Long-Term Follow-Up of a Family with Retinal Dystrophy Caused by RPE65 Mutation.

We present here the case histories of two siblings, a boy and a girl, with Leber's congenital amaurosis (LCA). The diagnosis was based on non-recordable full-field electroretinogram (ffERG). The long-term ophthalmologic follow-up included kinetic perimetry (Goldmann), visual evoked potentials with flash stimulation, optical coherence tomography (OCT: B-scan images at the area of fovea), and multifocal ERG. The boy (sibling 1, born in 1986) was sent for electrophysiological examination at the age of four because he had nystagmus from birth. The diagnosis would be LCA based on non-recordable ffERG. Four years later, his visual acuity decreased rapidly due to vitreous opacification, caused by the autoimmune reaction of the retinal pigment epithelial cells. This was treated successfully with steroid injections, administered parabulbarly. Retinal autoimmune panel was not performed. Genetic testing became available only in 2019, and it revealed a RPE65 gene mutation: (NM_000329.2) c.{442G>A};{442G>A} (p.{Glu148Lys}; {Glu148Lys}). His sister (sibling 2, born in 1993) showed similar symptoms, caused by the same genetic mutation. Even though their parents were free of symptoms, it appeared that they were heterozygous carriers of the same mutation. Research of the family tree revealed a consanguineous marriage four generations before. Both siblings received successful gene therapy relatively late in their age: sibling 1 was 35 and sibling 2 was 28 years old, meaning that they were at an advanced stage of the disease. Nevertheless, follow-up examinations showed measurable improvements in their retinal function. The study shows that electrophysiological examinations, including flash-evoked responses, are useful in the objective evaluation of the progression in the central photoreceptor loss during the follow-up of LCA. The results also show that gene therapy can have beneficial effects even at an advanced stage of the disease.

[Gene therapy treatment based on an ophthalmic indication in hereditary retinal dystrophy caused by RPE65 biallelic gene mutation.] / Szemészeti javallat alapján végzett génterápiás kezelés RPE65 biallelikus génmutáció okozta öröklodo ideghártya-dystrophiában.

INTRODUCTION: Leber's congenital amaurosis is a genetically determined disease belonging to the group of hereditary retinal dystrophies that leads to significant visual impairment in childhood. The disease initially causes a concentric narrowing of the visual field and, with time, loss of central vision. The RPE65 gene mutation-related retinal dystrophy is the first ophthalmic disease for which gene therapy is available using voretigene neparvovec (Luxturna®, Novartis Pharmaceuticals AG, Basel, Switzerland). OBJECTIVE: To present the treatment outcomes of Hungarian patients who were the first to receive voretigene neparvovec gene therapy for the RPE65 biallelic gene mutation. METHOD: Two patients with RPE65 biallelic gene mutations confirmed by genetic testing received voretigene neparvovec gene therapy in one eye each. Before treatment and during the follow-up period, we assessed the best corrected visual acuity, the central retinal thickness, the degree of visual field defects and performed electrophysiological studies. RESULTS: Both the best corrected visual acuity (+3 letters in the older sibling and +10 letters in the younger sibling) and the degree of visual field narrowing improved in both patients. The change in visual function resulted in a significant improvement in the quality of life of our patients. CONCLUSION: Postoperative outcomes of our patients correlate with the results of clinical trials. Orv Hetil. 2022; 163(48): 1923-1931.

Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family.

BACKGROUND: Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesis. RESULTS: We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation. CONCLUSIONS: This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease.

Immunohistochemical Analysis of a Vitreous Membrane Removed from a Patient with Incontinentia Pigmenti-Related Retinal Detachment.

This is a case history of a 23-year-old woman suffering from incontinentia pigmenti (IP). The patient's vision in the left eye started to deteriorate due to cataract progression at the age of 22, and by the age of 23, it dropped from 0.9 to 0.04. Ultrasound examination confirmed tractional vitreoretinal membranes. Vitrectomy was performed, therefore, on her left eye. The histological evaluation of vitreous membrane revealed a complex immunophenotype (positivity for glial fibrillary acidic protein (GFAP), vimentin, S-100, anti-pan cytokeratin antibody (AE/AE3), and smooth muscle-specific actin (SMA) to various extents). The right eye remained unsymptomatic throughout this course. Besides being the first to analyze the tractional vitreoretinal membrane in IP with immunohistochemical methods, this case study points out that extreme cases of asymmetric side involvement in IP do exist, even to the point of one eye being completely unsymptomatic.

Postnatal outcome and placental blood flow after plasmapheresis during pregnancy.

PURPOSE: Plasmapheresis in pregnancy adversely affects maternal hemodynamics, however there are studies suggesting it to reduce pregnancy loss in immunological diseases when medication is more harmful to the fetus. The overall optimal plasmapheresis treatment protocol remains unknown. MATERIALS AND METHODS: A pregnant with neuromyelitis optica was followed up after receiving six volumes of fresh frozen plasma via plasmapheresis. RESULTS: The placenta compensated the hemodynamic change until the 33rd week of gestation, resulting a small for gestational age, otherwise healthy girl. CONCLUSIONS: More research is needed on plasma exchange during pregnancy because in our observation placental circulation can adapt to the change in blood pressure.

The Development and Aging of the Magnocellular and Parvocellular Visual Pathways as Indicated by VEP Recordings between 5 and 84 Years of Age.

It is well known that pattern reversal visual evoked potentials (VEPs) are age-sensitive. Through the use of this technique, it is possible to assess both of the major visual pathways (i.e., the magnocellular and parvocellular ones) in terms of function and development. What developmental path these pathways follow, and if they develop/age in parallel across the human lifespan is a matter of ongoing debate, yet, only a few VEP studies have dealt with this issue. This cross-sectional study examined a sample of 115 healthy volunteers aged 5 to 84 years. Beyond the standard checkerboard pattern reversal stimulation at 97% contrast, we recorded pattern-reversal VEPs at 6% contrast to selectively stimulate the M pathway and isoluminant red and green checkerboard stimulation was also used to selectively stimulate the P pathway. Our results do not support the developmental advantage of any of the pathways. The development of both pathways appear to take a remarkably long time (well into the 30s), and the signs of aging become marked over 50 years of age, especially in the case of the magnocellular pathway.

Further Evidence for the Utility of Electrophysiological Methods for the Detection of Subclinical Stage Retinal and Optic Nerve Involvement in Diabetes.

OBJECTIVE: To assess the utility of visual electrophysiological methods, visual evoked potentials (VEPs) and pattern electroretinograms (PERGs) were recorded for the detection of subclinical optic nerve and retinal involvement in patients with diabetes mellitus. SUBJECTS AND METHODS: The data of 63 patients (126 eyes) with no vascular retinopathy or optic neuropathy were retrospectively analyzed. The patients were divided into polyneuropathic/nonpolyneuropathic groups to differentiate between early and late subclinical stages. The recorded parameters were compared with local reference values. RESULTS: 116 eyes (92%) had VEP and 76 (60%) had PERG abnormalities. The most frequent alteration was latency delay, but waveform and amplitude irregularities were also observed. The simultaneous use of the two methods allowed us to differentiate abnormal VEPs of purely optic nerve origin from those reflecting retinal involvement. CONCLUSIONS: We suggest that regular electrophysiological screening should receive more attention in the ophthalmological care of diabetic patients.

Lyme disease associated neuroretinitis - Case report.

We describe a rare case of Lyme disease complicated by unilateral neuroretinitis in the right eye. We report a case of a 27-year-old woman with blurred vision on her right eye. Because of the suspicion of optic neuritis (multiplex sclerosis) neurological examination was ordered. Surprisingly, computer tomography of the brain revealed incomplete empty sella, which generally results not monocular, but bilateral optic nerve swelling. Opthalmological examination (ophthalmoscopy and optical coherence tomography) indicated not only monocular optic nerve, but retinal oedema next to the temporal part of the right optic disk. Visual evoked potentials (VEP) demonstrated no P100 latency delay and mild differences between the amplitudes of the responses of the left and right eye. Optical coherence tomography (OCT) demonstrated the swelling of the optic nerve head and oedematous retina at the temporal part of the disk. Suspicion of an inflammatory cause of visual disturbance blood tests was ordered. Doxycycline treatment was ordered till the result of the blood test arrived. The Western blot and ELISA test were positive for Borrelia burgdorferi sensu lato. Following one week corticosteroide and ceftriaxone treatments, the patient displayed a clinical improvement. Unilateral neuroretinitis with optic disk swelling due to neuroborreliosis is a rare complication and in many cases it is difficult to distinguish between inflammatory and ischemic lesions. Further difficulty in the diagnosis can occur when intracranial alterations such as empty sella is demonstrated by CT examination.

Interocular amplitude and latency differences of pattern ERG and pattern VEP parameters.

PURPOSE: To determine the normal interocular differences in amplitudes and peak times of the pattern electroretinograms (PERGs) and pattern visual evoked potentials (PVEPs) and to investigate whether the PERG and PVEP parameters correspond in lateral dominance or whether the eye-side distributions of the functional parameters are similar. METHODS: The PERGs and PVEPs were recorded in healthy subjects (N = 77) according to the standards of the International Society for Clinical Electrophysiology of Vision, with the modification of the check size of the PERG to 0.5 degrees. This allows stimulation of the macular ganglion cells and their corresponding visual pathways in healthy subjects. RESULTS: Comparison of the averaged higher and lower response amplitudes and the shorter and longer response peak times showed significant differences (p < 0.001) in both the PERG and the PVEP parameters (median [5 to 95%]): the P50 (1.92% [0 to 5.48%]) and N95 (2.06% [0 to 13.95%]) peak times and the P50 (11.82% [1.32 to 29.93%) and N95 (9.45% [1.17 to 30.38%]) amplitudes of the PERGs and the P100 (1.04% [0 to 4.15%]) and N135 (1.96% [0 to 12.36%]) peak times and the P100 (9.86% [1.26 to 29.76%]) and N135 (11.19% [1.18 to 29.99%]) amplitudes of the PVEPs. No significant correlation was found concerning the eye dominance of the PERG and PVEP parameters. CONCLUSIONS: Our results reveal a significant interocular difference on PERG and PVEP recording, but this could not be ascribed to the anatomy of the retina and related visual pathways. If the difference between the eyes is not taken into account, misinterpretation may occur in a pathological process.

Achromatic luminance contrast sensitivity in X-linked color-deficient observers: an addition to the debate.

It is a matter of debate whether X-linked dichromacy is accompanied by enhanced achromatic processing. In the present study, we used sinusoidally modulated achromatic gratings under photopic conditions to compare the contrast sensitivity (CS) of protanopes, deuteranopes, and normal trichromats. 36 male volunteers were examined. CS was tested in static and dynamic conditions at nine different spatial frequencies. The results support the assumption that X-linked color-defective observers are at an advantage in terms of achromatic processing. Both protanopes and deuteranopes had significantly better CS than controls in both the static and the dynamic conditions. In the static condition, the advantage was observed especially at higher spatial frequencies, whereas in the dynamic condition, it was seen also at lower frequencies. The results are interpreted in terms of decreased chromatic modulation of the luminance channel and the early plasticity of the parvocellular system.

[Ophthalmologic manifestations of Bardet-Biedl syndrome]. / Tapasztalataink Bardet-Biedl-szindrómás gyermekek általános szemészeti és elektrofiziológiai vizsgálatával.

INTRODUCTION: Bardet-Biedl syndrome is characterised by retinal dystrophy, polydactily, obesity and slow mental development. AIM: The aim of the authors was to present ophthalmologic signs and symptoms of the syndrome. METHOD: Between 1980 and 2010, 4 children with Bardet-Biedl syndrome were evaluated at the Department of Ophthalmology, University of Szeged, Szeged, Hungary. Their age at the first visit was between 1 and 10 years. Basic ophthalmological and electrophysiological evaluation, as well as orthoptic examinations were performed. RESULTS: In two cases the electroretinographic curves were subnormal, and in two cases the electroretinographic curves showed no elevation. In the 4 children abnormal electroretinographic curves appeared at the ages of 1, 5, 10, and 18 years. Pigmentary changes on the periphery of the retina were detected in two cases. CONCLUSIONS: The different signs and symptoms of Bardet-Biedl syndrome may manifest at different ages. Electrophysiological changes failed to correlate with retinal alterations is these patients.

Parallel development of contour integration and visual contrast sensitivity at low spatial frequencies.

It has been suggested that visual contrast sensitivity and contour integration functions exhibit a late maturation during adolescence. However, the relationship between these functions has not been investigated. The aim of this study was to assess the development of visual contrast sensitivity and contour integration in 152 healthy volunteers aged between 5 and 30 years. The results revealed a significant maturation of contrast sensitivity at low spatial frequencies (0.5, 1.2, and 1.9 cycles/degree) and contour integration. The largest developmental step was observed for both contrast sensitivity and contour integration tasks when the 5-8-year olds were compared with the 9-11-year olds. There was a significant correlation between the development of low spatial frequency contrast sensitivity and contour integration. These results raise the possibility that the development of low spatial frequency processing may affect attentional mechanisms, which may have an impact on early contour integration.

Pattern-reversal electroretinograms and visual evoked potentials in retinitis pigmentosa.

OBJECTIVE: To analyze pattern electroretinograms (PERGs) and pattern visual evoked potentials (PVEPs) in retinitis pigmentosa (RP) patients. METHODS: PERGs and PVEPs were recorded in 106 eyes of 53 RP patients. A RETIport system was used for stimulation and recording. RESULTS: Reproducible PERGs were found in 17 (32%) of the patients, from only one eye in 4 of the 17 patients. We failed to record a normal PERG in any patient. All 53 patients gave reproducible PVEPs. The patients could be divided into three groups according to the waveform of the response. In the first group (n = 17), all patients produced PVEPs with a characteristic, triphasic shape, but with smaller amplitudes. In the second group (n = 16), the PVEPs displayed doubled P100 peaks, with components separated by about 50 ms. The recordings in the third group (n = 20) were broad in shape and characterized by a greatly increased N70-N170 latency difference and decreased amplitudes. CONCLUSIONS: In the population of RP patients, different types of PVEP waveform alterations can be observed. The appearance of both the responses with decreased amplitude and those with broad, doubled P100 waves might reflect differences in central retinal degeneration. The significance and pathological background of these PVEP alterations need further investigations.

Lateral interactions and speed of information processing in highly functioning multiple sclerosis patients.

Visual impairment is a common feature of multiple sclerosis. The aim of this study was to investigate lateral interactions in the visual cortex of highly functioning patients with multiple sclerosis and to compare that with basic visual and neuropsychologic functions. Twenty-two young, visually unimpaired multiple sclerosis patients with minimal symptoms (Expanded Disability Status Scale <2) and 30 healthy controls subjects participated in the study. Lateral interactions were investigated with the flanker task, during which participants were asked to detect the orientation of a low-contrast Gabor patch (vertical or horizontal), flanked with 2 collinear or orthogonal Gabor patches. Stimulus exposure time was 40, 60, 80, and 100 ms. Digit span forward/backward, digit symbol, verbal fluency, and California Verbal Learning Test procedures were used for background neuropsychologic assessment. Results revealed that patients with multiple sclerosis showed intact visual contrast sensitivity and neuropsychologic functions, whereas orientation detection in the orthogonal condition was significantly impaired. At 40-ms exposure time, collinear flankers facilitated the orientation detection performance of the patients resulting in normal performance. In conclusion, the detection of briefly presented, low-contrast visual stimuli was selectively impaired in multiple sclerosis. Lateral interactions between target and flankers robustly facilitated target detection in the patient group.

Hypobaric hypoxia reduces the amplitude of oscillatory potentials in the human ERG.

PURPOSE: To explore the retinal functions in healthy volunteers during acute hypoxic exposure, applying a set of electrophysiological tests. METHODS: Standard electroretinograms (ERGs) of the retina (rod-(scotopic) ERGs, cone-(photopic) ERGs, maximal responses and oscillatory potentials (OPs)) and 30-Hz flicker ERGs were recorded according to ISCEV (International Society of Clinical Electrophysiology of Vision) recommendations in 14 healthy volunteers during a 15-min exposure to a simulated altitude of 5500 m. RESULTS: The mean arterial oxygen saturation level was significantly reduced (P < 0.001) during the hypobaric challenge. It returned to the normal level very shortly after the end of the hypoxic exposure. No significant change in the latency or amplitude of the slow components of the ERG was found in any recording. The OPs of the ERG, however, revealed a significant decrease in amplitude during hypoxic exposure. Both OP1 and OP2 amplitudes were significantly different (P < 0.05) from the baseline values during hypoxia. Partial recovery of these waves occurred after termination of the hypoxia. CONCLUSIONS: These results appear to support the notion that the inner layers of the retina presumed to be the main source of the OPs, display the highest sensitivity towards circulatory and/or hypoxic challenges.

Multifocal ERG reveals several patterns of cone degeneration in retinitis pigmentosa with concentric narrowing of the visual field.

PURPOSE: To analyze multifocal ERGs (mfERGs) in patients with retinitis pigmentosa (RP), with constricted visual fields and visual acuity satisfactory for steady fixation. METHODS: The mfERGs of 86 eyes of 43 patients with various forms of inheritance and durations of RP were analyzed. A retinal scanning system with a 20-in. monitor was used to map central cone function. Electrical signals of the retina were detected by using DTL fiber electrodes. RESULTS: The site of the best response density of the mfERGs in the patients with RP was found in a central or eccentric position of the trace array. Depending on the position of the best response density in the two eyes, the patients were categorized into three groups. In the first group, the best response density was recorded from the central hexagon in both eyes, producing a central peak surrounded by very low responses in the three-dimensional presentation. In the second group of patients, the best responses were found to correspond to the central hexagon on only one side. In the fellow eye, however, the best response density appeared to be in an eccentric position. The patients in the third group did not present a central peak in the mfERG on either side. In scattered parts of the trace arrays, several acceptable responses were observed in all three groups that might represent patches of functioning retinal cone receptors. CONCLUSIONS: The results suggest highly variable central responses and groups of cones with preserved function in areas previously considered nonresponsive. The high variability of the central responses could be a result of variable foveal cone density, with differences in inheritance- and duration-related cone degeneration at the time of the examination. The authors stress the value of step-by-step analysis of the trace array of the mfERGs, which can reveal the still-functioning groups of cones.

[Parallel processing of visual information]. / A látási információ parallel feldolgozása.

This is a survey on the function of parallel visual pathway with a special emphasis on its clinical implications. It is based on data in the literature and own results of our group. The paper primarily deals with the X, Y, W pathways and by the magnocellular, parvocellular and koniocellular visual pathways characterized by cells of various size as well as by nerve fibers of various thickness. Electrophysiological, microelectrode recording of single-unit activity makes the distinction between the pathways available in animal model. Much more difficulties arise if we intend to characterize the pathways in humans or to detect the selective damage of one of these pathways in patients. The non-invasive diagnostic methods that could be used in the diagnosis are detailed here, too. Finally, the neurological, ophthalmological and psychological diseases are discussed in which a selective damage of any visual pathway is suspected. Summing it up, the survey provides evidences for the introduction of the novel concept of parallel pathways into the diagnostic aspects of ophthalmology, neurology and psychiatry.