects across age groups: relationship of visual sensitivity, retinal thickness and distance from the fovea

Abstract

Purpose: This study was designed to establish a normative database of macular microperimetry values and structural parameters of the macula from normal subjects without any ocular disease. These values were acquired to identify reference points for the evaluation of patients with macular disease. Information was gained regarding the relationship between retinal sensitivity and age, distance from the fovea, and retinal thickness.

We have used the OPKO SLO/SD-OCT with microperimetry exclusively since 2007,

performing over 2000 microperimetry exams, because of the following advantages:

• Integration of microperimetry with a high resolution SLO image and a spectral domain OCT, allowing

registration of all three modalities.

• Background illumination for the microperimeter is Humphrey VF equivalent (10 cd/m2) as compared to

the Nidek instrument with 1.27 cd/m2.

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• Tracking is enhanced with the SLO using 1000 scanning lines, allowing the use of small vascular

structures for tracking.

• e instrument has automatic focusing on the fundus. e Nidek uses manual input of the patient's

spherical equivalent distance correction.

• e OPKO uses continuous image capture with the SLO throughout the microperimetry exam. e

Nidek instrument requires the operator to capture a flash fundus photograph at the end of the exam that is

semi-automatically registered to the stimulus pattern.

• Focusing, tracking, and registration for "re-testing" is accomplished automatically with the OPKO

instrument. e process is semi-automatic with a manual assist from the operator of the Nidek instrument.

Methods: This is an institutional review board approved prospective study that recruited normal individuals of age 20 to 85 for full threshold macular microperimetry combined with the acquisition of structural parameters of the macula. Sensitivity was recorded at 28 points organized into 3 circles that were centered on the fovea and expressed on a scale of 0 (lowest) to 20 (highest) decibels. These circles were arranged concentrically within the macula with the OPKO Scanning Laser Ophthalmoscope (SLO) / Spectral Domain Optical Coherence Topography (SD-OCT) microperimeter (OPKO (OTI) SLO/SD-OCT microperimeter). Fixation data was recorded for each eye tested and expressed as the percentage that fixation was within 2 degrees of the fixation target, and the percentage within 4 degrees of the target. Retinal thickness was measured with the spectral domain OCT using a 200 line raster scan. The software then aligned the thickness map with the sensitivity map that was recorded at each point to correlate macular thickness with retinal sensitivity. All subjects selected to participate in this study had best corrected visual acuity of 20/25 or better measured with Snellen visual acuity chart at 20 feet. Subjects also underwent a dilated fundus examination and were excluded from the study if they had any media opacities, decreased visual acuity, or retinal pathology. Primary outcome determination was based on calculation of the Pearson product-moment correlation coefficient (r) for the different variables recorded.

Results: Mean retinal sensitivity was calculated for 192 healthy eyes that had been categorized evenly into age brackets by decade. The overall mean for retinal sensitivity at all points was 17.94 ± 2.30 dB. Fixation for all age categories was 98% or above within 4 degrees of the fixation target, and 91% or above within 2 degrees. Retinal thickness measurements were taken on 169 healthy eyes from the original dataset after 23 eyes were excluded. Mean retinal thickness in the center of the fovea was found to be 200 ± 28.40 μm. Mean retinal thickness in the area of the macula surrounding the foveal depression was found to be 289 ± 24 μm. The correlation coefficient for age vs sensitivity was r = -0.240 (n=169), for thickness vs sensitivity was r = +0.137 (n=169), and for thickness vs age was r = -0.065 (n=169).

Conclusions: Microperimetry with SLO/SD-OCT provides a way to measure macular sensitivity and retinal thickness around central fixation. This allows for correlation of functional sensitivity with the objective assessment of the macula by spectral domain OCT. The findings of this study serve as a basis for age-matched comparison of sensitivity values in patients with macular pathology. Increasing age resulted in a significant decline in retinal sensitivity. Increased distance from the fovea within the measured area did not result in a statistically significant decline in retinal sensitivity in this data set, although that has been found in prior studies. There was no relationship found between retinal thickness and retinal sensitivity in the area of the macula surrounding the foveal depression.

Introduction

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Visual acuity has long been used as a measure of macular function in assessing the need for intervention as well as for quantifying outcomes in clinical trials. 1 However, measuring visual acuity only partially defines the function of the macula. Visual acuity measurements can miss subtle macular dysfunction and can completely disregard paracentral scotomas.2 Paracentral scotomas can strongly affect the individuals' perception of vision. With advances in medical and surgical options for patients with macular disease, reproducible measurement of macular function is critical to tailor treatment to the individual patient.3

Standard Automated Perimetry (SAP), the current standard for assessing central visual field deficits4-6 has two major shortcomings when used to evaluate macular diseases. First, accurate assessment of the visual field with conventional testing is based on the assumption that fixation is centrally located on the fovea and stable during the exam.3 Patients with a diseased macula often do not have central and steady fixation. Secondly, the sensitivity map produced by SAP has only a general correlation to retinal structure as seen on a fundus photograph.

Advances in instrumentation have led to microperimetry, which incorporates placement of macular sensitivity values onto a macular fundus photograph. There are currently two instruments that have this capability: the Nidek MP-1 and the OPKO SLO/SD-OCT microperimeter. In addition, the OPKO instrument can correlate the microperimetry with a topographical map obtained by SD-OCT. This allows for precise mapping of the central visual field with correlation to the anatomy that is observed on clinical examination. A microperimeter system tracks movement of the eye during examination, allowing accurate placement of the stimulus in the same location for each presentation, thus eliminating poor fixation as an error factor in the examination.

The microperimeter provides information about macular function that is complementary to visual acuity measurements. Baseline values for macular sensitivity based on age and location within the macula are needed for comparison to determine the degree of impairment in disease states. This study was designed to address this critical need, and to establish a normative database of microperimetry values combined with structural information. Data acquisition was performed using the OPKO (OTI) SLO/SD-OCT microperimeter. Data sets were obtained to serve as age-matched reference points for evaluation of patients with macular disease. The unique ability of this technology to register retinal sensitivity measurements with retinal thickness has allowed us to also study this relationship systematically within the macula.

Methods

This is an institutional review board approved prospective study that recruited normal subjects age 20 to 85 for full threshold macular microperimetry combined with SLO/SD-OCT. After informed consent and instrument calibration, macular sensitivity was recorded at 28 points organized into 3 circles. The points that comprised these circles were centered on the fovea and expressed on a scale of 0 (lowest) to 20 (highest) decibels. These points were arranged into a central circle with 4 points, middle circle with 12 points, and an outer circle with 12 points. Each circle was arranged concentrically around the fovea and within the central 11 degrees of the macula with the OPKO (OTI) SLO/SD-OCT microperimeter (Figure 1).

The display type for this instrument is a color organic light emitting diode (OLED) screen with 10 cd/m2 background illumination. The stimulus range above background extends from 1.25 cd/m2 (2 dB) to 125 cd/m2 (20 dB). The subject's sensitivity threshold was established at each point with a 4-2 staircase strategy at randomly selected point locations. The luminance of each point tested was started at 10 dB, with subsequent change by the staircase strategy depending on the subjects' response. Fixation data was recorded for each eye tested and expressed as the percentage that fixation was within 2 degrees of the fixation target, and the percentage within 4 degrees of the target.. The instrument utilizes automated macular tracking to maintain precise placement of the stimulus on the desired testing points. An area of interest on the fundus image must be identified prior to the start of the examination for the instrument to follow for the eye tracking software. Ease of instrument tracking is usually best served by identifying prominent vessels that are visible with high contrast (Figure 2).

After microperimetry testing, each eye was scanned with spectral domain optical coherence tomography to produce a retinal topography (retinal thickness) map of the posterior pole of the eye. The topography scan contains 200 scan lines, with 200 A-scans per line, for a total of 40 thousand A-scans in the area scanned. Retinal thickness is defined as the distance between the retinal nerve fiber layer and the retinal pigment epithelial layer. For each scan line, the instrument software algorithm identifies each layer and measures the distance between the two layers. Retinal thickness in the macula was calculated using the CSME grid (Figure 3). This grid has a central circle that measures 1 mm in diameter and is centered on the fovea. It has a concentric inner circle that measures 2.2 mm in diameter, and it has a concentric outer circle that measures 3.5 mm in diameter. The inner and outer circles are divided into nasal, temporal, superior and inferior sections. Retinal thickness was averaged for the area within the central circle, as well as for each of the outer segments (Figure 3).

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The software of the instrument aligns, overlays and brings into registration both the retinal thickness and retinal sensitivity maps, thus visually facilitating the correlation of structural and functional parameters. The measured retinal sensitivity at each location was assigned to the corresponding average thickness for that segment in the CSME grid to compare these separate parameters for associated changes.

All subjects selected to participate in this study had best corrected visual acuity of 20/25 or better measured by Snellen visual acuity at 20 feet. Subjects also underwent a dilated fundus examination and were excluded from the study if they had any media opacities, decreased visual acuity, or retinal pathology. Each subject was randomized as to which eye was tested first. Testing was conducted in a dark room, with the contralateral eye occluded during testing. Refractive error ranged from a spherical equivalent of +3.00 D to 10.00 D.

Correlation between sensitivity and age or sensitivity and thickness was determined by calculation of a Pearson product-moment correlation coefficient (r) for each dataset. The strength of the association between two given variables was designated as no correlation for 0.0 ï‚£ r ï‚£ 0.2, weak correlation for 0.2 ï‚£ r ï‚£ 0.4, moderate correlation for 0.4 ï‚£ r ï‚£ 0.6, and strong correlation for 0.6 ï‚£ r ï‚£ 1.0.

Results

Mean retinal sensitivity was calculated for 192 healthy eyes that had been categorized evenly into age brackets by decade. The overall mean for retinal sensitivity at all points was 17.94 ± 2.30 dB. There was a trend towards decreasing sensitivity with increasing age (Table 1, Figures 4 and 5). The individual points were used to calculate the Pearson product-moment correlation coefficient (PMCC) in attempt to determine the potential linear dependence between age and retinal sensitivity. The correlation coefficient for this dataset between age and retinal sensitivity was -0.240, implying a weak negative correlation between age and retinal sensitivity. This is consistent with prior studies where authors have reported this relationship to be statistically significant.7-9

Mean retinal sensitivity was also calculated by location within the macula for all patients to compare sensitivity between the different circle locations (Table 2). There was a trend towards a mean sensitivity decrease with increasing distance from the fovea, which had been reported before in the literature.7-9 This trend was not statistically significant between the central, middle, or outer circles in this series of patients, however.

Mean retinal thickness was calculated for 169 healthy eyes that had been categorized into five age groups from age 20 through age 85. Topography scans that contained scanning errors or poor signal were removed from the analysis to prevent inaccurate thickness measurements. Thus there were 23 fewer eyes in the retinal thickness analysis than the total number of eyes in the retinal sensitivity analysis. Mean retinal thickness in the center of the foveal depression was 200 ± 28.40 μm. Mean retinal thickness was measured within a 3.5 mm diameter circle that was centered on the fovea and broken up into different segments (Figure 3). The mean for the entire area measured was calculated to exclude the central 1 mm diameter circle, which contains the foveal depression, and was found to be 289 ± 24 μm. The middle circle of the CSME grid had the thickest average retinal thickness and was measured at 300 ± 19 μm. The outer segments of the CSME grid that were measured had a lower average, with the average for these being 277 ± 24 μm. Excluding the foveal depression, the thinnest segment was the outer/temporal segment at 257 ± 17 μm (Figures 6 and 7). This data was similarly analyzed with the PMCC for a linear correlation between retinal thickness and sensitivity. The Pearson product correlation coefficient for retinal thickness and sensitivity was +0.137, which represents no significant correlation between increasing retinal thickness and increased sensitivity in normal subjects.

Retinal thickness was plotted against retinal sensitivity for 1352 data points (Figure 8). The central circle was removed from the calculation because it contains the foveal depression, and this could potentially skew results to imply that sensitivity actually increases with decreased retinal thickness. In the area of the macula that surrounds the foveal depression, there was no correlation found between retinal thickness and retinal sensitivity in normal subjects. This confirms a finding by Landa et al, although the sample size of normal subjects in their study was much smaller (n=15 vs N=169).10

Discussion

The functional evaluation of macular diseases has been based upon central visual acuity (EDTRS), and contrast sensitivity.1 Visual acuity is an important measure of visual resolution in the very center of the macula, but it is insufficient for a complete quantitative analysis of the visual function of the eye. Most clinical trials for macular disease therapies use visual acuity as a primary measure of efficacy while not taking into account the functional status of the macula as a whole.

Eye tracking assisted microperimetry supplies additional important quantitative information about macular function. It can determine the location and extent of scotomas, and the locus and stability of fixation. This information cannot be acquired with standard automated perimetry because this technology relies on central and steady fixation for reliability.

Microperimetry with SLO/SD-OCT provides a way to measure macular sensitivity and retinal thickness around central fixation. This technology also allows for the first time to correlate functional sensitivity with the objective assessment of the macular structure. The findings of the present study serve as a basis for age-matched comparison of structure and sensitivity parameters in patients with macular pathology. This technology provides sensitivity data that is complimentary to visual acuity data, and both should be used as primary outcome measures due to the relevance of visual function and its relationship to retinal structure.

Analysis of the effect of age on sensitivity measurements within the macula revealed correlation coefficients of -0.240. These results imply a weak negative correlation between age and sensitivity in normal subjects. This study did not reveal a statistically significant decline in sensitivity across age groups with increasing distance from the fovea, a finding that has been reported in prior studies.7-8 One reason for the lack of significant change is likely related to the smaller area of testing within the macula of 11 degrees conducted in this study. Other reports analyzed the change in sensitivity across the central 30 degrees, which was reported by Heijl, et al. In that study they also allowed for 20/30 visual acuity to participate in the study for patients over 50 years of age. Microperimetry testing within the central 11 degrees would be expected to have a smaller change in sensitivity compared to the decrease that would be observed 30 degrees from the fovea.

The calculated correlation coefficient for retinal thickness and sensitivity was +0.137. This finding has been previously reported and reflects a lack of significant change in sensitivity across age groups at varying retinal thickness measurements.10 We subsequently analyzed the association of thickness with age, and for these two variables calculated a coefficient of -0.065. This was done to entertain the idea that perhaps retinal thinning occurred with increasing age, and that this was the cause for decreased sensitivity in older subjects. However, although there was a weak association with decreased sensitivity and increasing age, there was no association between increasing age and decreased retinal thickness in this dataset. This finding would oppose the notion that decreased sensitivity measured in older patients occurs as a result of decreased retinal thickness.

Mean retinal sensitivity was calculated for 193 healthy eyes that had been categorized evenly into age brackets by decade. The overall mean for retinal sensitivity at all points was 17.92 ±??dB (AVG ± SD???). There was a trend towards decreasing sensitivity with increasing age, but this was not found to be statistically significant upon analysis (Table 1, Figures 3 and 4). Other authors have reported this relationship to be statistically significant.4,6,7

Retinal thickness was plotted against retinal sensitivity for 1352 data points (Figure 7). The central circle was removed from the calculation because it contains the foveal depression. In the area of the macula that surrounds the foveal depression, there was no correlation found between retinal thickness and retinal sensitivity. This confirms a finding by Landa et al, although the sample size in their study was much smaller (n=15 vs N=169).8

Conclusions

Mean retinal sensitivity as measured by microperimetry decreased slightly with increasing age. Mean retinal sensitivity did decrease with increasing distance from the fovea, but the relationship was not statistically significant. No relationship was detected between retinal thickness and retinal sensitivity in the macula outside of the foveal depression in this series of normal subjects. A database was established for retinal thickness and retinal sensitivity measurements in normal subjects with SLO / SD-OCT microperimetry.

Age

Mean Sensitivity, all

N

Mean Thickness, all

N

Mean Sensitivity, male

N

Mean Thickness, male

N

Mean Sensitivity, female

N

Mean Thickness, female

N

20 - 29

18.1 ± 2.3

37

291 ± 22

31

18.3 ± 2.3

14

300 ± 24

10

17.9 ± 2.3

23

287 ± 20

21

30 - 39

18.6 ± 1.8

33

288 ± 24

31

18.6 ± 1.8

18

291 ± 23

16

18.6 ± 1.8

15

285 ± 25

15

40 - 49

18.1 ± 2.3

38

291 ± 24

33

18.3 ± 2.4

14

291 ± 23

14

17.9 ± 2.4

24

291 ± 25

19

50 - 59

17.9 ± 2.4

27

283 ± 22

25

17.4 ± 2.6

13

284 ± 23

12

18.3 ± 2.0

14

282 ± 21

13

60 - 69

17.9 ± 2.2

30

290 ± 26

28

17.4 ± 2.5

10

294 ± 29

10

18.2± 2.0

20

287 ± 25

18

70 - 79

17.1 ± 2.3

28

287 ± 28

21

17.0 ± 2.4

14

293 ± 26

9

17.2 ± 2.2

13

283 ± 29

12

all

17.9 ± 2.4

192

289 ± 24

169

18.0 ± 2.3

83

292 ± 25

71

17.9 ± 1.0

110

286 ± 24

98

Table 1: Mean retinal sensitivity with standard deviation organized by age in decades. Mean sensitivity values were calculated for each age category at all points tested with associated standard deviation and number of participants.

Ethnicity

Age

Range/

mean

Mean Sensitivity, all

N

Mean Thickness, all

N

Mean Sensitivity, male

N

Mean Thickness, male

N

Mean Sensitivity, female

N

Mean Thickness, female

N

African-American

21-82

45

18.5 ± 1.9

25

284 ± 25

22

18.9 ± 1.7

5

287 ± 20

5

18.4 ± 2.0

20

283 ± 26

17

Caucasian

20-85

47

18.0 ± 2.3

150

290 ± 25

131

17.9 ± 2.3

69

293 ± 25

57

18.0 ± 2.3

82

287 ± 24

74

Hispanic-American

43-70

57

17.0 ± 2.4

9

287 ± 23

8

16.9 ± 2.5

3

303 ± 19

3

17.0 ± 2.4

6

278 ± 20

5

East

Indian

63-67

65

18.3 ± 1.9

5

285 ± 24

5

18.2± 1.9

3

274 ± 20

3

18.4 ± 2.0

2

302 ± 20

2

Other

37-50

43

17.5 ± 2.2

3

291 ± 23

3

17.5± 2.2

3

291 ± 23

3

Nil

0

Nil

0

ALL

20-85

48

17.9 ± 2.4

192

289 ± 24

169

18.0 ± 2.3

83

292 ± 25

71

17.9 ± 1.0

110

286 ± 24

98

Table 1a: Mean retinal sensitivity with standard deviation organized by ethnicity. Mean sensitivity values were calculated for each category at all points tested with associated standard deviation and number of participants.

Mean sensitivity, all points:

17.9 ± 2.4

Central Circle

Middle Circle

Outer

Circle

Number of subjects

Mean Sensitivity, all

19.4 ± 2.0

18.0 ± 2.2

17.4 ± 2.3

192

Mean Sensitivity, 20 - 29

19.1 ± 1.7

18.0 ± 2.1

17.8 ± 2.6

37

Mean Sensitivity, 30 - 39

20.0 ± 0

18.2 ± 1.5

17.9 ± 2.0

33

Mean Sensitivity, 40 - 49

19.6 ± 1.1

18.3 ± 2.4

17.3 ± 2.4

38

Mean Sensitivity, 50 - 59

19.7 ± .7

18.0 ± 2.0

17.2 ± 2.7

27

Mean Sensitivity, 60 - 69

19.7 ± .8

17.9 ± 2.2

17.4 ± 2.9

30

Mean Sensitivity, 70 +

18.5 ± 2.2

17.0 ± 2.3

17.4 ± 2.1

27

Table 2: Mean retinal sensitivity with standard deviation by circle location within the macula. Mean sensitivity was calculated by circle location within the macula for all points tested across all age groups. Associated standard deviation showed increased variability in the measured average upon increased distance from the fovea.

legends:

Figure 1:

Arrangement of test points within the macula showing sensitivity values in three concentric circles centered on the fovea.

Figure 2:

Black box indicating an area of prominent vessels used for eye tracking.

Figure 3:

CSME grid showing the central 1mm area containing the fovea, and the surrounding sections that contained areas of retinal thickness measurements.

Figure 4:

Bar graph of mean sensitivity measured across age groups in the nasal and temporal quadrants compared to the central circle.

Figure 5:

Bar graph of mean sensitivity measured across age groups in the superior and inferior quadrants compared to the central circle.

Figure 6:

Bar graph of mean retinal thickness in the nasal and temporal quadrants measured across age groups compared to the central circle.

Figure 7:

Bar graph of mean retinal thickness in the superior and inferior quadrants measured across age groups compared to the central circle.

Figure 8:

Scatter plot of the retinal sensitivity measured at each test point excluding the central circle (which contains the foveal depression) against mean retinal thickness for that location.