October 2008
Volume 49, Issue 10
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Visual Neuroscience  |   October 2008
Long-Term Follow-up of Retinitis Pigmentosa Patients with Multifocal Electroretinography
Author Affiliations
  • Ditta Nagy
    From the Centre for Ophthalmology, Institute for Ophthalmic Research, and the
  • Birgitt Schönfisch
    Department of Medical Biometry, University of Tübingen, Tübingen, Germany; and the
  • Eberhart Zrenner
    From the Centre for Ophthalmology, Institute for Ophthalmic Research, and the
  • Herbert Jägle
    From the Centre for Ophthalmology, Institute for Ophthalmic Research, and the
    Division of Motility Disorders, Periocular Surgery and Pediatric Ophthalmology, Centre for Ophthalmology, Tübingen, Germany.
Investigative Ophthalmology & Visual Science October 2008, Vol.49, 4664-4671. doi:10.1167/iovs.07-1360
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      Ditta Nagy, Birgitt Schönfisch, Eberhart Zrenner, Herbert Jägle; Long-Term Follow-up of Retinitis Pigmentosa Patients with Multifocal Electroretinography. Invest. Ophthalmol. Vis. Sci. 2008;49(10):4664-4671. doi: 10.1167/iovs.07-1360.

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      © 2016 Association for Research in Vision and Ophthalmology.

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Abstract

purpose. To study the rate of multifocal electroretinographic (mfERG) response amplitude changes and their relation to other parameters of disease development in retinitis pigmentosa (RP).

methods. Twenty-three patients (9 men and 14 women) with clinically defined RP were included in the study. Disease progression was monitored during a period of up to 10 years by psychophysical techniques and Ganzfeld electroretinography. In addition, ERGs were recorded with a mfERG imaging system (VERIS; Electro-Diagnostic Imaging, Inc., Redwood City, CA). The black and white stimulus consisted of 61 hexagons covering a visual field of approximately 60° × 55°. Responses were analyzed according to concentric ring averages.

results. The progression of visual field loss for target III4e was approximately 14.5%. Using the same type of regression model, the yearly progression according to the mfERG values was found to be approximately 6% to 10% in the outer three rings. Visual acuity (median 0.8) correlated well with the amplitude of the central segment of the mfERGs, ring 5 amplitudes of the mfERG strongly correlated with the scotopic Ganzfeld ERG mixed cone–rod response amplitude. However, in advanced cases, reliable mfERG responses could still be recorded, even if the ISCEV scotopic Ganzfeld ERG was not reproducible. MfERG ring 5 amplitudes as well as the Ganzfeld ERG mixed cone–rod response amplitude showed only a mild correlation with visual field area.

conclusions. The mfERG allows long-term follow-up of disease progression in retinitis pigmentosa. It does not replace, but complements psychophysical methods and could be used as an objective outcome measure in upcoming treatment studies involving patients with advanced retinal diseases.

Retinitis pigmentosa (RP) is a heterogenous group of degenerative retinal diseases, which is associated with night-blindness, progressive loss of the peripheral visual field and a slow reduction in central vision and Ganzfeld ERG abnormalities. RP diffusely and primarily affects the photoreceptors, predominantly the rod system, and as the disease progresses, the function of the cone system also declines. The age of onset, rate of progression, and presence or absence of associated ocular features are frequently related to the mode of inheritance, but the clinical appearance may vary, even among family members with the disease. 
Characterization and understanding of the visual loss is important for monitoring patients with RP. A detailed differential diagnosis and long-term follow-up are advisable for adequate patient counseling, for predicting visual outcome, and for monitoring the efficacy and safety of new therapeutic options. 1 2 3  
Clinical psychophysical and electrophysiological measurements have been used to provide objective information regarding changes in retinal function. Whereas examinations, like visual acuity testing and perimetry, rely on subjective responses, electrophysiological methods are used to quantify retinal function in a more objective way. The Ganzfeld ERG allows recording of electrical responses originating from the entire retina when stimulating with a full-field light source. 4 5 6 In contrast, the multifocal ERG (mfERG) allows assessment of a “map” of electrical activity based on a technique introduced by Sutter and Tran in 1992. 7 It has been applied to various retinal disorders 6 and a standard has become available 8 (see also www.iscev.org). With disease progression, the waveforms may no longer be detected by Ganzfeld ERG, whereas still some residual visual field can be measured. In such cases, localized responses may still be obtained using the mfERG. 
The purpose of our study therefore was to investigate the usefulness of the mfERG among other clinical psychophysical and electrophysiological techniques. This article also provides a review of the characteristics and natural course of retinitis pigmentosa. Emphasis is placed on determining the yearly progression of the mfERG responses. We also sought to compare mfERGs and other parameters of disease development. 
Methods
Twenty-three patients (9 men and 14 women; median age, 36 years; age at the first presentation, 12–66 years) with different Mendelian inheritance patterns of retinitis pigmentosa were selected from our patient database and included in the study, based on a minimum follow-up time of 3 years and reproducible mfERG responses at the time of the first investigation. The protocol of the study adhered to the provisions of the Declaration of Helsinki. The diagnosis of RP was based on the clinical features, ophthalmoscopic appearance, and the results of perimetry, dark-adapted thresholds, and Ganzfeld-flash ERGs according to the ISCEV (International Society for Clinical Electrophysiology of Vision) Standards. 5 Typical fundus changes and visual field and mfERG findings are presented in Figure 1 . Patient characteristics are presented in Table 1 . Disease progression in both eyes was followed up over a period of up to 10 years (median, 6 years). At each visit, all patients received standardized examinations including best corrected visual acuity, kinetic perimetry (Goldmann), color vision (Lanthony Panel D-15 test), dark adaptometry, and ISCEV Ganzfeld and multifocal mfERG. At the patients’ request, Ganzfeld ERG was not performed in patient 9 or mfERG in patients 4 and 13 at one visit each. 
A series of standardized questions was given to all patients at the first visit, to determine the age of onset (median, 20 years; range, 6–48) based on the appearance of one of the following signs: night blindness, light aversion, loss of peripheral visual field, or reduced visual acuity. 
Visual Field
Kinetic perimetry was performed with the Goldmann kinetic perimeter at each visit. To be able to compare the visual field loss to other parameters, fields for target size III4e were taken and computerized and residual field area was measured with a special computer program. The calculated visual field areas were compared with a normal visual field area for target III4e (normal visual field = 1.0). Although the estimated relative field area is subject to distortion and underestimation of the central field area, 9 10 11 the effect on our exponential model fit is small. 
Color Vision
Color vision was tested with the Lanthony panel D-15 desaturated test. The results were quantified according to Bowman’s Total Color Difference Score (TCDS), which provides a quantitative index of D-15 performance and color confusions, but does not necessarily differentiate defect type. 12 It is used to follow the progression of an acquired color vision disease process. 12 13 14 15 Three subjects (patients 14, 19, and 21) could perform only the Panel D-15 saturated test; their color vision results were excluded from the analysis. 
Dark Adaptation
Dark adaptation thresholds were obtained in one eye after 30 minutes of dark adaptation with the Tübingen hand perimeter (THP). A white target with 2° diameter was presented at 20° eccentricity in the nasal visual field for 1 second. Dark adaptation thresholds were ascertained five to six times. 
Electrophysiology
Pupils were dilated with tropicamide before the electrophysiological examination. After 30 minutes of dark adaptation, DTL fiber electrodes were positioned according to ISCEV Standards. 5 8 After scotopic measurements, photopic recordings were preceded by a light adaptation of 10 minutes to a background light of 30 cd/m2. Ganzfeld ERGs were recorded with one of two systems (Spirit; Nicolet Biomedical Instruments, Madison, WI, or UTAS 2000; LKC Technologies, Inc., Gaithersburg, MD). Maximum flash intensity (0 dB) was 2.4 and 2.3 cd · s · m−2 for the Nicolet and LKC systems, respectively. Attenuation of the standard rod flash was 24 dB for both systems. 
Multifocal ERGs were performed with a VERIS System (ver. 1-4.8; Electro-Diagnostic Imaging, Inc., Redwood City, CA) using the same amplifier (model 12; Grass, Quincy, MA). The stimulus, consisting of 61 scaled hexagonal elements covering a central visual field of 60° × 55°, was presented on a 19-in. monitor at a frame rate of 75 Hz at a distance of 32 cm from the subject’s eyes. DTL fiber electrodes were applied to both eyes, waveforms were recorded, amplified (200,000×), and bandpass-filtered (10–100 Hz). Responses were analyzed according to ring averages. 8  
Statistical Methods
Data were analyzed with commercial software (JMP 5.0.1; SAS Institute Inc., Cary, NC) and R 2.2.1 (R Foundation for Statistical Computing, Vienna, Austria). 
To describe disease progression, we formulated linear regression models of the response variables visual field and mfERG. The response variables were transformed by taking the logarithm to describe exponential decay of retinal function. In these models, disease duration was included as a fixed factor. Hence, we fit the following equation:  
\[response{=}e^{({\alpha}{+}{\beta}\ {\cdot}\ \mathrm{disease_duration})}\]
where response is visual field or one of the mfERG values and α and β are intercept and slope. 
For modeling repeated measurements, individuals were included as random factors on slope and intercept. The latter was included since disease onset data seemed not to be reliable (some patients could not remember correctly when they first noticed changes in their visual function), so that the slope of the logarithmic decay is estimated from the interval between visits. Including the factor “eye” (left/right) as a random effect nested in the factor “individual” did not increase model fit significantly (ANOVA of the two model versions for all responses with P > 0.99). Therefore, we omitted this factor, modeling for every individual the mean value of both eyes. In the plots data of both eyes are shown separately. Residuals’ normality and homoscedasticity were assessed by quantile–quantile plots (QQ plot) and residuals by predicted plots, respectively. To identify outliers with high leverage Cook’s distance was calculated, and the distribution of random parameters estimates was inspected by histograms. The quality of fits is recorded as adjusted coefficient of determination (adj R 2). 
To estimate correlations between the different examination methods describing macular function (mfERG, visual acuity, and color vision) Spearman’s r S was calculated and scatterplots were produced. Correlations and scatterplots were also produced for midperipheral retinal function variables (perimetry, dark adaptation thresholds, Ganzfeld- and mfERG). 
Results
The age of the patients at the first mfERG recordings ranged from 12 to 66 years (median, 36 years). Visual acuity at that time varied between 0.3 and 1.6 (median 0.8) consistent with preserved macular function. The change in visual field area for target III4e according to disease duration is presented in Figure 2A . The progression of visual field loss is fairly described by an exponential decay, which is similar to the description by Iannaccone et al. 16 From the estimated slopes (Table 2)we calculated the yearly progression for target III4e: approximately, 14.5% of the visual field area is lost by patients affected with retinitis pigmentosa every year. 
We were using the same type of regression model to define the natural progression of rod and cone functional loss measured by electrophysiological methods. For the Ganzfeld ERG and mfERG amplitudes a well-defined reduction was observed with disease duration. In general, these changes also fit an exponential curve (see Figs. 2B 2C 2D 2E 2Fand Supplementary Fig. S1), but for the estimates of the model we found a greater variation between mfERG ring analysis. We calculated the yearly progression according to the mfERG values. Approximately 6% to 10% of the amplitude is lost every year in the outer three rings (Table 3)
We also analyzed the changes in the implicit times of the mfERG, but the trend did not fit an exponential decay well. The implicit times of the central ring responses seemed to remain constant at the normal level. When responses from the outermost rings were measurable, their implicit times were always delayed up to 52 ms, but a clear tendency was not observed during long-term follow-up. 
We further compared parameters of disease development with the mfERG values. We categorized the different examination methods according to macular and mid peripheral retinal function. Macular function is usually characterized by means of the visual acuity and color vision test performance. Both involve not only photoreceptor but also postreceptoral retinal and visual pathway function. We found a strong correlation between best corrected visual acuity and mfERG response amplitude of the central hexagon (r S = 0.75; Fig. 3A ). In contrast, there was a weak correlation between the mfERG response amplitude of the central hexagon (r S = −0.40; Fig. 3B ) and the TCDS. 
Midperipheral retinal function may be characterized by visual field testing, dark adaptation thresholds or Ganzfeld- and mfERG. The mfERG ring 5 amplitude correlated strongly with the mixed cone–rod response amplitude (r S = 0.87, Fig. 4A ; see Table 4for details) and with the cone (r S = 0.85, Fig. 4B ) and 30-Hz flicker (r S = 0.85) response amplitude. Similar correlations were also seen between the implicit times of the cone (r S = 0.77 for ring 5) and 30-Hz flicker (r S = 0.72 for ring 5) response in the Ganzfeld and mfERG. Of interest, we found no correlation between the mixed cone–rod response and the mfERG response ring averages. 
In advanced cases, no reproducible ISCEV Ganzfeld ERG scotopic response was recorded, but with the mfERG, significant responses were still recordable (Fig. 5A)and dark-adaptation thresholds could be measured (Fig. 5B) . Interest, mfERG response amplitude of the outermost ring 5, as well as the Ganzfeld ERG mixed cone–rod response b-wave amplitude showed only a mild correlation with visual field area (r S = 0.61 and 0.58, respectively; Figs. 6A 6B ). 
Discussion
In our study, we examined the long-term changes of the mfERG responses in patients with retinitis pigmentosa. We also observed the changes of the visual field parameters and compared them with earlier findings by other authors. 17 18 19 20 21 22 23 24 25 26 27 28 29 30 In our group of patients, the progression of visual field loss followed an exponential decay, which was similar to the change described by Iannaccone et al. 16 (Table 2) . Our estimate for the yearly loss of visual field is 14.5%. The slope data (−0.156, respectively) is close to the −0.136 for target V4e and −0.172 for target I4e found by Iannaccone et al. 16 or −0.112 for target V4e found by Holopigian et al. 20 and thus confirm their data. Other studies, in which more patients were included found either somewhat higher 19 or lower slopes 21 22 (for details, see Table 2 ). 
Using a similar regression model, we found a well-defined reduction of Ganzfeld ERG and mfERG amplitudes of 6% to 10% per year of disease duration (see Table 3 ). To overcome or reduce possible problems arising from changes introduced by the development of the VERIS versions 1 to 4.8, we reanalyzed all data with VERIS version 4.8. Other factors like the onset of disease, which was only determined in case history, still affect our estimates. However, our estimates of amplitude loss per disease year for the mfERG ring averages are similar to those of the visual field with comparable error estimates and confidence limits. Because of averaging, the response waveforms of the hexagons of a given eccentricity the signal-to-noise ratio improves. Other factors like electrode placement or target fixation limit the test–retest reliability and may hide slight disease progression. One should keep in mind that two successive recordings can show 10% to 20% variation in amplitude. 31 32 33 34  
We further looked at the relationship between remaining visual field area and mfERG response amplitudes. Even though the loss of mfERG amplitude and the visual field show a similar decay, we found only a weak correlation between both (r S = 0.61). Similarly, we found a weak (r S = 0.58) correlation of the scotopic mixed cone–rod response with the visual field loss. Some studies emphasize the existence of a substantial correlation between visual field and Ganzfeld ERG response amplitude. 25 26 27 28 29 30 Iannaccone et al. 26 found a strong correlation between ERG mixed cone-rod response b-wave amplitude and visual field area determined for Goldmann I4e and III4e isopters (r = 0.89 and r = 0.87, respectively) but similar correlations to ours for the V4e isopter (r = 0.69). Others found only weak correlations between visual field diameter and ERG amplitudes. 28 29 Using a Naka-Rushton equation to estimate maximum amplitude of rod ERG-responses, Birch et al. 30 found a significant correlation of this amplitude to the size of the dark-adapted visual field, whereas Massof et al. 27 did not find a correlation using similar methods but light-adapted visual field testing. 
Of note, Sandberg et al. 25 found weak correlations of the 0.5- and 30-Hz ERG amplitudes with visual field area (r S = 0.54 and 0.60, respectively), but observed higher correlations (r S up to 0.85) in a subgroup analysis, suggesting that the relationship of visual field size to ERG amplitude depends on genetic type, the altered protein, and/or the specific mutation. Because we found a significant correlation between the outermost ring average amplitude with the Ganzfeld scotopic mixed cone–rod response amplitude (r S = 0.87) and the cone response amplitude (r S = 0.85), this may be true of the mfERG results as well. 
In conclusion, the mfERG provides a useful measure of the retinal function; it does not replace, but complements psychophysical methods including visual field and color vision testing. The response amplitude follows a similar exponential decay as the visual field and may provide reproducible responses, even if the Ganzfeld ERG is nearly extinguished. This issue is becoming more important, now that essential steps toward possible therapies for retinal degenerations are being made and reliable and objective testing methods are needed. The mfERG is well-suited for observation and long-term follow-up in disease development and—in addition to other psychophysical methods—it could be used as an objective outcome measure in upcoming treatment studies involving patients with advanced retinal diseases. 
 
Figure 1.
 
A typical fundus photograph of an eye with retinitis pigmentosa with optic disc pallor, bone spicule–like pigment changes, atrophy of the RPE and vessel narrowing (A), corresponding visual field defects (B), the topography of mfERG responses (C), and the ring average analysis used in this study (D). Ring average waveforms are shown with normalized root mean square (RMS) amplitude for easier waveform comparison.
Figure 1.
 
A typical fundus photograph of an eye with retinitis pigmentosa with optic disc pallor, bone spicule–like pigment changes, atrophy of the RPE and vessel narrowing (A), corresponding visual field defects (B), the topography of mfERG responses (C), and the ring average analysis used in this study (D). Ring average waveforms are shown with normalized root mean square (RMS) amplitude for easier waveform comparison.
Table 1.
 
Patient Characteristics
Table 1.
 
Patient Characteristics
Patient Sex Inheritance Pattern Age at Disease Onset Age at 1st mfERG Recording Age at Last mfERG Recording VA at 1st mfERG Recording (OD/OS) Number of Visits Years of Follow-up with mfERG
1 Female Ad 16 18 21 0.8/0.8 2 3
2 Female Ad 48 56 60 0.8/1.2 2 4
3 Female Ad 18 37 41 0.7/0.4 2 4
4 Female Ad 6 41 47 0.6/0.8 4 6
5 Male Ad 11 27 30 1.0/1.2 2 3
6 Female Ad 16 40 46 1.2/1.2 2 6
7 Female Ad 34 34 39 1.6/1.6 3 5
8 Male Ad 36 36 44 1.2/0.8 2 8
9 Male Ad 16 16 20 1.5/1.5 3 4
10 Male Ad 13 47 56 1.5/0.8 2 9
11 Male Ad 33 54 62 0.8/0.8 3 8
12 Male Ar 20 37 39 0.8/0.8 3 5
13 Male Ar 8 12 15 0.8/0.8 3 3
14 Female Ar 10 26 34 0.3/0.3 3 8
15 Female Ar 30 53 40 1.5/1.5 4 10
16 Female Simplex 20 28 35 0.8/0.8 3 7
17 Female Simplex 34 34 41 1.2/1.5 3 7
18 Male Simplex 20 42 51 1.0/0.8 4 9
19 Female Simplex 15 35 41 0.3/0.3 3 6
20 Female Simplex 10 23 32 0.8/0.5 4 9
21 Male Simplex 27 66 73 0.5/0.5 2 7
22 Male Usher II 22 39 48 0.9/0.9 5 9
23 Female Usher II 14 17 23 1.0/1.2 2 6
Figure 2.
 
Changes of residual visual field (A) and mfERG of the outermost ring 5 (B), rings 4 to 2 (CE), and the center hexagon (F) during disease progression. The progression of visual field loss and changes of the mfERG amplitudes were clearly described by an exponential decay. Symbols indicate heredity of the disease (• autosomal dominant; ▵ autosomal recessive; ⋄ simplex; and ▿ Usher syndrome).
Figure 2.
 
Changes of residual visual field (A) and mfERG of the outermost ring 5 (B), rings 4 to 2 (CE), and the center hexagon (F) during disease progression. The progression of visual field loss and changes of the mfERG amplitudes were clearly described by an exponential decay. Symbols indicate heredity of the disease (• autosomal dominant; ▵ autosomal recessive; ⋄ simplex; and ▿ Usher syndrome).
Table 2.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Visual Field Changes from the Literature and in the Present Study*
Table 2.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Visual Field Changes from the Literature and in the Present Study*
Study Target Adj R 2 Estimate SE 95% CI P
Lower Upper
Iannaccone et al. 16 (n = 19) I4e Intercept (α) 7.765 0.508 6.768 8.761 <0.0001
Slope (β) −0.172 0.023 −0.216 −0.127 <0.0001
V4e Intercept (α) 10.296 0.193 9.917 10.675 <0.0001
Slope (β) −0.136 0.010 −0.155 −0.117 <0.0001
Massof et al. 19 (n = 172) II4e Slope (β) −0.170 N/A N/A N/A N/A
V4e Slope (β) −0.145 N/A N/A N/A N/A
Holopigian et al. 20 (n = 23) V4e Slope (β) −0.112 N/A 0.032 −0.192 N/A
Grover et al. 22 (n = 71) II4e Slope (β) −0.102 N/A −0.078 −0.116 N/A
V4e Slope (β) −0.095 N/A −0.073 −0.144 N/A
Present study (n = 23) III4e 0.95 Intercept (α) 10.100 0.679 8.752 11.447 0.214
Slope (β) −0.156 0.030 −0.216 −0.096 <0.0001
Table 3.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Changes in the mfERG Amplitudes
Table 3.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Changes in the mfERG Amplitudes
mfERG Ring Amplitudes Adj R 2 Estimate SE 95% CI P
Lower Upper
Ring 5 (outermost) 0.83 Intercept (α) 1.498 0.235 1.030 1.965 <0.0001
Slope (β) −0.062 0.011 −0.085 −0.039 <0.0001
Ring 4 0.71 Intercept (α) 1.570 0.262 1.050 2.090 <0.0001
Slope (β) −0.073 0.014 −0.101 −0.045 <0.0001
Ring 3 0.74 Intercept (α) 2.257 0.255 1.751 2.764 <0.0001
Slope (β) −0.096 0.014 −0.126 −0.067 <0.0001
Ring 2 0.86 Intercept (α) 3.434 0.241 2.955 3.914 <0.0001
Slope (β) −0.109 0.015 −0.141 −0.078 <0.0001
Ring 1 (center) 0.77 Intercept (α) 3.792 0.206 3.382 4.201 <0.0001
Slope (β) −0.077 0.011 −0.101 −0.054 <0.0001
Figure 3.
 
Correlations between visual acuity and mfERG amplitude of the central hexagon (A, r S = 0.75) and between the mfERG central hexagon amplitude and the TCDS of the Lanthony Panel D-15 desaturated (B, r S = −0.40). Of interest, the color vision performance did not correlate with the amplitude of the central hexagon or with visual acuity.
Figure 3.
 
Correlations between visual acuity and mfERG amplitude of the central hexagon (A, r S = 0.75) and between the mfERG central hexagon amplitude and the TCDS of the Lanthony Panel D-15 desaturated (B, r S = −0.40). Of interest, the color vision performance did not correlate with the amplitude of the central hexagon or with visual acuity.
Figure 4.
 
Correlations of the mfERG ring 5 amplitudes with the ISCEV Ganzfeld mixed cone–rod response (A, r S = 0.87) and with the cone response amplitudes (B, r S = 0.85).
Figure 4.
 
Correlations of the mfERG ring 5 amplitudes with the ISCEV Ganzfeld mixed cone–rod response (A, r S = 0.87) and with the cone response amplitudes (B, r S = 0.85).
Figure 5.
 
Correlations of the ISCEV rod response amplitudes with the mfERG outermost ring 5 average amplitudes (A) and with the dark-adaptation thresholds (B) indicating that mfERG responses can be recorded and dark-adaptation thresholds can be estimated, even though reproducible Ganzfeld responses are no longer recordable.
Figure 5.
 
Correlations of the ISCEV rod response amplitudes with the mfERG outermost ring 5 average amplitudes (A) and with the dark-adaptation thresholds (B) indicating that mfERG responses can be recorded and dark-adaptation thresholds can be estimated, even though reproducible Ganzfeld responses are no longer recordable.
Figure 6.
 
Multifocal ERG ring 5 amplitudes (A, r S = 0.61) as well as Ganzfeld mixed cone–rod response amplitudes (B, r S = 0.58) show only a weak correlation to the residual visual field. Thus, psychophysiological and electrophysiological tests are complementary methods.
Figure 6.
 
Multifocal ERG ring 5 amplitudes (A, r S = 0.61) as well as Ganzfeld mixed cone–rod response amplitudes (B, r S = 0.58) show only a weak correlation to the residual visual field. Thus, psychophysiological and electrophysiological tests are complementary methods.
Figure 7.
 
Correlation Coefficients (Spearman’s Rho [r s]) for Electroretinogram Amplitudes (Light Grey Triangle) and Implicit Times (Unfilled Triangle)
Figure 7.
 
Correlation Coefficients (Spearman’s Rho [r s]) for Electroretinogram Amplitudes (Light Grey Triangle) and Implicit Times (Unfilled Triangle)
Supplementary Materials
Changes of residual visual field (A) and multifocal ERG of the outermost ring 5 (B), rings 4 to 2 (CE) and the centre hexagon (F) during disease progression. Using logarithmic axis, the progression of visual field loss and changes of the mfERG amplitudes are fairly described by a linear decay. In contrast to Figure 2, regression lines could not be extended to an amplitude level of 0 μV. Symbols indicate heredity of the disease (ad = filled circles, ar = triangles, simplex = diamond and Usher syndrome = upside down triangle). 
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Figure 1.
 
A typical fundus photograph of an eye with retinitis pigmentosa with optic disc pallor, bone spicule–like pigment changes, atrophy of the RPE and vessel narrowing (A), corresponding visual field defects (B), the topography of mfERG responses (C), and the ring average analysis used in this study (D). Ring average waveforms are shown with normalized root mean square (RMS) amplitude for easier waveform comparison.
Figure 1.
 
A typical fundus photograph of an eye with retinitis pigmentosa with optic disc pallor, bone spicule–like pigment changes, atrophy of the RPE and vessel narrowing (A), corresponding visual field defects (B), the topography of mfERG responses (C), and the ring average analysis used in this study (D). Ring average waveforms are shown with normalized root mean square (RMS) amplitude for easier waveform comparison.
Figure 2.
 
Changes of residual visual field (A) and mfERG of the outermost ring 5 (B), rings 4 to 2 (CE), and the center hexagon (F) during disease progression. The progression of visual field loss and changes of the mfERG amplitudes were clearly described by an exponential decay. Symbols indicate heredity of the disease (• autosomal dominant; ▵ autosomal recessive; ⋄ simplex; and ▿ Usher syndrome).
Figure 2.
 
Changes of residual visual field (A) and mfERG of the outermost ring 5 (B), rings 4 to 2 (CE), and the center hexagon (F) during disease progression. The progression of visual field loss and changes of the mfERG amplitudes were clearly described by an exponential decay. Symbols indicate heredity of the disease (• autosomal dominant; ▵ autosomal recessive; ⋄ simplex; and ▿ Usher syndrome).
Figure 3.
 
Correlations between visual acuity and mfERG amplitude of the central hexagon (A, r S = 0.75) and between the mfERG central hexagon amplitude and the TCDS of the Lanthony Panel D-15 desaturated (B, r S = −0.40). Of interest, the color vision performance did not correlate with the amplitude of the central hexagon or with visual acuity.
Figure 3.
 
Correlations between visual acuity and mfERG amplitude of the central hexagon (A, r S = 0.75) and between the mfERG central hexagon amplitude and the TCDS of the Lanthony Panel D-15 desaturated (B, r S = −0.40). Of interest, the color vision performance did not correlate with the amplitude of the central hexagon or with visual acuity.
Figure 4.
 
Correlations of the mfERG ring 5 amplitudes with the ISCEV Ganzfeld mixed cone–rod response (A, r S = 0.87) and with the cone response amplitudes (B, r S = 0.85).
Figure 4.
 
Correlations of the mfERG ring 5 amplitudes with the ISCEV Ganzfeld mixed cone–rod response (A, r S = 0.87) and with the cone response amplitudes (B, r S = 0.85).
Figure 5.
 
Correlations of the ISCEV rod response amplitudes with the mfERG outermost ring 5 average amplitudes (A) and with the dark-adaptation thresholds (B) indicating that mfERG responses can be recorded and dark-adaptation thresholds can be estimated, even though reproducible Ganzfeld responses are no longer recordable.
Figure 5.
 
Correlations of the ISCEV rod response amplitudes with the mfERG outermost ring 5 average amplitudes (A) and with the dark-adaptation thresholds (B) indicating that mfERG responses can be recorded and dark-adaptation thresholds can be estimated, even though reproducible Ganzfeld responses are no longer recordable.
Figure 6.
 
Multifocal ERG ring 5 amplitudes (A, r S = 0.61) as well as Ganzfeld mixed cone–rod response amplitudes (B, r S = 0.58) show only a weak correlation to the residual visual field. Thus, psychophysiological and electrophysiological tests are complementary methods.
Figure 6.
 
Multifocal ERG ring 5 amplitudes (A, r S = 0.61) as well as Ganzfeld mixed cone–rod response amplitudes (B, r S = 0.58) show only a weak correlation to the residual visual field. Thus, psychophysiological and electrophysiological tests are complementary methods.
Figure 7.
 
Correlation Coefficients (Spearman’s Rho [r s]) for Electroretinogram Amplitudes (Light Grey Triangle) and Implicit Times (Unfilled Triangle)
Figure 7.
 
Correlation Coefficients (Spearman’s Rho [r s]) for Electroretinogram Amplitudes (Light Grey Triangle) and Implicit Times (Unfilled Triangle)
Table 1.
 
Patient Characteristics
Table 1.
 
Patient Characteristics
Patient Sex Inheritance Pattern Age at Disease Onset Age at 1st mfERG Recording Age at Last mfERG Recording VA at 1st mfERG Recording (OD/OS) Number of Visits Years of Follow-up with mfERG
1 Female Ad 16 18 21 0.8/0.8 2 3
2 Female Ad 48 56 60 0.8/1.2 2 4
3 Female Ad 18 37 41 0.7/0.4 2 4
4 Female Ad 6 41 47 0.6/0.8 4 6
5 Male Ad 11 27 30 1.0/1.2 2 3
6 Female Ad 16 40 46 1.2/1.2 2 6
7 Female Ad 34 34 39 1.6/1.6 3 5
8 Male Ad 36 36 44 1.2/0.8 2 8
9 Male Ad 16 16 20 1.5/1.5 3 4
10 Male Ad 13 47 56 1.5/0.8 2 9
11 Male Ad 33 54 62 0.8/0.8 3 8
12 Male Ar 20 37 39 0.8/0.8 3 5
13 Male Ar 8 12 15 0.8/0.8 3 3
14 Female Ar 10 26 34 0.3/0.3 3 8
15 Female Ar 30 53 40 1.5/1.5 4 10
16 Female Simplex 20 28 35 0.8/0.8 3 7
17 Female Simplex 34 34 41 1.2/1.5 3 7
18 Male Simplex 20 42 51 1.0/0.8 4 9
19 Female Simplex 15 35 41 0.3/0.3 3 6
20 Female Simplex 10 23 32 0.8/0.5 4 9
21 Male Simplex 27 66 73 0.5/0.5 2 7
22 Male Usher II 22 39 48 0.9/0.9 5 9
23 Female Usher II 14 17 23 1.0/1.2 2 6
Table 2.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Visual Field Changes from the Literature and in the Present Study*
Table 2.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Visual Field Changes from the Literature and in the Present Study*
Study Target Adj R 2 Estimate SE 95% CI P
Lower Upper
Iannaccone et al. 16 (n = 19) I4e Intercept (α) 7.765 0.508 6.768 8.761 <0.0001
Slope (β) −0.172 0.023 −0.216 −0.127 <0.0001
V4e Intercept (α) 10.296 0.193 9.917 10.675 <0.0001
Slope (β) −0.136 0.010 −0.155 −0.117 <0.0001
Massof et al. 19 (n = 172) II4e Slope (β) −0.170 N/A N/A N/A N/A
V4e Slope (β) −0.145 N/A N/A N/A N/A
Holopigian et al. 20 (n = 23) V4e Slope (β) −0.112 N/A 0.032 −0.192 N/A
Grover et al. 22 (n = 71) II4e Slope (β) −0.102 N/A −0.078 −0.116 N/A
V4e Slope (β) −0.095 N/A −0.073 −0.144 N/A
Present study (n = 23) III4e 0.95 Intercept (α) 10.100 0.679 8.752 11.447 0.214
Slope (β) −0.156 0.030 −0.216 −0.096 <0.0001
Table 3.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Changes in the mfERG Amplitudes
Table 3.
 
Parameter Estimates and Statistics (Fixed Effects) for Disease Duration According to Changes in the mfERG Amplitudes
mfERG Ring Amplitudes Adj R 2 Estimate SE 95% CI P
Lower Upper
Ring 5 (outermost) 0.83 Intercept (α) 1.498 0.235 1.030 1.965 <0.0001
Slope (β) −0.062 0.011 −0.085 −0.039 <0.0001
Ring 4 0.71 Intercept (α) 1.570 0.262 1.050 2.090 <0.0001
Slope (β) −0.073 0.014 −0.101 −0.045 <0.0001
Ring 3 0.74 Intercept (α) 2.257 0.255 1.751 2.764 <0.0001
Slope (β) −0.096 0.014 −0.126 −0.067 <0.0001
Ring 2 0.86 Intercept (α) 3.434 0.241 2.955 3.914 <0.0001
Slope (β) −0.109 0.015 −0.141 −0.078 <0.0001
Ring 1 (center) 0.77 Intercept (α) 3.792 0.206 3.382 4.201 <0.0001
Slope (β) −0.077 0.011 −0.101 −0.054 <0.0001
Supplementary Figure S1
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