Abnormal Electroretinogram Research Articles

Bilateral multifocal retinal pigment epithelial detachments associated with abnormal multifocal electroretinograms

Bilateral multifocal retinal pigment epithelial detachments associated with abnormal multifocal electroretinograms

Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts

Neonatal epileptic encephalopathies with suppression bursts (SBs) are very severe and relatively rare diseases characterized by neonatal onset of seizures, interictal electroencephalogram (EEG) with SB pattern and very poor neurological outcome or death. Their etiology remains elusive but they are occasionally caused by metabolic diseases or malformations. Studying an Arab Muslim Israeli consanguineous family, with four affected children presenting a severe neonatal epileptic encephalopathy, we have previously identified a mutation in the SLC25A22 gene encoding a mitochondrial glutamate transporter. In this report, we describe a novel SLC25A22 mutation in an unrelated patient born from first cousin Algerian parents and presenting severe epileptic encephalopathy characterized by an EEG with SB, hypotonia, microcephaly and abnormal electroretinogram. We showed that this patient carried a homozygous p.G236W SLC25A22 mutation which alters a highly conserved amino acid and completely abolishes the glutamate carrier's activity in vitro. Comparison of the clinical features of patients from both families suggests that SLC25A22 mutations are responsible for a novel clinically recognizable epileptic encephalopathy with SB.

Visual neurophysiological dysfunction in infants exposed to hydroxychloroquine in utero

Hydroxychloroquine therapy during pregnancy is thought to be safe for foetuses. Normal visual function has been showed on clinical grounds in infants exposed in utero to hydroxychloroquine, but there are few visual neurophysiological data. Our study was designed to assess retina and visual pathways using electroretinogram and visual evoked potentials in a series of infants born to mothers treated by hydroxychloroquine for connective tissue diseases. Twenty-one infants (3-7 months of age) were consecutively examined between June 2002 and May 2007. Full-field electroretinogram was recorded by contact lens electrodes and visual evoked potentials were recorded by occipital surface electrodes using flash stimulation in mesopic condition. Analysis was focused on the amplitudes and latencies of the a- and b-waves of electroretinogram and the latency of the P(100) component of visual evoked potentials. Electroretinogram abnormalities were detected in six infants, associated with delayed visual evoked potentials in four of them. Early electroretinogram and visual evoked potentials testing evidenced neurophysiological visual disturbances in a subset of infants born to mothers treated by hydroxychloroquine. Systematic clinical and neurophysiological vision testing during childhood is needed to detect possible consequences of antenatal exposure to hydroxychloroquine.

G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy

The aim of this study was to characterize the pathological and functional consequences of the G1961E mutant allele in the Stargardt disease gene ABCA4. Data from 15 patients were retrospectively reviewed and all the patients had at least one G1961E mutation. Comprehensive ophthalmic examination, full-field and pattern electroretinograms, and fundus autofluorescence (FAF) imaging were performed on all patients. Microperimetry, spectral-domain optical coherence tomography (OCT), and fluorescein angiography were performed in selected cases. Genetic screening was performed using the ABCR400 micro-array that currently detects 496 distinct ABCA4 variants. All patients had normal full-field scotopic and photopic electroretinograms (ERGs) and abnormal pattern electroretinograms (PERGs) performed on both eyes, and all the fundi had bull's eye maculopathy without retinal flecks on FAF. On OCT, 1 patient had disorganization of photoreceptor outer segment, 2 had outer nuclear layer (ONL) thinning likely due to photoreceptor atrophy proximal to the foveal center, and 3 had additional retinal pigment epithelium (RPE) atrophy. On microperimetry, 6 patients had eccentric superior fixation and amongst this group, 5 had an absolute scotoma in the foveal area. DNA analysis revealed that 3 patients were homozygous G1961E/G1961E and the rest were compound heterozygotes for G1961E and other ABCA4 mutations. The G1961E allele in either homozygosity or heterozygosity is associated with anatomical and functional pathologies limited to the parafoveal region and a trend to delayed onset of symptoms, relative to other manifestations of ABCA4 mutations. Our observations support the hypothesis that the G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull's eye maculopathy in either the homozygosity or heterozygosity state. In addition, genetic testing provides precise diagnosis of the underlying maculopathy, and current non-invasive imaging techniques could be used to detect photoreceptor damage at the earliest clinical onset of the disease.

Antioxidant or neurotrophic factor treatment preserves function in a mouse model of neovascularization-associated oxidative stress

In several disease states, abnormal growth of blood vessels is associated with local neuronal degeneration. This is particularly true in ocular diseases such as retinal angiomatous proliferation (RAP) and macular telangiectasia (MacTel), in which, despite the absence of large-scale leakage or hemorrhage, abnormal neovascularization (NV) is associated with local neuronal dysfunction. We describe here a retinal phenotype in mice with dysfunctional receptors for VLDL (Vldlr-/- mice) that closely resembles human retinal diseases in which abnormal intra- and subretinal NV is associated with photoreceptor cell death. Such cell death was evidenced by decreased cone and, to a lesser extent, rod opsin expression and abnormal electroretinograms. Cell death in the region of intraretinal vascular abnormalities was associated with an increased presence of markers associated with oxidative stress. Oral antioxidant supplementation protected against photoreceptor degeneration and preserved retinal function, despite the continued presence of abnormal intra- and subretinal vessels. What we believe to be novel, Müller cell-based, virally mediated delivery of neurotrophic compounds specifically to sites of NV was also neuroprotective. These observations demonstrate that neuronal loss secondary to NV can be prevented by the use of simple antioxidant dietary measures or cell-based delivery of neurotrophic factors, even when the underlying vascular phenotype is not altered.

044: Smith-Lemli-Opitz syndrome—retinal pigment epithelial abnormalities and photoreceptor function determined by electroretinography

Background: Smith-Lemli-Opitz syndrome is caused by deficient 7-dehydrocholesterol reductase resulting in abnormal cholesterol metabolism. The severity of Smith-Lemli-Opitz syndrome depends on the serum cholesterol levels and can be mild, moderate, or severe. The purpose of this study is to determine whether the severity of the Smith-Lemli-Opitz syndrome correlates with the severity of retinal pigment epithelium changes noted on examination and electroretinogram abnormalities.

Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses

An electroretinogram (ERG) screen identified a mouse with a normal a-wave but lacking a b-wave, and as such it was designated no b-wave3 (nob3). The nob3 phenotype mapped to chromosome 11 in a region containing the metabotropic glutamate receptor 6 gene (Grm6). Sequence analyses of cDNA identified a splicing error in Grm6, introducing an insertion and an early stop codon into the mRNA of affected mice (designated Grm6(nob3)). Immunohistochemistry of the Grm6(nob3) retina showed that GRM6 was absent. The ERG and visual behaviour abnormalities of Grm6(nob3) mice are similar to Grm6(nob4) animals, and similar deficits were seen in compound heterozygotes (Grm6(nob4/nob3)), indicating that Grm6(nob3) is allelic to Grm6(nob4). Visual responses of Grm6(nob3) retinal ganglion cells (RGCs) to light onset were abnormal. Grm6(nob3) ON RGCs were rarely recorded, but when they were, had ill-defined receptive field (RF) centres and delayed onset latencies. When Grm6(nob3) OFF-centre RGC responses were evoked by full-field stimulation, significantly fewer converted that response to OFF/ON compared to Grm6(nob4) RGCs. Grm6(nob4/nob3) RGC responses verified the conclusion that the two mutants are allelic. We propose that Grm6(nob3) is a new model of human autosomal recessive congenital stationary night blindness. However, an allelic difference between Grm6(nob3) and Grm6(nob4) creates a disparity in inner retinal processing. Because the localization of GRM6 is limited to bipolar cells in the On pathway, the observed difference between RGCs in these mutants is likely to arise from differences in their inputs.

Vigabatrin in the treatment of childhood epilepsy: A retrospective chart review of efficacy and safety profile

To review the efficacy, cognitive outcome and safety profile in children treated with vigabatrin (VGB) for infantile spasms (IS) and partial epilepsies related to tuberous sclerosis complex (TSC) and other etiologies. Retrospective review of children followed in the Pediatric Epilepsy Program of Massachusetts General Hospital for Children between May 2001 and March 2006 who were treated with VGB. Eighty-four children were treated with VGB, 68 of them were treated for IS, and 59 were treated for partial seizures (PS). Etiology (TSC or other) was the only predictive factor for IS control with VGB (p < 0.0003). IS control was achieved in 73% of children with TSC and 27% of children with other etiologies (combined 56%). Partial onset seizures were controlled in 34% of all children, (17% seizure free,17%reduction in seizure frequency >50%) and no predictive factor was found. Shorter time from seizure onset to VGB treatment (p < 0.027) and longer total time on VGB (p < 0.045) was associated with better IQ-developmental quotient (DQ) outcome in children treated for IS, but not with IS control. Adverse events were seen in 13%. Electroretinogram and/or behavioral visual field (VF) testing was done in 52%. VGB was discontinued in one case due to abnormal electroretinogram (ERG) findings. We confirm the efficacy of VGB in the treatment of IS and PS in an American population. VGB may improve cognitive outcome in the absence of complete IS control, but this finding is of uncertain clinical significance. VGB was well tolerated, and ophthalmologic side effects were uncommon.

Background and history of autism in relation to vision care

Although autism existed before 1943, it was Leo Kanner who is credited with the first detailed description of autistic behavior. Before Kanner's report, the behavior was generally known as childhood schizophrenia. He noted that the outstanding common feature of all the children was certain parental personalities, like obsessiveness and lack of warm-heartedness. Concurrent with Kanner's report and observations were those of Asperger in 1944. However, Asperger's report, in a German-language journal, was not brought to the forefront until the 1980s. The children described by Asperger had milder forms of behavior disorders than those described by Kanner, with the resulting diagnosis of autism broadened and blurred. The main features of the new autistic spectrum included a triad of developmental deficiencies: recognition, communication, and understanding. Regardless of whose research is read, autistic behavior is considered peculiar and difficult to treat. Early treatments included LSD, tranquilizers, and developmental remediation. A later treatment, which proved to be the most successful, is applied behavior analysis (ABA), an outgrowth of B.F. Skinner's conditioning research. The etiology of autism remains a puzzle to scientists, with the most likely hypothesis being a central nervous system dysfunction. With regard to vision, people with autism tend to have abnormal electroretinograms, deficient evoked visual potentials, and atypical opticokinetic nystagmus. Other than a higher than expected incidence of strabismus and oculomotor deficiencies, refractive and binocular vision status of people with autism have been reported to be within normal ranges. Accordingly, the most useful tests for a patient with the diagnosis of autism are those for oculomotor function, opticokinetic nystagmus, and strabismus. The optometrist, thereby, becomes a member of the team helping to diagnose and treat the visual sequelae of autism.

Autoimmune retinopathy: A review and summary

Three main forms of autoimmune retinopathy (AIR) have been identified over the last 15 years: cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and nonneoplastic autoimmune retinopathy (npAIR). In this chapter, the term AIR will be used to encompass all three disorders where there is commonality to their features. Complicating the issue is that AIR can be a secondary complication of other conditions such as retinitis pigmentosa, ocular trauma, birdshot retinopathy, acute zonal occult outer retinopathy (AZOOR), or multiple evanescent white dot syndrome (MEWDS). The many forms of AIR tend to have common clinical features despite the fact that there has been no uniform set of anti-retinal antibodies circulating in these patients. Patients tend to have a wide variance of anti-retinal antibody activity often with three to six different antibodies found on immunoblots. Patients typically present with a sudden onset of photopsia, rapid visual loss, and abnormal electroretinograms (ERGs). Most patients have a panretinal degeneration without pigment deposits.

Two Cases of Occult Macular Dystrophy in a Family

Purpose: We report two familial cases of occult macular dystrophy (OMD) presenting with a progressive decrease in central vision. Case summary: Both patients exhibited a normal ophthalmologic examination including slit lamp biomicroscope, fundus examination, fluorescein angiography, and full-field electroretinogram. However, there were central visual field defects on a Humphrey static visual field test (C 24-2) and abnormal multifocal electroretinogram (mfERG) findings affecting the central portion of the test field. Foveal thinning was also observed by optical coherence tomography images in 1 case. These findings are consistent with the clinical characteristics of occult macular dystrophy, and close observation was recommended. Conclusions: OMD is a disease characterized by a reduction in central visual acuity without visible fundus abnormalities and full field ERG. It may be misdiagnosed as optic nerve disease, a central nervous system problem, non-organic visual disorder or malingering; therefore, mfERG is essential for the diagnosis of this rare type of macular dystrophy.

Multifocal Electroretinogram Changes and Normal Ganzfeld-ERG in Patients with AZOOR

Abnormal electroretinogram (ERG) findings are essential to the diagnosis of acute zonal occult outer retinopathy (AZOOR), however, the standard Ganzfeld-ERG can record only the mass retinal response. The multifocal electroretinogram (mfERG) can simultaneously evaluate the local function of numerous small retinal areas. A neuro-ophthalmologic examination including visual field, ERG, and mfERG was performed in two patients with presumed AZOOR. Two patients showed a normal response to the standard ERG and an abnormal response to mfERG. In conclusion, the mfERG may be essential in the diagnosis of AZOOR.

ERG variability in X-linked congenital retinoschisis patients with mutations in the RS1 gene and the diagnostic importance of fundus autofluorescence and OCT

X-linked congenital retinoschisis (RS) is a relatively frequent retinal dystrophy associated with RS1 gene mutations. A negative electroretinogram (ERG), i.e., a b/a wave ratio <1.0 in the standard combined response, is considered a key diagnostic feature of RS. Only a few cases without a negative ERG have been reported. This study includes 24 RS patients with RS1 mutations. ERGs (according to ISCEV standards, n = 23), ON-OFF-responses (n = 9), fundus autofluorescence (FAF, n = 8), and optical coherence tomography (OCT, n = 6) were performed. The mean age at examination was 22.6 years (0.5-53.2 years), and median visual acuity was 0.3 (no light perception to 0.6). A negative ERG was found in 13 of 23 patients (56.5%), of whom one patient presented a negative ERG at the 2-year follow-up, with an initial b/a wave ratio >1.0. Another patient had a b/a wave ratio of 0.96 in one eye and 1.02 in the fellow eye. In 10 of 23 patients, the b/a wave ratio ranged from 1.03 to 1.34. Single-flash cone and 30 Hz flicker responses were always reduced. FAF and OCT were pathologic in all patients tested. FAF was increased in the fovea. OCT revealed foveal schisis to various degrees and thinning of the retina in an older patient. Although ERG abnormalities were detected in all patients tested, more than 40% of patients with RS1 mutations did not have a negative ERG. In clinically suspected RS a combination of ERG, FAF, OCT, and molecular-genetic testing is advised to verify the diagnosis.

Six Patients with Bradyopsia (Slow Vision): Clinical Features and Course of the Disease

Recently, it was discovered that subjects who showed a prolonged response suppression on their electroretinogram (ERG) and had symptoms of photophobia, problems adjusting to bright light, and difficulties seeing moving objects shared a mutation in the RGS9 (regulator of G-protein signaling 9) gene that is involved in the deactivation of photoreceptor responses. The disorder was termed bradyopsia (slow vision). This paper reports the clinical presentation and long-term follow-up of 6 bradyopsia patients. Retrospective observational case series with a follow-up ranging from 6 to 30 years. Six patients with a homozygous mutation in the RGS9 gene. Clinical symptoms and signs were compared between the subjects and between their visits over time. Symptoms, visual acuity (VA), ocular findings, visual fields, dark-adaptation tests, color tests, fluorescein angiography, and ERG findings. Data showed a consistency in the individual symptoms and ERG recordings, but an extreme variation in VA between visits. Beside some irregularities in the macula in some patients, no other related eye abnormalities were seen. The low-to-subnormal VA varied with background luminance and typically increased by 2 to 3 lines when pinholes were used. Dark-adaptation tests, color tests, and fluorescein angiography were normal. Visual field tests showed a minor diffuse sensitivity loss. No progressive changes were seen over time. No signs of progression were noted in the 6 bradyopsia patients. Photophobia, impaired movement perception, variable reduced VA that improved with the use of pinholes and ERG abnormalities were typical for the disease.

Drosophila Ebony Activity Is Required in Glia for the Circadian Regulation of Locomotor Activity

Previous studies suggest that glia may be required for normal circadian behavior, but glial factors required for rhythmicity have not been identified in any system. We show here that a circadian rhythm in Drosophila Ebony (N-beta-alanyl-biogenic amine synthetase) abundance can be visualized in adult glia and that glial expression of Ebony rescues the altered circadian behavior of ebony mutants. We demonstrate that molecular oscillator function and clock neuron output are normal in ebony mutants, verifying a role for Ebony downstream of the clock. Surprisingly, the ebony oscillation persists in flies lacking PDF neuropeptide, indicating it is regulated by an autonomous glial oscillator or another neuronal factor. The proximity of Ebony-containing glia to aminergic neurons and genetic interaction results suggest a function in dopaminergic signaling. We thus suggest a model for ebony function wherein Ebony glia participate in the clock control of dopaminergic function and the orchestration of circadian activity rhythms.

Interpretation of the mouse electroretinogram

The mouse electroretinogram (ERG) consists of a complex set of signals or "waves" generated by multiple types of retinal cell. The origins of these waves are reviewed briefly for the C57BL/6J mouse. The differences in the properties of these waves are described for 34 strains of mice and 11 F1 hybrid mice, as is the way that inter-strain genetic polymorphisms can be exploited in order to help pin-point the genes responsible for ERG differences. There are certain technical difficulties, some subtle, that can arise in recording the ERG and these are classified and illustrated in order to facilitate their diagnosis. Forward genetic screens are described, along with abnormal mice that have been generated in a large screen. Several means are suggested for determining if a mouse having an abnormal ERG is a mutant.

Electrophysiological Findings in Persons With Nyctalopia

Ophthalmologists are occasionally confronted with an individual presenting with nyctalopia (i.e., a relatively greater difficulty seeing at night). When there is no accompanying abnormality seen in the fundus, visual electrophysiology becomes useful as an objective means of assessing rod (scotopic) photoreceptor function or pathway defects. A retrospective study was performed on 50 consecutive patients, aged less than 40 years, with seemingly normal fundi and good vision [visual acuity (VA) >6/12] presenting to the Visual Electrodiagnostic Unit, Singapore National Eye Centre, for the investigation of nyctalopia over a 2-year period. Subjective scotopic threshold sensitivity (STS) and objective full-field electroretinogram (ERG) were performed. Persons with abnormal test results were identified. Normal ERG scotopic responses were obtained in 74% of subjects. There was no significant difference in age, refraction and STS levels between subjects with abnormal and normal ERG. In the group with abnormal scotopic ERG responses, 9 were identified to have nonspecific rod dysfunction, 2 had rod-cone dystrophies and 2 had ERG changes suggestive of congenital stationary night blindness (CSNB). A large number of subjects presenting with nyctalopia had normal ERG findings. We can only assume that in these patients, no significant rod pathway dysfunction exists and that optical (e.g., night or instrument myopia) and psychological aetiologies should be considered. The fact that an abnormal result occurs in 26%, however, suggests that ncytalopia should be evaluated with electrophysiolgoical testing even when the fundi appear normal.

Localization of Multifocal Electroretinogram Abnormalities to the Lesion Site

To determine the association between multifocal electroretinogram (mfERG) abnormalities and macular lesions, as shown by retinal photography and optical coherence tomography (OCT), in a 3-generation family with vitelliform macular dystrophy. Five family members were examined using OCT, mfERG, and retinal photography. To localize mfERG abnormalities in relation to retinal findings, we overlaid the mfERG trace arrays on the retinal images and aligned the mfERGs and OCT images in the 180 degrees meridian. Family members had typical macular lesions, normal full-field ERGs, and reduced electro-oculogram light-dark ratios. The OCT images demonstrated variable lesion severity. Some individuals with good vision and normal-appearing fundi showed OCT abnormalities of the choroid and retinal pigment epithelium. The overlay technique revealed that the depressed mfERGs corresponded with the lesions detected by OCT and retinal photography. The latencies of mfERG components in the 2 central stimulus rings in our patients were often prolonged. The mfERG abnormalities matched the localization of the macular lesions in our patients. The latencies of the mfERG N1 and P1 components in the first 2 concentric stimulus rings were often significantly (>2 SDs) delayed, an observation that has not been previously reported, to our knowledge.

Electrophysiological Findings in Patients With Dengue-Related Maculopathy

To assess visual function in patients with dengue maculopathy using electrophysiological tests. Fifteen consecutive patients with dengue fever who experienced vision loss between July 2004 and July 2005 were included in this review. Full-field electroretinograms (ERG), pattern ERGs, and multifocal ERGs were performed. The most common electrophysiological finding (60%, 9/15) was a normal or mildly abnormal full-field ERG with reduced pattern ERG P50 amplitude and abnormal mfERG. Typically, multifocal ERG demonstrated a focal area of decreased macular response (especially between the fovea and optic nerve). Pattern ERG suggested normal optic nerve function in all but 1 case. Four patients had more severely reduced full-field ERG responses with reduced a-wave amplitude (suggestive of photoreceptor dysfunction), 3 of whom had an electronegative maximal response (suggestive of additional postreceptor dysfunction). Repeat multifocal ERG showed little change in 7 patients and incomplete resolution in 2 patients over 3 to 10 months. Retinal dysfunction associated with dengue maculopathy was localized mainly around the foveal region. It appeared to affect the outer and middle retina more severely with relative sparing of the inner retina. Retinal dysfunction may persist for several months. Longer follow-up is required to determine whether these changes are permanent.

Ophthalmic Manifestations of Danon Disease

To describe the ophthalmic findings in patients with Danon disease, an X-linked condition causing cardiomyopathy in males and females. Retrospective case series. Patients with genetically proven Danon disease. Retrospective chart review of complete eye examinations including electroretinogram, visual fields, and fluorescein angiography. Five females (4 affected) and 2 affected males were examined. The 4 affected females demonstrated a peripheral pigmentary retinopathy. Lens changes, myopia, abnormal electroretinogram and visual fields were also found. The males demonstrated a near-complete loss of pigment in the retinal pigment epithelium. We report the first description of a characteristic retinopathy in patients with Danon disease and the first extracardiac manifestations in affected females. Retinopathy potentially could be used to identify asymptomatic carriers.