Lucia Ziccardi

Intravitreal bevacizumab (Avastin®) in proliferative diabetic retinopathy

Purpose:  To evaluate the efficacy and safety of intravitreal bevacizumab in proliferative diabetic retinopathy (PDR) patients.

Optical Coherence Tomography in Alzheimer’s Disease: A Meta-Analysis

Background Alzheimer’s disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies. Methods and Findings Data sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls. Results 11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p<0.0001) patients compared to HC. RNFL in the 4 quadrants were all significantly thinner in AD superior (superior WMD = -24.0, 95% CI: -34.9 to -13.1, p<0.0001; inferior WMD = -20.8, 95% CI: -32.0 to -9.7, p<0.0001; nasal WMD = -14.7, 95% CI: -23.9 to -5.5, p<0.0001; and temporal WMD = -10.7, 95% CI: -19.9 to -1.4, p<0.0001); the same significant reduction in quadrant RNFL was observed in MCI patients compared with HC (Inferior WMD = -20.22, 95% CI: -30.41 to -10.03, p = 0.0001; nasal WMD = -7.4, 95% CI: -10.08 to -4.7, p = 0.0000; and temporal WMD = -6.88, 95% CI: -12.62 to -1.13, p = 0.01), with the exception of superior quadrant (WMD = -19.45, 95% CI: -40.23 to 1.32, p = 0.06). Conclusion Results from the meta-analysis support the important role of OCT for RNFL analysis in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments.

Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer

Strategies aimed at invoking synaptic plasticity have therapeutic potential for several neurological conditions. The human retinal synaptic disease X-linked retinoschisis (XLRS) is characterized by impaired visual signal transmission through the retina and progressive visual acuity loss, and mice lacking retinoschisin (RS1) recapitulate human disease. Here, we demonstrate that restoration of RS1 via retina-specific delivery of adeno-associated virus type 8-RS1 (AAV8-RS1) vector rescues molecular pathology at the photoreceptor-depolarizing bipolar cell (photoreceptor-DBC) synapse and restores function in adult Rs1-KO animals. Initial development of the photoreceptor-DBC synapse was normal in the Rs1-KO retina; however, the metabotropic glutamate receptor 6/transient receptor potential melastatin subfamily M member 1-signaling (mGluR6/TRPM1-signaling) cascade was not properly maintained. Specifically, the TRPM1 channel and G proteins Gαo, Gβ5, and RGS11 were progressively lost from postsynaptic DBC dendritic tips, whereas the mGluR6 receptor and RGS7 maintained proper synaptic position. This postsynaptic disruption differed from other murine night-blindness models with an electronegative electroretinogram response, which is also characteristic of murine and human XLRS disease. Upon AAV8-RS1 gene transfer to the retina of adult XLRS mice, TRPM1 and the signaling molecules returned to their proper dendritic tip location, and the DBC resting membrane potential was restored. These findings provide insight into the molecular plasticity of a critical synapse in the visual system and demonstrate potential therapeutic avenues for some diseases involving synaptic pathology.

Impact of regional retinal responses on cortical visually evoked responses: Multifocal ERGs and VEPs in the retinitis pigmentosa model

OBJECTIVE To determine the impact of the regional retinal responses on cortical visually evoked responses, by evaluating the relationship between multifocal ERG (mfERG) and multifocal VEP (mfVEP), in the retinitis pigmentosa (RP) model. METHODS MfERGs and mfVEPs were recorded from 20 typical RP patients. Response amplitude density (RAD, nV/deg(2)) and implicit time (ms) of the mfERG 1st order binary kernel (N1-P1) and mfVEP 2nd order binary kernel (P1) components were measured. Ring analysis, matched for mfERG and mfVEP stimuli, was performed between fovea and mid-periphery (0-2.5, 2.5-5, 5-10, 10-15 and 15-20deg). RESULTS At central and pericentral retinal regions (four eccentricities between 0 and 15deg), mfERG N1 RADs were positively correlated (r0.68, p<0.01) with corresponding mfVEP P1 RADs. Similarly, mfERG P1 implicit times were positively correlated (r>or=0.65, p<0.01) with corresponding mfVEP N1 implicit times. CONCLUSIONS There are quantitative correlations between mfERG and mfVEP components in RP. SIGNIFICANCE The data suggest that regional responses of the photoreceptors and off-bipolar cells, the main generators of mfERG N1, have a major impact on the corresponding cortical activity.

Investigation of Adaptive Optics Imaging Biomarkers for Detecting Pathological Changes of the Cone Mosaic in Patients with Type 1 Diabetes Mellitus.

Purpose To investigate a set of adaptive optics (AO) imaging biomarkers for the assessment of changes of the cone mosaic spatial arrangement in patients with type 1 diabetes mellitus (DM1). Methods 16 patients with ≥20/20 visual acuity and a diagnosis of DM1 in the past 8 years to 37 years and 20 age-matched healthy volunteers were recruited in this study. Cone density, cone spacing and Voronoi diagrams were calculated on 160x160 μm images of the cone mosaic acquired with an AO flood illumination retinal camera at 1.5 degrees eccentricity from the fovea along all retinal meridians. From the cone spacing measures and Voronoi diagrams, the linear dispersion index (LDi) and the heterogeneity packing index (HPi) were computed respectively. Logistic regression analysis was conducted to discriminate DM1 patients without diabetic retinopathy from controls using the cone metrics as predictors. Results Of the 16 DM1 patients, eight had no signs of diabetic retinopathy (noDR) and eight had mild nonproliferative diabetic retinopathy (NPDR) on fundoscopy. On average, cone density, LDi and HPi values were significantly different (P<0.05) between noDR or NPDR eyes and controls, with these differences increasing with duration of diabetes. However, each cone metric alone was not sufficiently sensitive to discriminate entirely between membership of noDR cases and controls. The complementary use of all the three cone metrics in the logistic regression model gained 100% accuracy to identify noDR cases with respect to controls. Conclusion The present set of AO imaging biomarkers identified reliably abnormalities in the spatial arrangement of the parafoveal cones in DM1 patients, even when no signs of diabetic retinopathy were seen on fundoscopy.

Regional cone-mediated dysfunction in age-related maculopathy evaluated by focal electroretinograms: relationship with retinal morphology and perimetric sensitivity.

Purpose: To assess regional cone-mediated function in age-related maculopathy (ARM) by focal electroretinograms (FERGs), and to compare FERGs with morphologic changes and perimetric sensitivity at corresponding locations. Methods: Twenty-six ARM patients and 12 age-matched controls were evaluated. FERGs were elicited by either a central (0–2.25°, C) or a paracentral annular (2.25–9°, PC) flickering (41 Hz) field, presented on a light-adapting background. Morphological changes (soft drusen and/or retinal pigment epithelium defects) at matched locations were assessed by fundus photography and fluorescein angiography. Perimetric sensitivity was measured by Octopus 10° program (tM2). Results: When compared to controls, mean C and PC FERG amplitudes of patients were reduced (p < 0.01), and the mean PC FERG phase was delayed (p < 0.01). Both FERG delays and morphologic lesions tended to involve to a greater extent the PC compared to the C region. In the C region, perimetric losses were correlated with the extent of morphologic lesions (p < 0.05). In the PC region, perimetric losses were correlated with FERG amplitudes (p < 0.05). Conclusions: In ARM, FERG losses are eccentricity-dependent, not quantitatively linked to retinal morphology, and correlated with perimetric losses, suggesting a heterogeneous dysfunction with loss of both C and PC perimetric sensitivities.

Pigmentary degenerative maculopathy as prominent phenotype in an Italian SPG56/ CYP2U1 family

SPG56 is an autosomal recessive form of hereditary spastic paraplegia (HSP) associated with mutations in CYP2U1. There is no clear documentation of visual impairment in the few reported cases of SPG56, although this form is complex on clinical ground and visual deficit are extremely frequent in complicated HSP. We report three patients in a consanguineous family harboring the novel homozygous c.1168C>T (p.R390*) in SPG56/CYP2U1, and showing a pigmentary degenerative maculopathy associated with progressive spastic paraplegia. Furthermore, we characterized precisely the ophthalmologic phenotype through indirect ophthalmoscopy, retinal optical coherence tomography and visual evoked potentials. This is the first formal report of pigmentary degenerative maculopathy associated with a CYP2U1 homozygous mutation.

Multimodal Approach to Monitoring and Investigating Cone Structure and Function in an Inherited Macular Dystrophy

PURPOSE To examine a female subject, her father, and a brother harboring a missense mutation of the retinitis pigmentosa 1-like 1 (RP1L1) gene, over 2 years of follow-up. DESIGN Observational case series. METHODS setting: Fondazione G.B. Bietti IRCCS, Rome, Italy. STUDY POPULATION RP1L1 family members and controls. MAIN OUTCOME MEASURES Images of the cone mosaic acquired with an adaptive optics retinal camera, spectral-domain optical coherence tomography (SD OCT), and full-field and multifocal electroretinography (mfERG). RESULTS In the proband, best-corrected visual acuity (≤0.7 logMAR) was stable in both eyes during follow-up, though analysis of adaptive optics images showed decreased cone density in the central 9 degrees from the fovea with respect to controls (P < .05) and cone density loss in the parafoveal area (2 degrees; <12%-16%) during follow-up. Texture analysis of SD OCT images identified abnormalities of the ellipsoid zone in the central 7 degrees, while mfERG response amplitudes were reduced only in the central 5 degrees relative to controls. In the probands father, who had 0.0 logMAR visual acuity, significant cone loss was found in the central 7 degrees from the fovea (P < .05); abnormal SD OCT and mfERG values with respect to controls were found in corresponding retinal areas. No defects in the cone structure and function were found in the probands brother, who had 0.0 logMAR visual acuity. CONCLUSIONS Occult macular dystrophy was diagnosed based on genetic and multimodal ophthalmic findings. The quantitative assessment of photoreceptor survival or loss, based on analysis of adaptive optics retinal images, was valuable to monitor disease progression at a cellular level.

Long-term decline of central cone function in retinitis pigmentosa evaluated by focal electroretinogram

PURPOSE We evaluated long-term changes of central cone-mediated function in retinitis pigmentosa (RP) patients by recording focal electroretinograms (fERG). METHODS A cohort of 43 RP patients was followed from 4 to 16 years (average follow-up 9.3 years, average 10 examinations/patient) by recording the fERG response to a flickering uniform red field overlaying the central 18° of visual field (VF). Statistical censoring led to a reduced dataset of 32 patients (autosomal dominant 9, recessive 5, sporadic 5, x-linked 1, Usher II 12), from which long-term decay rates were estimated by global fitting of individual fERG amplitude time-curves. RESULTS Long-term follow-up of central cone FERG amplitude showed two main features: short-term variability and long-term decline. fERG short-term variability range was 0.14 to 0.2 log units. Mean yearly decay rate of central fERG was 5.6% (95% confidence interval [CI] 4%-7%). Yearly decline depended on inheritance pattern, being significantly greater in autosomal recessive and sporadic compared to autosomal dominant RP. The degree of central cone fERG decline was unrelated to the size of the residual VF. CONCLUSIONS The decline of central cone function is significantly slower than global cone function decline in RP. Central cone fERG loss is independent of residual VF.

Macular function in eyes with open-angle glaucoma evaluated by multifocal electroretinogram

PURPOSE To evaluate macular function in patients with open-angle glaucoma (OAG) by means of multifocal electroretinogram (mfERG). METHODS Twenty-four OAG patients (mean age 54.6 ± 9.1 years) and 14 age-similar controls were enrolled. OAG patients had intraocular pressure (IOP) less than 18 mm Hg with topical medical treatment, 24-2 visual field (Humphrey Field Analyzer [HFA]) with mean deviation (MD) between -2 and -12 dB, and corrected pattern standard deviation (CPSD) between +2 and +10 dB and no history or presence of cataract and/or macular disease. MfERGs in response to 61 M-stimuli presented to the central 20° of the visual field were assessed in OAG patients (24 eyes) and in controls (14 eyes). Ring (R) analysis was performed every five retinal eccentricities in areas between the fovea and midperiphery: 0° to 2.5° (R1), 2.5° to 5° (R2), 5° to 10° (R3), 10° to 15° (R4), and 15° to 20° (R5). MfERG response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg(2)) and P1 implicit time (P1 IT, ms) of the first-order binary kernel were measured for each ring. RESULTS OAG patients showed a significant (P < 0.01) decrease in N1-P1 RADs and an increase in P1 IT in both R1 and R2 with respect to controls. The reduction in N1-P1 RADs was significantly (P < 0.01) correlated with HFA MD and CPSD. No other significant differences between OAG and controls were found. CONCLUSIONS OAG patients show macular dysfunction detectable by the mfERG technique. Since the mfERG N1-P1 component is thought to be generated by preganglionic elements (photoreceptors and OFF bipolar cells), our data support the functional impairment of the neural generators of the macular region in patients with glaucoma.