Clinical Manifestations and Genetic Analysis of 5 Korean Choroideremia Patients Initially Diagnosed With Retinitis Pigmentosa.

BACKGROUND: To investigate the clinical findings of choroideremia patients and perform genetic analysis by whole-exome sequencing (WES). METHODS: A total of 94 patients initially diagnosed with retinitis pigmentosa (RP) at another hospital, and who visited our hospital for genetic analysis by WES, were included in the study, along with 64 family members. All subjects underwent comprehensive ophthalmic evaluation, including best-corrected visual acuity, slit lamp examination, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FAG), visual field (VF), electroretinogram (ERG), and optical coherence tomography (OCT). RESULTS: In six male patients with suspected choroideremia, extensive retinal pigment epithelium (RPE) and severe loss of choroid were observed in the fundus, but not in the macula. CHM gene mutation was confirmed in five patients. A novel single nucleotide variant at a splice site was observed in one patient. OCT showed marked thinning of the outernuclear layer and choroid, except in the macula. FAF showed a small area of hyperfluorescence in the posterior pole. In addition, characteristic interlaminar bridges were observed in four patients. On FAG, hypofluorescence was seen up to the far-peripheral retina in five patients. CONCLUSION: Of the 94 patients initially diagnosed with RP, CHM mutation was identified in five (5.3%) by WES. Choroideremia should be considered as a differential diagnosis of RP. WES would be useful for identifying the causes of hereditary retinal disease.

USING RETeval SYSTEM FLICKER ELECTRORETINOGRAPHY FOR EVALUATION OF DENSE VITREOUS HEMORRHAGE.

PURPOSE: To determine whether the RETeval electroretinography (ERG) system can be used to evaluate eyes with dense vitreous hemorrhage (VH). METHODS: This retrospective case series study included 69 eyes of 69 patients with acute dense VH. Flicker ERGs were recorded by the RETeval system, an ERG device with adhesive skin electrodes. We evaluated the flicker ERG amplitudes in eyes with VH and the ratio of the VH eye amplitudes compared with the fellow eye amplitudes for each VH cause. RESULTS: In patients with rhegmatogenous retinal detachment, the amplitude ratios were extremely low (0.08 ± 0.03). To detect rhegmatogenous retinal detachment, the area under the receiver operating characteristic curve was 0.977 (95% confidence interval, 0.943-1.000) (best rhegmatogenous retinal detachment cutoff value, 0.14; sensitivity, 100.0%; and specificity, 95.4%). The flicker ERG amplitude was not significantly correlated with the initial visual acuity (ρ = -0.189, P = 0.120) but was positively correlated with the postoperative visual acuity in eyes with VH (ρ = -0.328, P = 0.006). CONCLUSION: The RETeval ERG system was found to be a useful diagnostic option in situations where dense VH precluded fundus examination or posterior vitreous detachment was indistinguishable from rhegmatogenous retinal detachment.

Current screening practice in patients under long-term hydroxychloroquine medication in Taiwan: A nationwide population-based cohort study.

Hydroxychloroquine (HCQ), an analog of chloroquine, is widely used in various rheumatologic and dermatologic disorders. However, it may cause severe retinopathy with long-term use. The guidelines proposed by the American Academy of Ophthalmology suggested a baseline fundus examination and an annual screening after 5 years by using automated visual fields (VF) plus spectral-domain optical coherence tomography (SD-OCT). Both multifocal electroretinogram (mfERG) and fundus autofluorescence (FAF) can also be used to improve the accuracy of diagnosis. The purpose of this study was to examine if the current HCQ screening practice in Taiwan was sufficient according to the guidelines to prevent severe macular complications.This study could remind every doctor to explain visual side effects thoroughly to every patient using HCQ, and refer patients for the ophthalmologic survey to eliminate potential visual impairment caused by this medicine.This nationwide population-based cohort study included all patients who started taking HCQ (n = 5826) from January 1, 1997, to December 31, 2007, in the Longitudinal Health Insurance Database 2000. The ICD codes used for HCQ retinopathy were 362.10, 362.55, 362.89, and 362.9. Patients previously diagnosed these retinal disorders were excluded. Demographic data including sex, age, diagnostic tools used, and the date of the initial diagnosis of the subsequent HCQ-related retinal disorder were collected. Patients were divided into 2 groups. The patients taking HCQ <5 years were defined as group 1, and >5 years as group 2. The risk of developing retinal diseases between these 2 groups was compared with a 2-sample t-test for continuous variables, and Fisher's exact test for discrete variables. Multiple logistic regressions were used for odds ratio calculation.The baseline examination ratio of the automated VF, SD-OCT scans, and multifocal electroretinograms (mfERGs) in the first 3 months were only 0.2% in both groups. The screening ratio of the 3 examination tools after 5 years were 1.1% in group 1 and 1.2% in group 2. 2.5% and 3.9% of patients developed a retinal disorder after HCQ use in group 1 and 2, respectively. The risk of developing retinal disorder was significantly higher in group 2 (relative risk = 1.53, P = .006). The odds ratio (OR) was also significantly higher in group 2 (1.67 with 95% cumulative incidence 1.20-2.30)The examination ratio according to the guidelines was very low in Taiwan. Thus, it is very important for doctors who prescribe HCQ to schedule both baseline and annual ophthalmology screening tests and inform patients of possible severe ocular complications, even in the patient taking HCQ <5 years. It is also important for ophthalmologists to review medical history carefully to find out the causes of retinotoxicity. Medications should be stopped, if possible when toxicity is recognized or strongly suspected.

Association Between Diabetic Macular Edema and Cardiovascular Events in Type 2 Diabetes Patients: A Multicenter Observational Study.

Diabetic macular edema (DME) is the main cause of visual loss associated with diabetes but any association between DME and cardiovascular events is unclear.This study aims to describe the possible association between DME and cardiovascular events in a multicenter cross-sectional study of patients with type 2 diabetes.Two thousand eight hundred seven patients with type 2 diabetes were recruited from diabetes and nephrology clinical institutional centers participating in the DIAB 2 NEPHROGENE study focusing on diabetic complications. DME (presence/absence) and diabetic retinopathy (DR) classification were based on ophthalmological report and/or on 30° color retinal photographs. DR was defined as absent, nonproliferative (background, moderate, or severe) or proliferative. Cardiovascular events were stroke, myocardial infarction, and lower limb amputation.Details regarding associations between DME and cardiovascular events were evaluated.The study included 2807 patients with type 2 diabetes, of whom 355 (12.6%) had DME. DME was significantly and independently associated with patient age, known duration of diabetes, HbA1c, systolic blood pressure, and DR stage. Only the prior history of lower limb amputation was strongly associated with DME in univariate and multivariate analyses, whereas no association was found with regard to myocardial infarction or stroke. Moreover, both major (n = 32) and minor lower limb (n = 96) amputations were similarly associated with DME, with respective odds ratio of 3.7 (95% confidence interval [CI], 1.77-7.74; P = 0.0012) and of 4.29 (95% CI, 2.79-6.61; P < 0.001).DME is strongly and independently associated with lower limb amputation in type 2 diabetic patients.

Use of the electroretinogram in a paediatric hospital.

BACKGROUND: To review the use of electroretinography and identify common reasons for referral and diagnoses at a tertiary paediatric hospital. DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred and eighteen patients (male 195, female 123) aged <18 years with 388 electroretinograms were included. METHODS: All electroretinograms performed at the Royal Children's Hospital, Brisbane from 1998 to 2005 were reviewed. Normative data and electroretinograms from patients aged ≥18 years were excluded. MAIN OUTCOME MEASURES: Reasons for referral and diagnoses were determined from each patient's first electroretinogram. Concordance between the first electroretinogram diagnosis and clinical referral was reviewed to determine whether the electroretinogram was normal, inconclusive, confirmed, excluded, or changed the clinical diagnosis or provided a new diagnosis. RESULTS: The median age at the time of the first investigation was 3.78 years (range 2.6 weeks to 17.5 years). The most common reasons for referral were nystagmus (n = 93), decreased vision (n = 33) and sensorineural deafness (n = 29). After one electroretinogram, 51% were normal (n = 162) and 15% were inconclusive (n = 49). The most common electroretinography diagnosis was cone rod dystrophy. The first electroretinogram for each patient confirmed the clinical suspicion in 17.6% (n = 56) and excluded it in 23% (n = 73) of cases. The electroretinogram resulted in a changed diagnosis in 0.9% (n = 3) and provided a new diagnosis in 15.1% (n = 48). Overall, the first electroretinogram was considered useful in 85% cases (n = 269). CONCLUSIONS: Electroretinography is a valuable investigation for evaluating paediatric eye disease and in this series confirmed, excluded, changed or provided a new diagnosis in 85% of cases.

Multifocal electroretinogram in mild to moderate essential hypertension.

PURPOSE: To investigate the local retinal dysfunctions in mild to moderate essential hypertensive patients by using multifocal electroretinogram (mfERG). METHODS: Thirty-one patients with stage 1 or stage 2 hypertension (HT) and 31 age- and sex-matched healthy normotensive (NT) subjects were included. Fourteen of the patients had stage 1 and 17 had stage 2 hypertension. Twenty had grade 1 and 11 had grade 2 hypertensive retinopathy. The local retinal functions from the fovea to the peripheral 30 degrees were evaluated by multifocal electroretinogram by dividing this area to central hexagonal area (CH) and four concentric rings around the central hexagon (Rings 1-4). The amplitude and the implicit times of the positive peak (P1) and the negative peak (N1) of the responses were compared between the control subjects and hypertensive patients. Only the right eyes were included. The differences between the hypertensive patients and control subjects were investigated using independent samples t test, and the differences between grade 1 and grade 2 hypertensive retinopathy and stage 1 and stage 2 hypertension were investigated using Mann-Whitney U test. RESULTS: P1 amplitudes in CH (HT: 129.0 +/- 29.5, NT: 149.1 +/- 45.5, p = 0.043) and in Ring 3 (HT: 37.0 +/- 8.0, NT: 41.7 +/- 7.8, p = 0.024) and N1 amplitude in Ring 1 (HT: 26.8 +/- 7.4, NT: 30.8 +/- 7.8, p = 0.048) in the hypertensive patients was significantly reduced when compared to healthy normotensive subjects. There was no significant difference in terms of P1 and N1 implicit times. There was also no significant difference between the patients with stage 1 or stage 2 hypertension and patients with grade 1 or grade 2 hypertensive retinopathy. CONCLUSION: Hypertensive subjects have local retinal dysfunctions with respect to healthy controls. This result probably originated from retinal ischemia due to changes in retinal and/or choroidal circulation in systemic arterial hypertension.

Training a learning vector quantization network using the pattern electroretinography signals.

In this study, the pattern electroretinography (PERG) signals derived from evoked potential across retinal cells of subjects after visual stimulation were analyzed using artificial neural network (ANN) with 172 healthy and 148 diseased subjects. ANN was employed to PERG signals to distinguish between healthy eye and diseased eye. Supervised network examined was a competitive learning vector quantization network. The designed classification structure has about 94% sensitivity, 90.32% specifity, 5.94% false negative, 9.67% false positive and correct classification is calculated to be 92%. Testing results were found to be compliant with the expected results that are derived from the physician's direct diagnosis. The end benefit would be to assist the physician to make the final decision without hesitation.

Classification of macular and optic nerve disease by principal component analysis.

In this study, pattern electroretinography (PERG) signals were obtained by electrophysiological testing devices from 70 subjects. The group consisted of optic nerve and macular diseases subjects. Characterization and interpretation of the physiological PERG signal was done by principal component analysis (PCA). While the first principal component of data matrix acquired from optic nerve patients represents 67.24% of total variance, the first principal component of the macular patients data matrix represents 76.81% of total variance. The basic differences between the two patient groups were obtained with first principal component, obviously. In addition, the graphic of second principal component vs. first principal component of optic nerve and macular subjects was analyzed. The two patient groups were separated clearly from each other without any hesitation. This research developed an auxiliary system for the interpretation of the PERG signals. The stated results show that the use of PCA of physiological waveforms is presented as a powerful method likely to be incorporated in future medical signal processing.

Timing of early activity in the visual cortex as revealed by simultaneous MEG and ERG recordings.

To clarify the latency of the earliest cortical activity in visual processing, electroretinograms (ERGs) and visual evoked magnetic fields (VEFs) following flash stimulation were recorded simultaneously in six human subjects. Flash stimuli were applied to the right eye and ERGs were recorded from a skin electrode placed on the lower lid. ERGs showed two major deflections in all subjects: an eyelid-negativity around 20 ms and a positivity around 60 ms corresponding to an a- and b-waves, respectively. The mean onset and peak latency of the earliest component of VEFs (37 M) was 30.2 and 36.9 ms, respectively. There was a linear correlation between the peak latency of the a-wave and the onset latency of the 37 M (r=0.90, P=0.011). When a single equivalent current dipole analysis was applied to the 37 M, four out of six subjects showed highly reliable results. The generator of the 37 M was estimated to be located in the striate cortex in all four subjects. Since post-receptoral activities in the retina are expected to start around the peak of the a-wave (20 ms), the early cortical activity, which appears 10 ms later than the a-wave peak, is considered to be the earliest cortical activity following flash stimulation.

Electro-oculography, electroretinography, visual evoked potentials, and multifocal electroretinography in patients with vigabatrin-attributed visual field constriction.

PURPOSE: Symptomatic visual field constriction thought to be associated with vigabatrin has been reported. The current study investigated the visual fields and visual electrophysiology of eight patients with known vigabatrin-attributed visual field loss, three of whom were reported previously. Six of the patients were no longer receiving vigabatrin. METHODS: The central and peripheral fields were examined with the Humphrey Visual Field Analyzer. Full visual electrophysiology, including flash electroretinography (ERG), pattern electroretinography, multifocal ERG using the VERIS system, electro-oculography, and flash and pattern visual evoked potentials, was undertaken. RESULTS: Seven patients showed marked visual field constriction with some sparing of the temporal visual field. The eighth exhibited concentric constriction. Most electrophysiological responses were usually just within normal limits; two patients had subnormal Arden electro-oculography indices; and one patient showed an abnormally delayed photopic b wave. However, five patients showed delayed 30-Hz flicker b waves, and seven patients showed delayed oscillatory potentials. Multifocal ERG showed abnormalities that sometimes correlated with the visual field appearance and confirmed that the deficit occurs at the retinal level. CONCLUSION: Marked visual field constriction appears to be associated with vigabatrin therapy. The field defects and some electrophysiological abnormalities persist when vigabatrin therapy is withdrawn.

[Changes in the oscillatory potentials in the electroretinogram during the evolution of diabetic retinopathy]. / Modificarea potentialelor oscilatorii pe electroretinograma din cursul evolutiei retinopatiei diabetice.

Oscillatory potentials where intensely studied in diabetic patients with various degrees of retinopathy. Classical reports pointed out the early reduction of their amplitude, as well as of their latency, while a and b waves remained still normal. A prognostic value was attached to these modifications, the reduction of oscillatory potentials being correlated with a ten time higher probability of developing a high risk retinopathy. 27 diabetic patients where investigated electroretinographically by us. No significant variation of the amplitude of oscillatory potentials was observed during the progression of diabetic retinopathy.

[The effects of photocoagulation on the electrical activity of the diabetic retina]. / Consecintele fotocoagularii asupra activitatii electrice a retinei diabetice.

The aim of photocoagulation in diabetic retinopathy is to destroy ischaemic retina because this produces a vasogenic factor, responsible of neovascularization. Retinal burn reduces the number of photoreceptors and effects the transmission of nervous impulse in areas close to those coagulated. It is presumable therefore that electroretinographic parameters will be significantly modified after treatment. 23 diabetic patients where investigated, resulting 43 scotopic electroretinograms, 41 photopic electroretinograms and 46 flicker electroretinograms, each eye being considered separately. The statistic analysis showed significant alterations with laser treatment of the amplitudes of a and b waves in both scotopic and photopic conditions as well as diminished amplitude of the flicker test.

The inverse problem in electroretinography: a study based on skin potentials and a realistic geometry model.

The problem of obtaining the retinal source distribution that generates the electroretinogram (ERG) from measured skin potentials is addressed. A realistic three-dimensional (3-D) volume conductor model of the head is constructed from magnetic resonance image (MRI) data sets. The skin potential distribution generated in this model by a dipole layer source at the retina is computed by using the boundary element method (BEM). The influence of the various compartments of the complete model on the results was investigated, and a simplified model was defined. An inverse procedure for estimating the source distribution at the retina from ERG's obtained from skin electrodes was developed. The procedure was tested on simulated potentials. A fair correspondence between the original and estimated source distribution was found. Furthermore, the ERG's measured at seven skin electrodes were used to estimate the source distribution at the retina. The ERG potential waveform at an additional skin electrode was computed from this source distribution and compared to the measured potential at this electrode. Again a fair correspondence was obtained. It is concluded that the methods may become a useful tool for clinical applications, i.e., for the assessment of localized defects in retinal function.

[Changes in the electroretinogram of Campbell rats with the development of hereditary retinal degeneration]. / Izmeneniia élektroretinogrammy krys linii Kémpbell pri razvitii nasledstvennoi degeneratsii setchatki.

We studied the dependence of amplitudes of a- and b-waves of electroretinogram on intensity of light stimulus in Campbell rats with inherited retinal degeneration. On 20-th-29-th day after birth the amplitude of these waves in Campbell rats is smaller than in Wistar rats. On 30-th-40-th day response significantly decreases, down to complete disappearance of reaction. Weak response appears only to stimulus with the maximal luminance. According to decrease of amplitude of the a- and b-waves of the ERG, Campbell rats are practically blind at 40th day of postnatal life. The analysis of the form of whole ERG curve using the Fourier transformation allowed us to establish, that in Campbell rats on 20-th day after birth the amplitude of the first and second harmonics grows with increasing of stimulus luminance. At 30-th day the amplitude of the second harmonic in Campbell rats is much smaller than in Wistar rats and does not vary with increasing of stimulus luminance.

[Clinical electro-ophthalmology at the Max Planck Institute of the Frankfurt University Ophthalmology Clinic 1970-1991]. / Klinische Elektroophthalmologie des Max-Planck-Instituts in der Universitäts-Augenklinik Frankfurt 1970-1991.

The survey shows the frequency and distribution of diseases evaluated by electroophthalmological methods. Patients with retinal diseases (51.2%) and those with diseases of the optic nerve (21.8%) were examined most frequently. In a high percentage these investigations lead to a clinically useful assessment: described as confirmation or exclusion of a clinical diagnosis, as establishing a possible differential diagnosis or clearing up formerly unknown aspects of a disease. In cases of hereditary retinal disorders only 11% remained unclear, with presumed optic neuritis only 6%. The importance of electroophthalmological investigations is there ability to assess functional deficits in the visual system especially in somehow more rare retinal and centrally located disorders, functional deficits of unknown origins or in general diseases including the visual system.

Parametric signal restoration using artificial neural networks.

The problem of parametric signal restoration given its blurred/nonlinearly distorted version contaminated by additive noise is discussed. It is postulated that feedforward artificial neural networks can be used to find a solution to this problem. The proposed estimator does not require iterative calculations that are normally performed using numerical methods for signal parameter estimation. Thus high speed is the main advantage of this approach. A two-stage neural network-based estimator architecture is considered in which the vector of measurements is projected on the signal subspace and the resulting features form the input to a feedforward neural network. The effect of noise on the estimator performance is analyzed and compared to the least-squares technique. It is shown, for low and moderate noise levels, that the two estimators are similar to each other in terms of their noise performance, provided the neural network approximates the inverse mapping from the measurement space to the parameter space with a negligible error. However, if the neural network is trained on noisy signal observations, the proposed technique is superior to the least-squares estimate (LSE) model fitting. Numerical examples are presented to support the analytical results. Problems for future research are addressed.

[The electroretinogram of the dark-adapted intact carp Carpio cyprinus L. to color substitution]. / Elektroretinogramma temnoadaptirovannogo intaktnogo karpa Carpio cyprinus L. na zamenu tsvetov.

Electroretinogram b-wave was studied in intact carp using instantaneous substitution of monochromatic stimulus for another one in the range of 404-681 nm. It was shown that the amplitude of the b-wave as a function of the wavelength was good approximated by the spectrum of a scotopic pigment (porphiropsin) with the absorbtion maximum near 530 nm. The amplitude of the b-wave recorded during alternation of different monochromatic stimuli was determined only by their intensity differences and the level of previous light adaptation.

Comparison of three methods of estimating the parameters of the Naka-Rushton equation.

The Naka-Rushton equation empirically describes the amplitude R of the dark-adapted electroretinogram b-wave, as a function of stimulus luminance L, as R/Rmax = Ln/(Ln + Kn). Estimating the three parameters Rmax, n, and K of this function from electroretinogram data is of both experimental and clinical interest. Several different approaches have been developed to accomplish this analysis, but these approaches may derive different estimates of the three parameters. To examine this possibility, we compared the results of three methods of fitting the Naka-Rushton equation to data sets obtained from 30 normal subjects. Two methods were nonlinear curve-fitting programs; the third method involved fitting a regression line to transformed data. The results indicate that solutions provided by these methods have consistent differences, which may be an important consideration when comparing results reported in studies that used different curve-fitting methods.