Cone Sensitivity Loss Research Articles

Mechanisms of cone sensitivity loss in retinitis pigmentosa.

To explore the mechanisms of cone sensitivity loss in retinitis pigmentosa by combining two-colour perimetry with threshold versus intensity (tvi) testing. Seven subjects with autosomal recessive retinitis pigmentosa and 10 normal subjects were recruited and underwent perimetric testing of one eye using 480- and 640-nm Goldman size V targets presented under scotopic conditions (no background illumination) and against a white background ranging in luminance from -1.5 to 2 log cd m-2 in 0.5 log cd m-2 steps. Data were fitted with tvi functions of the form logT = logT0 + log ((A + A0)/A0)n, where T is the threshold, T0 is the absolute threshold, A is the background intensity, A0 is the 'dark-light' constant and n is a gain constant. Reliable tvi functions could not be obtained within the region of the visual field corresponding to loss of the ellipsoid zone on optical coherence tomography. At fixation, changes in both T0 and A0 were observed, consistent with a d1 mechanism loss, which resulted in an upwards and rightwards shift of the tvi function. Losses at [±3°, ±3°] demonstrated changes in T0, consistent with a d3 mechanism loss, resulting in an upwards translation of the tvi curve. Although the absolute cone threshold was elevated at each location, shifts in the tvi function (so-called d1 mechanism loss) at fixation minimise threshold elevation in the presence of white adapting backgrounds, such as those typically employed in standard two-colour perimetry. At more peripheral testing locations, changes in threshold occurred independent of background luminance (so-called d3 mechanism loss). These findings suggest that backgrounds which selectively adapt rods while maintaining cones at, or near, absolute threshold may be preferable to conventional two-colour perimetry for assessing loss of cone sensitivity, especially at the point of fixation.

Short-term Assessment of Subfoveal Injection of Adeno-Associated Virus-Mediated hCHM Gene Augmentation in Choroideremia Using Adaptive Optics Ophthalmoscopy

Subretinal injection for gene augmentation in retinal degenerations forcefully detaches the neural retina from the retinal pigment epithelium, potentially damaging photoreceptors and/or retinal pigment epithelium cells. To use adaptive optics scanning light ophthalmoscopy (AOSLO) to assess the short-term integrity of the cone mosaic following subretinal injections of adeno-associated virus vector designed to deliver a functional version of the CHM gene (AAV2-hCHM) in patients with choroideremia. This longitudinal case series study enrolled adult patients with choroideremia from February 2015 to January 2016 in the US. To be included in the study, study participants must have received uniocular subfoveal injections of low-dose (5 × 1010 vector genome per eye) or high-dose (1 × 1011 vector genome per eye) AAV2-hCHM. Analysis began February 2015. The macular regions of both eyes were imaged before and 1 month after injection using a custom-built multimodal AOSLO. Postinjection cone inner segment mosaics were compared with preinjection mosaics at multiple regions of interest. Colocalized spectral-domain optical coherence tomography and dark-adapted cone sensitivity was also acquired at each time point. Nine study participants ranged in age from 26 to 50 years at the time of enrollment, and all were White men. Postinjection AOSLO images showed preservation of the cone mosaic in all 9 AAV2-hCHM-injected eyes. Mosaics appeared intact and contiguous 1 month postinjection, with the exception of foveal disruption in 1 patient. Optical coherence tomography showed foveal cone outer segment shortening postinjection. Cone-mediated sensitivities were unchanged in 8 of 9 injected and 9 of 9 uninjected eyes. One participant showed acute loss of foveal optical coherence tomography cone outer segment-related signals along with cone sensitivity loss that colocalized with disruption of the mosaic on AOSLO. Integrity of the cone mosaic is maintained following subretinal delivery of AAV2-hCHM, providing strong evidence in support of the safety of the injections. Minor foveal thinning observed following surgery corresponds with short-term cone outer segment shortening rather than cone cell loss. Foveal cone loss in 1 participant raises the possibility of individual vulnerability to the subretinal injection.

Progression in X-linked Retinitis Pigmentosa Due to ORF15-RPGR Mutations: Assessment of Localized Vision Changes Over 2 Years.

To determine the progression rate and the variability of rod and cone sensitivities in patients with X-linked retinitis pigmentosa (XLRP) caused by mutations in ORF15-RPGR. ORF15-RPGR-XLRP patients (n = 15) were studied prospectively over 2 years with static perimetry sampling the visual field under dark-adapted and light-adapted conditions on a 12° square grid covering 168° width and 84° height. Natural history of rod and cone sensitivity loss and test-retest variability were estimated. Data were analyzed pointwise as well as averaged across small regions of neighboring loci of approximately 80 mm2 (900 deg2) in size representing the likely extent of localized gene therapy injections. Retinal loci with mild to moderate loss of sensitivity tended to be in the mid- to far-peripheral retina in most patients. When averaged across small regions, dark-adapted rod vision progressed at an average of 2 dB per year with a coefficient of repeatability (CR) of 6.3 dB, and light-adapted cone vision with white stimulus progressed at an average of 0.9 dB per year with a CR of 3.8 dB. For an average patient enrolled in an early-phase clinical trial, significant (α = 0.05) progression would be predicted to occur with 80% power in 4.5 years for rod vision and 6.1 years for cone vision. Localization of regions in the temporal hemifield and grouping of results from multiple patients would permit trial designs of shorter duration. Measurement of rod sensitivity under dark-adapted conditions averaged across a small region showed the greatest potential for detectability of progression in the shortest period.

Outer Retinal Changes Including the Ellipsoid Zone Band in Usher Syndrome 1B due to MYO7A Mutations.

To study transition zones from normal to abnormal retina in Usher syndrome IB (USH1B) caused by myosin 7A (MYO7A) mutations. Optical coherence tomography (OCT) scattering layers in outer retina were segmented in patients (n = 16, ages 2-42; eight patients had serial data, average interval 4.5 years) to quantify outer nuclear layer (ONL) and outer segments (OS) as well as the locus of EZ (ellipsoid zone) edge and its extent from the fovea. Static perimetry was measured under dark-adapted (DA) and light-adapted (LA) conditions. Ellipsoid zone edge in USH1B-MYO7A could be located up to 23° from the fovea. Ellipsoid zone extent constricted at a rate of 0.51°/year with slower rates at smaller eccentricities. A well-defined EZ line could be associated with normal or abnormal ONL and/or OS thickness; detectable ONL extended well beyond EZ edge. At the EZ edge, the local slope of LA sensitivity loss was 2.6 (±1.7) dB/deg for central transition zones. At greater eccentricities, the local slope of cone sensitivity loss was shallower (1.1 ± 0.4 dB/deg for LA) than that of rod sensitivity loss (2.8 ± 1.2 dB/deg for DA). In USH1B-MYO7A, constriction rate of EZ extent depends on the initial eccentricity of the transition. Ellipsoid zone edges in the macula correspond to large local changes in cone vision, but extramacular EZ edges show more pronounced losses on rod-based vision tests. It is advisable to use not only the EZ line but also other structural and functional parameters for estimating natural history of disease and possible therapeutic effects in future clinical trials of USH1B-MYO7A.

Chromatic Pupillometry Dissects Function of the Three Different Light-Sensitive Retinal Cell Populations in RPE65 Deficiency

The aim of the study was to objectively characterize the function of rods, cones, and intrinsic photosensitive retinal ganglion cells (ipRGCs) in patients with RPE65 mutations by using two published protocols for chromatic pupillometry, and to correlate the data with the clinical phenotype. The study group comprised 11 patients with RPE65 mutations, and for control purposes, 32 healthy probands and 2 achromats. A custom-made binocular chromatic pupillometer (Bino I) connected to a ColorDome Ganzfeld stimulator was used to assess changes in pupil diameter in response to red (640 nm) and blue (462 nm) light stimuli. Light intensities, stimulus duration, and background varied depending on the protocol used. Results were compared to the clinical phenotype, that is, visual field (Goldmann perimetry), best corrected visual acuity, and full-field stimulus testing (FST). No significant differences in any of the pupil response parameters were observed in intraday or intervisit variability tests. Pupil responses to rod-weighted stimulation were significantly diminished in all RPE65 patients. Pupil responses to cone-weighted stimuli differed among RPE65 patients and did not always correlate with residual visual field and cone sensitivity loss in FST. Pupil responses to ipRGC-weighted answers were slightly but significantly diminished, and the postillumination pupil response was significantly increased. Chromatic pupillometry represents a highly sensitive and objective test to quantify the function of rods, cones, and ipRGCs in patients with RPE65 mutations.

Fructose diet induced short‐term impairment of cone sensitivity and gene expression in rat retina

AbstractPurpose A high fructose diet has been widely used to trigger insulin resistance in rodent; insulin resistance is one of the major risk factor for the development of type 2 diabetes. Thirty to 40% of diabetic patients develop diabetic retinopathy. In this study, we aimed to evaluate the short‐term effect, at 1, 3, 5, 8 days, of a 60% fructose diet, on photoreceptor sensitivity and gene expression in the retina of Brown Norway rats.Methods Flicker electroretinograms (8Hz) were recorded under anesthesia, from both eyes simultaneously in order to study sensitivity of photoreceptors. Then, rats were euthanized and enucleated. Retinae and posterior poles were collected to analyze gene expression by RT‐PCR. We specifically focused on 45 genes involved in cholesterol homeostasis, lipid trafficking, vascular changes and inflammation.Results Our data showed that a short period of fructose feeding induced early changes in retinal functionality and homeostasis. Interestingly, we reported a partial loss of cone sensitivity after 8 days of feeding rats with the high‐fructose diet. No effect was found in rod sensitivity.Conclusion These findings are consistent with the sensibility and susceptibility of cones to dietary changes. These data deserve further investigations on the cross‐talk between cones and rods upon metabolic changes associated with aging.

Fundus Autofluorescence in Carriers of Choroideremia and Correlation with Electrophysiologic and Psychophysical Data

To describe fundus autofluorescence (FAF) in carriers of choroideremia (CHM), and to compare FAF findings with ophthalmoscopy and electrophysiologic and psychophysical data. Prospective, observational case series and systematic review. Six unrelated carriers of CHM. Clinical examination included a comprehensive ophthalmic examination, fundus photography, FAF, kinetic perimetry, 2-color threshold perimetry (2CTP), full-field electroretinography (ERG), and multifocal ERG (mfERG). All 6 carriers (33-60 years of age) were screened for mutations in the coding region of Rab Escort Protein 1 gene (REP1) including close flanking intronic sequence and deletions within 2160 bp of 5' untranslated sequence. Intensity and distribution of FAF, rod sensitivity loss, cone sensitivity loss in 2CTP, amplitude and latency in full-field ERG, amplitude in mfERG, and correlation of all 3 parameters. Mutations in the coding region of REP1 were identified in 3 of 6 carriers. All 6 carriers had good visual acuity. Three carriers complained of photophobia and 1 of impaired vision in dim light. Ophthalmoscopy revealed peripapillary atrophy and retinal pigment epithelium (RPE) mottling mainly in the macular region, and additional RPE clumping and flecks of atrophy in the periphery. A very irregular pattern of low- and high-density FAF speckles was seen. Low-density FAF surrounding the optic nerve head corresponded with the peripapillary atrophy. In areas of major FAF changes, mfERG was deteriorated. The 2CTP images revealed functional disturbances in rods and cones. No general pattern was observed. On MfERG, reduced amplitudes in areas with normal cone sensitivity in 2CTP were seen. All 6 carriers of CHM showed a characteristic FAF pattern that can guide mutation analysis. Even when other functional testing is inconspicuous, FAF is a rapid, noninvasive indicator. The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Rods induce transient tritanopia in blue cone monochromats.

Transient tritanopia is a cone-cone post-receptoral interaction between short-wavelength (S) cones and medium (M) and long (L) wavelength cones. Blue cone monochromats have rods and S cones of normal sensitivity but lack functional M/L cones. All blue cone monochromats tested (n = 8) show significant amounts of transient tritanopia mediated by rods. Attempts to find a similar rod-S cone interaction while silencing the L/M cones in normals yielded only a small amount of S cone sensitivity loss. The results suggest an exaggerated influence of rods on the S cone pathway in the retina of blue cone monochromats.

Occult Macular Dystrophy

Occult macular dystrophy is a hereditary macular dystrophy without any visible abnormality of the fundus or abnormality indicated by fluorescein angiography even when visual acuity is decreased. Normal full-field electroretinogram in both cone and rod components with abnormal focal macular cone electroretinogram is the key to diagnosing this disorder. The purpose of this study was to identify the function of the macular rods and to provide detailed clinical findings in occult macular dystrophy. Thirteen patients from eight families were examined. The fundi of 12 patients were essentially normal (occult macular dystrophy), and the oldest patient in one family disclosed bull's eye maculopathy. In the 12 patients, including the patient with bull's eye maculopathy, the profiles of cone and rod absolute thresholds were performed across the 60-degree horizontal meridian of the posterior pole. All 12 patients showed cone sensitivity loss only in the macular area. Six relatively young patients revealed normal rod sensitivity, whereas six older patients showed borderline rod sensitivity or abnormal rod sensitivity in the macular area. The pathology of occult dystrophy involves either only the macular cone system or macular cone and rod systems without any visible abnormality. This difference of the pathology suggests a different clinical entity or a different stage of occult macular dystrophy.

Macular edema reduces B cone sensitivity in diabetics

A simple clinical test of B cone pathway sensitivity shows that a group of 45 diabetics (of which 31 have VA >/= 20/20) are 40 times less sensitive than a group of 57 normals. By contrast, the diabetic group is less than 2.2 times less sensitive than the normals for R and/or G cone pathway sensitivity. The selective B cone sensitivity loss is seen even in patients who have no macular edema; however, the presence of edema is associated with significantly greater sensitivity loss. Age differences between the groups cannot account for the differences seen between normals and diabetics.

Two forms of autosomal dominant primary retinitis pigmentosa.

Two types of autosomal dominant retinitis pigmentosa (RP) are identified on the basis of perimetric measures of rod sensitivity relative to cone sensitivity. Type 1 dominant RP patients are characterized by an early diffuse loss of rod sensitivity with a later loss of cone sensitivity and by childhood onset of night blindness. Type 2 dominant RP patients are characterized by a regionalized and combined loss of rod and cone sensitivity with adulthood onset of nightblindness. Comparisons of losses in the photopic and scotopic electroretinogram amplitudes corroborate the psychophysical results. Clinical findings are similar for the two dominant RP subtypes, however, there are differences in natural history.