Maria Sole Sartini

Clinical Features of Dysthyroid Optic Neuropathy: A European Group on Graves Orbitopathy (EUGOGO) Survey

Background: This study was performed to determine clinical features of dysthyroid optic neuropathy (DON) across Europe. Methods: Forty seven patients with DON presented to seven European centres during one year. Local protocols for thyroid status, ophthalmic examination and further investigation were used. Each eye was classified as having definite, equivocal, or no DON. Results: Graves’ hyperthyroidism occurred in the majority; 20% had received radioiodine. Of 94 eyes, 55 had definite and 17 equivocal DON. Median Clinical Activity Score was 4/7 but 25% scored 3 or less, indicating severe inflammation was not essential. Best corrected visual acuity was 6/9 (Snellen) or worse in 75% of DON eyes. Colour vision was reduced in 33 eyes, of which all but one had DON. Half of the DON eyes had normal optic disc appearance. In DON eyes proptosis was > 21 mm (significant) in 66% and visual fields abnormal in 71%. Orbital imaging showed apical muscle crowding in 88% of DON patients. Optic nerve stretch and fat prolapse were infrequently reported. Conclusion: Patients with DON may not have severe proptosis and orbital inflammation. Optic disc swelling, impaired colour vision and radiological evidence of apical optic nerve compression are the most useful clinical features in this series.

Macular pucker: To peel or not to peel the internal limiting membrane? a microperimetric response

Background: To compare functional and anatomical outcomes after idiopathic macular pucker removal between eyes that underwent internal limiting membrane (ILM) peeling and eyes that did not. Methods: In this multicentric, randomized clinical trial, 60 eyes of 60 patients affected with idiopathic macular pucker were enrolled. Thirty eyes underwent 23-gauge pars plana vitrectomy associated with ILM peeling (“ILM peeling group”), whereas 30 eyes did not undergo ILM peeling (“ILM not peeling group”). Retinal sensitivity, frequency of microscotomas, and all the other microperimetric parameters were tested by MP1 microperimetry. Best-corrected visual acuity was investigated with the Early Treatment Diabetic Retinopathy Study chart. Anatomical outcomes were analyzed with spectral domain optical coherence tomography. Results: After a 12-month follow-up, the mean retinal sensitivity in the 4° central area showed a greater and faster recovery in the ILM not peeling group than in the ILM peeling group (P = 0.041). The number of absolute microscotomas (0 dB) within the 12° central retinal area was significantly higher in the ILM peeling group than in the ILM not peeling group (P = 0.044). Conclusion: The ILM not peeling group seems to show better outcomes than the ILM peeling group as measured by mean retinal sensitivity and number of microscotomas after a 12-month follow-up.

Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration

Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruchs membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions.

VEGF-A polymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration

AIM To investigate the association between VEGF gene SNPs and early response to intravitreal ranibizumab for exudative age-related macular degeneration. MATERIALS & METHODS Sixty-four patients (64 eyes) were prospectively enrolled and treated for neovascular age-related macular degeneration with ranibizumab monotherapy. Visual acuity was measured using the ETDRS chart. A loading phase of 3 monthly intravitreal injections of ranibizumab 0.5 mg/0.05 ml was performed. The analyzed VEGF-A gene SNPs were rs699947 (-2578A/C) and rs1570360 (-1154G/A); the allelic discrimination was performed in real-time PCR platform. The difference of best corrected visual acuity (ETDRS letters) read before and after treatment was considered as functional outcome. RESULTS Ranibizumab was significantly more effective as measured by best corrected visual acuity in patients harboring the VEGF-A -2578C allele (from +6.26 to +7.44 ETDRS letters), whereas patients carrying the VEGF-A -2578AA genotype revealed an absence of early functional response to ranibizumab (-1.78 ETDRS letters; p = 0.0192). CONCLUSION This study suggests that the VEGF-A -2578A/C SNP may represent an important molecular determinant of the early functional outcome of ranibizumab. Original submitted 3 December 2012; Revision submitted 18 February 2013.

Aflibercept administration in neovascular age-related macular degeneration refractory to previous anti-vascular endothelial growth factor drugs: a critical review and new possible approaches to move forward

PurposeThe recent introduction of anti-VEGF drugs has widely changed the prognosis of exudative age-related macular degeneration (AMD), even if a variable percentage of patients showed an insufficient response. Aflibercept is a new anti-VEGF drug approved by FDA for the treatment of exudative AMD with a wider binding capacity than either bevacizumab or ranibizumab. Therefore, the purposes were as follows: (i) to report anatomical and functional outcomes of switching from bevacizumab/ranibizumab to aflibercept previously described in the scientific literature, (ii) to hypothesize the possible pathophysiological mechanisms of the resistance and tachyphylaxis to anti-VEGF drugs, and (iii) to suggest possible clinical actions to increase the chances of success for such difficult cases.MethodsWe reviewed the available scientific literature in Medline, Cochrane database, Current Contents, PubMed, and cross-referencing from identified articles, regarding the treatment of exudative AMD patients refractory to bevacizumab and/or ranibizumab and switched to aflibercept monotherapy. We included in this review all the cases in which the diagnosis of refractory or resistant exudative AMD was properly made, and the results of at least one aflibercept injection were described.FindingsWe reported the outcomes of 21 papers for a total of 1066 eyes affected by exudative AMD resistant to previous anti-VEGF drug injections and switched to aflibercept. Enrolled reports were divided into two groups: 5 prospective reports and 16 retrospective reports. All the reported papers conclude their analysis, stating that switching from bevacizumab/ranibizumab to aflibercept injections can improve outcomes successfully in refractory neovascular AMD patients.ImplicationsAnalysis of the papers reported in this review demonstrates that switching from bevacizumab/ranibizumab to aflibercept injections can improve outcomes successfully in refractory neovascular AMD patients. The mechanism for these effects is not yet completely understood.

The rs2071559 AA VEGFR-2 Genotype Frequency Is Significantly Lower in Neovascular Age-Related Macular Degeneration Patients

In this prospective, case-control genetic study, 120 consecutive neovascular age-related macular degeneration (AMD) cases and 78 controls were enrolled. Two SNPs (rs2071559 and rs1870377) of VEGF-A receptor-2 (VEGFR-2) gene were analyzed with the technique of Real-Time PCR to investigate a genetic link between AMD and VEGFR-2 gene polymorphisms in Italian patients. The frequency of the VEGFR-2 genotype rs2071559 AA was significantly lower (18.33%) in patients with AMD than in the control subjects (34.62%; P = 0.0095, chi-square test; P corr = 0.038; OR = 0.42, 95% CI 0.22 to 0.82). In conclusion, although with the limitations of a small sample size and the few SNPs studied, this study demonstrates a lower frequency of VEGFR-2 rs2071559 AA genotype in an AMD patient population, suggesting future studies on the role VEGFR-2 SNPs.

IL-8 and VEGFR-2 polymorphisms modulate long-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration.

AIM To investigate possible associations between VEGFR-2 and IL-8 gene SNPs and 1-year response to intravitreal ranibizumab for exudative age-related macular degeneration. MATERIALS & METHODS Sixty-four eyes underwent a loading phase of three monthly intravitreal injections of ranibizumab 0.5 mg/0.05 ml followed by Pro Re Nata retreatment. VEGFR-2 rs2071559 (-604 A/G) and IL-8 rs4073 (-251 A/T) were analyzed. RESULTS Ranibizumab was significantly more effective as measured by visual acuity in patients harboring the IL-8 rs4073 TT genotype (p = 0.045), whereas patients carrying the VEGFR-2 rs2071559 CC genotype revealed better functional response as measured by mean retinal sensitivity (p = 0.034). CONCLUSION IL-8 rs4073 and VEGFR-2 rs2071559 genotypes may represent important molecular determinants to modulate final outcomes in neovascular age-related macular degeneration patients.

Bimatoprost 0.01% vs bimatoprost 0.03%: a 12-month prospective trial of clinical and in vivo confocal microscopy in glaucoma patients

PurposeTo evaluate the safety of two commercially available formulations of bimatoprost eye drops: 0.03 and 0.01% ophthalmic solutions.MethodsThis was a randomized, prospective, parallel-group, open-label, cohort study. A total of 60 glaucoma patients (60 eyes) under bimatoprost 0.03% monotherapy since at least 1 year were enrolled. Selected patients were randomized to receive a single drop of bimatoprost 0.01% (n=30) or bimatoprost 0.03% (n=30) ophthalmic solutions for 12 months. Statistical analysis was performed using paired t-test and repeated measures ANOVA test.ResultsGlobal clinical score (the sum of pruritus, stinging/burning, blurred vision, sticky eye sensation, eye dryness sensation, and foreign body sensation) significantly decreased in the bimatoprost 0.01% group from baseline 4.7±3.8 to 2.9±2.3 (P<0.001) and 2.5±2.0 (P<0.001) at 6-month and 12-month follow-ups, respectively. Comparison between groups showed differences at both follow-up visits (P=0.003 and P<0.001, respectively). In vivo confocal microscopy revealed a significant increase in goblet cell density in the bimatoprost 0.01% group compared with the bimatoprost 0.03% group (P<0.001 at both follow-up visits). All functional parameters and conjunctival hyperemia improved in the bimatoprost 0.01% group at each follow-up visit (P<0.05) and in comparison with bimatoprost 0.03% (P<0.05).ConclusionThe results of this trial suggest that bimatoprost 0.01% eye drops seem to decrease the ocular discomfort with respect to bimatoprost 0.03% eye drops.

Analysis of Functional Dissociations between Best Corrected Visual Acuity and Microperimetric Parameters in Neovascular Age-Related Macular Degeneration Patients Underwent to Three Monthly Ranibizumab Injections

Background: To analyze the sensitivity of best corrected visual acuity and microperimetry to detect significant visual changes after 3 intravitreal ranibizumab in exudative age-related macular degeneration. Design: Prospective, open-label study. Participants: 50 eyes of 50 naive patients affected by neovascular age-related macular degeneration were enrolled. Methods: Enrolled patients underwent to a loading phase of 3 monthly intravitreal injections of ranibizumab. Best-corrected visual acuity was investigated with the ETDRS chart at 4 m. Central retinal sensitivity was tested with microperimetry using a Goldmann III stimulus to 33 points over the 12° central of the macula with a 4-2 double staircase strategy. Main outcome measures: Comparison of changes in mean 4° central retinal sensitivity and best-corrected visual acuity in “BCVA relatively stable patients” (defined as change ≤ ± 4 ETDRS letters after treatment). Analysis of a possible relationship between changes in best-corrected visual acuity and 4° central retinal sensitivity in “mean 4° central retinal sensitivity relatively stable patients” (defined as change in mean retinal sensitivity ≤ ± 2dB) Results: Mean best-corrected visual acuity improved of 5.90 ± 11.29 ETDRS letters (P=0.0006). Total mean retinal sensitivity improved +1.59 ± 2.12 dB (P<0.0001), while in the 4° central retinal area the increase was +1.36 ± 3.45 dB (P=0.0078). 38% of patients (19 eyes) were considered as “BCVA relatively stable patients”. In this subgroup, Pearson’s correlation analysis showed a direct correlation between changes observed with both methods (r = 0.71; P = 0.002). 48% of patients (24 eyes) were considered as “Mean 4° central retinal sensitivity relatively stable patients”. In this subgroup, Pearson’s correlation analysis didn’t show a relationship between changes observed with both methods (r = 0.11; P = 0.56). Conclusions: Microperimetry central retinal sensitivity seems to be an important to complete the functional evaluation in patients with wet age-related macular degeneration after 3 intravitreal ranibizumab.