Full-field ERG as a predictor of the natural course of ABCA4-associated retinal degenerations

Abstract

Purpose: To assess retinal function in combination with the retinal structure in ABCA4-associated retinal degenerations. Moreover, to evaluate the possibility of predicting the natural course of these disorders.

Methods: 34 patients with Stargardt disease or cone rod dystrophy carrying confirmed mutations in ABCA4 were selected from our retinitis pigmentosa (RP) register. Sequence analysis of the entire coding region of the ABCA4 gene was performed. The patients were subdivided into three groups based on their most recent visual fields. Group 1 included ten patients with central scotomas within 10°, group 2 included 19 patients with larger central scotomas of 10-35°, and group 3 included five patients with mere temporal residues. The patients underwent slit-lamp and fundus examinations, visual acuity testing, optical coherence tomography (OCT), fundus photography (color, red-free, and autofluorescence (AF) images), full-field electroretinography (ffERG), and multifocal electroretinography (mERG). FfERG and mERG results were analyzed statistically. Total rod and cone function, as well as macular function, was compared between the three groups and of each group to a normal material. In 23 patients who had undergone ffERG on a previous occasion, the 30 Hz flicker implicit time (IT) from the first visit was also analyzed.

Results: The ffERG statistics revealed significant differences between the groups regarding cone and rod function with group 1 showing the highest amplitudes and the shortest ITs while group 3 demonstrated the lowest amplitudes and the most delayed ITs. When compared to controls, group 1 did not show any significant changes while groups 2 and 3 demonstrated reduced amplitudes and delayed 30 Hz ITs. Regarding estimation of the natural course, identical results of the 30 Hz IT were encountered for the groups also at the first visit early in the course of disease. Comparison of the mERGs showed significant differences with group 1 demonstrating the highest amplitudes and group 3 the lowest for all rings but rings 2 and 3 in the right eye for which the amplitudes were the second highest. The mERGs for each group were also compared to controls showing reduced mERG amplitudes for all rings in all groups, except group 1, left eye. OCT showed macular attenuation in all patients. Evaluation of the inner and outer photoreceptor junction (IS/OS) morphology revealed alterations related to macular function measured with mERG in all eyes. Eight patients in group 1 showed foveal IS/OS junction loss, one had foveal IS/OS junction disorganization, and one had IS/OS loss also beyond the fovea. In group 2, one patient had IS/OS junction loss confined to the fovea, and the rest showed total loss of IS/OS junctions. Group 3 was devoid of IS/OS junctions. Concerning the AF images, group 1 showed small areas of absent AF in the macula, peripapillary sparing, and flecks of increased and reduced AF in the posterior pole. In group 2, the central areas of absent AF were larger. Flecks of reduced AF were the most dominant and reached beyond the posterior pole. Seven of 19 patients had peripapillary sparing. In group 3, large confluent areas of reduced AF were found in the posterior pole and beyond with small areas of increased AF in the far periphery. No peripapillary sparing was seen.

Conclusions: The current study demonstrates a significant difference in total retinal function, as well as macular function, between patients with ABCA4-associated retinal degeneration and a different degree of visual field defects with gradual deterioration of function along with increased visual field constriction. Likewise, the morphological changes, including the deviant AF pattern and loss of IS/OS junctions, that were related to macular function measured with mERG worsened with the degree of visual field defects. Moreover, in these groups of patients with ABCA4-associated retinal degenerations, full-field cone 30 Hz flicker IT seems to be a predictor of the natural course of the disease also on long-term follow-up.

Figure 1

Examples of Goldmann visual field plots from one patient in each of the three groups. A: Typical Goldmann visual fields for group 1 with small central scotomas less than 10° (patient 10). B: Group 2 with larger central scotomas from 10° to 35° (patient 24). C: Typical for group 3 with temporal visual field residues (patient 30).

Figure 2

Representative red-free and color fundus photographs of patients from the three groups. A and B: Patient 10 in group 1 shows subtle pigmentary irregularity in the macular region as in most patients in the group. C and D: Subject 24 in group 2 demonstrates a slightly pale optic disc, more widespread pigmentary changes in the posterior pole, as well as deep yellow flecks in the midperiphery; in this subject most apparent nasal and inferior of the optic nerve. More extensive flecks were encountered in some other subjects in the group. E and F: Patient 30 reveals a pale optic disc, narrow retinal vessels, extensive pigmentary changes in the macular region, and bone corpuscle pigmentations in the periphery.

Figure 3

Representative autofluorescence images from one patient of each group. A and B: Patient 10 in group 1 shows reduced autofluorescence (AF) in the fovea with a surrounding ring of increased AF. Similar findings were encountered in all patients in group 1 except patient 1 who also demonstrated a pisciform pattern of increased and reduced AF beyond the central decreased AF. C and D: Patient 24 in group 2 shows a larger central area with the absence of AF surrounded by widespread mottling of increased and reduced AF. AF images from the other patients in group 2 are similar. E and F: Patient 30 in group 3 is in line with the other patients of the group demonstrating a large central area of absent AF, as well as widespread rounded flecks of reduced AF around the vascular arcades.

Figure 4

OCT images of one representative patient from each group. A: Loss of the photoreceptor integrity line (PIL; indicated by the white brace) in the macular region in patient 10 from group 1. The PIL corresponds to the junction of the inner and outer segments of the photoreceptors. The same pattern was encountered in all but two patients in group 1. One of those two patients showed more extensive PIL loss, and the other had better preserved but disorganized PIL. B: Representative total PIL loss and RPE atrophy in patient 24 from group 2. All but one patient in group 2 showed the same optical coherence tomography (OCT) changes. Patient 19 had a defect PIL in the center but a preserved PIL beyond this. C: Patient 30 from group 3 also shows total PIL loss and extensive RPE atrophy as observed in the other patients in group 3.