Natural History of Stargardt Disease: The Longest Follow-Up Cohort Study.

Long-term natural history studies are important in rare disease research. This study aimed to assess electrophysiological and fundus autofluorescence (FAF) progression rate in 18 genetically confirmed Stargardt disease (STGD1) patients with a minimum follow-up of 10 years. Age at the first and last exams, age at onset, Snellen decimal visual acuity (VA), electroretinography (ERG), and FAF images were evaluated. Patients were classified into four Fishman stages and three electroretinography groups, and areas of definitely decreased autofluorescence (DDAF) were measured. Patients were further substratified based on genotype, and phenotype-genotype correlations were performed. The median follow-up was 18 (range 10-26) years. The median yearly VA loss was 0.009 (range 0.002-0.071), while the median progression rate of the DDAF area was 0.354 (range 0.002-4.359) mm2 per year. Patients harbouring p.(Gly1961Glu) or p.(Asn1868Ile) allele had significantly slower DDAF area progression when compared to patients with other genotypes (0.07 mm2 vs. 1.03 mm2, respectively), as well as significantly later age at onset (20 years vs. 13 years, respectively). Results showed that structural and functional parameters, together with genotype, should be considered when counselling patients regarding prognosis and monitoring disease progression. Patients harbouring hypomorphic variants p.(Gly1961Glu) or p.(Asn1868Ile) presented with overall milder disease than patients with other genotypes.

Analysis of the slope between P50 and N95 waves of the large field pattern electroretinogram as an additional indicator of ganglion cell dysfunction.

AIM: Dysfunction of the retinal ganglion cells (RGC) can be detected by the pattern electroretinogram (PERG) as a reduction of the N95 amplitude, a decrease of the ratio between N95 and P50 amplitude and/or a shortening of P50 peak time. Additionally, the slope from the top of the P50 towards the N95 (P50-N95 slope) is less steep than in control subjects. The aim of the study was to quantitatively evaluate this slope in large field PERGs in controls and patients with RGC dysfunction due to optic neuropathy. SUBJECTS AND METHODS: Large field (21.6°X27.8°) PERGs and optical coherence tomography (OCT) data from 30 eyes of the 30 patients with different types of clinically confirmed optic neuropathies, and with P50 amplitudes within normal limits and abnormal PERG N95 were retrospectively analysed and compared to 30 healthy eyes of 30 control subjects. The P50-N95 slope was analysed with a linear regression from 50 to 80 ms after the stimulus reversal. RESULTS: The patients with optic neuropathy exhibited a significant reduction of the N95 amplitude (p < 0.001) and N95/P50 ratio (p < 0.001), the P50 peak time was mildly shorter (p = 0.03). The P50-N95 slope was significantly less steep in eyes with optic neuropathies (- 0.089 ± 0.029 vs. - 0.220 ± 0.041, p < 0.001). Thickness of temporal RNFL and the P50-N95 slope appeared to be the most sensitive and specific parameters for detecting RGC dysfunction (AUC = 1.0). CONCLUSIONS: The slope between the P50 and N95 waves of a large field PERG is considerably less steep in patients with RGC dysfunction and could thus be an efficient biomarker, particularly in the diagnosis of early or borderline cases.

Leber Hereditary Optic Neuropathy in a Family of Carriers of MT-ND5 m.13042G>T (A236S) Novel Variant.

BACKGROUND: A Slovenian three-generation family with 3 individuals with bilateral optic neuropathy and 2 unaffected relatives with a novel homoplasmic missense variant m.13042G > T (A236S) in the ND5 gene is described. A detailed phenotype at initial diagnosis and a follow-up of bilateral optic neuropathy progression is presented for 2 affected individuals. METHODS: A detailed phenotype analysis with clinical examination in the early and chronic phase with electrophysiology and OCT segmentation is presented. Genotype analysis with full mitochondrial genome sequencing was performed. RESULTS: Two affected male individuals (maternal cousins) had a profound visual loss at an early age (11 and 20 years) with no recovery. The maternal grandmother exhibited bilateral optic atrophy with a history of visual loss at the age 58 years. The visual loss of both affected male individuals was characterized by centrocecal scotoma, abnormal color vision, abnormal PERG N95, and VEP. Later with disease progression, retinal nerve fiber layer thinning was observed on OCT. We observed no other extraocular clinical features. Mitochondrial sequencing identified a homoplasmic novel variant m.13042G > T (A236S) in the MT-ND5 gene, belonging to a haplogroup K1a. CONCLUSIONS: Novel homoplasmic variant m.13042G > T (A236S) in the ND5 gene in our family was associated with Leber hereditary optic neuropathy-like phenotype. However, predicting the pathogenicity of a novel ultra-rare missense variant in the mitochondrial ND5 gene is challenging. Genetic counseling should consider genotypic and phenotypic heterogeneity, incomplete penetrance, haplogroup type, and tissue-specific thresholds.

Case report: Long-term follow-up of two patients with LHON caused by DNAJC30:c.152G>A pathogenic variant-case series.

Background: We present the disease course and long-term follow-up of two patients who were phenotypically diagnosed with atypical Leber Hereditary Optic Neuropathy (LHON) 14 and 12 years ago, respectively, whereby whole exome sequencing revealed recently described recessive DNAJC30:c.152G>A 152 A>G (p.Tyr51Cys) homozygous pathogenic variant with significant spontaneous visual acuity recovery in one. Case presentation: Two presented unrelated males with atypical LHON with sequential visual acuity (VA) loss were followed for many years. Both patients had negative family history. At the presentation at ages 17 (Case 1) and 18 years (Case 2), both had reduced visual acuity (Snellen): (Case 1) right eye (RE):CF 3m, left eye (LE):0.6, (Case 2) RE:0.2, LE:0.15; and color vision (Ishihara): (Case 1) 1/15 and 13/15; (Case 2) 2/15 and 3/15. Both had hyperemic optic disks (PNO) and central scotoma in their visual fields. Electrophysiology in the acute phase showed reduced and delayed visually evoked potentials (VEP) P100 in both patients, with reduced N95 amplitude in Case 2, and initially normal N95 amplitude in Case 1. Fluorescein angiography showed no early leakage with some late pooling at optic disks. Extensive clinical workout, including brain magnetic resonance imaging (MRI), aquaporin 4 (Aq4), and anti-myelin oligodendrocyte protein (anti-MOG) antibodies, was negative. Intravenous corticosteroids did not improve vision. Both experienced further deterioration several months after the onset accompanied by thinning of the peripapillary retinal nerve fiber layer (RNFL). Genetic testing for typical LHON pathogenic variants and whole mitochondrial DNA (mtDNA) sequencing was negative. 1 year after the onset, modest VA improvement began in Case 2 and continued over the next 3 years. VA improved bilaterally to 0.7, color vision 15/15, and islands of vision appeared within the visual field scotoma. VEP P100 peak time shortened, and amplitude increased, despite further RNFL thinning on optical coherent tomography (OCT). The patient's visual function remained stable during the entire 12-year follow-up period. Case 1 experienced modest VA improvement to 0.1 with some improvement in the visual field seven years after the disease onset, remaining stable during the entire 14-year follow-up period. VEP P100 wave remained undetectable. Conclusions: Presented are two autosomal recessive LHON (arLHON, OMIM:619382) cases with the same DNAJC30:c.152G>A pathogenic variant and different degrees of spontaneous visual recovery despite progressive RNFL thinning during a long-term follow-up. This mutation should be screened in every atypical LHON patient.

Electrophysiological and SD-OCT findings in patients receiving chloroquine therapy in relation to cumulative dosage and duration of treatment.

PURPOSE: Assessment of multifocal ERG (mfERG) changes in patients treated with chloroquine and their correlation with morphological abnormalities, detected by spectral-domain optical coherence tomography in relation to cumulative dosage. METHODS: Data from 37 eyes of 20 patients were retrospectively collected, and one randomly selected eye per patient was considered for statistical analysis. Eyes were divided into three groups according to mfERG and visual acuity findings: normal, early and advanced maculopathy. Functional measures of the first three mfERG rings were compared with retinal thickness measures of the corresponding OCT ETDRS circles. Data on cumulative dose and duration of therapy were also evaluated. RESULTS: The mean mfERG values progressively decreased according to the stage of the disease. In particular in the early maculopathy group, amplitudes were significantly reduced in all the three central rings. The mean ring ratio R1/R2 was abnormal only in the early maculopathy group. OCT thickness measures were significantly lower in all the three ETDRS circles in the advanced maculopathy group, and in the paracentral circle in the early maculopathy group. Considering all the eyes, there was a statistically significant correlation between functional and morphological values (p < 0.001). High chloroquine cumulative dosages were always associated with retinal toxic effects, whereas lower cumulative dosages generated different levels of toxicity. CONCLUSIONS: This study shows a strong association between mfERG ring values and the corresponding OCT thickness measures; however, mfERG may enhance early detection of functional changes in patients treated with chloroquine, especially in ambiguous cases. At low chloroquine cumulative dosages, different subjects might have different susceptibilities to the drug.

Electroretinograms in idiopathic infantile nystagmus, optic nerve hypoplasia and albinism.

PURPOSE: To study electroretinograms in infantile nystagmus syndrome associated with idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism. METHODS: A total of 30 children with idiopathic infantile nystagmus, 18 with optic nerve hypoplasia, and 18 with albinism were studied. Three electroretinogram protocols were applied according to child's age: 58 (mean: 2.0 years) were recorded with skin electrode to Great Ormond Street Hospital protocol, 11 (mean: 5.3 years) with skin electrode to International Society for Clinical Electrophysiology of Vision protocol, and 7 children (mean: 12.2 years) with HK electrode to International Society for Clinical Electrophysiology of Vision protocol. The electroretinograms were compared to those of age-matched controls. RESULTS: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were comparable to controls in all protocols. Electroretinogram amplitudes in idiopathic infantile nystagmus group showed increased white scotopic and photopic electroretinograms in 26 children (skin electrode to Great Ormond Street Hospital protocol), no difference to the controls in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol), and increased rod electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol). Optic nerve hypoplasia group showed increased white scotopic, photopic, and blue electroretinograms in 15 children (skin electrode to Great Ormond Street Hospital protocol); increased 30-Hz electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol); and reduced combined rod-cone, cone, and 30-Hz electroretinograms in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Albinism group showed increased white scotopic, photopic, and 30-Hz electroretinograms in 17 children (skin electrode to Great Ormond Street Hospital protocol), while it showed reduced cone and 30-Hz electroretinograms in 5 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Implicit times were shorter in albinism. CONCLUSION: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were normal with mostly increased electroretinograms, while reduced electroretinograms did not show a specific pattern as in early-onset retinal dystrophies.

Double Hyperautofluorescent Rings in Patients with USH2A-Retinopathy.

USH2A mutation is the most common cause of retinitis pigmentosa, with or without hearing impairment. Patients most commonly exhibit hyperautofluorescent ring on fundus autofluorescence imaging (FAF) and rod-cone dystrophy on electrophysiology. A detailed study of three USH2A patients with a rare pattern of double hyperautofluorescent rings was performed. Twenty-four patients with typical single hyperautofluorescent rings were used for comparison of the ages of onset, visual fields, optical coherence tomography, electrophysiology, and audiograms. Double rings delineated the area of pericentral retinal degeneration in all cases. Two patients exhibited rod-cone dystrophy, whereas the third had a cone-rod dystrophy type of dysfunction on electrophysiology. There was minimal progression on follow-up in all three. Patients with double rings had significantly better visual acuity, cone function, and auditory performance than the single ring group. Double rings were associated with combinations of null and missense mutations, none of the latter found in the single ring patients. According to these findings, the double hyperautofluorescent rings indicate a mild subtype of USH2A disease, characterized by pericentral retinal degeneration, mild to moderate hearing loss, and either a rod-cone or cone-rod pattern on electrophysiology, the latter expanding the known clinical spectrum of USH2A-retinopathy.

Quantifying the ON and OFF Contributions to the Flash ERG with the Discrete Wavelet Transform.

PURPOSE: Discrete wavelet transform (DWT) analyses suggest that the 20- and 40-Hz components of the short-flash photopic electroretinogram (ERG) are closely related to the ON and OFF pathways, respectively. With the DWT, we examined how the ERG ON and OFF components are modulated by the stimulus intensity and/or duration. METHODS: Discrete wavelet transform descriptors (20, 40 Hz and 40:20-Hz ratio) were extracted from ERGs evoked to 25 combinations of flash durations (150-5 ms) and strengths (0.8-2.8 log cd.m-2). RESULTS: In ERGs evoked to the 150-ms stimulus (to separate the ON and OFF ERGs), the 40:20-Hz ratio of ON ERGs (mean ± SD: 0.49 ± 0.04) was significantly smaller (P < 0.05) than that of OFF ERGs (1.71 ± 0.18) owing to a significantly (P < 0.05) higher contribution of the 20 and 40 Hz components to the ON and OFF ERGs, respectively. With brighter stimuli, the ON and OFF components increased similarly (P < 0.05). While progressively shorter flashes had no impact (P > 0.05) on the ON component, it exponentially enhanced (P < 0.05) the OFF component. CONCLUSIONS: Discrete wavelet transform allows for an accurate determination of ON and OFF retinal pathways even in ERGs evoked to a short flash. To our knowledge, the significant OFF facilitatory effect evidenced with shorter stimuli has not previously been reported. TRANSLATIONAL RELEVANCE: The DWT approach should offer a rapid, easy, and reproducible approach to retrospectively and prospectively evaluate the function of the retinal ON and OFF pathways using the standard (short-flash duration) clinical ERG stimulus.

Clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy.

BACKGROUND: To report clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy (LHON). METHODS: Eight patients with LHON (11-26 years; one female and seven males) were examined in acute stages and at follow-up visits by means of Snellen visual acuity, Ishihara color vision, Goldmann or Octopus G2TOP perimetry, fluorescein angiography (FAG), pattern electroretinogram (PERG), visual evoked potentials (VEP) and genetic testing. RESULTS: Patients presented with typical LHON phenotype with bilateral visual acuity loss, abnormal color vision, central scotoma and hyperemic discs with no leakage on FAG. In the acute stage, electrophysiology was performed in 7/8 patients. The PERG P50 component was normal in 14/14 eyes, while the N95 component was reduced in 7/14 eyes. VEP wave P100 was reduced and delayed in 14/14 eyes. In this stage, temporal pallor of the optic disc was visible in 4/7 eyes with reduced PERG N95. At follow-up (1-11 months after), a reduced PERG N95 component was seen in 13/14 eyes and severely affected VEP in all eyes. In the only eye with a normal PERG N95, hyperemic optic disc was seen 5 months after visual acuity loss, while it was atrophic in all the others. Known mutations (14484T>C, 3460G>A) were found in 2/8 patients, while in others high-throughput sequencing identified new potentially pathogenic mutations. CONCLUSIONS: In Leber hereditary optic neuropathy, a reduced N95 component of PERG and severely reduced VEP P100 may be present already in the acute stage of disease, before optic disc pallor appears, suggesting primary dysfunction of retinal ganglion cells.

Electroretinographic characteristics in children with infantile nystagmus syndrome and early-onset retinal dystrophies.

PURPOSE: To differentiate early-onset retinal dystrophies on the basis of electroretinogram (ERG) characteristics in children with infantile nystagmus syndrome (INS). METHODS: Thirty-seven children with INS and early-onset retinal dystrophies were included, with diagnosis according to clinical and ERG findings. Three ERG protocols were used according to the child's age and 17 children were followed with 2 protocols: 27 (mean 2.1 years) were recorded with skin electrodes to flash stimulation, 16 (mean 6.5 years) with skin electrodes to full-field stimulation, and 11 (mean 12.2 years) with HK electrodes to full-field stimulation. The ERGs were compared to those of age-matched controls, with differences significant if p<0.05. RESULTS: Clinical and electrophysiologic findings were in agreement across all of the children. In nine children with Leber congenital amaurosis, the scotopic and photopic ERGs were not recordable under all protocols. Six children with congenital stationary night blindness (CSNB) had electronegative scotopic ERG under all protocols, those with complete CSNB had absent rod ERG, and those with incomplete CSNB had reduced rod ERG. Eight children with achromatopsia had nonrecordable photopic and subnormal scotopic ERG under all protocols. The implicit times of the scotopic b-waves were prolonged. One child had blue-cone monochromatism and reduced photopic and normal S-cone ERG. Six children with cone-rod dystrophy without systemic disorder, and seven children with systemic disorder, had affected photopic and scotopic ERGs under all protocols. CONCLUSIONS: In children with INS, some early-onset retinal dystrophies can be differentiated through ERGs, also with skin electrodes.

Morphological and electrophysiological outcome in prospective intravitreal bevacizumab treatment of macular edema secondary to central retinal vein occlusion.

PURPOSE: To evaluate intravitreal bevacizumab (IVB) treatment in patients with central retinal vein occlusion (CRVO) by spectral domain optical coherence tomography (OCT) and electroretinography (ERG). METHODS: Twenty-two CRVO patients were treated with IVB injections and followed for 1 year. Morphological effect of treatment was observed with fluorescent angiography and OCT. Functional effect was followed with best corrected visual acuity (BCVA) and ERG: combined rod-cone response of the standard full-field ERG (dark adapted 3.0 ERG), photopic negative response (PhNR), and pattern ERG (PERG). RESULTS: Best corrected visual acuity (BCVA) improved by 18.2 letters after 6 months (p ≤ 0.001) and additional 4.7 letters by the 12th month (p ≤ 0.001). The central retinal thickness of 829.8 ± 256.7 µm decreased to 398.8 ± 230 µm (p ≤ 0.001) after 6 months and to 303.7 ± 128.9 µm during the following 6 months (p ≤ 0.001). The total macular volume (14.4 ± 4.2 mm(3)) decreased to 9.6 ± 3.2 mm(3) and 8.5 ± 2.0 mm(3) after 6 months and 1 year of treatment, respectively (p ≤ 0.001). Electrophysiological measures improved significantly after 6 months and 1 year of treatment: the a-wave implicit time of dark adapted 3.0 ERG from 25.6 ± 2.3 to 24.1 ± 2.1 and 24.1 ± 2.0 ms (p ≤ 0.01); the PhNR from -5.9 ± 6.6 to -9.4 ± 6.1 and -10.4 ± 4.6 µV (p ≤ 0.05); the PERG P50 amplitude from 0.2 ± 0.3 to 0.9 ± 0.6 and 1.1 ± 0.6 µV (p ≤ 0.001); and N95 amplitude from 0.4 ± 0.6 to 1.2 ± 0.9 and 1.6 ± 0.9 µV (p ≤ 0.001). CONCLUSIONS: Intravitreal bevacizumab (IVB) treatment of macular edema due to CRVO improved standard morphological measures and the electrophysiological function of outer and inner retinal layers, which was most evident in central retina.

Visual electrophysiology in the clinical evaluation of optic neuritis, chiasmal tumours, achiasmia, and ocular albinism: an overview.

BACKGROUND AND METHODS: In routine clinical evaluation of optic neuritis and chiasmal tumours, pattern electroretinography and visual evoked potentials (VEPs) to pattern-reversal stimulation are useful examinations. Similarly, in achiasmia and ocular albinism, VEPs to flash and pattern-onset stimulation provide relevant information. RESULTS: The role of visual electrophysiology in these diseases is to assess potential dysfunction of the visual pathway: (a) at the acute stage of optic neuritis, to determine the magnitude of conduction block of the optic nerve fibres; (b) at the clinical recovery stage of optic neuritis, to determine optic nerve conduction delay due to demyelination, and to follow possible remyelination; (c) at the recovery of optic neuritis when visual acuity does not normalise, to define loss of optic nerve fibres and retrograde degeneration of retinal ganglion cells; (d) in tumours at the chiasm, to detect abnormal conduction along the crossed and/or uncrossed fibres; and (e) in achiasmia or albinism, which are both congenital disorders associated with nystagmus, to detect achiasmia and absence of or reduced optic nerve fibre decussation at the chiasm, or to detect ocular albinism and excess of optic nerve fibre decussation at the chiasm. In optic neuritis, two recent examinations have been used to detect retrograde axonal degeneration: photopic negative response of the electroretinogram, to assess dysfunction of ganglion cell axons; and optic coherence tomography, to measure thinning of the retinal nerve fibre layer. In optic neuritis, multifocal VEPs provide a promising clinical examination, because this can show areas that are associated with normal or abnormal optic nerve fibre function. CONCLUSIONS: Visual electrophysiology defines function of the visual pathway and is relevant: (1) in optic neuritis, when visual acuity does not recover well; (2) in tumours of the chiasm with normal visual fields, as in paediatric patients who cannot adequately perform perimetry; and (3) in children with congenital nystagmus and suspected achiasmia or ocular albinism.

Chromatic visual evoked potentials in young patients with demyelinating disease.

The purpose of this study was to evaluate color vision in young patients with demyelinating disease both clinically and electrophysiologically. Thirty young patients (8-28 years, mean age 19 years) with demyelinating disease with or without a history of optic neuritis (ON) were investigated. Color vision was evaluated clinically with the Ishihara test and the Farnsworth-Munsell 100 hue (FM 100 hue) test and electrophysiologically with chromatic visual evoked potentials (cVEPs). Color deficiency axis and error score (ES) obtained with the FM 100 hue test were analyzed. cVEPs to isoluminant red-green (R-G) and blue-yellow (B-Y) stimuli were recorded. The stimulus was a 7 deg circle composed of horizontal sinusoidal gratings with a spatial frequency of 2 cycles/deg and 90% chromatic contrast. Onset-offset mode of stimulation (ON:OFF=300∶700 ms) was used. Since the majority of the patients were adults (>18 years), the negative wave (N wave) of the cVEP respones is the prominent part and therefore was analyzed. Sixty eyes were studied-22 with at least one episode of ON (ON group) and 38 without any clinically evident episode of ON (nON group). The average ES in the ON group was 179.18±171.8, whereas in the nON group it was 87.60±65.34. The average N-wave latency in the ON group was 144±44 ms for the R-G stimulus and 146±56 ms for the B-Y stimulus, whereas in the nON group, it was 117±13 ms for the R-G stimulus and 121±22 ms for the B-Y one. The average N-wave amplitude in the ON group was 9.3±7.1 µV for the R-G stimulus and 5.1±3.9 µV for the B-Y one, whereas in the nON group, it was 10.8±8.3 µV for the R-G stimulus and 6.4±4.3 µV for the B-Y one. A significant difference between the ON and the nON group was found: in the ON group, ES was higher (p=0.01) and N-wave latency was longer (p=0.01) compared with those in the nON group. The study showed that color vision is expectedly more affected in the ON group, but also often in the nON group, which may indicate increased parvocellular visual pathway vulnerability in demyelinating diseases.

Chromatic visual evoked potentials in paediatric population.

BACKGROUND: The purpose of this study was to investigate chromatic visual evoked potential (cVEP) response characteristics during the first year of life and to collect as large database of healthy baby responses as possible. This study also complements our previous studies on cVEP in schoolchildren and preschool children. METHODS: Forty-four healthy babies aged 3-12 months were binocularly tested. cVEP were recorded to isoluminant red-green (R-G) and blue-yellow (B-Y) stimuli. The stimulus represented a circle composed of horizontal sinusoidal gratings with 90 % chromatic contrast and spatial frequency of 2 cycles/deg. Two stimulus sizes (7° and 21°) and onset-offset mode of stimulation (On-300 ms, Off-700 ms) were used. cVEP were recorded from Oz (mid-occipital) position with the reference at Fz. Waveform characteristics and its changes throughout the first year of life were studied. RESULTS: Chromatic visual evoked potential responses were reliably recorded in all but two youngest babies. Characteristic cVEP response consisted of negative-positive-negative complex, positive (P) wave being far more prominent than both negative waves (N1 and N2). cVEP response to larger stimulus size (21°) showed shorter latency and higher amplitude to both (R-G) and (B-Y) stimuli compared to smaller stimulus size (7°). The same was true when comparing R-G versus B-Y stimulus: R-G responses showed higher amplitude and shorter latency than B-Y response, for both stimulus sizes. P wave latency shortened with increasing age throughout the first year of life, both for R-G (R (2) = 0.59) and B-Y (R (2) = 0.41) 21° stimulation. P wave amplitude did not show significant changes throughout the first year of life. CONCLUSIONS: Chromatic visual evoked potential can be reliably recorded after the age of 3 months and show significant maturational changes throughout the first year of life.

Enhanced S-cone syndrome with preserved macular structure and severely depressed retinal function.

We present ophthalmic features and genetic analysis findings of a 44-year-old croatian patient with enhanced S-cone syndrome (ESCS). Complete ophthalmic examination, Ishihara colour vision test, dark adaptometry, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, Goldmann visual field and automated perimetry, full-field electroretinography (ERG), multifocal ERG, S-cone ERG and ON-OFF ERG were performed. Mutation screening of the NR2E3 gene, which encodes a photoreceptor-specific orphan nuclear receptor, was performed with polymerase chain reaction amplification and direct sequencing. The patient has good visual acuity and normal colour vision. Fundus examination showed normal posterior pole and nummular pigment depositions at the level of the retinal pigment epithelium in the mid-periphery of the retina. The SD-OCT images showed normal macular structure and thickness. The ERG showed characteristic findings: photopic and scotopic responses to the same stimulus had a similar waveform and were dominated by short-wavelength-sensitive mechanisms. Mutation analysis revealed the known NR2E3 mutation c.481delA (p.Thr161HisFsX18) and the novel NR2E3 variant c.1120C > T (p.Leu374Phe). To the best of our knowledge, this is the only ESCS patient older than 40 years who phenotypically has preserved macular structure, good central visual acuity and severely depressed full-field ERG as well as the first reported patient with NR2E3 mutation from Croatia.

VEP characteristics in children with achiasmia, in comparison to albino and healthy children.

Achiasmia is a rare disorder of visual pathway maldevelopment that can show diverse clinical and magnetic resonance imaging spectra. The aim of this study was to define the characteristics of visual evoked potentials (VEPs) that differentiate abnormal optic-nerve-fibre decussation in children with achiasmia versus children with albinism and healthy children. In four children with achiasmia, the following VEP characteristics were studied and compared to children with ocular albinism and with healthy control children: (a) flash and pattern onset VEP interhemispheric asymmetry; (b) flash N2, P2 and onset C1 amplitudes and latencies; (c) interocular polarity differences in interhemisphere potentials; and (d) chiasm coefficients (CCs). In the children with achiasmia, VEPs were related to an absence of or reduced optic-nerve-fibre decussation at the chiasm and showed: ipsilateral asymmetry, significantly higher VEP amplitudes over the ipsilateral hemisphere (p < 0.05), interocular inverse polarity and negative CC. Other VEP features (uncrossed asymmetry and positive CC) were also seen if additional visual pathway maldevelopment (such as severe optic nerve hypoplasia and/or absence of the optic tractus on one side) were associated with achiasmia. In the children with albinism, the VEPs were related to excess optic-nerve-fibre decussation at the chiasm and showed: contralateral asymmetry, significantly higher VEP amplitudes over the contralateral hemisphere (p < 0.001), interocular inverse polarity and negative CC. In achiasmia and albinism, the VEPs to flash stimulation were more robust and more clearly distinguished between the conditions compared with the VEPs to pattern onset stimulation. VEPs in achiasmia are associated with absent or reduced optic-nerve-fibre decussation, where ipsilateral interhemispheric asymmetry is associated with interocular inverse polarity and a negative CC.

Chromatic visual evoked potential responses in preschool children.

The purpose of the study was to analyze chromatic visual evoked potential (VEP) responses to isoluminant red-green (R-G) and blue-yellow (B-Y) stimuli in 30 preschool children (1.5-6 years). The predominant part of the response consisted of a positive (P) wave, which showed age-related latency changes (linear decrease). P wave latency was shorter when using 21° compared to 7° R-G (p=0.004) and B-Y (p=0.044) stimulus and also when using 21° R-G compared to 21° B-Y stimulus (P=0.000). P wave amplitude did not show age-related changes. However, a lower amplitude was recorded when using 7° R-G stimulus (p=0.0013) and also when using B-Y compared to R-G stimulus. We may conclude that chromatic VEP to R-G and B-Y stimuli is reliably recorded in preschool children and that P wave to R-G stimulation shows a higher amplitude and shorter latency than to B-Y stimulus.

Electroretinographic evaluation of the retinal S-cone system.

The aim of this study was to differentiate S-cone responses from other retinal activities using various recording conditions and to optimize these recording conditions for clinical diagnostics. S-cone responses to blue stimuli (449 nm) were studied in 20 healthy subjects and four patients with enhanced S-cone syndrome. The time-integrated luminance of the stimulus varied from 0.008 to 1.0 cd s/m2. Three isoluminant backgrounds were used (100 ph cd/m2=40 sc cd/m2): amber (594 nm), green (513 nm), and red (635 nm). With low flash strengths (from 0.008 to 0.032 cd s/m2), the S-cone response appeared as a single positive peak, while with higher strengths (≥0.064 cd s/m2), it appeared as a second peak that followed the L-cone and M-cone components. With a further increase in flash strength (≥0.25 cd s/m2), the S-cone response interfered with the i-wave of the L-cone and M-cone systems. The wavelength and luminance of the background influenced the suppression of the rods, as well as the L-cone- and M-cone-system activities. The S-cone response was measurable in the presence of the amber and green backgrounds, but its amplitude was higher if a strong red background was used. Thus, the function of the retinal S-cone system can be measured if possible interference from other retinal sources can be minimized by the appropriate combination of stimulus and background parameters.

Chromatic VEP in children with congenital colour vision deficiency.

Visual evoked potentials to chromatic stimulus (cVEP) are believed to selectively test the parvocellular visual pathway which is responsible for processing information about colour. The aim was to evaluate cVEP in children with red-green congenital colour vision deficiency. VEP responses of 15 colour deficient children were compared to 31 children with normal colour vision. An isoluminant red-green stimulus composed of horizontal gratings was presented in an onset-offset manner. The shape of the waveform was studied, as well as the latency and amplitude of positive (P) and negative (N) waves. cVEP response did not change much with increased age in colour deficient children, whereas normative data showed changes from a predominantly positive to a negative response with increased age. A P wave was present in 87% of colour deficient children (and in 100% of children with normal colour vision), whereas the N wave was absent in a great majority of colour deficient children and was present in 80% of children with normal colour vision. Therefore, the amplitude of the whole response (N-P) decreased linearly with age in colour deficient children, whereas in children with normal colour vision it increased linearly. P wave latency shortened with increased age in both groups. cVEP responses differ in children with congenital colour vision deficiency compared to children with normal colour vision.

The effect of broadband and monochromatic stimuli on the photopic negative response of the electroretinogram in normal subjects and in open-angle glaucoma patients.

The aim was to investigate the effects of monochromatic and broadband stimuli on the amplitude of the photopic negative response (PhNR) and to compare the sensitivities of these stimuli for the detection of ganglion cell damage in glaucoma patients. Forty-one healthy subjects were studied, along with 16 patients with open-angle glaucoma. Photopic electroretinograms (ERGs) were elicited with monochromatic red, amber, green, and broadband white stimuli of progressively brighter intensities in a blue background. Pattern ERGs were also recorded using a 0.8 degrees checkerboard pattern on a 21.6 degrees x 27.8 degrees screen. In the photopic ERGs of the control subjects, the PhNR amplitude was significantly higher (P < 0.01) to red than to monochromatic amber, green, and broadband white stimuli of the same intensity. In glaucoma patients, the percentage of amplitude reduction was greater for the PhNR to red (68%, P < 0.001) than to the broadband stimulus (38%, P = 0.001). The PhNR to red monochromatic stimulus appeared to be a more sensitive parameter, with a larger area enclosed by the receiver-operating characteristic curve (0.97) than for the PhNR to broadband stimulus (0.76). Also, the PhNR to red stimulus showed a more significant correlation with the pattern ERG and the visual field defects (P < 0.05) than the PhNR elicited with broadband stimulus. These findings suggest that ganglion cell activity can be more efficiently evaluated with the PhNR elicited with a red than with a broadband stimulus. The PhNR thus appears to be a promising test for the diagnostics of the ganglion cell dysfunction.