Evangelia E. Tsironi

Intravitreal adalimumab for refractory uveitis-related macular edema.

OBJECTIVE To evaluate the safety and efficacy of intravitreal adalimumab injections on refractory cystoid macular edema (CME) secondary to noninfectious uveitis. DESIGN Prospective, noncomparative, interventional case series. PARTICIPANTS Eight consecutive patients with controlled uveitis and chronic, refractory CME who had failed steroid treatment. INTERVENTION Intravitreal adalimumab injections were given monthly for 3 months. MAIN OUTCOME MEASURES Mean change in central retinal thickness (CRT) on optical coherence tomography (OCT); secondary objective was the mean change in best-corrected visual acuity (BCVA). RESULTS Five of the eight patients completed the 6-month follow-up. For all 5 patients, the changes in BCVA from baseline to 3 months were not statistically significant (P=0.070). Similarly, the change in BCVA from baseline to 6 months was not statistically significant (P=1.0). The mean CRT at baseline was 692 microm. The changes from baseline to 3 months were not statistically significant (P=0.466); the changes from baseline to 6 months were also not statistically significant (P=0.808). We did not observe any ocular or systemic adverse effects. CONCLUSIONS Intravitreal adalimumab showed no efficacy in improving BCVA or reducing CRT in patients with chronic uveitic macular edema.

Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration

Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance.Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurses Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.

Novel Twinkle (PEO1) gene mutations in mendelian progressive external ophthalmoplegia

Multiple deletions of mitochondrial DNA (mtDNA) are associated with different mitochondrial disorders inherited as autosomal dominant and recessive traits. Causative mutations have been found in five genes, mainly involved in mtDNA replication and stability. They include POLG1, the gene encoding the catalytic subunit of mtDNA polymerase (polγ), POLG2 encoding its accessory subunit, ANT1 coding the adenine nucleotide translocator and PEO1 which codes for Twinkle, the mitochondrial helicase. Finally OPA1 missense mutations are involved in phenotypes presenting optic atrophy as a major feature.To define the relative contribution of POLG1, POLG2, ANT1 and PEO1 genes to the mtDNA multiple deletion syndromes, we analysed them in a cohort of 67 probands showing accumulation of multiple mtDNA deletions in muscle. The patients were predominantly affected with a mitochondrial myopathy with or without progressive external ophthalmoplegia (PEO). Genetic analysis revealed that 1) PEO1 has a major role in determining familial PEO, since it accounts for 26.8 % of familial cases, followed by ANT1 (14.6 %) and POLG1 (9.8 %); 2) no mutations in any of the known genes were found in 53.7 % of probands of this series. Six novel missense mutations contributing to the mutational load of PEO1 gene (p.R334P, p.W315S, p. S426N, p.W474S, p.F478I, p.E479K) were associated with an adult onset PEO phenotype.

Perimetric and retinal nerve fiber layer findings in patients with Parkinson’s disease

BackgroundVisual dysfunction is common in Parkinson’s disease (PD). It remains, however, unknown whether it is related to structural alterations of the retina. The aim of this study is to compare visual field (VF) findings and circumpapillary retinal nerve fiber layer (RNFL) thickness in a series of PD patients and normal controls, in order to assess possible retinal anatomical changes and/or functional damage associated with PD.MethodsPD patients and controls were recruited and underwent VF testing with static automated perimetry and RNFL examination with optical coherence tomography (OCT). Cognitive performance using Mini Mental State Examination (MMSE), PD staging using modified Hoehn and Yahr (H-Y) scale and duration of the disease was recorded in PD patients.ResultsOne randomly selected eye from each of 24 patients and 24 age-matched controls was included. OCT RNFL thickness analysis revealed no difference in the inferior, superior, nasal or temporal sectors between the groups. The average peripapillary RNFL was also similar in the two groups. However, perimetric indices of generalized sensitivity loss (mean deviation) and localized scotomas (pattern standard deviation) were worse in patients with PD compared to controls (p < 0.01). 73% of eyes of PD patients had glaucomatous-like asymmetrical hemifield defects with abnormal Glaucoma Hemifield Test and various combinations of arcuate defects (n = 12), nasal steps (n = 11) and paracentral scotomas (n = 16). Bilateral defects were found in 14 patients (58%). No correlation was found between VF indices and MMSE or H-Y scores.ConclusionPD patients may demonstrate glaucomatous-like perimetric defects even in the absence of decreased RNFL thickness.

Rare and common variants in extracellular matrix gene Fibrillin 2 (FBN2) are associated with macular degeneration

Neurodegenerative diseases affecting the macula constitute a major cause of incurable vision loss and exhibit considerable clinical and genetic heterogeneity, from early-onset monogenic disease to multifactorial late-onset age-related macular degeneration (AMD). As part of our continued efforts to define genetic causes of macular degeneration, we performed whole exome sequencing in four individuals of a two-generation family with autosomal dominant maculopathy and identified a rare variant p.Glu1144Lys in Fibrillin 2 (FBN2), a glycoprotein of the elastin-rich extracellular matrix (ECM). Sanger sequencing validated the segregation of this variant in the complete pedigree, including two additional affected and one unaffected individual. Sequencing of 192 maculopathy patients revealed additional rare variants, predicted to disrupt FBN2 function. We then undertook additional studies to explore the relationship of FBN2 to macular disease. We show that FBN2 localizes to Bruchs membrane and its expression appears to be reduced in aging and AMD eyes, prompting us to examine its relationship with AMD. We detect suggestive association of a common FBN2 non-synonymous variant, rs154001 (p.Val965Ile) with AMD in 10 337 cases and 11 174 controls (OR = 1.10; P-value = 3.79 × 10(-5)). Thus, it appears that rare and common variants in a single gene--FBN2--can contribute to Mendelian and complex forms of macular degeneration. Our studies provide genetic evidence for a key role of elastin microfibers and Bruchs membrane in maintaining blood-retina homeostasis and establish the importance of studying orphan diseases for understanding more common clinical phenotypes.

Influence of ROBO1 and RORA on risk of age-related macular degeneration reveals genetically distinct phenotypes in disease pathophysiology.

ROBO1 is a strong candidate gene for age-related macular degeneration (AMD) based upon its location under a linkage peak on chromosome 3p12, its expression pattern, and its purported function in a pathway that includes RORA, a gene previously associated with risk for neovascular AMD. Previously, we observed that expression of ROBO1 and RORA is down-regulated among wet AMD cases, as compared to their unaffected siblings. Thus, we hypothesized that contribution of association signals in ROBO1, and interaction between these two genes may be important for both wet and dry AMD. We evaluated association of 19 single nucleotide polymorphisms (SNPs) in ROBO1 with wet and dry stages of AMD in a sibling cohort and a Greek case-control cohort containing 491 wet AMD cases, 174 dry AMD cases and 411 controls. Association signals and interaction results were replicated in an independent prospective cohort (1070 controls, 164 wet AMD cases, 293 dry AMD cases). The most significantly associated ROBO1 SNPs were rs1387665 under an additive model (meta P = 0.028) for wet AMD and rs9309833 under a recessive model (meta P = 6×10−4) for dry AMD. Further analyses revealed interaction between ROBO1 rs9309833 and RORA rs8034864 for both wet and dry AMD (interaction P<0.05). These studies were further supported by whole transcriptome expression profile studies from 66 human donor eyes and chromatin immunoprecipitation assays from mouse retinas. These findings suggest that distinct ROBO1 variants may influence the risk of wet and dry AMD, and the effects of ROBO1 on AMD risk may be modulated by RORA variants.

Ocular rigidity, ocular pulse amplitude, and pulsatile ocular blood flow: the effect of axial length.

PURPOSE Previous studies have shown a negative correlation between axial length (AL) and pulsatile ocular blood flow (POBF). This relation has been questioned because of the possible confounding effect of ocular volume on ocular rigidity (OR). The purpose of this study was to investigate the relation between AL, as a surrogate parameter for ocular volume, and OR, ocular pulse amplitude (OPA), and POBF. METHODS Eighty-eight cataract patients were enrolled in this study. A computer-controlled device comprising a microdosimetric pump and a pressure sensor was used intraoperatively. The system was connected to the anterior chamber and used to raise the intraocular pressure (IOP) from 15 to 40 mm Hg, by infusing the eye with a saline solution. After each infusion step, the IOP was continuously recorded for 2 seconds. Blood pressure and pulse rate were measured during the procedure. The OR coefficient was calculated from the pressure volume data. OPA and POBF were measured from pressure recordings. RESULTS Median AL was 23.69 (interquartile range 3.53) mm. OR coefficient was 0.0218 (0.0053) μL(-1). A negative correlation between the OR coefficient and AL (ρ = -0.641, P < 0.001) was documented. Increasing AL was associated with decreased OPA (ρ = -0.637, P < 0.001 and ρ = -0.690, P < 0.001) and POBF (ρ = -0.207, P = 0.053 and ρ = -0.238, P = 0.028) at baseline and elevated IOP, respectively. CONCLUSIONS Based on manometric data, increasing AL is associated with decreased OR, OPA, and POBF. These results suggest decreased pulsatility in high myopia and may have implications on ocular pulse studies and the pathophysiology of myopia.

Ocular Rigidity, Outflow Facility, Ocular Pulse Amplitude, and Pulsatile Ocular Blood Flow in Open-Angle Glaucoma: A Manometric Study

PURPOSE To compare ocular rigidity (OR) and outflow facility (C) coefficients in medically treated open-angle glaucoma (OAG) patients and controls, and to investigate differences in ocular pulse amplitude (OPA) and pulsatile ocular blood flow (POBF) between the two groups. METHODS Twenty-one OAG patients and 21 controls undergoing cataract surgery were enrolled. Patients with early or moderate primary or pseudoexfoliative OAG participated in the glaucoma group. A computer-controlled system, consisting of a pressure transducer and a microstepping device was employed intraoperatively. After cannulation of the anterior chamber, IOP was increased by infusing the eye with microvolumes of saline solution. IOP was recorded after each infusion step. At an IOP of 40 mm Hg, an IOP decay curve was recorded for 4 minutes. OR coefficients, C, OPA, and POBF were estimated from IOP and volume recordings. RESULTS There were no differences in age or axial length in the two groups. The OR coefficient was 0.0220 ± 0.0053 μl(-1) in the OAG and 0.0222 ± 0.0039 μl(-1) in the control group (P = 0.868). C was 0.092 ± 0.082 μL/min/mm Hg in the glaucoma group compared with 0.149 ± 0.085 μL/min/mm Hg in the control group at an IOP of 35 mm Hg (P < 0.001) and 0.178 ± 0.133 μL/min/mm Hg vs. 0.292 ± 0.166 μL/min/mm Hg, respectively, at an IOP of 25 mm Hg (P < 0.001). There were no differences in OPA or POBF between the two groups in baseline and increased levels of IOP (P > 0.05). CONCLUSIONS Manometric data reveal lower C in OAG patients and increased C with increasing IOP. There were no differences in the OR coefficient, OPA, and POBF between medically treated OAG patients and controls, failing to provide evidence of altered scleral distensibility and choroidal blood flow in OAG.

Plasma and aqueous humour levels of ghrelin in open-angle glaucoma patients.

Background:  To compare aqueous humour and plasma levels of ghrelin, a peptide recently identified in human eyes, in patients with open‐angle glaucoma and controls.

Resolution of Macular Edema in Idiopathic Juxtafoveal Telangiectasis Using PDT

A 57-year-old woman was treated by photodynamic therapy for macular edema due to idiopathic juxtafoveal telangiectasis (presumed type 1A) without subretinal neovascularization. Initial visual acuity of the treated eye was 20/200 and it improved to 20/40 by 3 months after the photodynamic therapy session. Visual acuity remained stable 32 months after the treatment. Color photographs and fundus fluorescein angiography before and after photodynamic therapy revealed regression of hemorrhages, exudates, and fluorescein leakage. Photodynamic therapy has long-term benefits for the patient with idiopathic juxtafoveal telangiectasis, presumed type 1A, because it can improve visual acuity and macular edema.