Assessment of intravitreal anti-VEGF drugs and dexamethasone for retinal diseases in real world setting: A multi-centre prospective study from Southern Italy.

Describe drug utilisation and clinical outcomes of intravitreal anti-VEGF drug and dexamethasone use in the real-world setting in Southern Italy using data from multi-centre study of retinal disease. Clinical data of retinal disease patients treated with anti-VEGF drugs and dexamethasone implant in 6 out-patient ophthalmology centres from Southern Italy were collected by means of an electronic case report form. Patients receiving at least one intravitreal injection/implant of the study drugs were followed for up to two years and described in terms of demographics and clinical characteristics. Drug utilisation patterns were described. A sign-rank test was used to compare clinical data on visual acuity and other ophthalmic parameters from baseline at different follow-up times for each indication. Data from 1327 patients was collected. Most patients were diagnosed with age-related macular degeneration (AMD) (660, 49.7%), followed by diabetic macular oedema (423, 31.9%), retinal vein occlusion (164, 12.3%), and myopic choroidal neovascularization (80, 6.0%). Patients were followed for a median of 10.3 months (interquartile range: 3.6 - 24.7 months). Mean patient age was 69.7 (±10.9) years and 54.2% were males. Ranibizumab (55.4%) and aflibercept (27.5%) were the most commonly used drugs. Baseline visual acuity significantly improved by about 0.05 to 0.1 logMAR at all follow-up times for AMD and RVO but less consistently for the other diseases. Intravitreal ranibizumab use accounted for half of all treatment for retinal diseases in a Southern Italian out-patient setting. Patients treated with anti-VEGF drugs for AMD and RVO in Southern Italy experienced significant improvement in VA.

Optical Coherence Tomography Predictors of Favorable Functional Response in Naïve Diabetic Macular Edema Eyes Treated with Dexamethasone Implants as a First-Line Agent.

PURPOSE: To evaluate efficacy and safety of intravitreal dexamethasone 0.7 mg implant in treatment-naïve DME patients and to assess the utility of OCT structural biomarkers as predictors of functional response after treatment. METHODS: Thirty-nine eyes of 39 diabetic patients with center involving DME were enrolled. Best-corrected visual acuity (BCVA) and SS-OCT (DRI SS-OCT Triton, Topcon, Japan) to evaluate central retinal thickness (CRT), serous retinal detachment (SRD), intraretinal cysts (IRC), number of hyper-reflective spots (HRS), integrity of the ellipsoid zone (EZ), disorganization of the inner retinal layers (DRIL), vitreomacular adhesion (VMA), vitreomacular traction (VMT), and posterior vitreous detachment (PVD) were evaluated at baseline and at 3, 6, and 12 months after treatment. Multiple logistic analysis was performed to evaluate the possible OCT biomarker as predictive factors for final visual acuity improvement at the end of treatment. RESULTS: At 12 months after treatment, the mean BCVA improved from 51.6 ± 17.5 to 56.9 ± 17.3 ETDRS letters (p=0.03). Furthermore, there were statistically significant changes in CRT, IRC, HRS, and SRD. Nineteen patients presented a >10-letters improvement in BCVA; the presence of SRD at baseline was a predictor of good functional treatment response at 12 months (OR 2.1; 95% C.I. 1.2-4.9; p=0.001) as well as the presence of EZ integrity preoperatively (OR 1.3; 95% C.I. 0.5-2.4; p=0.001) and the absence of vitreoretinal interface alteration (OR 1.1; 95% C.I. 0.3-2.3; p=0.02). No significant changes in the IOP and lens status were observed throughout the follow-up period. CONCLUSION: This study empathized the importance of structural biomarkers as predictors of favorable response and confirmed the efficacy and safety of intravitreal dexamethasone implant in treatment-naïve DME patients showing a better functional response in the presence of SRD integrity of EZ and absence of vitreoretinal alterations.

Foveal avascular zone analysis by optical coherence tomography angiography in patients with type 1 and 2 diabetes and without clinical signs of diabetic retinopathy.

PURPOSE: To analyze the early macular microvascular alterations in patients with type 1 and 2 diabetes mellitus (DM) without diabetic retinopathy (DR), using optical coherence tomography angiography (OCT-A), and compare these with nondiabetic patients. METHODS: This prospective study involved 93 patients with type 1 diabetes (DM1), 104 patients with type 2 diabetes (DM2) without signs of DR, and 71 healthy subjects for the control group. The foveal avascular zone (FAZ) area and the vessel density (VD) at the superficial capillary plexus (SCP) and deep capillary plexus (DCP) were evaluated. RESULTS: The SCP and DCP FAZ areas were significantly larger in the DM1 group in comparison with the controls (p = .001), while no significant differences were observed between the DM2 group and the healthy control group (p = .12). Additionally, no significant differences in FAZ area were found between the DM1 and DM2 groups (p = .26). The VD was significantly reduced in DM1 and DM2 groups compared to controls. A direct correlation was found between the duration of diabetes and SCP FAZ area (r = 0.44; R2 = 0.19; p = .0001). Statistically significant differences in the FAZ area at SCP and DCP were observed when comparing patients with a diabetes duration > 10 years and < 10 years in the DM2 group (p = .0001, respectively) and only in the FAZ area at the DCP in the DM1 group (p = .0001). CONCLUSION: Diabetic patients without DR demonstrate early microvascular alteration in the macular area on OCT-A, which is more pronounced in type I DM, and correlates with the duration of the disease.

The Application of Structural Retinal Biomarkers to Evaluate the Effect of Intravitreal Ranibizumab and Dexamethasone Intravitreal Implant on Treatment of Diabetic Macular Edema.

BACKGROUND: The aim of this study was to compare the therapeutic effect of intravitreal treatment with ranibizumab and dexamethasone using specific swept-source optical coherence tomography retinal biomarkers in patients with diabetic macular edema (DME). METHODS: 156 treatment-naïve patients with DME were divided in two groups: 75 patients received 3 monthly intravitreal injections of ranibizumab 0.5 mg (Lucentis®) (Group 1) and 81 patients received an intravitreal implant of dexamethasone 0.7 mg (Ozurdex®) (Group 2). Patients were evaluated at baseline (V1), at three months post-treatment in Group 1, and at two months post-treatment in Group 2 (V2). Best-corrected visual acuity (BCVA) and swept source-OCT were recorded at each interval. Changes between V1 and V2 were analyzed using the Wilcoxon test and differences between the two groups of treatment were assessed using the Mann-Whitney test. Multiple regression analysis was performed to evaluate the possible OCT biomarker (CRT, ICR, CT, SND, HRS) as predictive factors for final visual acuity improvement. RESULTS: In both groups, BCVA improved (p-value < 0.0001), and a significant reduction in central retinal thickness, intra-retinal cysts, red dots, hyper-reflective spots (HRS), and serous detachment of neuro-epithelium (SDN) was observed. A superiority of dexamethasone over ranibizumab in reducing the SDN height (p-value = 0.03) and HRS (p-value = 0.01) was documented. CONCLUSIONS: Ranibizumab and dexamethasone are effective in the treatment of DME, as demonstrated by functional improvement and morphological biomarker change. DME associated with SDN and HRS represents a specific inflammatory pattern for which dexamethasone appears to be more effective.

How Have Intravitreal Anti-VEGF and Dexamethasone Implant Been Used in Italy? A Multiregional, Population-Based Study in the Years 2010-2016.

PURPOSE: To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions. METHODS: Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data. RESULTS: Overall, 41,836 patients received ≥1 study drug in 2010-2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with ≥1 year of follow-up (N = 30,745), 16.0% (N = 30,745), 16.0% (N = 30,745), 16.0% (. CONCLUSION: Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits.

Long-Term Intravitreal Ranibizumab as a Potential Additional Risk Factor for Neurodegeneration in Parkinson's Disease: A Case Report.

In November 2012, a 72-year old patient was diagnosed with left eye wet age-related macular degeneration. The patient received three monthly intravitreal injections of ranibizumab, with complete resolution of retinal hemorrhage and edema and reinstatement of visual acuity. In May 2015, symptomatic relapse was detected. The patient was again treated with intravitreal ranibizumab, with overall six injections till the end of February 2016. In May 2016, the patient complained of left hand resting tremor, bradykinesia, and postural rigidity of head and trunk. A diagnosis of clinically established PD was made based on new criteria of the Movement Disorders Society. Single Photon Emission Computerized Tomography of the Dopamine Transporter with (123I) ioflupane documented a low Dopamine Transporter (DAT) uptake mostly in the right striatum. Due to the documented protective role of vascular endothelial growth factor (VEGF) on the dopaminergic neurons, intensive intravitreal injections of the anti-VEGF agent ranibizumab may have played as an additional risk factor accelerating the neurodegeneration process related to PD and the onset of the related clinical signs and symptoms.

Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System.

INTRODUCTION: Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear. OBJECTIVE: The aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS). METHODS: We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA®) queries (SMQs). RESULTS: Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders). CONCLUSIONS: This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs.

Syndromic parkinsonism and dementia associated with OPA1 missense mutations.

OBJECTIVE: Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia. METHODS: Patients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements. RESULTS: Affected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase-negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy. INTERPRETATION: The association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism.

A randomized trial of intravitreal bevacizumab vs. ranibizumab for myopic CNV.

AIMS: The aim was to compare the efficacy of intravitreal therapy with bevacizumab and ranibizumab for choroidal neovascularization (CNV) in pathologic myopia (PM). METHODS: This was a prospective multicenter randomized nonblinded trial. RESULTS: In seven centers, 78 eyes were randomized 1:1 to treatment with bevacizumab (group B, 40 eyes) or ranibizumab (group R, 38 eyes) given with an "on demand" regimen (PRN). The mean follow-up was 19 months (SD 2, range 12-24). The mean BCVA at baseline was 0.60 logMAR (20/80 Snellen equivalent, Seq) and 50 letter score (ls). Mean final BCVA was 0.51 LogMAR (20/63 Seq) and 57 ls (p = 0.0009 and p = 0.0002, respectively). In group B, mean basal BCVA was 0.52 logMAR (20/63 Seq) and 54 ls, and final BCVA was 0.51 logMar (20/63 Seq) and 57 ls. In group R, mean basal BCVA was 0.62 logMAR (20/80 Seq) and 45 ls, and the final values were 0.50 logMAR (20/63 Seq) and 58 ls. Statistical comparison of the two groups showed no significant difference (logMAR p = 0.90 and letters p = 0.78). Multivariate analysis showed no influence of age or previous photodynamic treatment (PDT) on final visual changes. The mean number of treatments in the first year was 2.7 in group B and 2.3 in group R (p = 0.09). CONCLUSION: Myopic CNV equally benefits from on-demand intravitreal injection of either bevacizumab or ranibizumab; the therapeutic effect is independent of previous PDT and age.

Radioiodine ablation of postsurgical thyroid remnants after treatment with recombinant human TSH (rhTSH) in patients with moderate-to-severe graves' orbitopathy (GO): a prospective, randomized, single-blind clinical trial.

CONTEXT: Recent evidence suggests thyroidectomy (Tx) followed by radioiodine remnant ablation to be beneficial to Graves' orbitopathy (GO) patients. OBJECTIVE: The aim of the study was to evaluate the effect of (131)I thyroid ablation after recombinant human TSH stimulation in patients with moderate-to-severe GO. DESIGN, PATIENTS, AND INTERVENTIONS: The study was prospective, randomized, and single-blind, and it included 40 consecutive patients with moderate-to-severe GO randomized into: 1) a Tx-radioactive iodine (RAI) group (20 subjects who underwent total-Tx and (131)I ablation after recombinant human TSH stimulation); and 2) a Tx group (20 subjects who underwent total-Tx alone). OUTCOME MEASURES: The overall GO outcome 12 months after Tx/radioiodine ablation was the main measure. RESULTS: GO evaluation at the end of iv glucocorticoids showed eye disease to be improved in 65% of the Tx-RAI group and 60% of the Tx group patients. At 6 and 12 months, no further changes in the GO outcome could be observed in the Tx-RAI group. Conversely, five patients from the Tx group exhibited a deterioration in GO. At 12 months, GO was found to be improved in 70% of the Tx-RAI and 20% of the Tx group patients, the latter being found to be stable (55%) or worse (25%) than at baseline evaluation. At 12 months, GO was found to be inactive in a significantly higher percentage of patients in the Tx-RAI than in the Tx group (75 vs 30%; P < .01). CONCLUSIONS: Postoperative radioiodine ablation proved more effective than Tx alone in inducing earlier and steadier GO improvement in patients with moderate-to-severe GO treated with iv glucocorticoids over a 24-month follow-up period.

Hyperhomocysteinemia and retinal vascular changes in patients with epilepsy.

The possible occurrence of asymptomatic retinal vascular damage was investigated in 87 hyperhomocysteinemic (plasma total homocysteine >13micromol/L) adult epileptic patients (46 M, 41 F; age 34.2+/-7.5 years; mean plasma homocysteine levels 29.8+/-15.4micromol/L; duration of epilepsy 11.5+/-2.4 years) with no other risk factors for atherosclerosis. Plasma total homocysteine (t-Hcy) levels were assayed by high performance liquid chromatography. Retina vascular status was assessed by fundus oculi ophthalmoscopy performed in blind conditions by two skilled ophthalmologists and compared with that obtained from 102 randomly chosen epileptic patients and 94 healthy subjects, matched for age and sex, showing normal t-Hcy levels. No retina abnormality was detected in any of the subjects belonging to the three groups. Based on these results, we conclude that epileptic patients with mild to intermediate hyperhomocysteinemia are not at risk to develop retinal vascular disease.