Moreno Menghini

Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD.

PURPOSE Neovascular age-related macular degeneration (AMD) resulting in decreased central vision severely impairs affected individuals. Current standard treatment is an intravitreal anti-VEGF therapy (ranibizumab), but responses to treatment show large variability. Genetic factors that influence AMD and that affect the outcome of ranibizumab treatment were sought within a sample of Swiss patients. METHODS Changes in visual acuity (VA) after initiation of anti-VEGF treatment were observed during 12 months, and percentiles of VA were calculated. Genotypes of polymorphisms in known AMD susceptibility loci (CFH, CFB, HTRA1, AMRS2, and VEGFA) as well as not yet reported AMD-associated genes (KDR, LRP5, and FZD4) were determined, and their frequencies were compared. RESULTS Of the 309 eyes included in the study, 243 completed VA assessment. On average, 3.9 ±2.6 ranibizumab injections were administered. Based on the change in visual acuity, two responder groups were established: 63 eyes were assigned to the poor responders (≤25th percentile) and 63 eyes to the good responders (≥75th percentile). Individuals with genotype CC of p.Y402H in CFH had a decreased chance of positive treatment outcome compared with those with the CT and TT genotypes (P = 0.005 and P = 0.006). In this study, the genotype combination of AG at CFH with CT at FZD4 (SNP rs10898563) promised an increased chance of positive treatment outcome (P = 0.004). Furthermore, the association with the known genetic susceptibility loci CFH, HTRA1, and AMRS2 were confirmed, and a risk-conferring polymorphism in one new locus, LRP5, was identified. CONCLUSIONS Genetic predisposition may account for the variability in response to anti-VEGF treatment.

Impact of Loading Phase, Initial Response and CFH Genotype on the Long-Term Outcome of Treatment for Neovascular Age-Related Macular Degeneration

Objective Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome. Methods Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr). Results 204 eyes were included. A change of +5.0 [−1;+11] letters and +1.5 [−5.5;+9.5] was observed with a median of 4 [3]; [7] and 10 [7]; [14] ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01). Conclusions Our data suggest that clinical decisions regarding treatment may be guided by observing patients’ initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value.

Response to Ranibizumab Therapy in Neovascular AMD – An Evaluation of Good and Bad Responders

BACKGROUND Treatment of neovascular age-related macular degeneration (AMD) with Lucentis shows a broad spectrum regarding the course of visual acuity (VA). While some patients show a good response (increase in VA), others disclose much less promising results. PATIENTS AND METHODS A retrospective data analysis of all eyes treated for neovascular AMD at the University Hospital of Zurich, Switzerland for at least 12 months was carried out. The courses of VA between the 90th (good responders, GR) and the 10th (bad responders, BR) percentiles were compared at 3, 12 and 24 months from baseline. An analysis regarding demographic data, lesion type and size as well as injection frequency and visits was done and predictive factors for GR and BR were evaluated. RESULTS Marked differences in the course of VA between GR (n = 30) and BR (n = 30) are already observed 3 months from baseline. In GR the gains in VA after 3, 12 and 24 were 15.7 +/- 9 letters ETDRS, 25.3 +/- 7 and 14.0 +/- 14. BR showed a deterioration of 8.3 +/- 11 letters ETDRS after 3, 22.1 +/- 8 after 12 and 23.6 +/- 13 after 24 months. The gender distribution was equal with a higher percentage of female patients (64 % in BR and 66 % in GR). The baseline VA was statistically significantly lower in GR (45.7 +/- 10 vs. 55.4 +/- 11, p < 0.05) than in BR. No other significant differences in baseline data were found, and no predictor for group membership could be identified. CONCLUSIONS Only the course of VA in the first three months seems to be of value for an estimation of the response to treatment. In the future the response to treatment in the early phase may influence the treatment algorithm and the injection frequency.

Treatment of traumatic corneal abrasions: a three-arm, prospective, randomized study.

Purpose: To compare three different treatment modalities for traumatic corneal abrasions. Methods: We conducted a prospective, randomized, masked, three-arm clinical study of patients presenting with superficial corneal foreign bodies. Treatment modalities were: (1) pressure patching with ofloxacin ointment (patch group, PG, n = 18), (2) therapeutic contact lens with ofloxacin eye drops (contact lens group, CLG, n = 20) and (3) ofloxacin ointment alone (ointment group, OG, n = 28). Primary outcome measure was the difference of the mean corneal abrasion area between the three groups at 3 different time points (baseline, day 1 and day 7). Results: A total of 66 patients were included in the study over a period of 2 years. Mean initial corneal abrasion area was 3.6 ± 3.4 mm2 in the PG, 4.2 ± 4.0 mm2 in the CLG and 3.7 ± 3.1 mm2 in the OG (p = 0.875). Differences in corneal abrasion area at any time point were not statistically significant (abrasion area decrease from presentation to day 1 was 3.4 ± 3.3 mm2 in the PG, 4.1 ± 4.0 mm2 in the CLG and 3.5 ± 3.1 mm2 in the OG, p = 0.789). The epithelium was healed in all patients at day 7. Conclusions: Treating traumatic corneal abrasions by pressure patching, a bandage contact lens or ointment alone was equal in reducing the abrasion area or reducing pain. According to our results the treatment of choice for traumatic abrasions may be adapted to the needs and preferences of the patient.

The ocular pulse amplitude as a noninvasive parameter for carotid artery stenosis screening: a test accuracy study.

PURPOSE To investigate a potential correlation between the ocular pulse amplitude (OPA; i.e., the intraocular pressure difference between the systolic and diastolic phases of the heartbeat) and the severity of carotid artery stenosis (CAS) and to test its role as a screening parameter for CAS during routine ophthalmic examination. DESIGN Test accuracy study. PARTICIPANTS Patients referred for color duplex ultrasound examination of the extra- and intracranial cerebral arteries were enrolled consecutively. METHODS We measured OPA on both eyes by dynamic contour tonometry. Multivariate analyses were performed with risk factors for CAS (age, total cholesterol, low-density lipoprotein, and triglycerides) to compare the diagnostic value of OPA measurements with other non- or minimally invasive screening parameters. MAIN OUTCOME MEASURES The difference between OPA measurements in patients with no (<50%) and patients with severe CAS (>70%) as well as the value of OPA measurements to predict the severity of CAS taking further risk factors of CAS into consideration. RESULTS One hundred thirty-four eyes of 67 patients (25 women, 42 men) with a mean age of 67±13 years (range, 25-87) were included. The means of the OPA values of those patients showing no CAS (<50%) differed significantly (P = 0.036) from those with a stenosis of ≥70%. The multivariate model produced a statistically significant odds ratio (0.46; P = 0.007) for CAS of ≥70%. CONCLUSIONS The results of the present study provide proof of principle that the OPA is reduced in patients with CAS and may be used as a noninvasive, inexpensive, readily available, and unconfounded screening parameter to detect CAS and possibly to reduce the incidence of stroke. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Corneal melting two weeks after pterygium excision with topical mitomycin C: successfully treated with lamellar keratoplasty and amnion membrane transplantation.

Purpose: To report the management of a case of corneal melting two weeks after pterygium excision with intraoperative topical mitomycin C (MMC). Methods: Case report. Results: A 57-year-old male was referred to our Department for therapy of rapidly progressive corneal melting two weeks after primary pterygium surgery with MMC (0.2 mg/ml) in September 2009. Initial treatment consisted of topical and systemic immunosuppression along with topical antibiotics. Eight days after presentation, the patient underwent successful lamellar keratoplasty and amnion membrane transplantation. Subconjunctival injection of triamcinolone (40 mg/ml) and topical bevacizumab were used to manage the increased fibrovascular activity around the site of the former pterygium. Conclusion: Topical use of MMC during pterygium surgery may be related to serious postoperative complications such as progressive inflammatory corneal melting. The etiology may be multifactorial, which is related to MMC-induced inflammation and/or induced apoptosis. A therapeutic option is the described combination of systemic and local anti-inflammatory treatment along with lamellar keratoplasty and amniotic membrane transplantation. Adjunctive therapy may be needed if recurrence occurs.

The predictive value of OCT characteristics for the visual outcome in neovascular AMD.

BACKGROUND The intravitreal injection of an anti-VEGF compound is the current standard of care in neovascular AMD. The response to this therapy varies greatly. To date it was not possible to determine clear predictive factors in regard to therapy response, thus making it difficult when counselling patients regarding the probability for visual improvement. The aim of this study was to evaluate baseline OCT characteristics in regard to their predictive value on the outcome of visual acuity (VA) after 12 months. PATIENTS AND METHODS A retrospective analysis of 75 eyes with neovascular AMD treated with intravitreal anti-VEGF injections at the University Hospital of Zurich with a documented follow-up of at least 12 months. Measurement and comparison of the following OCT structures were undertaken: central retinal thickness (CRT), integrity of the IS/OS junction, and presence of intra- or subretinal fluid. VA at baseline and after 12 months was evaluated. OCT findings were compared between eyes that gained ≥ 5 letters ETDRS (group 1) and eyes that did not (group 2). RESULTS 75 eyes with a mean baseline VA of 57.2 ± 15 letters and a mean baseline CRT of 430 ± 226 μm were analyzed. Although baseline VA did not differ statistically significantly, eyes in group 2 had a higher VA than eyes in group 1 (60.2 ± 16.2 vs. 54.9 ± 13.6, p = 0.123). In group 1 the change of VA after 12 months was 12.6 ± 8.0 letters while it was -5.0 ± 7.8 letters in group 2. No statistically significant differences between the two groups with respect to the analyzed OCT parameters were found. None of the analyzed OCT factors had a predictive value regarding the VA outcome at month 12. CONCLUSIONS Our study was not able to find baseline OCT parameters that could predict the course of VA after 12 months. However, eyes with a thicker central retinal thickness at presentation showed a greater reduction in CRT during the analyzed period. This was associated with a more favourable course in VA. Perhaps this might be due to a less pronounced initial morphological retinal damage.

Regulatory regions of the paraoxonase 1 (PON1) gene are associated with neovascular age-related macular degeneration (AMD)

Physiological stress response and oxidative damage are factors for aging processes and, as such, are thought to contribute to neovascular age-related macular degeneration (AMD). Paraoxonase 1 (PON1) is an enzyme that plays an important role in oxidative stress and aging. We investigated association of DNA sequence variants (SNP) within the upstream regulatory region of the PON1 gene with neovascular AMD in 305 patients and 288 controls. Four of the seven tested SNPs (rs705379, rs705381, rs854573, and rs757158) were more frequently found in AMD patients compared to controls (P = 0.0099, 0.0295, 0.0121, and 0.0256, respectively), and all but one (SNP rs757158) are in linkage disequilibrium. Furthermore, haplotype TGGCCTC conferred protection (odds ratio (OR) = 0.76, (CI) = 0.60–0.97) as it was more frequently found in control individuals, while haplotype CGATGCT increased the risk (OR = 1.55, CI = 1.09–2.21) for AMD. These results were also reflected when haplotypes for the untranscribed and the 5′untranslated regions (5′UTR) were analyzed separately. To assess haplotype correlation with levels of gene expression, the three SNPs within the 5′UTR were tested in a luciferase reporter assay. In retinal pigment epithelium-derived ARPE19 cells, we were able to measure significant differences in reporter levels, while this was not observed in kidney-derived HEK293 cells. The presence of the risk allele A (SNP rs705381) caused an increase in luciferase activity of approximately twofold. Our data support the view that inflammatory reactions mediated through anti-oxidative activity may be relevant to neovascular age-related macular degeneration.

Hyaloidotomy for subhyaloidal hemorrhage: OCT findings of two different treatment modalities.

Premacular subhyaloidal hemorrhage typically causes acute profound visual deterioration. Common causes for a subhyaloidal hemorrhage are retinal arterial macroaneurysms, arterial hypertension, diabetic retinopathy, hematological disorders and ocular trauma [1], [2], [3], [4]. In healthy adults it can be caused by a Valsalva maneuver leading to spontaneous rupture of superficial retinal capillaries [5]. Using spectral-domain optical coherence tomography (SD-OCT) the anatomical location of the hemorrhage can be exactly determined. Controversy still exists about the best time for treatment and the specific treatment modality [6], [7]. Nd:YAG-laser-hyaloidotomy has been suggested in recent years to facilitate blood drainage and restoring vision faster [8], [9]. Thanks to the introduction of SD-OCT we are now able to precisely image the site of laser impact and to compare different lasers used for hyaloidotomy. We describe a case where both diode- and Nd:YAG-laser treatment have been consecutively applied with only the latter being successful at drainage and showing a visible effect on SD-OCT.