Different amino acid substitutions at the same position in rhodopsin lead to distinct phenotypes

PURPOSE: Identification of a novel rhodopsin mutation in a family with retinitis pigmentosa and comparison of the clinical phenotype to a known mutation at the same amino acid position. METHODS: Screening for mutations in rhodopsin was performed in 78 patients with retinitis pigmentosa. All exons and flanking intronic regions were amplified by PCR, sequenced, and compared to the reference sequence derived from the National Center for Biotechnology Information (NCBI, Bethesda, MD) database. Patients were characterized clinically according to the results of best corrected visual acuity testing (BCVA), slit lamp examination (SLE), funduscopy, Goldmann perimetry (GP), dark adaptometry (DA), and electroretinography (ERG). Structural analyses of the rhodopsin protein were performed with the Swiss-Pdb Viewer program available on-line (http://www.expasy.org.spdvbv/ provided in the public domain by Swiss Institute of Bioinformatics, Geneva, Switzerland). RESULTS: A novel rhodopsin mutation (Gly90Val) was identified in a Swiss family of three generations. The pedigree indicated autosomal dominant inheritance. No additional mutation was found in this family in other autosomal dominant genes. The BCVA of affected family members ranged from 20/25 to 20/20. Fundus examination showed fine pigment mottling in patients of the third generation and well-defined bone spicules in patients of the second generation. GP showed concentric constriction. DA demonstrated monophasic cone adaptation only. ERG revealed severely reduced rod and cone signals. The clinical picture is compatible with retinitis pigmentosa. A previously reported amino acid substitution at the same position in rhodopsin leads to a phenotype resembling night blindness in mutation carriers, whereas patients reported in the current study showed the classic retinitis pigmentosa phenotype. The effect of different amino acid substitutions on the three-dimensional structure of rhodopsin was analyzed by homology modeling. Distinct distortions of position 90 (shifts in amino acids 112 and 113) and additional hydrogen bonds were found. CONCLUSIONS: Different amino acid substitutions at position 90 of rhodopsin can lead to night blindness or retinitis pigmentosa. The data suggest that the property of the substituted amino acid distinguishes between the phenotypes.

A new method to monitor visual field defects caused by photoreceptor degeneration by quantitative optical coherence tomography

PURPOSE: To correlate the dimension of the visual field (VF) tested by Goldman kinetic perimetry with the extent of visibility of the highly reflective layer between inner and outer segments of photoreceptors (IOS) seen in optical coherence tomography (OCT) images in patients with retinitis pigmentosa (RP). METHODS: In a retrospectively designed cross-sectional study, 18 eyes of 18 patients with RP were examined with OCT and Goldmann perimetry using test target I4e and compared with 18 eyes of 18 control subjects. A-scans of raw scan data of Stratus OCT images (Carl Zeiss Meditec, AG, Oberkochen, Germany) were quantitatively analyzed for the presence of the signal generated by the highly reflective layer between the IOS in OCT images. Starting in the fovea, the distance to which this signal was detectable was measured. Visual fields were analyzed by measuring the distance from the center point to isopter I4e. OCT and visual field data were analyzed in a clockwise fashion every 30 degrees , and corresponding measures were correlated. RESULTS: In corresponding alignments, the distance from the center point to isopter I4e and the distance to which the highly reflective signal from the IOS can be detected correlate significantly (r = 0.75, P < 0.0001). The greater the distance in VF, the greater the distance measured in OCT. CONCLUSIONS: The authors hypothesize that the retinal structure from which the highly reflective layer between the IOS emanates is of critical importance for visual and photoreceptor function. Further research is warranted to determine whether this may be useful as an objective marker of progression of retinal degeneration in patients with RP.

Recovery of visual field and acuity after removal of epiretinal and inner limiting membranes

BACKGROUND: Visual acuity serves as only a rough gauge of macular function. The aim therefore was to ascertain whether central an assessment of the central visual field afforded a closer insight into visual function after removal of epiretinal membranes and Infracyanine-Green- or Trypan-Blue-assisted peeling of the inner limiting membrane. Patients and methods: Fourty-three patients undergoing pars-plana vitrectomy for the removal of epimacular membranes and dye-assisted peeling of the inner limiting membrane using either Infracyanine Green (n = 29; group 1) or Trypan Blue (n = 14; group 2) were monitored prospectively for 12 months. Preoperatively, and 1, 6 and 12 months postoperatively, distance and reading visual acuities were evaluated; the central visual field was assessed by automated static perimetry. RESULTS: Twelve months after surgery, distance and reading visual acuities had improved in both groups, but to a significant degree only in Trypan-Blue-treated eyes. The difference between the two groups was not significant. Likewise at this juncture, the mean size of the visual-field defect remained unchanged in Trypan-Blue-treated eyes (preoperative: 4.3 (SD 2.1) dB; 12 months: 4.0 (2.1) dB (p = 0.15)), but had increased in Infracyanine-Green-treated ones (from 5.3 (3.7) dB to 8.0 (5.2) dB (p = 0.027)). CONCLUSION: Unlike visual acuity, the central visual field had deteriorated in Infracyanine-Green-treated eyes but not in Trypan-Blue-treated eyes 12 months after surgery. Hence, as a predictor of functional outcome, testing of the central visual field may be a more sensitive gauge than visual acuity. Furthermore, Infracyanine Green may have a chronic and potentially clinically relevant effect on the macula which is not reflected in the visual acuity.

Nouvelle méthode d’analyse de l’exploration visuelle

The term visual field corresponds to the angular field of view that is seen by the eyes when they are fixed on a point straight-ahead. In neurological patients--e.g. stroke, trauma, or tumour patients--visual field function can be restricted, depending on lesion site and size. In contrast, the term "functional visual field" describes the area of visual field responsiveness under more ordinary viewing conditions. The visual exploration, i.e. the capacity to explore and analyze our visual world, is dependent on the integrity of the visual system and the oculomotor system which has to move the fovea from one object of interest to the next. In this paper, we present a new method to assess the functional visual field, conceptualized as the area that a patient actively scans with eye movements to detect predefined targets placed on everyday scenes. This method allows us to compare three levels of visual field function: (a) the spatial distribution of successful search (hits, i.e. which targets did the patient find?), (b) the spatial distribution of fixations (i.e. where did the patient preferentially search for targets?), and (c) the retinotopic level (i.e. the visual field assessed by perimetry). By integrating these three levels, one can evaluate functional outcomes of visual field disorders. Of particular importance is the question of how a patient compensates for a visual field loss with appropriate eye movements. A further clinical application of this method is the comparison of pre- with post-treatment data. Patients with visual field disorders usually undergo specific exploration trainings, aimed at enhancing the number and amplitude of saccades towards the region of the visual field deficit. The first experiences and clinical application with this method are presented here.

Multifocal posterior uveitis in Crohn's disease

PURPOSE To report a case of rare posterior eye manifestation of Crohn's disease preceding recurrence of inflammatory bowel disease. METHODS Case report with ophthalmoscopic findings, fluorescein/indocyanin green angiograms, automated perimetry and multifocal-ERG. RESULTS The perimetry revealed absolute and relative scotomas corresponding to multifocal inflammatory lesions in the retina and choroid, reduced a/b amplitudes in multifocal-ERG and hypofluorescent dots in angiography. Under oral prednisolone visual defects, ophthalmoscopic and angiographic findings resolved, while a/b amplitudes remained mildly reduced. The ocular changes occurred without systemic hypertension and were followed by a new episode of intestinal symptoms. CONCLUSION Multifocal inflammatory lesions in the retina and choroid in patients with Crohn's disease may occur and may precede a recurrent intestinal episode. Crohn's patients should be carefully followed up in collaboration with internal medicine specialists.

Do optic nerve head and visual field parameters in patients with obstructive sleep apnea syndrome differ from those in control individuals?

BACKGROUND It has been suggested that sleep apnea syndrome may play a role in normal-tension glaucoma contributing to optic nerve damage. The purpose of this study was to evaluate if optic nerve and visual field parameters in individuals with sleep apnea syndrome differ from those in controls. PATIENTS AND METHODS From the records of the sleep laboratory at the University Hospital in Bern, Switzerland, we recruited consecutive patients with severe sleep apnea syndrome proven by polysomnography, apnea-hypopnea index >20, as well as no sleep apnea controls with apnea-hypopnea index <10. Participants had to be unknown to the ophtalmology department and had to have no recent eye examination in the medical history. All participants underwent a comprehensive eye examination, scanning laser polarimetry (GDx VCC, Carl Zeiss Meditec, Dublin, California), scanning laser ophthalmoscopy (Heidelberg Retina Tomograph II, HRT II), and automated perimetry (Octopus 101 Programm G2, Haag-Streit Diagnostics, Koeniz, Switzerland). Mean values of the parameters of the two groups were compared by t-test. RESULTS The sleep apnea group consisted of 69 eyes of 35 patients; age 52.7 ± 9.7 years, apnea-hypopnea index 46.1 ± 24.8. As controls served 38 eyes of 19 patients; age 45.8 ± 11.2 years, apnea-hypopnea index 4.8 ± 1.9. A difference was found in mean intraocular pressure, although in a fully overlapping range, sleep apnea group: 15.2 ± 3.1, range 8-22 mmHg, controls: 13.6 ± 2.3, range 9-18 mmHg; p<0.01. None of the extended visual field, optic nerve head (HRT) and retinal nerve fiber layer (GDx VCC) parameters showed a significant difference between the groups. CONCLUSION Visual field, optic nerve head, and retinal nerve fiber layer parameters in patients with sleep apnea did not differ from those in the control group. Our results do not support a pathogenic relationship between sleep apnea syndrome and glaucoma.

Localization of visual stimuli after striate cortex damage in monkeys: parallels with human blindsight.

Blindsight is a phenomenon in which human patients with damage to striate cortex deny any visual sensation in the resultant visual field defect but can nonetheless detect and localize stimuli when persuaded to guess. Although monkeys with striate lesions have also been shown to exhibit some residual vision, it is not yet clear to what extent the residual capacities in monkeys parallel the phenomenon of human blindsight. To clarify this issue, we trained two monkeys with unilateral lesions of striate cortex to make saccadic eye movements to visual targets in both hemifields under two conditions. In the condition analogous to clinical perimetry, they failed to initiate saccades to targets presented in the contralateral hemifield and thus appeared "blind." Only in the condition where the fixation point was turned off simultaneously with the onset of the target--signaling the animal to respond at the appropriate time--were monkeys able to localize targets contralateral to the striate lesion. These results indicate that the conditions under which residual vision is demonstrable are similar for monkeys with striate cortex damage and humans with blindsight.

Visual function alterations in essential tremor: A case report

Our purpose is to report alterations in contrast sensitivity function (CSF) and in the magno, parvo and koniocellular visual pathways by means of a multichannel perimeter in case of an essential tremor (ET). A complete evaluation of the visual function was performed in a 69-year old patient, including the analysis of the chromatic discrimination by the Fansworth–Munsell 100 hue test, the measurement of the CSF by the CSV-1000E test, and the detection of potential alteration patterns in the magno, parvo and koniocellular visual pathways by means of a multichannel perimeter. Visual acuity and intraocular pressure (IOP) were within the ranges of normality in both eyes. No abnormalities were detected in the fundoscopic examination and in the optical coherence tomography (OCT) exam. The results of the color vision examination were also within the ranges of normality. A significant decrease in the achromatic CSFs for right eye (RE) and left eye (LE) was detected for all spatial frequencies. The statistical global values provided by the multichannel perimeter confirms that there were significant absolute sensitivity losses compared to the normal pattern in RE. In the LE, only a statistically significant decrease in sensitivity was detected for the blue-yellow (BY) channel. The pattern standard deviation (PSD) values obtained in our patient indicated that there were significant localized losses compared to the normality pattern in the achromatic channel of the RE and in the red-green (RG) channel of the LE. Some color vision alterations may be present in ET that cannot be detected with conventional color vision tests, such as the FM 100 Hue.

Determination of motor vehicle eye height for highway design : final report /

Mode of access: Internet.

Function and Regulation of Cytochrome P450 4V2 and the Implications in Bietti’s Crystalline Dystrophy

Thesis (Ph.D.)--University of Washington, 2016-06

Visual field and structural alterations in age-related macular degeneration

The thesis investigated progression of the central 10° visual field with structural changes at the macula in a cross-section of patients with varying degrees of agerelated macular degeneration (AMD). The relationships between structure and function were investigated for both standard and short-wavelength automated perimetry (SWAP). Factors known to influence the measure of visual field progression were considered, including the accuracy of the refractive correction on SWAP thresholds and the learning effect. Techniques of assessing the structure to function relationships between fundus images and the visual field were developed with computer programming and evaluated for repeatability. Drusen quantification of fundus photographs and retro-mode scanning laser ophthalmoscopic images was performed. Visual field progression was related to structural changes derived from both manual and automated methods. Principal Findings: • Visual field sensitivity declined with advancing stage of AMD. SWAP showed greater sensitivity to progressive changes than standard perimetry. • Defects were confined to the central 5°. SWAP defects occurred at similar locations but were deeper and wider than corresponding standard perimetry defects. • The central field became less uniform as severity of AMD increased. SWAP visual field indices of focal loss were of more importance when detecting early change in AMD, than indices of diffuse loss. • The decline in visual field sensitivity over stage of severity of AMD was not uniform, whereas a linear relationship was found between the automated measure of drusen area and visual field parameters. • Perimetry exhibited a stronger relationship with drusen area than other measures of visual function. • Overcorrection of the refraction for the working distance in SWAP should be avoided in subjects with insufficient accommodative facility. • The perimetric learning effect in the 10° field did not differ significantly between normal subjects and AMD patients. • Subretinal deposits appeared more numerous in retro-mode imaging than in fundus photography.

Investigating the effects of antiepileptic drugs on the electrophysiology of vision

The principal aim of this work was to examine the effects of antiepileptic drugs (AEDs) on vision. Vigabatrin acts by increasing GABA at brain inhibitory synapses by irreversibly binding to GABA-transaminase. Remacemide is a novel non-competitive NMDA receptor antagonist and fast sodium channel inhibitor that results in the inhibition of the NMDA receptors located in the neuronal membrane calcium channels increasing glutamate in the brain. Vigabatrin has been shown to cause a specific pattern of visual field loss, as one in three adults taking vigabatrin have shown a bilateral concentric constriction. Remacemide has unknown effects on vision. The majority of studies of the effects of AEDs on vision have not included the paediatric population due to difficulties assessing visual field function using standard perimetry testing. Evidently an alternative test is required to establish and monitor visual field problems associated with AEDs both in children and in adults who cannot comply with perimetry. In order to test paediatric patients exposed to vigabatrin, a field-specific visual evoked potential was developed. Other tests performed on patients taking either vigabatrin or remacemide were electroretinograms, electro-oculograms, multifocal VEPs and perimetry. Comparing these tests to perimetry results from vigabatrin patients the field specific VEP was found to have a high sensitivity and specificity, as did the 30Hz flicker amplitude. The modified VEP was also found to provide useful results in vigabatrin patients. Remacemide did not produce a similar visual field loss to vigabatrin although macular vision was affected. The field specific VEP is a useful method for detecting vigabatrin associated visual field loss that is well tolerated by young children. This technique combined with the ERG under light adapted (30Hz flicker) condition is presently the superior method for detecting vigabatrin-attributed peripheral field defects present in children below the developmental age of 9. The effects of AEDs on vision should be monitored carefully and the use of multifocal stimulation allows for specific areas of the retina and visual pathway to be monitored.

Topographic, haemodynamic and psychophysical investigation of glaucomatous optic neuropathy

Loss of optic nerve head (ONH) axons in primary open angle glaucoma (POAG) has been attributed to both mechanical and vascular factors. Confocal scanning laser ophthalmoscopy (cSLO) provides a promising tool for the topographic follow-up of the ONH in glaucoma, while scanning laser Doppler flowmetry (SLDF) facilitates the rapid non-invasive assessment of retinal capillary blood flow. The purposes of these investigations were to optimise the techniques and explore their potential to classify and monitor disease. Preliminary investigations explored the reproducibility and validity of cSLO and SLDF and showed that: For cSLO: In a model eye, measurements are accurate over a range of axial lengths. For best reproducibility, seven images per visit are required, with a contour line located on Elschnig's scleral ring and transferred automatically between images. For SLDF: Three perfusion images are required for optimum reproducibility. Physiological changes induced by gas perturbation can be measured. Cross-sectional comparison of groups of normal subjects and early POAG patients showed that: cSLO parameters differentiate the early POAG group. Blood volume measured by SLDF showed group differences in superior nasal retina only. Longitudinal investigation of ONH topography, haemodynamic and visual field indices in normal subjects and POAG patients showed that: cSLO detects topographical change over time more frequently in the POAG group. Important parameters include: C:D area ratio, cup and rim area, mean depth in contour, volumes above and below reference and surface. Factor analysis identified "cup" and "rim" factors that can be used to detect change over time in individual patients. Blood flow changes were most apparent in the inferior nasal peripapillary retina of the POAG group. Perimetry is of clinical value for the identification of glaucoma but is less sensitive than cSLO for monitoring glaucomatous change.

Structure and function in primary open angle glaucoma

The study utilised a Normal group, an Ocular Hypertensive (OHT) group and a Primary Open Angle Glaucoma (POAG) group to investigate two aspects. Firstly, the within- and between-visit variability for stereometric measurements of the optic nerve head (ONH) using the Heidelberg Retina Tomograph (HRT); retinal nerve fibre layer (RNFL) thickness using the HRT and using optical coherence tomography with the Optical Coherence Tomography Scanner (OCT); the visual field using white-on-white (W-W), short-wavelength (SWAP) and Frequency Doubling perimetry (FDT); and retinal haemodynamics using the Heidelberg Retinal Flowmeter (HRF). Secondly, the association demonstrated between some of the derived variables. The within- and between-visit variability for stereometric measurements of the entire ONH and the between-visit variability for sectoral measurements were similar for Normals and OHTs but greater for POAGs. The within-visit variability of the visual field pointwise parameters for SWAP were greater than for W-W and FDT particularly with increase in eccentricity and for the OHT group. The between-visit variability increased with increase in defect depth for the POAG group, across all types of perimetry. The MS was greater, the MD and PSD smaller and the examination duration shorter in FDT compared to W-W and SWAP across all groups. The within-visit variability was less than the between-visit variability for the OCT circumferential and sector RNFL thickness using the 1.5R, 2.0R and the fixed 1.73mm circular scan radii, across the three groups. The variability increased with decrease in the RNFL thickness, and was least for the 2.0R scan radius.

The investigation of the sensitivity gradient of the visual field, as a function of stimulus dynamic range, in the normal and abnormal eye

The study utilized the advanced technology provided by automated perimeters to investigate the hypothesis that patients with retinitis pigmentosa behave atypically over the dynamic range and to concurrently determine the influence of extraneous factors on the format of the normal perimetric sensitivity profile. The perimetric processing of some patients with retinitis pigmentosa was considered to be abnormal in either the temporal and/or the spatial domain. The standard size III stimulus saturated the central regions and was thus ineffective in detecting early depressions in sensitivity in these areas. When stimulus size was scaled in inverse proportion to the square root of ganglion cell receptive field density (M-scaled), isosensitive profiles did not result, although cortical representation was theoretically equivalent across the visual field. It was conjectured that this was due to variations in the ganglion cell characteristics with increasing peripheral angle, most notably spatial summation. It was concluded that the development of perimetric routines incorporating stimulus sizes adjusted in proportion to the coverage factor of retinal ganglion cells would enhance the diagnostic capacity of perimetry. Good general and local correspondence was found between perimetric sensitivity and the available retinal cell counts. Intraocular light scatter arising both from simulations and media opacities depressed perimetric sensitivity. Attenuation was greater centrally for the smaller LED stimuli, whereas the reverse was true for the larger projected stimuli. Prior perimetric experience and pupil size also demonstrated eccentricity-dependent effect on sensitivity. Practice improved perimetric sensitivity for projected stimuli at eccentricities greater than or equal to 30o; particularly in the superior region. Increase in pupil size for LED stimuli enhanced sensitivity at eccentricities greater than 10o. Conversely, microfluctuation in the accommodative response during perimetric examination and the correction of peripheral refractive error had no significant influence on perimetric sensitivity.