Documenta Ophthalmologica

Correlation between electroretinography, foveal anatomy and visual acuity in albinism Abstract Background Albinism patients have poor visual acuity in addition to hypopigmentation. Their foveal anatomy is abnormal, but correlation with function is incompletely understood. This study correlates retinal electrophysiology, visual acuity and optical coherence tomography (OCT) anatomy in albinism patients and compares with age-similar controls. Methods Institutional Review Board approval was obtained (IRB# 201408782). Patients were recruited from clinical practice. Inclusion criteria were at least three clinical features of albinism including iris transillumination, nystagmus, fundus hypopigmentation, or foveal hypoplasia on OCT and/or molecular genetic confirmation. Diagnosys (Lowell, Mass) full-field ERG (ffERG) and VERIS multifocal ERG (mfERG; Electro-Diagnostic Imaging, Milpitas, California) were obtained using standard International Society for Clinical Electrophysiology of Vision protocols. The mfERG protocol was a 4-min 103-hexagon protocol covering approximately 40° in diameter of central retina. Control subjects without albinism were recruited by in-hospital notices and invitations in clinic. OCT central thickness was recorded, and an OCT foveal score was calculated. Nonparametric permutation testing was utilized to determine the statistical significance. Results A total of 16 albinism patients and 19 age-similar controls were recruited. Four of 16 albinism patients had no nystagmus. Seventeen non-albinism controls had no ocular disorder other than refractive error. Two controls had infantile nystagmus with normal maculas on OCT. There was no statistically significant difference in mfERG amplitude or latency between albinism patients with or without nystagmus (lowest p = 0.68; 0.54, respectively). mfERG: 12 of 16 (75%) albinism patients had average ring 1 amplitudes within one standard deviation of controls despite having abnormal foveal anatomy on OCT. Patients averaged shorter latencies in rings 1 and 2 than controls (p = 0.005, p = 0.02). Patients averaged higher amplitudes than controls in rings 4, 5 and 6 (p = 0.03, p = 0.006, p = 0.004). There was no significant correlation between visual acuity and mfERG amplitudes in any ring (smallest p = 0.15). ffERG: Patients averaged higher amplitudes on 30 Hz flicker (p = 0.008). In all conditions, albinism patients had higher amplitude a-waves (p ≤ 0.03). B-waves were higher amplitude than controls in light-adapted 3.0 (p = 0.03). There was no statistical correlation between ffERG amplitudes and visual acuity (smallest p = 0.45). OCT: In albinism patients, thicker central macula on OCT correlated with lower mfERG amplitudes in all rings except for ring 1 (p < 0.05) and lower ffERG a-wave amplitudes on dark-adapted 0.01 (p = 0.003). Macular thickness on OCT did not correlate with visual acuity (p = 0.51); OCT foveal score did (p = 0.0004). Conclusions Amplitude of mfERG does not correlate with visual acuity in any ring in patients with albinism. The slope of the change in amplitude from central to peripheral rings on the mferg is significantly different in albinism patients versus controls whether or not nystagmus is present. The decreased slope of change in amplitudes from center to periphery of the macula in albinism patients indicates changes in macular topography that are more important to visual deficits than the foveal depression

Flicker electroretinogram recorded with portable ERG device in prematurely born schoolchildren with and without ROP Abstract Purpose The purpose of this study was to compare electroretinographic (ERG) responses of preterm schoolchildren, with and without a history of retinopathy of prematurity (ROP) with those of full-term schoolchildren by using a portable ERG device (RETeval system). Methods Twenty five prematurely born schoolchildren with a mean gestational age of 27 + 1/7w (range 23–30w) and a mean birth weight of 1030 g (range 580–1700 g) who were 6.9 ± 2.2 years old participated in the study (premature group). A further subdivision according to a history of ROP (ROP+ group) or its absence (ROP− group) was introduced. Twenty eight healthy full-term schoolchildren with an average age of 8.6 ± 1.9 years participated as the control group. 30-Hz flicker ERG responses were obtained, and implicit times and amplitudes were compared between the groups. Results 30-Hz flicker ERG implicit times showed a significant difference between all three groups of children. The mean value of the implicit time in the term group was 25.76 ± 0.9 ms, whereas in the preterm ROP + group it was 28.96 ± 1.0 ms and in the preterm ROP− group it was 26.87 ± 1.5 ms. 30-Hz flicker ERG amplitudes did not show significant difference between term children and children born prematurely with or without ROP. Conclusions Prematurely born schoolchildren exhibit longer implicit time of the 30-Hz flicker ERG response compared to controls, suggesting a possible abnormality of the retinal cone system function. Under such circumstances, portable ERG device might be used clinically as a screening tool for retinal function evaluation in prematurely born children.

A case of X-linked retinoschisis with atypical fundus appearance Abstract Purpose Mutations in the RS1 gene are known to cause retinoschisis, an X-linked hereditary retinal degeneration. Here, we present a case of atypical retinoschisis with clinical findings of retinoschisis and retinitis pigmentosa. Methods This report is an observational case report. The detailed ophthalmological examinations included visual field determination, multimodal imaging and electrophysiological recordings. Targeted next-generation sequencing of a retinal disease gene panel was performed. Results The 55-year-old male, highly hyperopic patient, presented with a best-corrected Snellen visual acuity of 20/100 in the right eye and 20/400 in the left eye. In the kinetic visual field, there was a superior scotoma, as well as a ring scotoma in the inferior hemisphere in the right eye and a concentric visual field constriction to 10° in the left eye. Funduscopy revealed marked pigmentary changes (i.e. bone spicules) in the mid-periphery bilaterally and symmetrically, as well as two small intra-retinal haemorrhages in the left eye. Full-field electroretinography recordings showed extinguished rod and cone responses. Diagnostic–genetic testing revealed a hemizygous missense mutation in the RS1gene (c.305G > A; p.Arg102Gln) was identified. Conclusion We present a case of atypical retinoschisis with clinical findings of retinitis pigmentosa.

Comparison of electroretinographic measurements between tabletop and handheld stimulators in healthy subjects Abstract Purpose To compare full-field electroretinography (ffERG) parameters obtained from handheld and tabletop electroretinography (ERG) devices in normal subjects. Methods Twenty volunteers underwent ffERG using a tabletop and handheld stimulator. The responses obtained from the right eyes were compared. The coefficient of variation and intraclass correlation coefficient (ICC) were derived to assess inter- and intra-individual reliability. Results The b-wave in the rod response, a- and b-waves in the maximal combined response, a-wave in the cone response, and the 30-Hz flicker response showed significantly greater amplitudes when recorded with the tabletop stimulator than with the handheld stimulator. The implicit time of response (ITR) in the 30-Hz flicker response was longer when recorded with the handheld stimulator than when recorded with the tabletop stimulator. With regard to amplitude, the ICC indicated moderate-to-high reliability in the measurement of the b-wave in the rod response, and a- and b-waves in the maximal combined response. With regard to ITR, measurement of the b-wave in the rod response and a-wave in the maximal combined response showed moderate-to-high reliability. Conclusion Despite the significantly lower ERG amplitude measurements recorded by the handheld stimulator, there were no significant differences in variability between the two stimulators.

Adaptation time, electroretinography, and pupillography in healthy subjects Abstract Purpose To investigate the relationship between adaptation time and the parameters of electroretinography (ERG) and pupillography in healthy subjects. Methods Forty-six eyes of 23 healthy women (mean age 21.7 years) were enrolled. ERG and pupillography were tested in each of the right and left 23 eyes, respectively. ERG with a skin electrode was used to determine amplitude and implicit time by the records of rod-, flash-, cone-, and flicker-responses with white light (0.01–30 cd s/m2). Infrared pupillography was used to record the pupillary light reflex to 1-s stimulation of red light (100 cd/m2). Cone- and flicker- (rod-, flash- and pupil) responses were recorded after light (dark) adaptation at 1, 5, 10, 15, and 20 min. Results Amplitude (µV) was significantly different between 1 min and ≥ 5 or ≥ 10 min after adaptation in b-wave of cone- or rod-response, respectively. Implicit time (ms) differed significantly between 1 min and ≥ 5 min after adaptation with b-wave of cone- and rod-response. There were significant differences between 1 min and ≥ 10 or ≥ 5 min after dark adaptation in parameter of minimum pupil diameter (mm) or constriction rate (%), respectively. Conclusions Cone-driven ERG can be recorded, even in 5 min of light adaptation time without any special light condition, whereas rod-driven ERG and pupillary response results can be obtained in 10 min or longer of dark adaptation time in complete darkness.

Two-color pupillometry in KCNV2 retinopathy Abstract Purpose To investigate receptor and post-receptor function in KCNV2 retinopathy [cone dystrophy with supernormal rod electroretinogram (ERG)], using the pupillary light reflex (PLR) and the ERG. Methods Two unrelated patients (1 male and 1 female) with molecularly confirmed KCNV2 retinopathy underwent full-field two-color pupillometry testing in one eye, with monitoring of the stimulated eye by an infrared digital camera. Pupillometry stimuli consisted of 1-s duration, short-wavelength (465-nm, blue) and long-wavelength (642-nm, red) stimuli. Pupillometry intensity series were performed under both a dark-adapted condition and a light-adapted condition (on a 0.76-log cd m−2 blue background). The transient PLR, defined as the maximum constriction following flash onset, was measured under all conditions. The melanopsin-mediated sustained constriction was measured 5–7 s following flash offset for the highest flash luminance presented in the dark. Both patients were also tested in one eye with the full-field ERG, including a dark-adapted intensity series and ISCEV standard stimuli. Results Dark-adapted PLRs were markedly attenuated or extinguished for low-luminance stimuli, but the responses to higher-luminance blue stimuli were within normal limits. Light-adapted PLRs to blue stimuli were generally within normal limits, exceeding the responses to photopically matched red stimuli. Thus, light-adapted responses were consistent with either rod or S-cone mediation of the PLR. Melanopsin-mediated sustained PLRs were within normal limits. ERG showed the characteristic findings previously reported in this condition. Cone-mediated ERG responses were markedly decreased in amplitude. Rod-mediated ERG responses were absent for low-luminance stimuli (− 3 log cd s m−2), but had normal amplitude for stimuli of − 2 log cd s m−2 and above (although none were “supernormal”). The b-wave for the dark-adapted ISCEV standard − 2 log cd s m−2 stimulus was markedly delayed, whereas the b-wave timing was generally normal for higher flash luminances. Conclusions The abnormalities measured by pupillometry have a similar pattern to the outer-retinal abnormalities measured by ERG in KCNV2 retinopathy. These findings as well as the normal sustained PLR suggest that inner-retinal function may be preserved in KCNV2 retinopathy and highlight the potential for therapies designed to restore outer-retinal function in these individuals.

Macular function following intravitreal ranibizumab for macular edema associated with branch retinal vein occlusion Abstract Purpose To determine the physiology of the macula by the focal macular electroretinograms (fmERGs) in patients with branch retinal vein occlusion with macular edema (BRVOME) treated by intravitreal injections of ranibizumab (IVR). Methods We studied 17 eyes of 17 patients with BRVOME. The contralateral unaffected eyes served as controls. All patients were treated with an IVR at monthly intervals for 3 consecutive months. The baseline best-corrected visual acuity (BCVA), optical coherence tomographic (OCT) findings, and fmERGs were compared to the post-treatment values. The fmERGs were elicited by a 15° circular spot or a superior or inferior semicircular spot. The center of the spot was placed on the fovea. The amplitudes of the a- and b-waves, photopic negative response (PhNR), and sum of the oscillatory potentials (ΣOPs: sum of OP1, OP2, and OP3 amplitudes) were measured. In addition, the implicit times of the a- and b-waves were also measured. Results The BCVA improved significantly from 0.39 ± 0.28 logMAR units to 0.17 ± 0.18 logMAR units after the resolution of the central macular edema (P < 0.01). All components of the fmERGs elicited by the semicircular stimulus spot placed on the occluded side were smaller than that elicited from the corresponding area of the control eyes. The b-wave amplitudes increased significantly from 0.49 ± 0.25 to 0.75 ± 0.36 µV following the IVR injections, but the amplitudes of the a-wave and PhNR remained reduced (P < 0.05). The amplitudes of the PhNR and ΣOPs elicited by stimulating the non-occluded side were reduced with relative preservation of the a- and b-waves (P < 0.05). They recovered after the treatment from 0.27 ± 0.15 to 0.50 ± 0.30 and 0.33 ± 0.15 to 0.53 ± 0.19 µV, respectively. Conclusions IVRs improved the macular function not only on the occluded side but also on the non-occluded side. On the occluded side, the BRVOME affects the function of all retinal layers of the macula. Even after the IVR, the function of the photoreceptors and retinal ganglion cells remained abnormal. On the non-occluded side, the inner retinal function improved after the IVR.

Retinal dystrophies with bull’s-eye maculopathy along with negative ERGs Abstract Purpose The aim of this study was to examine the ophthalmological characteristics and genotypes of patients with congenital retinal pathologies, who display a bull’s-eye maculopathy in the fundus, along with a negative scotopic electroretinogram. Methods We analysed the results of five patients showing both a bull’s-eye maculopathy, as well as a negative scotopic ERG evoked by a bright flash. Their median age was 39 years (range 11–63 years): three males and two females. All underwent a comprehensive examination with determination of distant visual acuity (ETDRS) and recording of the full-field ERG (scotopic and photopic). Fundus, OCT, and FAF images were obtained, the kinetic visual field was determined, and colour vision (D-15) was tested in most patients. Targeted gene panel sequencing was performed on peripheral blood. Results One patient carried a homozygous ABCA4 mutation and an additional heterozygous variant in CRX. Two of the five patients were shown to have a heterozygous mutation in the CRX gene, one of whom had an additional heterozygous ABCA4 mutation. Two patients had the common heterozygous mutation c.2413G>A;p.Arg838His in GUCY2D. In all of the patients, there was a reduction in the amplitude of the b-wave with a regular a-wave amplitude in the scotopic bright-flash ERG. Conclusions The five patients with bull’s-eye maculopathy along with a negative ERG had differing genotypes. Mutations were found in the CRX gene (2 patients), the ABCA4 gene (1 patient), and the GUCY2D gene (2 patients).

Test–retest repeatability of the pattern electroretinogram and flicker electroretinogram Abstract Purpose To evaluate the repeatability of the steady-state pattern electroretinogram (PERG) and full-field flicker electroretinogram (Flicker ERG) protocols, delivered by the office-based Neuro Optic Vision Assessment (NOVA)™ testing platform, in healthy subjects. Methods Healthy individuals underwent PERG (16° and 24°) and Flicker ERG [fixed luminance (FL) and multi-luminance (ML)] testing protocols. Test–retest repeatability of protocols was calculated using intra-class correlation coefficients (ICC). Reference values of the parameters of the aforementioned tests were also calculated. Results The ICCs for the PERG parameters ranged from 0.793 to 0.911 (p < 0.001). The ICCs for the Flicker ERG parameters ranged from 0.968 to 0.994 (p < 0.001). A linear regression analysis was applied to assess the impact of age on ERG responses. Age had a significant impact on all PERG parameters (16° or 24°). The phase response of the FL Flicker ERG significantly decreased with age (β = − 0.837, p ≤ 0.001). The FL Flicker ERG Magnitude was also impacted with a significant quadratic effect of age (β = − 0.0047, p = 0.0004). Similarly, the Phase Area Under the Curve (Phase AUC) of the ML Flicker ERG significantly declined with age (β = − 0.007, p = 0.009), and the impact on the Magnitude AUC was significant as well, with a negative quadratic age effect. Conclusions The PERG and Flicker ERG protocols, delivered by an office-based testing platform, were shown to have good-to-excellent test–retest repeatability when tests were performed in the same order and in immediate succession.

Novel findings in enhanced S-cone syndrome: a case with macular retinal neovascularization and severe retinal vasculitis Abstract Purpose To describe a novel association of enhanced S-cone syndrome (ESCS) with macular retinal neovascularization and severe retinal vasculitis. Methods Clinical examination, spectral domain optical coherence tomography, fluorescein angiography, fundus autofluorescence, infrared reflectance and electroretinography were used to study a 25-year-old male with a history of night blindness from early childhood and recent accelerated visual loss in right eye. Results Pigmented lesions were observed along the arcades without peripheral retinal involvement. Intraretinal cystoid spaces, retinal neovascularization of posterior pole and severe peripheral and posterior retinal vasculitis were found on clinical examination and multimodal imaging. Based on characteristic clinical and electroretinographic findings, a diagnosis of ESCS was made. Conclusion This case highlights novel associations of retinal neovascularization and vasculitis with ESCS.