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(Investigative Ophthalmology and Visual Science. 2003;44:3544-3550.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-1278
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Pattern ERG Correlates of Abnormal Fundus Autofluorescence in Patients with Retinitis Pigmentosa and Normal Visual Acuity

Anthony G. Robson,1 Ahmed El-Amir,2 Claire Bailey,2 Catherine A. Egan,2 Frederick W. Fitzke,3 Andrew R. Webster,2,3 Alan C. Bird,2,3 and Graham E. Holder1

1From the Departments of Electrophysiology and 2Clinical Ophthalmology, Moorfields Eye Hospital, London, United Kingdom; and the 3Institute of Ophthalmology, London, United Kingdom.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 Conclusions
 References
 
PURPOSE. To examine the functional significance of central abnormalities present in fundus autofluorescence (AF) images in patients with rod–cone dystrophy and good visual acuity.

METHODS. Thirty patients were selected according to three criteria: a clinical diagnosis of retinitis pigmentosa (RP) confirmed with International Society for Clinical Electrophysiology of Vision (ISCEV) standard ERGs, a parafoveal ring of increased high density on fundus AF imaging, and a visual acuity of 20/30 or better. Macular function was assessed with pattern electroretinography (PERG) to checkerboard stimuli of different field sizes. Fundus AF imaging was performed with a confocal scanning laser ophthalmoscope.

RESULTS. The radius of the parafoveal ring of high density varied between 1.5° and 9°. The PERG P50 amplitude correlated highly with the radius of the ring of increased autofluorescence (r = 0.80, P < 0.0005, n = 30). PERGs to smaller circular field sizes were present, but increasing field size to beyond that of the high-density autofluorescence ring did not produce further increases in P50 amplitude. There was a high correlation between the minimum stimulus size required to elicit a maximum-amplitude PERG and the radius of the ring (r = 0.87).

CONCLUSIONS. The high correlation between AF imaging and PERG, an established technique in the assessment of central retinal function, demonstrates the likelihood that autofluorescence abnormalities have functional significance and may therefore be a valuable additional parameter in the monitoring of these patients.

Retinitis pigmentosa (RP) refers to a heterogeneous group of genetically determined retinal degenerations characterized by peripheral photoreceptor dysfunction, affecting rods more than cones.1 2 3 Typical symptoms include nyctalopia and visual field constriction. Classic clinical signs include intraretinal bone-spicule pigment, vessel attenuation, and pale discs. Autosomal dominant disease has been reported as having generally a better visual prognosis than recessive or X-linked disease4 although there is wide mutation-specific variability. Central vision may or may not be involved and may deteriorate at a slower rate than in the periphery. Monitoring of central cone function may be of value in predicting retention of central vision.5

Pattern electroretinography (PERG) is an established technique for objective assessment of central retinal function.6 7 The normal PERG consists of two main components: P50 and N95. The latter arises in relation to retinal ganglion cell function and although some of PERG P50 has similar origins, a significant contribution arises more distally.8 This inner retinal response is driven by macular photoreceptors. The PERG P50 is a valuable indicator of macular function9 10 11 12 13 14 15 and may play a role in detecting early macular involvement in RP.6

Fundus autofluorescence (AF) imaging is a relatively new technique that allows the distribution of lipofuscin at the level of the retinal pigment epithelium (RPE) to be visualized16 17 18 and the technique has been useful in the evaluation of macular disease.12 13 15 17 19 20 21 22 Abnormal high-density areas of autofluorescence are likely to represent accumulation of lipofuscin. This manifestation of abnormal metabolism may result from high turnover of photoreceptor outer segments,23 24 25 disrupted phagocytosis,26 or an intrinsic defect in the ability of the RPE to recycle metabolites.27 28 Absence of autofluorescence may reflect photoreceptor cell death, with or without RPE atrophy. However, the presence of lipofuscin suggests continuing metabolic demand.17

Our experience with AF imaging suggests that some patients with RP have abnormal fundus autofluorescence in the form of a parafoveal ring of high density. The objective of this study was to assess macular function, using the PERG, to elucidate the significance of the fundus autofluorescence abnormalities in these patients. All patients had normal visual acuity—that is, there was no clinical evidence of central retinal dysfunction.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 Conclusions
 References
 
The tenets of the Declaration of Helsinki were followed, and the study was approved by the local ethics committee. The 30 patients selected for the study had Snellen visual acuity of 20/30 or better, a clinical diagnosis of RP confirmed by full-field ERGs, and abnormal autofluorescence in the posterior pole in the form of a high-density parafoveal ring. Patients were aged between 9 and 63 years, with a mean and median age of 31 ± 13 years (SD).

Full-field ERGs were performed according to extended testing protocols incorporating the International Society for Clinical Electrophysiology of Vision (ISCEV) minimum standard29 for assessment of generalized retinal function. Typical normal traces appear in Figure 3E and show the rod-specific response, the maximum (mixed rod–cone) response, the 30-Hz flicker response, and the (single-flash) photopic response. The oscillatory potentials are visible on the ascending limb of the b-wave. A stimulus 0.6 log units greater than the ISCEV maximum was used to elicit the maximum ERG, to demonstrate the a-wave better under conditions of dark adaptation. Approximately the first 10 ms of the descending limb of the maximum ERG a-wave is related to photoreceptor hyperpolarization30 and the slope of the a-wave can be related to the kinetics of rod phototransduction.31 The higher intensity stimulus thus allows a more direct assessment of photoreceptor function (for review, see Fishman et al.14 ). Pupils in all patients were dilated with tropicamide (1%) and/or phenylephrine hydrochloride (2.5%), before full-field ERG testing. Gold foil corneal recording electrodes were used. They do not interfere with the optics of the eye and can therefore also be used to obtain PERG recordings.



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  		FIGURE 3. Full-field ERGs, PERGs, and AF images from the right eyes of four patients with rod–cone dystrophy (A–D) and in a normal subject (E). AF images show an abnormal high-density ring of parafoveal autofluorescence that varied in size between patients. Corresponding clinical details are summarized in Table 1 . Images (A) to (D) are from patients 3, 7, 6, and 24, respectively.

 
PERGs evoked by high-contrast checkerboard reversal were recorded before mydriasis and with optimal refraction according to ISCEV recommendations7 using standard parameters: reversal rate 2.2 Hz, checkerboard size 12° x 15°, check size 45 minutes, and Michelson contrast 0.98. Recordings were performed binocularly to facilitate optimal fixation. Typically, more than 100 sweeps were averaged by using "interrupted stimulation" to minimize eye-movement artifacts.10 Patients were instructed to concentrate on the stimulus for 4 to 5 seconds without blinking, averaging was then suspended, and the patient was told to blink before again concentrating on the fixation spot. The PERG P50 component was used as an index of macular function. Additional PERG testing was performed with circular checkerboard fields ranging from 3° to 18° in diameter presented in a random order. Check size within these circular fields was constant at 45 or 23 minutes.

All patients underwent AF imaging, according to previously described techniques.17 The imaging was usually obtained on the same day, with the pupils dilated and always after full-field ERG testing, but in a few cases AF images were obtained some weeks before electrophysiological testing. The topographic distribution of autofluorescence across the retina was measured using a gray-scale index of intensity (0–255 units), along the vertical and horizontal meridians, intersecting the foveal pixel,32 and scaled in degrees by assuming a visual angle of 15° between the center of the optic disc and fovea.

Some patients underwent automated static perimetry (program 30-2 or 24-2; Humphrey Field Analyzer; Zeiss Humphrey Systems, Dublin, CA).


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 Conclusions
 References
 
All patients had a clinical diagnosis of RP. The main symptoms and signs are summarized in Table 1 , and corresponding full-field ERG amplitudes are summarized in Figure 1 . In patients with detectable flicker ERGs, 26 of 27 were delayed (mean delay, 11 ms). There was a high degree of interocular symmetry in all full-field ERGs (Fig. 2) . Representative ERG waveforms are shown in Figure 3 .


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  		TABLE 1. Retrospective Summary of Clinical Findings

 


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  		FIGURE 1. Summary of full-field ERG parameters in the right eyes of patients with rod–cone dystrophy. Rod ERG b-wave, maximum ERG a-wave, transient photopic ERG b-wave and the 30-Hz flicker ERG amplitudes are shown. Data are arranged according to ascending order of maximum ERG a-wave amplitudes. Rod-specific ERGs show proportionately greatest reduction consistent with high rod system stimulus selectivity.

 


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  		FIGURE 2. Interocular symmetry of ISCEV standard full-field ERG amplitudes in patients with rod–cone dystrophy. Scotopic rod-specific ERG (r = 0.97), scotopic maximum ERG a-wave (r = 0.95), photopic 30-Hz flicker ERG (r = 0.97), and transient photopic ERG b-wave (r = 0.95). All values, r = 0.94.

 
PERG P50 components varied greatly in amplitude. P50 was normal (>2 µV) in some subjects and subnormal in others, consistent with various degrees of macular involvement. There was a high degree of interocular symmetry in PERG P50 amplitudes (r = 0.94) although there were exceptions. Five had a P50 amplitude difference greater than 25% and an additional two had a difference greater than 75%. PERG P50 amplitude was not related to visual acuity (as an inclusion criterion, visual acuity was 20/30 or better in all patients). There was no correlation between PERG P50 and the severity of generalized rod and cone dysfunction for the patient group as a whole. Linear correlation between PERG P50 and maximum ERG a-wave amplitude and with photopic 30-Hz flicker ERG amplitude accounted for less than 5% and 1% of the variance, respectively (Fig. 4) .



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  		FIGURE 4. Comparison of PERG P50 with maximum ERG a-wave (black symbols) and 30-Hz flicker ERG amplitudes (gray symbols) from the right eyes of 30 patients. Lines are for a cohort of four patients with RP18 and compare PERG P50 with cone flicker ERGs (large gray diamonds) and with maximum ERG a-wave amplitudes (large black squares). Correlation coefficients for all patients are 0.09 (PERG P50 versus 30-Hz ERG) and 0.28 (PERG P50 versus Max ERG).

 
The internal radius of the high-density rings of autofluorescence varied between approximately 1.5° and 9°, and there was a high degree of interocular symmetry (r2 = 0.94). Comparison of PERG P50 amplitude with the radius of the high-density rings revealed a linear relationship (Fig. 5) . There was positive correlation that was statistically significant; Spearman rank correlation coefficients were 0.81 (P < 0.0005) for right eyes and 0.79 (P < 0.0005) for left eyes. This high correlation suggests that only the area of central macula encircled by the high-density ring contributes to the PERG.



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  		FIGURE 5. Comparison of high-density ring inner radius with PERG P50 amplitude for 30 patients. Right eyes (black diamonds), Spearman rank correlation coefficient (r) = 0.81 (P < 0.0005); left eyes (gray circles), r = 0.79 (P < 0.0005). Linear regression line is for averaged right and left eye data (r = 0.80, P < 0.0005).

 
To test this hypothesis, we recorded PERGs to circular checkerboards of different diameters (3°–18°) in 13 patients. Check size was constant at 45 minutes or 23 minutes. Figure 6 shows the relationship between PERG P50 amplitude and stimulus field in six representative patients compared with a group of normal subjects. There was a linear relationship between PERG P50 and field size in the normal subjects. In the patient group, the response to the 3° stimulus field was present, but the expected enlargement was not always seen: increasing the circular checkerboard beyond the diameter of the high-density ring produced no significant increase in PERG P50 regardless of whether 45 -or 23-minute checks were used. One patient showed almost linear enlargement of PERG P50 as the field size was increased up to the largest checkerboard (diameter 18°), consistent with the presence of a high-density ring of similar size (Fig. 6K) . Figure 7 summarizes data from the 13 subjects tested and shows high correlation between autofluorescence ring size and the minimum size of checkerboard needed to elicit a maximum PERG (r = 0.87).



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  		FIGURE 6. Comparison of PERG P50 amplitude with the diameter of circular checkerboard stimulus in six patients (F–K): right eye ({blacksquare}), left eye ({triangleup}). Check size 45 minutes (F, H–K), check size 23 minutes (G). Mean values in normal subjects (n = 8) are plotted for comparison (•). Error bars, SD. Right columns: corresponding AF images.

 


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  		FIGURE 7. Comparison of the minimum stimulus size necessary to elicit a maximum PERG P50, with the radius of the high-density ring. Check size: 45 (black circles) and 23 (gray diamonds) minutes. Data are for right eyes of 13 patients (r = 0.87).

 
Figure 8 compares visual fields and AF images from three patients. Greater central areas of visual field preservation were present in patients with larger high-density rings.



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  		FIGURE 8. Comparison of visual fields with corresponding AF images from three patients with different sizes of high-density ring.

 
The presence of a high-density ring was not associated with a single-inheritance pattern (Table 1) . There was no relationship between the nature of the autofluorescence or PERG abnormality and the nature of the disorder. Patients with autosomal dominant disease included three belonging to the same pedigree (Table 1 , patients 3, 23, and 24), with a mutation mapping to the RP18 locus on chromosome 1.33 34 Two children of patient 3, aged 10 and 5 years, although clinically and electrophysiologically affected, did not have high-density rings of autofluorescence (data not shown). Another patient included in the study (patient 25) had RP18, but belonged to a second pedigree.35 One patient had a clinical diagnosis of Usher syndrome type 1, and four patients had Usher syndrome type 2, also diagnosed on clinical grounds (Table 1) .


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
Conclusions
 References
 
The data demonstrate high correlation between the size of the abnormal parafoveal ring of high-density autofluorescence and the degree of macular dysfunction in patients with RP and normal visual acuity who manifest such a ring. The high-density areas thus probably represent a boundary of demarcation between normal and severely abnormal retinal function. Generally, the extent of macular involvement could not be predicted from visual acuity or from the full-field ERGs (but see later discussion).

The data in Figure 5 suggest that the area encircled by the high-density ring retains function at suprathreshold levels, with concentric areas surrounding the ring making minimal or no contribution to the PERG P50. This conclusion is supported by the observation that there is a clear response to stimuli that fall within the high-density ring, but no further enlargement of PERG P50 occurs when surrounding areas are stimulated with larger circular fields (Figs. 6 7) . Preserved responses to the smaller stimulus fields (Fig. 6) and to smaller checks (Fig. 6G) also suggest that the reduction in the standard PERG P50 component associated with larger checkerboards predominantly reflects a localized loss of function peripheral to the ring, rather than dysfunction across the whole macula. Responses to small fields are of similar amplitude, regardless of whether 23- or 45-minute checks are used, in keeping with normative data showing relatively flat PERG P50 spatial tuning over this range.9 36 37 38 39 40

In a small cohort of patients with RP18, the maximum ERG a-wave (related to rod phototransduction) and the 30-Hz flicker ERG (a measure of cone system activity) appeared to be proportional to the PERG P50 amplitude (Fig. 4) . It is possible that similar correlations will emerge as other genotypes are ascertained. The lack of correlation in the group as a whole may also relate to differences in the extent of far-peripheral visual field loss. Preserved peripheral areas (e.g., Fig. 8M ) may contribute to the full-field ERG but not to the PERG, the amplitude of which is related to the area of central sparing.

There was some variability in the relationship between the autofluorescence ring size and circular stimulus size necessary to elicit a maximum PERG (Fig. 7) . This may be largely attributable to the coarseness of angular sampling. Smaller increases in field size would be necessary to demonstrate more accurate correspondence.

Preliminary studies in four patients showed no significant change in either the autofluorescence inner ring size or the PERG P50 over a 17- to 33-month interval. This is perhaps not surprising, given that visual acuity is preserved in classic RP. Indeed, spared or slowly progressive macular involvement has been demonstrated in patients with RP.5 It is tempting to speculate that the high-density ring may be a relatively late manifestation of slowly progressive RP and may constrict as the disease advances. Longitudinal studies are needed to investigate this proposal.

The PERG was used in the present study because it provides an objective and reproducible index of macular function39 43 and is not prone to the same intra- and intersession variabilities associated with visual field testing, shown to occur in patients with RP.44 PERG recording may be conveniently incorporated within routine ERG testing protocols as a complement to full-field ERG and/or VEP6 14 testing and has established clinical value.9 10 11 12 13 15 The linear relationship between P50 amplitude and stimulus field radius, for the check and checkerboard sizes used, suggests that the PERG is weighted in favor of the central macular areas, as reported previously.36 37 38 41 42

Marked PERG P50 reduction could be present with preservation of normal visual acuity. The PERG P50 component may therefore be of prognostic value in detecting macular dysfunction and thus predicting the possibility of central visual deterioration in patients with RP who have normal visual acuity.6 It is possible that high-density areas may demarcate the edge of peripheral dysfunction as the process advances and encroaches on central macular areas. Such encroachment would be consistent with previous accounts of progressive visual field loss in RP.45 46 47 Figure 8 suggests correspondence between the area of central visual field preservation and the area within the high-density ring of autofluorescence, corroborating PERG data (Figs. 5 6 7) . However, the coarse spatial resolution of routine visual field perimetry does not permit analysis over the relatively narrow width of most high-density rings. Preliminary results from high spatial resolution perimetry (fine matrix mapping) suggest dramatically changing photopic sensitivity across the width of the high-density ring and a profound reduction in sensitivity in the surrounding retinal area (Robson AG, et al. IOVS 2002;43:ARVO E-Abstract 1771).

It is believed that autofluorescence at the level of the RPE is maintained by metabolic demand driven by outer segment renewal. If this notion is correct, the homogeneous autofluorescence on either side of the high-density ring implies that the loss of function at this stage is due to photoreceptor dysfunction, rather than to cell death. Alternatively, there may be a normal population of rod photoreceptors outside the ring, because the PERG is driven solely by cones.


   Conclusions
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 Conclusions
References
 
AF retinal imaging is a powerful technique in the objective assessment of changes consequent on retinal dysfunction. A proportion of patients with RP have a parafoveal ring of increased autofluorescence. The high correlation with the PERG, an established technique in the assessment of central retinal function, suggests that the autofluorescence abnormalities have functional significance and may therefore be an important additional parameter in the monitoring of such patients.


   Footnotes
 
Supported by The Foundation Fighting Blindness (AGR).

Submitted for publication December 13, 2002; revised March 5, 2003; accepted March 16, 2003.

Disclosure: A.G. Robson, None; A. El-Amir, None; C. Bailey, None; C.A. Egan, None; F.W. Fitzke, None; A.R. Webster, None; A.C. Bird, None; G.E. Holder, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Anthony G. Robson, Department of Electrophysiology, Moorfields Eye Hospital, City Road, London EC1V 2PD, UK; anthony.robson{at}moorfields.nhs.uk.


   References
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 Materials and Methods
 Results
 Discussion
 Conclusions
 References
 

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