Documenta Ophthalmologica最新文献

Background: Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness caused by disease-causing variants in the rhodopsin kinase gene (GRK1) or the arrestin gene (SAG). Our study aims to describe the clinical features and identify the genetic defects for three Chinese patients with Oguchi disease.

Methods: We conducted detailed ophthalmologic examinations for three patients from three unrelated non-consanguineous Chinese families. Targeted next-generation sequencing (targeted NGS) and copy number variations (CNVs) analysis were applied to screen pathogenic variants. Sanger sequencing validation, quantitative real-time PCR (qPCR), and segregation analysis were further performed for confirmation. Subsequently, a combined genetic and structural biology approach was used to infer the likely functional consequences of novel variants.

Results: All three patients presented with typical clinical features of Oguchi disease, including night blindness, characteristic fundus appearance (Mizuo-Nakamura phenomenon), attenuated rod responses, and negative ERG waveforms. Their visual acuity and visual field were normal. Genetic analysis revealed two pathogenic variants in SAG and four pathogenic variants in GRK1. Patient 1 was identified to harbor compound heterozygous SAG variants c.874C > T (p.R292*) and exon2 deletion. Compound heterozygous GRK1 variants c.55C > T (p.R19*) and c.1412delC (p.P471Lfs*52) were found in patient 2. In patient 3, compound heterozygous GRK1 variants c.946C > A (p.R316S) and c.1388 T > C (p. L463P) were detected.

Conclusions: We reported the first two Chinese Oguchi patients with novel GRK1 pathogenic variants (P471Lfs*52, R316S, L463P) and one Oguchi case with SAG, indicating both GRK1 and SAG are important causative genes in Chinese Oguchi patients.

Purpose: Macular involvement in optic neuritis (ON) is well-recognised but poorly understood and may be of clinical relevance. This study explores macular structure-function correlates in acute ON.

Methods: This cross-sectional cohort study recruited ON patients within 14 days of symptom onset. Subjects underwent pattern electroretinography (PERG), pattern visual evoked potentials (PVEP) and optical coherence tomography (OCT) imaging. PERG P50 and N95 components were correlated with OCT data.

Results: Twenty-six individuals with ON were recruited, comprising eleven multiple sclerosis (MS-ON), six myelin oligodendrocyte glycoprotein associated (MOG-ON) and nine with isolated ON. These were compared with 28 healthy controls. PVEPs were undetectable in 11 (42%) of individuals with ON. When detectable, PVEP P100 was delayed (median 136 ms range 110-173 ms) and amplitude reduced (median 6 μV, range 3-14 μV) in ON compared with controls (both p < 0.001). PERG P50 component amplitudes, largely reflecting macular function, were reduced in affected eyes (median 2.3 μV; range 0.8-5.0 μV) compared with controls (3.3 μV; range 2.8-5.7 μV) and compared with fellow eyes (p < 0.001). The N95:P50 ratio was below the reference range in the affected eyes of five patients. Eight cases (32%) had subnormal P50 amplitudes (< 2.0 μV), and these patients had poorer visual acuity (p = 0.020). P50 amplitudes were positively correlated with an increase in inner nuclear layer thickness (r_s = 0.36; p = 0.009) and macular ganglion cell and inner plexiform layer (mGCIPL) thickness (r_s = 0.44, p = 0.022).

Conclusion: PERG P50 component reduction reveals dysfunction of inner macular layers in acute ON and correlates with structural alterations on OCT. These early macular pathologic processes are likely to contribute to the visual loss.

Purpose: To describe cases of unilateral cone-rod dysfunction presenting in two middle-aged females.

Methods: This case series highlights two middle-aged female patients with progressive visual decline in one eye. Fundus photography, fundus autofluorescence (FAF), spectral-domain optical coherence tomography (SD-OCT), multi-focal electroretinogram (mfERG), full-field electroretinogram(ffERG), and genetic testing were obtained.

Results: In the first patient, mfERG showed an extinguished response and ffERG demonstrated markedly reduced a-wave and b-wave amplitudes (more pronounced under photopic conditions) in the right eye. SD-OCT showed attenuation of the ellipsoid zone of the right eye. Similar findings were appreciated in the second patient. Genetic testing in the first patient identified three heterozygous variants in PRPH2, RCBTB1, and USH2A. The second patient was found to have heterozygous variants in BBS1 and ABCA4.

Conclusion: These two cases add to the literature of case reports of unilateral cone-rod and rod-cone dystrophies. However, the underlying etiology of the unilateral pattern of cone-rod dysfunction and the significance of the heterozygous mutations found in both cases remains uncertain.

Purpose: To develop and validate a flicker electroretinogram (ERG) protocol in term-born neonates as a potential tool for assessing preterm infants at risk of developing retinopathy of prematurity.

Methods: A custom flicker ERG protocol was developed for use with the hand-held RETeval® electrophysiology device. Feasibility of measuring flicker ERG through closed eyelids and without mydriasis was established in a pilot study enabling optimisation of the test protocol. Following this, healthy term-born neonates (gestational age 37-42 weeks) were recruited at the Neonatology clinic of the University Hospital Zurich. Flicker ERG recordings were performed using proprietary disposable skin electrodes during the first four days of life when the infants were sleeping. Flicker stimuli were presented at 28.3 Hz for a stimulus series at 3, 6, 12, 30, and 50 cd·s/m², with two measurements at each stimulus level. Results were analysed offline. Flicker ERG peak times and amplitudes were derived from the averaged measurements per stimulus level for each subject.

Results: 28 term-born neonates were included in the analysis. All infants tolerated the testing procedure well. Flicker ERG recording was achieved in all subjects with reproducible flicker ERG waveforms for 30 and 50 cd·s/m² stimuli. Reproducible ERGs were recorded in the majority of infants for the weaker stimuli (with detectable ERGs in 20/28, 25/28, and 27/28 at 3, 6, and 12 cd·s/m², respectively). Flicker ERG amplitudes increased with increasing stimulus strength, with peak times concurrently decreasing slightly.

Conclusion: Flicker ERG recording is feasible and reliably recorded in sleeping neonates through closed eyelids using skin electrodes and without mydriasis. Flicker ERG amplitude decreases for lower luminance flicker but remains detectable for 3 cd·s/m² flicker in the majority of healthy term-born neonates. These data provide a basis to study retinal function in premature infants using this protocol.

Background: To report the clinical features of a patient with melanoma-associated retinopathy (MAR) with anti-transient receptor potential cation channel, subfamily M, member 1 (TRPM1) autoantibodies showing concomitant Off-bipolar cell dysfunction.

Methods: We evaluated a patient with a past history of scalp melanoma presented with sudden-onset shimmering photopsia in both eyes. MAR was confirmed with complete ophthalmic examinations, electronegative electroretinogram (ERG), and the presence of anti-TRPM1 autoantibodies by Western blot analysis. S-cone ERG and photopic On-Off ERG were studied in this patient as well.

Results: The patient's best-corrected visual acuity was 6/30 in the right eye and 6/8.6 in the left eye. Fundus and OCT findings were unremarkable. Visual field test showed severe constriction in both eyes. His full-field ERG was electronegative. S-cone ERG recorded preservation of L/M-cone-mediated response and undetectable S-cone-mediated response. Photopic On-Off ERG disclosed attenuated On- and Off-response. Western blot analysis confirmed immunoreactivity of the patient's serum to a 30 kDa TRPM1 recombinant protein. Whole-body positron emission tomography scan detected lymph node metastases in the neck.

Conclusions: Anti-TRPM1 autoantibody-positive MAR varies greatly in its presentation and clinical course. We present a case of anti-TRPM1 autoantibody-positive MAR with atypical feature of Off-bipolar cell involvement. A complete electroretinographic study together with identification of the pathogenic antiretinal autoantibodies may help better understand and subclassify the disease in the future.

Purpose: To derive and validate structure-function models for estimating retinal ganglion cell (RGC) count using optical coherence tomography (OCT) and steady-state pattern electroretinography (ssPERG) parameters in glaucoma suspects (GS) and preperimetric glaucoma (PPG).

Methods: In this prospective cross-sectional study, 25 subjects (50 eyes) were recruited at the Manhattan Eye, Ear, and Throat Hospital. Subjects underwent comprehensive eye examinations, OCT, standard automated perimetry (SAP), and ssPERG testing. Eyes were divided into three groups based on the Global Glaucoma Staging System: healthy (N = 30), GS (N = 10), and PPG (N = 10) eyes. The combined structure-function index (CSFI), which estimates retinal ganglion cell count (eRGC_CSFI) from SAP and OCT parameters, was calculated in each study subject. Two prediction formulas were derived using a generalized linear mixed model (GLMM) to predict eRGC_CSFI from ssPERG parameters, age, and average retinal nerve fiber layer thickness (ARNFLT) in 30 eyes selected at random (training group). GLMM predicted values were cross-validated with the remaining 20 eyes (validation group).

Results: The ARNFLT, ssPERG parameters magnitude (Mag) and magnitudeD (MagD), and eRGC_CSFI were significantly different among study groups (ANOVA p ≤ 0.001). Pearson correlations demonstrated significant associations among ARNFLT, ssPERG parameters, and eRGC_CSFI (r² ≥ 0.31, p < 0.001). Two GLMMs predicted eRGC_CSFI from Mag (eRGC_Mag) and MagD (eRGC_MagD), respectively, with significant equations (F(3,18), F(3,19) ≥  58.37, R² = 0.90, p < 0.001). eRGC_Mag and eRGC_MagD in the validation group (R² = 0.89) correlated with eRGC_CSFI similarly to the training group. Multivariate pairwise comparisons revealed that eRGC_Mag and eRGC_MagD distinguished between healthy, GS, and PPG eyes (p ≤ 0.035), whereas independent Mag, MagD, and ARNFLT measures did not distinguish between GS and PPG eyes.

Conclusion: This pilot study offers the first combined structure-function models for estimating RGC count using ssPERG parameters. RGC counts estimated with these models were generalizable, strongly associated with CSFI estimates, and performed better than individual ssPERG and OCT measures in distinguishing healthy, GS, and PPG eyes.

Purpose: Visual evoked potentials (VEP) present an important diagnostic tool in various ophthalmologic and neurologic diseases. Quantitative response data varied among patients but are also dependent on the recording and stimulating equipment. We established VEP reference values for our setting which was recently modified by using a curved OLED display as visual stimulator. Distinction is made between fullfield (FF) and extrafoveal (EF) conduction, and the effect of sex, age and lens status was determined.

Methods: This prospective cross-sectional study included 162 healthy eyes of 162 test persons older than 10 years. A fullfield pattern-reversal visual evoked potential (FF-PR-VEP) with two stimulus sizes (ss) (20.4' and 1.4°) as well as an extrafoveal pattern onset-offset VEP (EF-P-ON/OFF-VEP) (ss 1.4° and 2.8°) was derived in accordance with the International Society for Clinical Electrophysiology of Vision guidelines. Amplitudes and latencies were recorded, and the mean values as well as standard deviations were calculated. Age- and sex-dependent influences and the difference between phakic and pseudophakic eyes were examined. A subanalysis of EF-P-ON/OFF-VEP and fullfield pattern onset-offset VEP (FF-P-ON/OFF-VEP) was performed. A 55-inch curved OLED display (LG55EC930V, LG Electronics Inc., Seoul, South Korea) was used as visual stimulator.

Results: Mean P100 latency of the FF-PR-VEP was 103.81 ± 7.77 ms (ss 20.4') and 102.58 ± 7.26 ms (ss 1.4°), and mean C2 latency of the EF-P-ON/OFF-VEP was 102.95 ± 11.84 ms (ss 1.4°) and 113.58 ± 9.87 ms (ss 2.8°). For all stimulation settings (FF-PR-VEP, EF-P-ON/OFF-VEP), a significant effect of age with longer latencies and smaller amplitudes in older subjects and higher amplitudes in women was observed. We saw no significant difference in latency or amplitude between phakic and pseudophakic eyes and between EF-P-ON/OFF-VEP and FF-P-ON/OFF-VEP.

Conclusions: A curved OLED visual stimulator is well suited to obtain VEP response curves with a reasonable interindividual variability. We found significant effects of age and gender in our responses but no effect of the lens status. EF-P-ON/OFF-VEP tends to show smaller amplitudes.

Purpose: To investigate ocular safety of intravitreal metoprolol in eyes with central serous chorioretinopathy.

Methods: Five eyes of five patients diagnosed with chronic central serous chorioretinopathy (cCSC) previously treated unsuccessfully with oral spironolactone, micropulse laser and intravitreal anti-vascular endothelial growth factor agents were enrolled and received off-label intravitreal metoprolol (50 µg/0.05 ml). Baseline and follow-up examinations included measurement of best-corrected visual acuity (BCVA), intraocular pressure, anterior chamber cellular/flare scores, vitritis classification, fluorescein and indocyanine green angiography, spectral domain optical coherence tomography and electroretinography (ERG), recorded by means of DTL electrodes and following the standard suggested by the International Society for Clinical Electrophysiology of Vision (ISCEV). The total follow-up period was 4 weeks.

Results: There were no significant differences between baseline and follow-up ERG parameters: scotopic or photopic, a- and b-wave amplitude and implicit time, nor oscillatory potentials amplitude, or whatsoever. No intraocular inflammation sign was observed. In addition, BCVA showed small improvement in 4 or kept baseline values in 1 patient. The subretinal and/or intraretinal fluid volume reduced in all patients at 1 month after treatment.

Conclusion: Patients with refractory cCSC treated with intravitreal 50 µg/0.05 ml metoprolol showed no signs of acute ocular toxicity, along with intraretinal fluid reduction and slight BCVA improvement 1 month after injection. This data suggest that intravitreal metoprolol may be a safe alternative for cCSC.

Introduction: Neurotoxicity, including optic nerve injury, is one of the most common adverse effects of tacrolimus, the principal calcineurin inhibitor used after kidney transplantation (KTx). The electrophysiologic measurements of both pattern visual evoked potentials (PVEP) and flash visual evoked potentials (FVEP) are valuable when drug-induced optic neuropathy is suspected.

Objectives: To determine whether VEP measurement is a sensitive and repeatable method for monitoring tacrolimus neurotoxicity.

Material and methods: This prospective study focused on 35 patients (20 M, 15F, 69 eyes, mean age 43 ± 11 years) who were at a median of 3.0 (IQR, 2.2-3.7) months after KTx at the time of the initial VEP evaluation and were treated with tacrolimus since KTx. The follow-up VEP examination was done after a median of 24 (22-27) months (both VEP measurements followed the ISCEV standards). The P100 wave latency and amplitude for the 1° and 15' PVEP simulations, and the P2 wave latency and amplitude for the FVEP were analyzed.

Results: For the 1° checks, the P100 wave latency and amplitude values were significantly worse in the follow-up examination compared to the early post-transplant time-point. Independent associations between FVEP parameters and the tacrolimus blood trough level were observed in the follow-up examination but not at the early post-transplant period. The P2 wave latency correlated with the tacrolimus trough level only in patients treated with the twice-daily, but not the once-daily, tacrolimus formulation. The brain derived neurotrophic factor (BDNF) level correlated with the P100 (15') latency (R = 0.499; p = 0.005) and the P2 latency (R = 0.409; p = 0.025) only in patients treated with the once-daily, but not the twice-daily, tacrolimus formulation.

Conclusion: The observations in this study may support the rationale for the use of VEP measurements as non-invasive monitoring of subclinical tacrolimus neurotoxicity.