A form of Leber's congenital amaurosis is caused by mutant
RPE65
, a critical component of the visual cycle. Two early clinical trials to assess subretinal injection of a viral vector containing
...RPE65
in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function.
Two early clinical trials to assess subretinal injection of a viral vector containing RPE65 in young adults with advanced retinal degeneration show that this approach is generally safe in the short term, although one group reported an adverse event: macular hole. The authors observed improvement in some measures of visual function.
Leber's congenital amaurosis is a term used to describe a group of recessively inherited, severe, infantile-onset rod–cone dystrophies.
1
Mutation of one of several genes, including
RPE65
, causes disease that involves impaired vision from birth
2
,
3
and typically progresses to blindness in the third decade of life. There is no effective treatment.
RPE65
is expressed in the retinal pigment epithelium and encodes a 65-kD protein that is a key component of the visual cycle,
1
,
4
–
8
a biochemical pathway that regenerates the visual pigment after exposure to light.
9
–
14
A lack of functional RPE65 results in deficiency of 11-
cis
. . .
We characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease.
Full clinical examination and AF ...imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken.
The mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype.
The AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.
IMPORTANCE: Clinical observations suggest that patients with age-related macular degeneration (AMD) have vision problems, particularly in dim light conditions. Previous studies on ...structural-functional analysis in patients with AMD with reticular drusen (RDR) have focused on photopic sensitivity testing but have not specifically assessed scotopic function. OBJECTIVE: To evaluate retinal function by scotopic and photopic microperimetry in patients with AMD and a well-demarcated area of RDR. DESIGN, SETTING, AND PARTICIPANTS: Prospective case series in a referral center of 22 eyes from 18 patients (mean age, 74.7 years; range, 62-87 years). The study was conducted from June 1, 2014, to October 31, 2014. INTERVENTIONS: With the use of combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging, retinal areas with RDR (category 1) and no visible pathologic alterations (category 2) were identified in each eye. Scotopic and photopic microperimetry (MP-1S; Nidek Technologies) was performed using a grid with 56 stimulus points. MAIN OUTCOMES AND MEASURES: Comparison of mean threshold sensitivities for each category for scotopic and photopic microperimetry. RESULTS: In all eyes, areas of category 1 showed a relative and sharply demarcated reduction of scotopic threshold values compared with areas of category 2, but only less-pronounced differences were seen for photopic testing. Statistical analysis in the 18 eyes in which the 1.0–log unit neutral density filter was applied revealed a difference of scotopic threshold values in areas of category 1 (mean, 13.5 dB 95% CI, 12.1-15.0) vs category 2 (mean, 18.3 dB; 95% CI, 17.4-19.3 (P ≤ .001). For photopic testing, the mean threshold values were 16.8 dB (95% CI, 15.5-18.2) in category 1 and 18.4 dB (95% CI, 17.1-19.6) in category 2 (P = .03). CONCLUSIONS AND RELEVANCE: The results of this study suggest that rod function is more severely affected than cone function in retinal areas with RDR. This differential structural-functional correlation underscores the functional relevance of RDR in patients with AMD.
Age-related macular degeneration is the most common form of legal blindness in westernized societies, and polymorphisms in the gene encoding complement factor H (CFH) are associated with ...susceptibility to age-related macular degeneration in more than half of affected individuals. To investigate the relationship between complement factor H (CFH) and retinal disease, we performed functional and anatomical analysis in 2-year-old CFH-deficient (cfh⁻/⁻) mice. cfh⁻/⁻ animals exhibited significantly reduced visual acuity and rod response amplitudes on electroretinography compared with age-matched controls. Retinal imaging by confocal scanning laser ophthalmoscopy revealed an increase in autofluorescent subretinal deposits in the cfh⁻/⁻ mice, whereas the fundus and vasculature appeared normal. Examination of tissue sections showed an accumulation of complement C3 in the neural retina of the cfh⁻/⁻ mice, together with a decrease in electron-dense material, thinning of Bruch's membrane, changes in the cellular distribution of retinal pigment epithelial cell organelles, and disorganization of rod photoreceptor outer segments. Collectively, these data show that, in the absence of any specific exogenous challenge to the innate immune system, CFH is critically required for the long-term functional health of the retina.
To assess the neuroprotective effects of different glutamate modulation strategies, with a nonselective (MK801) and a selective (ifenprodil) NMDA receptor antagonist and a metabotropic glutamate ...receptor agonist (mGluR Group II, LY354740), in glaucoma-related in vivo rat models of retinal ganglion cell (RGC) apoptosis.
RGC apoptosis was induced in Dark Agouti (DA) rats by staurosporine (SSP) treatment. Single agents MK801, ifenprodil, or LY354740, or MK801 and LY354740 combined, were administrated intravitreally at different doses. Eyes were imaged in vivo using a recently established technique and the results confirmed histologically. The most effective combined therapy regimen of MK801 and LY354740 was then assessed in a chronic ocular hypertension (OHT) rat model with application at 0, 1, and 2 weeks after OHT surgery and the effects assessed as described before.
All strategies of glutamate modulation reduced SSP-induced-RGC apoptosis compared with the control, in a dose-dependent manner: MK801 (R2= 0.8863), ifenprodil (R2= 0.4587), and LY354740 (R2= 0.9094), with EC50s of 0.074, 0.0138, and 19 nanomoles, respectively. The most effective combination dose of MK801 and LY354740 was 0.06 and 20 nanomoles (P < 0.05), respectively, and the optimal timing of the therapy was 0 weeks after OHT surgery (P < 0.05).
This novel SSP model was validated as a useful tool for screening neuroprotective strategies in vivo. Group II mGluR modulation may be a useful treatment for RGC death. Combination therapy optimized to limit neurotoxic effects of MK801 may be an effective neuroprotective approach in retinal degenerative disease. Furthermore, treatments that minimize secondary RGC degeneration may be most useful in glaucoma.
To determine the sensitivity to change and specificity achieved when published test-retest variability (TRV) data are used to determine whether measured changes in ETDRS logarithm of the minimum ...angle of resolution (logMAR) visual acuity reflect true clinical change or are attributable to measurement error alone.
Various degrees of change in visual acuity were simulated in a group of normal subjects by adjusting test difficulty through manipulation of viewing distance. Sensitivity to simulated change and specificity were determined with change criteria derived from published Bland-Altman 95% ranges for TRV.
The relationship between viewing distance and measured acuity was as predicted theoretically. Simulated acuity change of 0.2 logMAR (two lines of letters) or greater can be reliably distinguished from no change (both sensitivity and specificity >95%) with the ETDRS chart, but a change of 0.1 logMAR or less cannot.
The use of 95% ranges for TRV to establish the smallest measured visual acuity change that can be reliably detected ensures a high specificity but does not take account of sensitivity. Use of change criteria derived from published 95% ranges results in a sensitivity of approximately 50% (assuming identical levels of TRV). Sensitivity may be improved by using a change criterion that is smaller than the minimum change sought, providing the change criterion is still at least as large as the 95% range for TRV, so that specificity is maintained. Reducing TRV allows smaller changes in acuity to be reliably detected.
To document the evolution and functional and structural significance of parafoveal rings of high-density fundus autofluorescence (AF) in patients with retinitis pigmentosa and preserved visual ...acuity.
Fifty-two patients with nonsyndromic retinitis pigmentosa or Usher syndrome, who had a parafoveal ring of high-density AF and a visual acuity of 20/30 or better, were ascertained. All had international standard full-field electroretinography and pattern electroretinography. Autofluorescence imaging was repeated in 30 patients after periods of up to 9.3 years. Of the 52 patients, 35 underwent optical coherence tomography.
Progressive constriction of the ring was detected in 17 patients. Ring radius reduced by up to 40% at a mean rate of between 0.8% and 15.8% per year. In 1 patient, a small ring was replaced by irregular AF; visual acuity deteriorated over the same period. There was a high correspondence between the lateral extent of the preserved optical coherence tomography inner segment/outer segment band and the diameter of the ring along the same optical coherence tomographic scan plane (slope, 0.9; r = 0.97; P < 0.005; n = 35) and between preserved inner segment/outer segment lamina and the pattern electroretinography P50 measure of macular function (R = 0.72; P < 0.005; n = 34).
Rings of increased AF surround areas of preserved outer retina and preserved photopic function. Serial fundus AF may provide prognostic indicators for preservation of central acuity and potentially assist in the identification and evaluation of patients suitable for treatment aimed at preservation of remaining function.
Scotopic function is an important marker of many retinal diseases and is increasingly used as an outcome measure in clinical trials, such as those investigating gene therapy for Lebers congenital ...amaurosis. Scotopic visual function has traditionally been measured using an adapted perimetry system such as the Humphrey field analyser (HFA). However this system does not control for fixation errors or poor fixation stability. Here we evaluate the use of an adapted microperimeter to measure visual function at defined retinal regions under scotopic conditions.
A MP-1 microperimeter (Nidek Technologies, Italy) was modified by adding a 1 log unit Neutral Density filter and a 530 nm shortpass filter within the optical path of the instrument. Stray light was shielded. Fine matrix mapping perimetry was performed on five younger (< 35 years) and five older (> 65 years) subjects with no eye disease and good vision. All subjects were fully dark adapted before testing and pupils were dilated with 1% tropicamide. Tests was performed once on the modified MP-1 microperimeter and once using a modified HFA, in a counterbalanced order.
A foveal scotopic scotoma with a sensitivity reduction of >1 log unit was found using each instrument. In addition, the MP-1 system showed the retinal location of the foveal scotoma. Mean test time was 25 minutes for the MP-1 and 32 minutes for the HFA.
A modified MP-1 microperimeter can be used to measure scotopic retinal function, creating results which are comparable to the modified Humphrey field analyser. Advantages of the MP-1 system include the ability to track the retina through testing, retinal localisation of the scotoma and a faster test time.
To assess the significance and evolution of parafoveal rings of high-density fundus autofluorescence (AF) in 12 patients with retinitis pigmentosa (RP).
Twelve patients with autosomal recessive RP or ...Usher syndrome type 2 were ascertained who had a parafoveal ring of high-density AF and a visual acuity of 20/30 or better at baseline. Photopic and scotopic fine matrix mapping (FMM) were performed to test sensitivity across the macula. AF imaging and FMM were repeated after 4 to 8 years and optical coherence tomography (OCT) performed.
The size of the AF ring reduced over time and disappeared in one subject. Photopic thresholds were normal over the fovea; thresholds were elevated by 0.6 log units over the ring and by 1.2 log units external to the ring at baseline and differed by less than 0.1 log unit at follow-up. Mild photopic losses close to the internal edge of the ring were detected at baseline or follow-up in all. Mean scotopic thresholds over parafoveal areas within the ring were markedly elevated in 8 of 10 at baseline and were severely elevated in 9 of 11 at follow-up. The eccentricity of the inner edge of the AF ring corresponded closely with the lateral extent of the inner segment ellipsoid band in the OCT image.
Ring constriction was largely coincident with progressive centripetal photopic threshold elevation led by worsening of rod photoreceptor function. The rate of constriction differed across patients, and a ring may reach a critical minimum before disappearing, at which stage central visual loss occurs. The structural and functional changes associated with rings of increased autofluorescence confirm that they provide an objective index of macular involvement and may aid the management of RP patients and the monitoring of future treatment efficacy.
To evaluate the relationship between electrophysiological, psychophysical, and structural measurements in normal and glaucomatous eyes and to test the hypothesis that there is a continuous ...structure-function relationship between ganglion cell numbers and visual field sensitivity.
Thirty-four normal subjects and 40 patients with glaucoma were examined with the pattern electroretinogram (PERG), perimetry and retinal tomography. Transient and steady state (SS) PERGs were recorded, and peak (P)-to-trough (N) amplitude was measured. The unit of differential light sensitivity (DLS) in perimetry is the decibel. The decibel is 10. log(1/Lambert), where the Lambert is the unit of test spot intensity. PERG amplitudes were correlated with decibel and 1/Lambert DLS for the central 18 degrees of the visual field and with neuroretinal rim area in the temporal part of the optic disc. Age-related changes in the structural and functional measurements were sought. The correlation between variables was investigated by linear and quadratic regression analysis. A quadratic (y = ax + bx(2) + c) fit was taken to be significantly better than a linear fit, if the coefficient (b) for the x(2) term was significant at P < 0.05.
A quadratic fit between decibel DLS and PERG amplitude (transient PERG: R(2) = 0.40, P = 0.0000; SS PERG: R(2) = 0.32, P = 0.0000) was significantly better than a linear fit. There was a linear correlation between 1/Lambert DLS and PERG amplitude (transient PERG: R(2) = 0.44, P = 0.0000; SS PERG: R(2) = 0.35, P = 0.0000). There was a linear correlation between temporal neuroretinal rim area and PERG amplitude (transient PERG: R(2) = 0.17, P = 0.0003; SS PERG: R(2) = 0.20, P = 0.0001). A quadratic fit between decibel DLS and temporal neuroretinal rim area (R(2) = 0.38, P = 0.0000) was significantly better than a linear fit. There was a linear correlation between 1/Lambert DLS and temporal neuroretinal rim area (R(2) = 0.30, P = 0.0000). Both DLS and PERG amplitude declined with age in the normal subjects. The rate of decline was -0.17%, -0.74%, -0.75%, and -0.78% per year for decibel DLS, 1/Lambert DLS, transient PERG, and SS PERG, respectively.
There is a curvilinear relationship between decibel DLS and both PERG amplitude and neuroretinal rim area, and a linear relationship between 1/Lambert DLS and PERG amplitude and neuroretinal rim area. These findings support the hypothesis that there is no ganglion cell functional reserve but a continuous structure-function relationship, and that the impression of a functional reserve results from the logarithmic (decibel) scaling of the visual field.
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