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Correlation of Macular Focal Electroretinogram with Ellipsoid Zone Extension in Stargardt Disease.

1. Introduction

Autosomal recessive Stargardt disease (STGD1) is the most frequent childhood hereditary macular dystrophy, affecting 1 per 10000 individuals [1].

STDGD1 is caused by the mutation of the ATP-binding cassette, subfamily A, member 4 (ABCA4) gene, which encodes a transport protein localized in photoreceptor outer segments [2, 3]. The main role of ABCA4 protein is to remove potentially toxic retinoids, such as N- retinylidenephosphatidylethanolamine (NRPE) and phosphatidylethanolamide (PE), which originated from the phototransduction process [4].

Mutations of ABCA4 gene determine an increase of NRPE and PE with generation of N-retinylidene-Nretinylethanolamine (A2E), a lipofuscin fluorophore.

The shedding and phagocytosis of photoreceptors outer segments lead to lipofuscin accumulation in the retinal pigment epithelium (RPE) with subsequent RPE apoptosis and photoreceptor degeneration [5].

In the past 20 years, pattern electroretinogram (PERG) has been extensively used to assess macular function in patients with STGD1 [6, 7]. PERG is not recordable in almost all patients with STGD1 even in the case of preserved visual acuity and in the absence of clear signs of macular degeneration at fundus examination. As a consequence, PERG is a valuable tool to establish the diagnosis of STDG1, especially in the earlier phases of the disease. However, for the same reason, PERG may be inappropriate to estimate the degree of macular dysfunction and to assess disease progression. Furthermore, PERG signal reflects the activity of retinal ganglion cells and the inner retina [8] while STDG1 primarily affects the RPE and photoreceptor cells.

Flicker focal electroretinogram (FERG) is a diagnostic tool that selectively assesses macular cone photoreceptor and bipolar cell activity [9]. In previous clinical studies, this technique showed good test-retest repeatability, allowing a long term follow-up of macular dysfunction in retinitis pigmentosa [10] and cone-rod dystrophy [11]. Furthermore, it has been demonstrated that, in cone-rod dystrophies, FERG amplitude decline may anticipate visual acuity loss of several years [12].

Spectral domain optical coherence tomography (SDOCT) is a noninvasive imaging technique that provides information about the morphology of all distinct retinal layers and enables reliable and repeatable measurements of macular thickness. In patients with STDG1, SD-OCT has allowed clinicians to accurately visualize the extent and the degree of the degeneration of both inner and outer retinal layers [13-15]. More specifically, ellipsoid zone extension can be considered an important imaging parameter that allows clinicians to evaluate to the extent of damage of macular photoreceptors [16].

The aim of our study was to assess macular cone function by FERG recording in STDG1 and to explore the correlation between photoreceptor function and structure as determined by FERG and SD-OCT, respectively.

2. Methods

Patients with STDG1 evaluated at the Department of Ophthalmology of the Catholic University of Rome between June 2012 and June 2015 were retrospectively enrolled. The diagnosis of STDG1 was clinically established and then confirmed, in all patients, by genetic testing with next generation sequencing (NGS) technology. The examination protocol included best-corrected visual acuity (BCVA) measurement with Snellen charts, slit-lamp biomicroscopy, indirect ophthalmoscopy, spectral domain optical coherence tomography (SD-OCT), and FERG recording. Twenty age-matched healthy patients were also enrolled and served as controls for FERG amplitude.

The study followed the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Catholic University of Sacred Heart of Rome. All patients signed a written informed consent before the enrollment.

2.1. Imaging. SD-OCT scans were performed using the Cirrus OCT (Carl Zeiss Meditec Inc., Dublin, California, USA). The examination protocol consisted of a 6 x 6 mm macular cube, centered on the fovea, composed of 128 horizontal b-scans of 512 a-scans each. Retinal thickness values were automatically calculated by Cirrus OCT software for each of the nine areas corresponding to the Early Treatment Diabetic Retinopathy Study Research Group (ETDRS) [17, 18]. Both the average macular thickness (AMT) and the central macular thickness (CMT) were recorded. The AMT and CMT correspond to the mean retinal thickness in the circular zones of 6 and 1 mm diameter, respectively, centered in the fovea.

Cirrus software was also used to navigate the acquired macular cube in order to identify the horizontal b-scan with the largest interruption of photoreceptor ellipsoid zone (EZ). The maximum extent of EZ interruption was then manually measured by two independent examiners using the calipers of Cirrus software. In the case of foveal sparing, the amplitude of EZ zone interruption nasally and temporally to the fovea was measured and summed.

2.2. Focal Electroretinography. FERG recording was performed in accordance to a previously described technique [9-19]. Before examination, pupils were pharmacologically dilated with tropicamide 1% eye drops to at least 8 mm diameter. FERGs were recorded monocularly with an Ag-AgCl electrode taped on the skin over the lower eyelid. A similar electrode was placed over the eyelid of the contralateral patched eye and was used as reference.

Stimuli consisted of flickering uniform fields generated by an array of 8 red light-emitting diodes covering a 18[degrees] diameter with a mean luminance of 80 cd/m2 and a temporal frequency of 41 Hz. The dominant wavelength of the stimulus was 630 nm. The flickering stimulus was sinusoidally driven by a custom-made digital frequency generator and presented on the rear of a modified Ganzfeld bowl (Primus; LACE Elettronica, Pisa, Italy) illuminated at the same mean luminance as the stimulus.

A diffusing filter was placed in front of the LED array in order to make it appear as a circle of uniform red light. A steady DC signal maintained the mean luminance of the stimulus. A small square marker was placed in the center of the Ganzfeld bowl to allow the investigator maintaining steady fixation on the foveal region. The examined patients were placed at 30 cm distance from the stimulus.

FERG signals were amplified, filtered (band pass filter between 1 and 250 Hz), and averaged (12-bit resolution, 2 kHz sampling rate, 1600 repetitions in 8 blocks). Signals exceeding the threshold voltage (25 mV) were rejected to minimize noise coming from blinks or eye movements. After the recording, a Fourier discrete analysis was performed to isolate the FERG's first harmonic (1F), and its peak-to-peak amplitude was measured. Averaging and Fourier analysis were also performed on signals sampled asynchronously at 1.1 times the temporal frequency of the stimulus, to estimate the background noise at the fundamental component. Under these conditions, the FERGs recorded were above the noise level (noise amplitude <0.08 mV in all cases) and sufficiently reliable (the variation coefficient in amplitude was 20%).

2.3. Statistical Analysis. Data from the right eye of both patients with STGD1 and controls were used for the analysis to reduce the risk of data redundancy. Two-tailed unpaired t-test was used to compare FERG 1F amplitude between the two groups and to compare BCVA and FERG amplitude between STGD1 patients with or without foveal involvement. Analysis of variance and Sidak post hoc test was performed to compare macular functional and anatomical impairment between patients with different mutation severity and patient with early (<17 years) and late (>17 years) age of onset. Receiving operating characteristic (ROC) curves were performed to assess whether FERG alterations may be useful to diagnose STGD1 and to predict photoreceptors loss in these patients.

Pearson's correlation test was used to correlate macular functional and anatomical parameters. A p value < 0.05 was considered statistically significant.

3. Results

Thirty-three patients (18 males and 15 females) with STGD1 were included in this study. Patients' demographics and molecular and functional characteristics are reported in Table 1, while the results of OCT examination are reported in Table 2.

Mean age at observation was 34.4 [+ or -] 16.5 years while mean age of symptoms onset was 15.8 [+ or -] 8.9 years. Eight patients had one missense mutation in each allele (24.2%), and 16 patients (48.5%) had two or more missense mutations in at least one allele while the remaining 9 patients (27.3%) had a null mutation in at least one allele. Mean CMT, AMT, and EZ interruption were 141 [+ or -] 40, 217 [+ or -] 35, and 3911 [+ or -] 1423 fim, respectively.

FERG was recordable in all patients of both study groups. FERG 1F amplitude was significantly reduced in patients with STGD1 compared to controls (0.35 [+ or -] 0.22 and 1.68 [+ or -] 0.27, resp., p <0.0001). The diagnostic accuracy of FERG amplitude to distinguish STGD1 and healthy patients, assessed by ROC analysis, was 100% (area under the curve 1.0). The corresponding ROC curve is shown in Figure 1.

Interestingly, while FERG 1F amplitude was significantly reduced (<1 [mu]V) in all patients with STGD1, six patients (18%), due to foveal sparing, had a good visual acuity ([greater than or equal to] 0.8) in one or both eyes despite a remarkable interruption of EZ (Figure 2). Patients with foveal sparing had significantly better BCVA than those with foveal involvement (0.90 [+ or -] 0.05 and 0.13 [+ or -] 0.02, resp., p <0.0001) while no differences were noted in FERG 1F amplitude between these two groups of patients (0.20 [+ or -] 0.04 and 0.38 [+ or -] 0.04, resp., p = 0.07).

Correlations between macular functional and structural parameters are summarized in Table 3.

FERG 1F amplitude was negatively correlated with the extension of EZ interruption ([R.sup.2] = 0.54, p = 0<0001) (Figure 3) and positively correlated with AMT ([R.sup.2] =0.16, p = 0.02). Conversely, no correlation was noted between FERG amplitude and CMT ([R.sup.2] = 0.003, p = 0.76). BCVA did not correlate with anatomical alterations, except a weak negative relationship with CMT ([R.sup.2] = 0.12, p = 0.04).

Interestingly, no differences were noted regarding FERG 1F amplitude, BCVA, and OCT parameters between patients with early or late onset or with different molecular mutation severity (p > 0.05 for all analyses).

4. Discussion

The aim of our study was to explore the correlation between functional and anatomical photoreceptor alterations in patients with STDG1, as evaluated by FERG and SD-OCT, respectively. Compared to controls, FERG 1F amplitude was reduced in patients with STDG1 and ROC analysis showed that focal electroretinogram had a diagnostic accuracy of 100% in discriminating healthy and STDG1 patients. These results indicate that, similarly to PERG, FERG recording may be useful to establish the diagnosis of STDG1. Interestingly, despite the significant reduction of macular function, FERG 1F amplitude was recordable in all STDG1 patients, suggesting that this test may be a valuable tool also to assess the deterioration of macular dysfunction in these subjects. A recent study demonstrated that FERG fundamental harmonic alterations anticipate by several years the deterioration of visual acuity in patients affected by cone-rod dystrophies [12]. Longitudinal studies are warranted to determine whether FERG alterations may predict visual acuity decrease in STDG1.

Surprisingly, no significant correlation was noted between BCVA and the entity of photoreceptor loss, determined as the maximal linear EZ interruption. This finding is in contrast with a previous observational case series of 14 patients by Ergun et al. [13] reporting a negative relationship between the extent of ellipsoid zone disruption and visual acuity.

This apparent discrepancy may be related to a relatively high number of patients with foveal sparing in our study. In these cases, the integrity of photoreceptor layers in the foveal region lead to a preservation of visual acuity despite a substantial loss of EZ in the surrounding retina. This assumption seems to be confirmed by the observation that while no relationship was evident between AMT and BCVA, a weak even if significant positive correlation was found between CMT and visual acuity.

Conversely, FERG 1F amplitude showed a significantly negative correlation with the extent of EZ loss and was markedly altered also in cases with foveal sparing whereas, in these patients, BCVA was largely preserved. These data would suggest that BCVA measurement reflects only roughly the function of the foveal region, while FERG signals evocated by an 18[degrees] flickering stimulus may provide an objective and reliable quantification of macular cone function.

The exact quantification of macular cone residual activity may play an important role for the optimal enrollment of patients in future clinical trials.

In particular, this assessment may be critical for therapies aimed at preservation or restoration of photoreceptor function such as nutritional treatments [20, 21], growth factor administration [22-25], and gene augmentation [26, 27].

Hence, these findings suggest that FERG recording may be a useful adjunct tool to increase the accuracy of patient's selection in promising future clinical trials.

Interestingly, even if FERG fundamental harmonic amplitude was also correlated with AMT, this correlation was notably weaker.

Our study failed to demonstrate a correlation between early onset and disease severity and the decay of retinal function in patients with STDG1. This finding is apparently in contrast with the results of a previous study by Fujinami et al. [28], showing that childhood onset is associated with a more severe alteration of retinal function. However, that study found only an increased proportion of patients with diffuse impairment of retinal function which was noted in patients with early onset of STDG1 disease compared with adults while visual acuity was not significantly different in the two study groups. This data would suggest that macular function is immediately altered in STDG1 causing an early decay of focal ERG and visual acuity in both adult and childhood onset patients while retinal-wide involvement develops more frequently in patients with early disease onset.

In summary, FERG recording is significantly altered in STDG1 and has an optimal diagnostic accuracy in detecting Stargardt disease. The reduction of FERG 1F amplitude is closely related to the extent of macular photoreceptor disruption. These findings suggest that FERG recording may be a useful tool to monitor the progression of macular dysfunction in Stargardt disease. Furthermore, an accurate estimation of residual cone function will be important to optimize the design and inclusion criteria of future clinical trials to treat STDG1.

https://doi.org/10.1155/2017/3643495

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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Edoardo Abed, Giorgio Placidi, Luigi Calandriello, Marco Piccardi, Francesca Campagna, Matteo Bertelli, Angelo Maria Minnella, Maria Cristina Savastano, and Benedetto Falsini

Ophthalmology Department, Universita Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, 00168 Rome, Italy

Correspondence should be addressed to Edoardo Abed; edoardoabed@yahoo.it

Received 19 January 2017; Revised 2 July 2017; Accepted 26 July 2017; Published 20 August 2017

Academic Editor: Biju B. Thomas

Caption: Figure 1: ROC curve showing diagnostic accuracy of FERG 1F amplitude in detecting Stargardt macular dystrophy.

Caption: Figure 2: SD-OCT scans of the right and left eye of a patient with significant disruption of macular photoreceptors and foveal sparing. While FERG 1F amplitude was severely reduced, BCVA was 1.0 in both eyes.

Caption: Figure 3: Scatter plot illustrating the significant correlation between FERG first harmonic amplitude and ellipsoid zone interruption.
Table 1: Demographics and clinical characteristics of patients
with Stargardt macular dystrophy.

Patient   Sex   Age   Age at       First allele         Second allele
number                onset

1          F    22      15           p.R1098C                --
2          F    33      10           p.V767D              p.R2030X
3          M    25      15        p.Gly1961Glu,       p.Val2026ThrfsX52
                               p.Gln1332_cys1339dup
4          F    63      35         p.Gly1961Glu              --
5          M    58      32        p.Gly991Arg,          p.Arg1300Gln
                                   p.Glu1087Lys
6          M    33      14          p.Asn78Ser           p.Trp880Cys
7          M    50      24           p.R1098C                --
8          F    16      9            p.Q2220X              p.R943Q
9          M    41      16           c.634C>T             c.1497G>C
10         F    37      21          c.4771G>A                --
11         M    11      8          c.247_250dup           c.4139C>T
12         M    41      5          p.His423Arg           p.Arg943Gln
13         F    18      10          IVS35+2T>C           IVS40+5G>A
14         M    48      43         c.5714+5G>A               --
15         F    39      9           p.Arg18Trp           p.Val767Asp
16         M    15      9          p.Gly1961Glu         p. Ser2255Ile
17         M    47      19         p.Thr897Ile               --
18         M    36      31         p.Gln21Ter,         p. Arg212His,
                                   p.Arg943Gly          p.Gly1961Glu
19         M    16      13         p.Trp821Arg          p. Tyr850Cys
                                   p.Gly1961Glu
20         F    31      21         p.Thr977Pro          c.IVS40+5G>A
21         F    22      15         p.Gly1961Glu        c.4709_4711delA
22         M    48      13         p.Gly1961Glu       p.His1406ProfsX29
23         M    16      8          p.Val931Met           p.Val931Met
24         M    42      8         p.Val256splice         p.Trp1479X
25         M    21      14          IVS13+1g>a           IVS40+5g>40
26         F    23      17        p.Tyr850Cys,          p.Gly1961Glu
                                   p.Thr959Ala
27         F    56      23         p.Gly1961Glu         p.Gly1961Glu
28         M    52      20         p.Arg1108His         p.Gly1961Glu
29         F    31      14           p.P1486L              p.W700X
30         F    12      8           p.Tyr1400X           p.Val931Met
31         F    77      13         p.Ala1598Asp       p.Val2062fsX2113
32         F    11      10          IVS6-1G>T           p.Asn1436Ile
33         M    44      10          IVS45+1G>A          p.Gly1961Glu

Patient   BCVARE (Snellen   BCVA LE        FERG 1F         FERG 1F
number       decimals)      (Snellen     RE ([micro]V)   LE ([micro]V)
                            decimals)

1               0.1            0.1           0.51            0.28
2              0.05            0.1           0.17             0.2
3               0.4            0.4           0.52            0.43

4              0.15           0.15           0.68            0.38
5              0.02           0.02           0.52            0.52

6              0.02           0.01           0.21            0.15
7               0.4            0.8           0.52            0.59
8               0.1            0.1           0.08            0.06
9               0.2            0.2           0.74            0.39
10              0.1            0.1           0.2             0.22
11              0.8            0.8           0.26            0.34
12              0.1           0.02           0.18            0.15
13              0.2            0.2           0.63             0.3
14              1.0            1.0           0.33            0.46
15             0.05            0.1           0.33            0.35
16              0.1            0.1           0.79             0.7
17             0.01           0.05           0.1             0.09
18              0.1            0.1           0.37            0.46

19              0.9            0.9           0.1              0.2

20              0.2            0.1           0.46            0.15
21              0.1            0.1           0.57            0.45
22              0.1            0.1           0.19            0.25
23              0.1            0.1           0.57             0.4
24             0.01           0.005          0.14            0.16
25              0.1           0.15           0.2             0.17
26              0.3            0.3           0.07            0.09

27              0.8            0.1           0.16            0.31
28              0.1            0.4           0.48            0.93
29              1.0            1.0           0.13            0.03
30              0.2            0.2           0.45            0.46
31              0.1            0.1           0.24            0.33
32              0.2            0.2           0.66            0.95
33              0.1            0.1           0.14            0.15

Table 2: OCT data of individual patients with Stargardt disease.

Patient         EZ interruption   EZ interruption    AMT RE
number           RE ([micro]m)     LE ([micro]m)    ([micro]m)

1                    2922              3665            257
2                    6000              6000            289
3                    2092              2728            255
4                    2872              3428            262
5                    3384              3401            237
6                    6000              6000            134
7                    3398              3145            207
8                    5866              5916            154
9                    3444              4272            215
10                   4156              4453            198
11                   3857              3688            185
12                   6000              6000            195
13                   3600              3445            225
14                   5261              4241            224
15                   5421              5578            212
16                   2353              2535            253
17                   3906              4453            248
18                   3214              2896            225
19                   4370              3999            243
20                   3827              4972            212
21                   2741              2895            223
22                   3585              3352            244
23                   2936              3336            243
24                   6000              6000            135
25                   3575              3936            221
26                   5308              6000            212
27                   3315              2980            194
28                   2867              2100            258
29                   5370              5227            218
30                   3557              3715            192
31                   6000              6000            174
32                   1868              1632            227
33                   6000              6000            194

Patient          AMT LE       CMT RE        CMT LE
number          ([micro]m)   ([micro]m)   ([micro]m)

1                  256          121          118
2                  289          266          273
3                  257          138          147
4                  255          155          133
5                  249           99           80
6                  145           97           95
7                  199          186          253
8                  135          112           98
9                  198          135          112
10                 204          121          125
11                 176          117          113
12                 187          147          132
13                 234          145          138
14                 235          241          251
15                 203          144          143
16                 243          166          153
17                 241          183          157
18                 231          149          158
19                 239          160          159
20                 208          145          134
21                 243          138          146
22                 250          104          108
23                 254          173          171
24                 147           74           81
25                 236          125          144
26                 201          139          127
27                 197          131          124
28                 260          100          108
29                 223          189          209
30                 185           89           91
31                 188           95          101
32                 234          154          161
33                 187          103          112

Table 3: Results of correlation analyses between macular functional
and anatomical alterations in patients with Stargardt macular
dystrophy.

BCVA               FERG 1 F       [R.sup.2] = 0.04, p = 0.27
BCVA            EZ interruption   [R.sup.2] = 0.01, p = 0.56
BCVA                  CMT         [R.sup.2] = 0.12, p = 0.04
BCVA                  AMT         [R.sup.2] = 0.0001, p = 0.95
FERG 1F         EZ interruption   [R.sup.2] = 0.54, p = 0.0001
FERG 1F               CMT         [R.sup.2] = 0.003, p = 0.76
FERG 1F               AMT         [R.sup.2] = 0.16, p = 0.02
EZ interruption       CMT         [R.sup.2] = 0.14, p = 0.03
EZ interruption       AMT         [R.sup.2] = 0.57, p <0.0001
CMT                   AMT         [R.sup.2] = 0.30, p = 0.001
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Title Annotation:Research Article
Author:Abed, Edoardo; Placidi, Giorgio; Calandriello, Luigi; Piccardi, Marco; Campagna, Francesca; Bertelli
Publication:Journal of Ophthalmology
Article Type:Report
Date:Jan 1, 2017
Words:4484
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