Our quantitative assessment of photoreceptor activity (a-wave responses) showed significant reductions in amplitude parameters (
RROD and
RCONE ) in patients with CSNB. Photoreceptor sensitivity (
SROD and
SCONE ) estimated from the models (
equations 1 and
3) did not differ between patients and controls; this is evidence that activation of phototransduction is normal in these patients. Significant deficits in postreceptor activity were found for both rod-driven and cone-driven responses. Consistent with the hypothesis that there is a functional disconnect between the photoreceptors and postreceptor neural retina in CSNB,
1,6,20,35 we found no significant relationship between rod and rod-driven postreceptor response parameters.
Low
RROD could be explained by a reduction either in rod outer segment length or in the number of rod photoreceptors. However, no changes in retinal structure were apparent in two anatomic studies of eyes with CSNB.
56,57 Retinal imaging using adaptive optics found normal rod density (cells/area) 10° from fixation and a normal rod photoreceptor mosaic in the perifoveal region in patients with CSNB.
58 Thus, the significant deficits in
RROD found in our patients must have some other explanation. Jamison et al.
59 used APB (2-amino-4-phosphonobutyric acid) to block the activity of simian ON bipolar cells and found that
RROD decreased but
SROD did not change. They concluded that the postreceptor cells scaled the rod dark current leading to the decrease in a-wave amplitude and low
RROD . Perhaps the low
RROD values in our patients are explained by this mechanism, by the absence of early postreceptor components,
60 or by an as yet unidentified feedback mechanism or anomalous cell-to-cell interaction.
Under rod-mediated conditions, the normal postreceptor b-wave reflects the activity of ON bipolar cells and other second- and third-order neurons.
49–51,61,62 In our patients, we designated the small positive potential that followed the a-wave as the b-wave and used it to estimate postreceptor activity (
Figs. 1,
3). Over the stimulus range used to fit
equation 2, the implicit time of this potential was similar to that in controls, and at higher stimulus strengths, the implicit time of this potential was shorter than in controls (
Fig. 1). Other studies of CSNB have demonstrated similar shortening of b-wave implicit time.
25,26 As for the mechanism, we are reminded that Jamison et al.
59 showed that block of both ON and OFF pathways by administration of APB
plus PDA (piperidine-dicarboxylic acid) led to short implicit time of the small positive potential following the a-wave. They speculated that this potential was produced by photoreceptors or other light-sensitive postreceptor cells rather than by bipolar cells. In intact human records, we cannot specify with certainty the origin of the small (b-wave) potential.
The photoreceptor results in photopic conditions were similar to those in scotopic conditions in that
RCONE was significantly lower in patients than in controls but
SCONE was normal (
Fig. 6). The reduced amplitude and prolonged implicit time of the photopic b-wave in patients suggests defects in the ON pathway (
Fig. 7). The photopic hill that characterizes the normal b-wave stimulus response function and is attributed to the interaction between ON and OFF bipolar cell activity
63 was not found in our CSNB patients. A decrease in the amplitude of the ON bipolar cell response and a delay in the peak of the OFF response with increasing stimulus intensity is thought to account for the photopic hill in the normal cone-mediated ERG. Altered interplay between the ON and OFF bipolar circuitry may account in part for the lack of a photopic hill in CSNB. In the cCSNB patients who were tested with the long (150-ms) flash, the b-wave amplitude was markedly attenuated, indicating an ON pathway abnormality, coupled with prolonged d-wave implicit time, indicating an OFF pathway defect (
Fig. 2D). Together these alterations in retinal circuitry could account for the absence of a photopic hill in cCSNB. Sustar et al.
64 have reported abnormal long-flash responses in a larger sample of patients with CSNB.
We can find no explanation for the normal dark-adapted threshold in five of our patients (
Fig. 5A). All five had a negative ERG, and four of the five had additional ERG characteristics of iCSNB; all had normal fundi on serial examinations. Prior studies of CSNB have reported dark-adapted thresholds ranging from 0.5 to 3.6 log units above normal.
37,65–68 Our average threshold elevation was 1.4 log units, whereas final thresholds measured following a bleaching exposure were elevated up to 3.6 log units. Thresholds in our patients were measured after dark adapting from room light rather than following a bleaching exposure. Recovery of threshold from room light has a shorter time course than recovery from a bleach. Thus, procedural differences, the known slow kinetics of recovery in several forms of CSNB,
37,69 and the small sample size may explain, in part, the apparent discrepancy between our results and those previously reported.
In summary, we interpret our results as indicative of robust and normal photoreceptor function in CSNB despite the low saturated photoresponse amplitude. Postreceptor function in our patients shows evidence of anomalous retinal circuitry that varies with type of CSNB. Among animal models of CSNB,
70–72 postreceptor retinal circuitry, which varies with genetic diagnosis, may be analyzed by pharmacological dissection.
73 Study of the ERG in these animal models using the approach applied in the present study would be a step in translating the knowledge to the human retina. Another step would be further noninvasive study of retinal processes in genotyped patients with CSNB. This is expected to advance knowledge of CSNB circuitry in particular and of human retinal circuitry more generally.