Vittoria Murro

Systematic reviews of diagnostic test accuracy and the Cochrane collaboration

Since Cochrane’s Corner focuses on Cochrane systematic reviews, it is important that readers be informed about new publication types within the Cochrane Library (http://www. thecochranelibrary.com), for example systematic reviews of diagnostic test accuracy (DTA). This commentary serves to explain that research on diagnostic test efficacy and impact has recently begun to be based on an expanding set of complex methodological rules. These rules may still be unfamiliar to doctors who rely on and use tests for clinical decisions. A historical perspective

Long-Term Results of Photodynamic Therapy for Choroidal Neovascularization in Pediatric Patients with Best Vitelliform Macular Dystrophy

Abstract Purpose: To report long-term results of photodynamic therapy (PDT) in young patients affected by Best vitelliform macular dystrophy (VMD) complicated by choroidal neovascularization (CNV). Methods: We evaluated a group of 30 VMD patients with confirmed mutations in the BEST1 gene. Five of these patients had been diagnosed with CNV when younger than 15 years of age and three of them were treated by PDT. After the treatment they were followed for an average period of 77 months (range 62–99). Results: In all the treated eyes visual acuity was stable during the first year of follow-up and then slowly improved even some years after the treatment. The improvement in visual acuity was associated with the development of fibrous tissue in the macula. Conclusions: PDT was a safe procedure in our series of pediatric patients with VMD complicated by CNV. It was followed by a CNV regression and a consequent improvement in visual acuity which continued to progress even several years after the treatment.

Retinal capillaritis in a CRB1-associated retinal dystrophy

ABSTRACT Purpose: To report a case of CRB1-associated retinal dystrophy characterized by vitritis, retinal capillaritis, and cystoid macular edema (CME). Methods: A case report. Results: An 8-year-old boy was diagnosed with intermediate uveitis and treated with corticosteroids. He was subsequently diagnosed with retinal dystrophy and found to have two CRB1 mutations. Conclusions: Retinal capillaritis, vitritis, and CME could be inflammatory features of CRB1 retinal dystrophy in our young patient.

Pharmacological Treatments for Neovascular Age-Related Macular Degeneration: Can Mixed Treatment Comparison Meta-Analysis be Useful?

OBJECTIVE To investigated the use of mixed treatment comparison (MTC) meta-analysis models to summarize results from randomized clinical trials (RCTs) on approved pharmacological treatments for neovascular age-related macular degeneration (AMD). METHODS The number of patients with visual loss or visual gain of 3 or more lines of visual acuity (15 ETDRS letters) at 1 year was extracted from 10 RCTs including patients with neovascular AMD and comparing at least one of the following drugs to sham treatment (1080 control patients, 8 studies) or to each other: verteporfin photodynamic therapy (PDT, 1124 patients, 4 studies), pegaptanib (904 patients, 2 twin studies), ranibizumab (984 patients, 4 studies). Both frequentist and Bayesian methods were used to conduct MTCs. RESULTS Direct and indirect evidence was available and found to be overall in good agreement for the comparisons: PDT vs. control, ranibizumab vs. control, ranibizumab vs. PDT. Bayesian model fit was better for a model including a covariate coding for the PIER study ranibizumab regimen, i.e. quarterly injections after three initial monthly doses. In the MTC model, monthly ranibizumab was superior to PDT and pegaptanib, and could not be shown to be better than PIER ranibizumab regarding visual loss, being estimates imprecise. Ranibizumab PIER retreatment regimen was better than PDT and pegaptanib regarding visual loss, whereas an advantage over them regarding visual gain was suggested by a frequentist MTC approach, but not by a Bayesian approach, which was more conservative. A limitation of our MTC model was that only two twin studies connected pegaptanib to the treatment network, and only one study was available for the PIER ranibizumab regimen. CONCLUSION The clinically heterogeneous and sparse typology of the evidence is a limitation to carry out MTC meta-analyses of approved pharmacological treatments for neovascular AMD. Ranibizumab was found to be the most effective treatment compared to PDT and pegaptanib, although this superiority cannot be demonstrated regarding visual gain for the PIER ranibizumab regimen in a Bayesian analytic setting. We did not find RCTs which investigated the current ranibizumab as needed retreatment regimen approved in Europe.

Optical coherence tomography morphology and evolution in cblC disease-related maculopathy in a case series of very young patients

To describe the retinal structure of a group of patients affected by methylmalonic aciduria with homocystinuria cblC type, caused by mutations in the MMACHC gene, using spectral domain optical coherence tomography (SD‐OCT).

Computer-Assisted Evaluation of Retinal Vessel Diameter in Retinitis Pigmentosa

Purpose: The evaluation of retinal vessel attenuation is very subjective and not sufficiently reliable in patients with retinitis pigmentosa (RP). We tested semiautomatic software capable of obtaining real-time measurements of vessel diameter. Methods: Retinal vessel diameter was calculated in 25 RP subjects and in 20 healthy controls. The Mann-Whitney test was used to compare the average values of RP patients with those of controls and subgroups of RP patients with different clinical features. Results: The retinal vessel diameter was significantly smaller in RP patients than in controls (p < 0.001). In particular, vessel diameters were smaller in older subjects, in patients with worse ERG responses, and in patients with more severe visual field loss. Conclusions: Computer-assisted analysis of retinal fundus pictures may be helpful in the diagnosis of RP and in monitoring disease progression.

A novel GRK1 mutation in an Italian patient with Oguchi disease

Oguchi disease is a rare autosomal recessive, non-progressive retinal disorder, first described in the Japanese population. It refers to cases of congenital stationary night blindness (CSNB) in which patients have a characteristic golden-yellow fundus reflex which returns to its normal appearance after long dark adaptation. This particular finding, known as the MizuoNakamura phenomenon, is characteristic but not exclusively of Oguchi disease. In fact, it has been reported in X-linked cone-rod dystrophy and X-linked retinoschisis. Two genes are known causing Oguchi disease: arrestin gene (s-antigen; SAG) and rhodopsin kinase gene (g protein-coupled receptor kinase 1; GRK1), both are involved in rod phototransduction; however, the pathogenesis has not been elucidated. In this report, we identified a novel GRK1 mutation; in particular, this is the first report of GRK1 gene mutation in an Italian patient with Oguchi disease. In November 2014, a 28year-old female was referred to our hospital for a suspected retinal dystrophy. Her parents were consanguineous and family history was positive for inherited retinal disease: a cousin was affected with retinitis pigmentosa (RP). She complained night blindness since her childhood without other ophthalmological symptoms. At presentation, visual acuity was 20/20 in both eyes, no refractive errors were present, anterior segment and intraocular pressure were unremarkable. Fundus appearance showed characteristic golden-yellow reflex throughout the posterior pole to mid-peripheral retina and the Mizuo-Nakamura phenomenon in both eyes, in which the distinctive color of the fundus changed to normal after prolonged dark adaptation (3 hours; Figure 1). Neither vascular attenuation nor degenerative change was seen throughout the retina. Goldmann visual field was within normal limits in each eye. Optical coherece tomography (OCT) was normal in the right eye, and in the left eye it was normal except for the presence of a small subretinal drusenoid-like deposit at the posterior pole, inside the vascular arcades (Figure 1). If we consider peripheral OCT scan, where golden-yellow reflex was present, the OCT image showed a hyper-reflective alteration in correspondence of photoreceptor outer segments. After patching application (prolonged dark adaptation), in the absence of the characteristic reflex, OCT showed a normal outer retinal layer OCT segmentation in the same scan. Full-field standard electroretinogram (ERG) examination demonstrated an estinguished scotopic response, a reduction in both a-wave and b-wave amplitudes in the standard combined ERG with a predominant reduction in b-waves (“negative” configuration) and almost normal photopic amplitudes. When full-field standard ERG was repeated after patching, it was possible to record a scotopic response. Finally, fundus autofluoresence (FAF) was substantially normal in both eyes, in the left eye there was a small hyper-fluorescent dot corresponding to the small subretinal drusenoid-like deposit. Next-generation sequencing genetic screening was performed using the Illumina platform (NextSeqTM500), and a novel mutation in GRK1 gene was reported: c.470T>C (p.Leu157Pro). Sanger method was performed to validate this rare variant sequence. Our reported mutation was probably pathogenetic; in fact, it resulted in an amino acid change from leucine to proline at position 157, which was demonstrated to be in a phylogenetically conserved region (regulatory region of G protein signaling domain) by amino acid alignment analysis. Furthermore, two of the most popular bioinformatics tools [Sorting Intolerant from Tolerant (SIFT, Singapore) and Polymorphism Phenotyping version 2 (Polyphen-2, Boston, MA)], which are used to predict whether the amino acid substitution identified in the our study affected protein function, confirmed this change to be damaging. Further analysis is required in healthy populations to confirm pathogenicity. Mutations in GRK1 are mainly associated with Oguchi disease, although the association of GRK1 mutations with RP has been described. In patient family, a RP-affected relative was reported. Unfortunately, we did not visit him, so we are not sure of the RP diagnosis. However, there is evidence that Oguchi disease and RP can coexist in the same family or even in the same individual, and RP clinical findings even may mask Oguchi ophthalmic signs; furthermore, Oguchi patients can develop RP advanced stage. We have to consider that if there is significant retinal pigment epithelium (RPE) and rod degeneration, the characteristic reflex may be not seeable. Finally, the presence of single subretinal drusenoid-like deposit at the posterior pole of the left eye may represent an isolated finding as reported sometimes in young healthy subjects, or due to underlying retinal dystrophy. In fact, in many inherited conditions, it is easy to recognize different drusenoid deposits

EDI-OCT evaluation of choroidal thickness in retinitis pigmentosa

Purpose: To evaluate choroidal thickness (CT) in retinitis pigmentosa (RP) using enhanced depth imaging (EDI) optical coherence tomography (OCT). Methods: A retrospective analysis of a group of patients with RP who underwent EDI-OCT was performed. Choroidal thickness measurements were compared with those of age- and sex-matched healthy subjects. In the RP group, the possible association between subfoveal CT and some clinical parameters (visual acuity, age, age at disease onset, duration of the disease, macular thickness, visual field loss, electroretinography [ERG]) was evaluated. Results: The study recruited 39 patients with RP with an average age of 43.3 ± 11.3 years while the control group consisted of 73 healthy subjects with an average age of 42.9 ± 12.10 years. On average, CT was significantly thinner in the RP group compared to the controls (p<0.0001). In the RP group, we could not find any significant association between CT and the considered clinical parameters even if there was a trend for decreasing CT with increasing age (r = −0.23, p = 0.096). In the control group, subfoveal CT showed a slightly significant correlation with age (r = −0.21, p = 0.04) but not with macular thickness and visual acuity. Conclusions: In our series, CT was significantly lower in the RP group in comparison with the controls, as measured by EDI-OCT, but did not correlate with age, age at onset, duration of the disease, macular thickness, visual acuity, visual field loss, or ERG responses. Although the clinical implications of choroidal changes in RP have not yet been clearly determined, the evaluation of choroidal features may provide information that could be useful to clarify the pathophysiology of the disease.

Long-Term Follow-Up of Choroidal Neovascularization due to Angioid Streaks with pro re nata Intravitreal Anti-VEGF Treatment

Purpose: To evaluate the long-term outcomes of intravitreal anti-vascular endothelial growth factor (VEGF) drugs with a pro re nata (PRN) regimen for the treatment of choroidal neovascularization (CNV) secondary to angioid streaks (AS). Methods: This is a retrospective, multicenter, noncomparative case series of consecutive AS eyes affected by treatment-naïve CNV. A complete ophthalmologic examination was performed every 30-45 days after the loading phase, including fluorescein angiography and/or optical coherence tomography. Results: In all, 52 eyes of 39 patients were treated with intravitreal bevacizumab and/or ranibizumab and followed up for a mean of 33.8 months. The best corrected visual acuity at baseline was 20/40, and it deteriorated by an average of 6.8 ETDRS letters per year (p < 0.001). We performed an average of 5.1, 6.5, and 6.8 injections at the 1-, 2-, and 3-year follow-up, respectively. Conclusions: Intravitreal anti-VEGF drugs in a PRN regimen with close monitoring appear to slow the progression of CNV in AS, but they do not prevent the affected eyes from progressive visual loss.

Reading ability and quality of life in Stargardt disease

Purpose To study the reading performance of patients with Stargardt disease (STGD) and the relationship between clinical vision measurements and vision-related quality of life (VRQOL). Methods We studied both eyes of 16 patients with STGD. Each patient was examined for best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS]), reading ability (MNREAD and REX charts), contrast sensitivity (Pelli-Robson charts), fixation study (MP1 microperimeter), and VRQOL (25-item National Eye Institute Visual Function Questionnaire [NEI VFQ-25]). The correlation pattern among these variables was examined and an exploratory factor analysis was used to investigate dimensionality of both visual function and VRQOL. Results Mean ETDRS visual acuity was about 20/160 (0.9 logMAR). All studied psychophysical measures were highly or moderately correlated with MNREAD reading speed (p<0.05 level). A similar correlation was found between psychophysical measures and VRQOL, which was higher for MNREAD measures of acuity (r = -0.75) and speed (r = 0.74). Accordingly, exploratory factor analysis suggested that a single latent dimension explained most of the variance of vision psychophysical measures as well as of VRQOL. Conclusions We propose that reading ability should be assessed in patients with STGD, since we found that both MNREAD reading speed and visual acuity are strong determinants of quality of life. The observed relation between reading ability and VRQOL in STGD suggests that in these patients appropriate low vision rehabilitation can improve both reading performance and consequently VRQOL. Finally, our data support the use of reading speed and visual acuity as important outcome measures for monitoring STGD progression.