Untreated Contralateral Eyes Research Articles

Lacrimal drainage function after cheese wiring of lacrimal passage intubation.

To investigate how cheese wiring affects lacrimal drainage function by quantitative assessment of tear function and punctal dimensions. Patients who underwent lacrimal passage intubation between January 2017 and September 2018 were enrolled prospectively. Among these patients, those with postoperative cheese wiring who received lacrimal passage intubation in one eye met the criteria for further investigation. The subjective symptoms of epiphora, dimensions of puncta, lower tear meniscus, and tear clearance were assessed postoperatively in both the involved eye and untreated contralateral eye. Punctum dimensions were analysed using the digital slit-lamp image. Tear meniscus and tear clearance were assessed by anterior segment optical coherence tomography. Postoperative cheese wiring was observed in 68 of 314 eyes. Among these cases, 36 patients (age 70.5 ± 11.7years) had cheese wiring only in one eye: with the involvement of both puncta in 15 patients (group A) and only the lower punctum in 21 patients (group B). There was no patient with the involvement of only the upper punctum. While tear function of the involved eyes in group B did not differ from that of the untreated eye, it was significantly decreased in group A compared with that in untreated control eyes (p < 0.05). The tear clearance rate correlated significantly with the upper punctum dimensions (p < 0.05), but not with the lower punctum. Analysis of cheese wiring after lacrimal passage intubation with tear function demonstrated that the integrity of the puncta and the canaliculus is important for lacrimal drainage.

Effect of intravitreal aflibercept treatment on retinal vessel parameters in diabetic macular oedema: Arteriolar vasoconstriction

Purpose: To evaluate the effects of intravitreal aflibercept (IVA) treatment on retinal vein parameters and choroidal thickness used in the treatment of diabetic macular oedema (DME).Methods: This retrospective study administered Afyonkarahisar Health Sciences University Department of Ophthalmology. Twenty-nine patients who were diagnosed with naive DME in a single eye were included in the study. A three consecutive, monthly intravitreal injection of 2 mg aflibercept were administered to patients. Each patient’s contralateral (untreated) eyes, which did not diagnose DME and did not receive any treatment, were the control group. The central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and artery–vein ratio (AVR) values were measured using a semi-automatically computer-based software before the first IVA injection and 30 d after the first, second, and third injections. The main outcome measurements were the central macular thickness (CMT), best-corrected visual acuity (BCVA), subfoveal choroidal thickness (sf-CT), CRAE, CRVE, and AVR.Results: The mean age of patients was 59.25 ± 9.48 years. Patients were 15 males and 14 females. A significant vasoconstriction of the retinal arterioles, a thinning of sf-CT and CMT, and an increase of BCVA have observed in IVA-treated eyes compared to baseline (respectively, p < 0.001, p < 0.001, p < 0.001, p < 0.001). But, no significant differences were found for CRVE and AVR in IVA-treated eyes compared to baseline. No significant difference was found for all parameters in untreated eyes compared to baseline.Conclusions: This study demonstrates that IVA treatment can change retinal blood flow by reducing retinal artery diameter and thinning in the choroid.

The penetration and distribution of topical atropine in animal ocular tissues.

To conduct a multi-tissue investigation on the penetration and distribution of topical atropine in myopia treatment, and determine if atropine is detectable in the untreated contralateral eye after uniocular instillation. Nine mature New Zealand white rabbits were evenly divided into three groups. Each group was killed at 5, 24 and 72hr, respectively, following uniocular instillation of 0.05ml of 1% atropine. Tissues were sampled after enucleation: conjunctiva, sclera, cornea, iris, ciliary body, lens, retina, aqueous, and vitreous humors. The assay for atropine was performed using liquid chromatography-mass spectrometry (LC-MS), and molecular tissue distribution was illustrated using matrix-assisted laser desorption ionization-imaging mass spectrometry (MALDI-IMS) via an independent experiment on murine eyes. At 5hr, the highest (mean±SEM) concentration of atropine was detected in the conjunctiva (19.05±5.57ng/mg, p<0.05) with a concentration gradient established anteriorly to posteriorly, as supported by MALDI-IMS. At 24hr, preferential binding of atropine to posterior ocular tissues occurred, demonstrating a reversal of the initial concentration gradient. Atropine has good ocular bioavailability with concentrations of two magnitudes higher than its binding affinity in most tissues at 3days. Crossing-over of atropine to the untreated eye occurred within 5hr post-administration. Both transcorneal and transconjunctival-scleral routes are key in atropine absorption. Posterior ocular tissues could be important sites of action by atropine in myopic reduction. In uniocular atropine trials, cross-over effects on the placebo eye should be adjusted to enhance results reliability. Combining the use of LC-MS and MALDI-IMS can be a viable approach in the study of the ocular pharmacokinetics of atropine.

Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration

PurposeTransplantation of human embryonic stem cell (hESC)-derived retinal pigment epithelial (RPE) cells offers the potential for benefit in macular degeneration. Previous trials have reported improved visual acuity (VA), but lacked detailed analysis of retinal structure and function in the treated area.DesignPhase 1/2 open-label dose-escalation trial to evaluate safety and potential efficacy (clinicaltrials.gov identifier, NCT01469832).ParticipantsTwelve participants with advanced Stargardt disease (STGD1), the most common cause of macular degeneration in children and young adults.MethodsSubretinal transplantation of up to 200 000 hESC-derived RPE cells with systemic immunosuppressive therapy for 13 weeks.Main Outcome MeasuresThe primary end points were the safety and tolerability of hESC-derived RPE cell administration. We also investigated evidence of the survival of transplanted cells and measured retinal structure and function using microperimetry and spectral-domain OCT.ResultsFocal areas of subretinal hyperpigmentation developed in all participants in a dose-dependent manner in the recipient retina and persisted after withdrawal of systemic immunosuppression. We found no evidence of uncontrolled proliferation or inflammatory responses. Borderline improvements in best-corrected VA in 4 participants either were unsustained or were matched by a similar improvement in the untreated contralateral eye. Microperimetry demonstrated no evidence of benefit at 12 months in the 12 participants. In one instance at the highest dose, localized retinal thinning and reduced sensitivity in the area of hyperpigmentation suggested the potential for harm. Participant-reported quality of life using the 25-item National Eye Institute Visual Function Questionnaire indicated no significant change.ConclusionsSubretinal hyperpigmentation is consistent with the survival of viable transplanted hESC-derived RPE cells, but may reflect released pigment in their absence. The findings demonstrate the value of detailed analysis of spatial correlation of retinal structure and function in determining with appropriate sensitivity the impact of cell transplantation and suggest that intervention in early stage of disease should be approached with caution. Given the slow rate of progressive degeneration at this advanced stage of disease, any protection against further deterioration may be evident only after a more extended period of observation.

Response of the Retinal Nerve Fiber Layer Reflectance and Thickness to Optic Nerve Crush.

PurposeTo study the effects of acute optic nerve damage on the reflectance of the retinal nerve fiber layer (RNFL) and to compare the time courses of changes of RNFL reflectance and thickness.MethodsA rat model of optic nerve crush (ONC) was compared with previously studied normal retinas. The reflectance and thickness of the RNFL were studied at 1 to 5 weeks after ONC. Reflectance spectra from 400 to 830 nm were measured for eyes with ONC, their contralateral untreated eyes, and eyes with sham surgery. Directional reflectance was studied by varying the angle of light incidence. RNFL thickness was measured by confocal microscopy.ResultsAfter ONC, the RNFL reflectance remained directional. At 1 week, RNFL reflectance decreased significantly at all wavelengths (P < 0.001), whereas there was no significant change in RNFL thickness (P = 0.739). At 2 weeks, both RNFL reflectance and thickness decreased significantly, and by 5 weeks they declined to approximately 40% and 30%, respectively, of the normal values. Although RNFL reflectance decreased at all wavelengths, there was a greater reduction at short wavelengths. Spectral shape at long wavelengths was similar to the normal. Some of these changes were also found in the contralateral untreated eyes, but none of these changes were found in eyes with sham surgery.ConclusionsDecrease of RNFL reflectance after ONC occurs prior to thinning of the RNFL and the decrease is more prominent at short wavelengths. Direct measurement of RNFL reflectance, especially at short wavelengths, may provide early detection of axonal damage.

Effects of orthokeratology on axial length growth in myopic anisometropes.

To investigate the effect of orthokeratology (ortho-k) lens wear on axial length (AL) growth in juvenile myopic anisometropes. This retrospective study consisted of two parts. In Part One, 25 anisometropic participants (mean age, 11.2 ± 1.9 years; 11 females and 14 males) were fitted with ortho-k lenses in the more myopic eye only, and the rate of AL growth was compared between the ortho-k lens wearing eye and the untreated contralateral eye over an average period of 23.1 ± 8.3 months. In Part Two, 8 participants who developed myopia in the contralateral eye received ortho-k treatment in both eyes for an average of 12 months; the rate of AL growth before and after ortho-k treatment in the newly developed myopic eye was compared. In Part One, the rate of AL elongation in the ortho-k treated eye (0.08 ± 0.15 mm/year) was significantly slower than in the contralateral eye (0.39 ± 0.32 mm/year) (P < 0.001). At the completion of Part One, 16 out of 25 participants (64%) developed myopia in the initially non-myopic eye. In Part Two, the rate of AL elongation after ortho-k treatment in the newly developed myopic eye (0.20 mm/year) was significantly slower than that before ortho-k treatment in the same eye (0.49 mm/year) (P = 0.012). Ortho-k treatment slows AL growth in the more myopic eye of anisometropic patients; should the contralateral eye develop myopia in the future, ortho-k is capable of slowing down AL growth in that eye as well.

Early signs of microglial activation in mice retinas contralateral to experimental glaucoma: quantitative analysis of cells number, processes retraction and reorientation

PurposeTo quantify retinal microglia signs of activation after 24 h of unilateral laser‐induced ocular hypertension (OHT) in OHT‐eyes and their contralateral eyes.MethodsAlbino Swiss mice were divided into two groups, naïve (n = 6) and lasered (n = 6). Retinal whole‐mounts were immunolabeled with anti Iba‐1 to quantify the: i) number of microglial cells in the photoreceptor layer (PRL), outer plexiform layer (OPL) and inner plexiform layer (IPL); ii) the area of the retina occupied by Iba‐1 + in the nerve fiber layer‐ganglion cells layer (NFL‐GCL) and; iii) the arbor area of microglial cells in the OPL and IPL. iv) the number of microglial vertical processes connecting the OPL and PRL.ResultsIn OHT eyes and contralateral eyes had no significant differences in cell number with respect to naïve. OHT eyes presented a significant decrease in microglial arbor area in the OPL in comparison with control (p &lt; 0.01) and in the IPL in comparison with control and contralateral eyes (p &lt; 0.01 and p &lt; 0.05 respectively). However the retinal area occupied by Iba‐1 + cells in the NFL‐GCL was significantly increased: i) in both contralateral and OHT eyes with respect to control (p &lt; 0.01 in both instances); and ii) in OHT eyes with respect to contralateral eyes (p &lt; 0.05). In contralateral untreated eyes, the number of microglial vertical processes connecting the OPL and PRL were significantly increased in comparison with control and OHT eyes (p &lt; 0.01 and p &lt; 0.05 respectively).ConclusionsAt 24 h, laser‐induced OHT produces a reactive non‐proliferative microgliotic response both in OHT eyes and in contralateral untreated eyes. Whether this response favors neuroprotection or neurodegeneration needs to be clarify.

Qualitative early signs of microglial activation in mice retinas contralateral to experimental glaucoma

PurposeTo analyze qualitative retinal microglia signs of activation after 24 h of unilateral laser‐induced ocular hypertension (OHT) in OHT‐eyes and their contralateral eyes.MethodsAlbino Swiss mice were divided into two groups, naïve (n=6) and lasered (n=9). Retinal whole mounts were immunolabeled with antibodies against Iba‐ 1 and MHC‐II.ResultsBoth in OHT eyes and in contralateral eyes Iba‐1+ cells: i)had morphological signs of activation, being these more intense in OHT eyes than in the contralateral eyes. Iba‐1+cells showed hypertrophy, soma displacement both in their own retinal layer and towards the nearest one and in some instances, reoriented microglial processes from being parallel to being perpendicular to the retinal surface. ii) were dystrophic in some instances in the photoreceptor layer (PRL); iii) in the outer plexiform layer sent processes to the PRL and this was mainly found in contralateral eyes; iv) overall, did not up‐regulate the expression of MHCII .Only in OHT eyes MHCII+ rounded cells were observed in the nerve fiber layer‐ganglion cell layer, being more numerous in the peripheral superior zone of the retina and near the optic disc. These cells were surrounded and phagocyted by numerous ameboid Iba‐1+ cells. In addition, beneath the retinal areas where this event was occurring, microglial cells of the inner plexiform layer and outer plexiform layer oriented their processes towards those areas and surrounding them.ConclusionsAt 24 h after unilateral OHT, microglial features of activation were observed not only in OHT eyes but, interestingly, also in the contralateral untreated eyes. Whether this activation favors neuroprotection or neurodegeneration needs to be clarify.

Macrogilal retinal cells show a bilateral early activation in a mouse model of unilateral laser‐induced experimental glaucoma

PurposeTo describe macroglial morphological features of activation after 24 h of unilateral laser‐induced ocular hypertension (OHT) in OHT‐eyes and their contralateral eyes.MethodsAlbino Swiss mice were divided into two groups, naïve (n = 6) and lasered (n = 6). Retinal whole‐mounts were immunolabeled with antibodies against GFAP and MHC‐II.ResultsWith respect to naïve, OHT eyes and contralateral eyes showed different features of macroglial activation in some retinal areas: i) Müller cells were reactive and expressed GFAP; ii) astrocytes were more robust and had more primary and secondary processes; and iii) MHCII was up‐regulated in astrocytes and in some Müller cells. In contralateral eyes, these signs were observed mainly in the periphery. In addition, in the OHT eyes: i) in some retinal vessels near the optic disc, the astroglial reactivity was so intense that the entire vascular walls were sheathed by astroglial cells; ii) in some areas of the retina, astrocytes and Müller cells formed glial scars. iii) MHC‐II immunoreaction in astrocytes varied depending on the retinal area; in those in which MHC‐II immunostaining was less intense, only astrocyte primary processes could be recognized;ConclusionsAt 24 h after unilateral OHT, macroglia showed features of activation not only in OHT eyes, but also in untreated contralateral eyes. Early up‐regulation of MHC‐II in macroglial cells in both OHT retinas and contralateral retinas, suggest an immune system‐related inflammation early after the induction of ocular hypertension.

Retrospective analysis of the effect of aflibercept loading dose on the retinal vessel diameters in patients with treatment-naive neovascular AMD

Background: To evaluate the effects of intravitreal aflibercept (IVA) on retinal vessel diameters in patients with neovascular age-related macular degeneration (AMD).Design, setting, and participants: A retrospective study conducted at the Kutahya Dumlupinar University Faculty of Medicine included 15 eyes of 15 patients with treatment naive neovascular AMD.Methods: All eyes received IVA injections once per month for 3 months; untreated contralateral eyes were used as controls. The central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), and artery-vein ratio (AVR) values were measured using a computer-based program before the first IVA injection and 30 days after the first, second, and third injections. The main outcome measurements were the central macular thickness (CMT), best-corrected visual acuity (BCVA), choroidal thickness, CRAE, CRVE, and AVR.Results: Significant vasoconstriction of the retinal arterioles was observed in all eyes treated with IVA when compared to baseline (p = 0.009). However, no significant differences were found for CRVE or AVR throughout the study period in treated eyes. In the control group, all parameters measured during each visit were similar to baseline measurements (p > 0.05). The mean BCVA significantly improved at the end of the loading dose of IVA, when compared to baseline (p = 0.006). After the IVA injections, the mean CMT and choroidal thickness were significantly reduced at all visits, compared to baseline (p < 0.001).Conclusions: The current study showed that IVA led to significant retinal arteriolar vasoconstriction and choroidal thinning, which may cause reduced retinal blood flow.

Biomechanics of sclera crosslinked using genipin in rabbit.

To strengthen the biomechanics of collagen by crosslinking rabbit scleral collagen with genipin to develop a new therapy for preventing myopic progression. Ten New Zealand rabbits were treated with 0.5 mmol/L genipin injected into the sub-Tenon's capsule in the right eyes. Untreated contralateral eyes served as the control. The treated area was cut into scleral strips measuring 4.0 mm×10.0 mm for stress-strain measurements (n=5). The remaining five treated eyes were prepared for histological examination. Compared to the untreated scleral strips, the genipin-crosslinked scleral strips showed that the ultimate stress and Young's modulus at 10% strain were increased by the amplitude of 130% and 303% respectively, ultimate strain was decreased by 24%. There had no α-smooth muscle actin (α-SMA) positive cells in control and treated sclera. Histologically, there was no sign of apoptosis in the sclera, choroid, and retina; and no side effects were found in the peripheral cornea and optic nerve adjacent to the treatment area. Genipin induced crosslinking of collagen can increase its biomechanical behavior by direct strengthening of the extracellular matrix in rabbit sclera, with no α-SMA expression seen in the myofibroblasts. As there is no evidence of cytotoxicity in the scleral, choroidal, and retinal cells, genipin is likely a promising agent to strengthen the weakened sclera to prevent myopic progression.

Mechanism of Action of Selective Laser Trabeculoplasty and Predictors of Response.

PurposeThis study was designed to evaluate the changes in aqueous humor dynamics (AHD) produced by selective laser trabeculoplasty (SLT) and to explore if baseline AHD parameters are predictive of IOP response to SLT.MethodsThirty-one consecutive subjects diagnosed with ocular hypertension or primary open-angle glaucoma scheduled to undergo SLT as their primary IOP-lowering therapy were enrolled in this prospective observational study. Subjects underwent baseline assessment of AHD in both eyes. Variables assessed were IOPs at 9 AM and noon, aqueous humor flow rate (fluorophotometry), episcleral venous pressure (EVP, venomanometry), outflow facility (pneumatonography and fluorophotometry) and uveoscleral outflow (calculated using modified Goldmann equation). All subjects underwent 360 degrees SLT and AHD measurements were repeated 3 months later.ResultsCompared with baseline, IOPs after SLT were significantly lower at 9 AM (22.9 ± 5.1 vs. 19.7 ± 3.0 mm Hg; P = 0.001) and noon (23.4 ± 4.6 vs. 20.0 ± 3.5 mm Hg; P < 0.001). Outflow facility by fluorophotometry was significantly increased from 0.17 ± 0.11 μL/min/mm Hg at baseline to 0.24 ± 0.14 μL/min/mm Hg at 3 months (P = 0.008). Outflow facility by tonography (baseline: 0.16 ± 0.07 μL/min/mm Hg vs. 3 months: 0.22 ± 0.16 μL/min/mm Hg; P = 0.046) was similarly increased. No change in aqueous flow or EVP was observed. There were no changes in IOP or AHD in the contralateral untreated eye. Using multiple linear regression models, higher baseline aqueous flow, lower baseline outflow facility, and possibly lower uvescleral outflow were associated with more IOP lowering with SLT.ConclusionsThe IOP-lowering effect of SLT is mediated through an increase in outflow facility. There is no contralateral effect. Higher aqueous flow and lower outflow facility may be predictive of better response to SLT.

Ocular pulse amplitude after panretinal photocoagulation in normotensive eyes with proliferative diabetic retinopathy.

To assess the effect of panretinal laser photocoagulation on ocular pulse amplitude (OPA) in normotensive eyes with proliferative diabetic retinopathy. Prospectively, we performed unilateral argon laser panretinal photocoagulation (PRP) in 30 patients with diabetes mellitus type II and previously untreated bilateral proliferative diabetic retinopathy. Before and 7 and 30 days after the treatment, OPA was measured using dynamic contour tonometer. Compared with the untreated contralateral eyes, laser photocoagulation led to a reduction of OPA. Ocular pulse amplitude did not significantly differ in photocoagulated eyes 7 days after the treatment, but there was a significant difference in OPA 30 days after the treatment. The decrease in OPA values was 15% 7 days after PRP and 40% 30 days after PRP. Ocular pulse amplitude reduction after PRP indirectly informs us about choriocapillary closure, already reported in previous studies.

Natural history of corneal haze after corneal collagen crosslinking in keratoconus using Scheimpflug analysis

To analyze corneal haze after corneal collagen crosslinking (CXL) for progressive keratoconus using Scheimpflug densitometry. Auckland District Health Board, Auckland, New Zealand. Prospective randomized controlled study. Both eyes of all patients were examined preoperatively and 1, 3, 6, and 12months postoperatively. One eye of each patient was treated with corneal CXL, with the contralateral eye serving as the control. Examinations included uncorrected distance visual acuity and corrected distance visualacuity (CDVA), slitlamp biomicroscopy, and Scheimpflug tomography (Pentacam). Thirty-six eyes of 36 patients were enrolled. The mean preoperative corneal densitometry was 19.0±3.2 (SD). Postoperatively, the mean densitometry peaked at 1month, decreasing to baseline level after 6months without application of topical corticosteroids. The development of haze was significant compared with the contralateral untreated eyes (P<.01). The anterior (120μm) and inner (central 0.0 to 2.0mm) zones of the cornea had the highest densitometry after treatment. Lower preoperative central corneal thickness (CCT) was significantly correlated with higher corneal densitometry (P=.03). However, the preoperative CCT, keratometry, and astigmatism did not influence the difference in densitometry between the treated eyes and untreated eyes. There was no evidence of a relationship between densitometry and CDVA (P=.30). After corneal CXL, patients with keratoconus developed transient corneal haze in the anterior central cornea that might not require specific treatment. Thin corneas were associated with higher densitometry; thus, there might be a greater expectancy of corneal haze in patients with advanced keratoconus. None of the authors has a financial or proprietary interest in any material or method mentioned.

Short-Term Moderately Elevated Intraocular Pressure Is Associated With Elevated Scotopic Electroretinogram Responses.

PurposeModerately elevated intraocular pressure (IOP) is a risk factor for open-angle glaucoma. Some patients suffer glaucoma despite clinically measured normal IOPs. Fluctuations in IOP may have a significant role since IOPs are higher during sleep and inversion activities. Controlled transient elevations of IOPs in rats over time lead to optic nerve structural changes that are similar to the early changes observed in constant chronic models of glaucoma. Because early intervention decreases glaucoma progression, this study was done to determine if early physiological changes to the retina could be detected with noninvasive electrophysiological and optical imaging tests during moderately elevated IOP.MethodsIntraocular pressures were raised to moderately high levels (35 mm Hg) in one eye of Sprague-Dawley rats while the other (control) eye was untreated. One group of rats underwent scotopic threshold response (STR) and electroretinogram (ERG) testing, while another 3 groups underwent optical coherence tomography (OCT) imaging, Western blot, or histologic evaluation.ResultsThe amplitudes of the STR and ERG responses in eyes with moderately elevated IOPs were enhanced compared to the values before IOP elevation, and compared to untreated contralateral eyes. Structural changes to the optic nerve also occurred during IOP elevation.ConclusionsAlthough ischemic IOP elevations are well-known to globally reduce components of the scotopic ERG, acute elevation in rats to levels often observed in untreated glaucoma patients caused an increase in these parameters. Further exploration of these phenomena may be helpful in better understanding the mechanisms mediating early retinal changes during fluctuating or chronically elevated IOP.

Effects of intravitreal ranibizumab on the untreated eye and systemic gene expression profile in age-related macular degeneration.

The purpose of this study was to evaluate the systemic effects of intravitreal ranibizumab (Lucentis) treatment in patients with neovascular age-related macular degeneration (AMD). The impact of intravitreal ranibizumab injections on central retinal thickness (CRT) of treated and contralateral untreated eyes, and differences in gene expression patterns in the peripheral blood mononuclear cells were analyzed. The study included 29 patients aged 50 years old and over with diagnosed neovascular AMD. The treatment was defined as 0.5 mg of ranibizumab injected intravitreally in the form of one injection every month during the period of 3 months. CRT was measured by optical coherence tomography. The gene expression profile was assigned using oligonucleotide microarrays of Affymetrix HG-U133A. Studies have shown that there was a change of CRT between treated and untreated eyes, and there were differences in CRT at baseline and after 1, 2, and 3 months of ranibizumab treatment. Three months after intravitreal injection, mean CRT was reduced in the treated eyes from 331.97±123.62 to 254.31±58.75 μm, while mean CRT in the untreated fellow eyes reduced from 251.07±40.29 to 235.45±36.21 μm at the same time. Furthermore, the research has shown that among all transcripts, 3,097 expresses change after the ranibizumab treatment in relation to controls. Among these transcripts, 1,339 were up-regulated, whereas 1,758 were down-regulated. Our results show the potential systemic effects of anti-VEGF therapy for AMD. Moreover, our study indicated different gene expression in peripheral blood mononuclear cells before and after intravitreal ranibizumab treatment.

The Long-term Clinical Outcome after Corneal Collagen Cross-linking in Korean Patients with Progressive Keratoconus

PurposeTo evaluate the long-term clinical effectiveness and safety of corneal collagen cross-linking (CXL) in progressive keratoconus compared with untreated contralateral eyes.MethodsIn this retrospective study, nine eyes of nine patients with progressive keratoconus who received CXL (treatment group) and nine untreated contralateral eyes with keratoconus (control group) were included. All patients were followed for at least 5 years and assessed with best-corrected visual acuity, maximum keratometry, mean keratometry, corneal astigmatism, and corneal thickness. Clinical data were collected preoperatively and at 1, 3, 6, 12, 24, 36, 48, and 60 months, postoperatively.ResultsMean best-corrected visual acuity improved significantly from 0.58 ± 0.37 logarithm of minimum angle of resolution preoperatively to 0.39 ± 0.29 logarithm of minimum angle of resolution at 5 years after corneal CXL (p = 0.012). There was significant flattening of the maximum keratometry and mean keratometry from preoperative values of 63.39 ± 10.89 and 50.87 ± 6.27 diopter (D) to postoperative values of 60.89 ± 11.29 and 49.54 ± 7.23 D, respectively (p = 0.038, 0.021). Corneal astigmatism decreased significantly from 7.20 ± 1.83 D preoperatively to 5.41 ± 1.79 D postoperatively (p = 0.021). The thinnest corneal thickness decreased from 434.00 ± 54.13 to 365.78 ± 71.58 µm during 1 month after treatment, then increased to 402.67 ± 52.55 µm at 5 years, which showed a statistically significant decrease compared to the baseline (p = 0.020). In the untreated contralateral eyes, mean keratometry increased significantly at 2 years compared with the baseline (p = 0.043).ConclusionsCXL seems to be an effective and safe treatment for halting the progression of keratoconus over a long-term follow-up period of up to 5 years in progressive keratoconus.

600. Human Gene Therapy for a Synaptic Disease: X-Linked Retinoschisis (XLRS)

We have initiated a clinical trial for an ocular condition that has prominent synaptic dysfunction caused by mutations in an extracellular matrix protein, RS1 (retinoschisin). This report describes our findings on dissection of the molecular pathology at the synapse and reversal of the structural and functional defects when RS1 is introduced into mature Rs1-KO mouse retina using an AAV8 vector. We have started a human trial (NCT02317887) using the same vector, which will probe the synaptic plasticity in XLRS patients. RS1 mutations result in XLRS, a rare but recognized ocular condition that causes splitting of the neural retinal layers and results in intraretinal cysts. Medical attention generally was focused on the structural abnormalities of XLRS. However, visual function testing shows a selective depression of the electroretinogram (ERG) b-wave despite a normal a-wave, indicating intact photoreceptor responses but deficient post-synaptic signaling.The AAV8-RS1 vector for the murine studies and the clinical trial contains a self-complementary vector genome with the human RS1 promoter and the RS1 cDNA. For synaptic structural studies in adult Rs1-KO retina, 2.5e9 viral vector genomes (vg)/eye were administered by intravitreal injection at postnatal day 30. Retinal morphology, function and pathology were evaluated 2 months post injection, with contralateral untreated eyes as controls.The photoreceptor-depolarizing bipolar cell (DBC) synapse initially develops normally in Rs1 -KO mice, but the mGluR6-TRPM1 signaling cascade elements in the post-synaptic structure are progressively delocalized to the dendritic shaft and soma of the DBC. Concomitantly, the DBC resting membrane potential is altered. This molecular pattern of post-synaptic disruption is different from several other murine night-blindness models which share a “negative-going” ERG response that characterizes murine and human XLRS. Following AAV8-RS1 gene transfer to the XLRS mouse eye, TRPM1 and the signaling molecules return to their proper location at the dendritic tips, and the proper DBC resting membrane potential is restored, along with the ERG b-wave.The clinical trial utilizing the same vector is a prospective, dose-escalation, single-center study conducted at the National Eye Institute. One eye of each participant receives the RS1 gene vector given by intravitreal injection. While the primary outcome is safety, the dose range is scaled to probe possible efficacy.Invoking synaptic plasticity for therapeutic repair would be a desirable treatment strategy for a number of neurological conditions. These findings in Rs1 -KO mice provide insight into the molecular pathology of XLRS disease and demonstrate remarkable plasticity of a critical synapse in the visual system. Reversal of synaptic pathology by an AAV8-RS1 gene construct demonstrates novel possible therapeutic avenues for this and other diseases involving synaptic pathology.

IKK2 inhibition using TPCA-1-loaded PLGA microparticles attenuates laser-induced choroidal neovascularization and macrophage recruitment.

The inhibition of NF-κB by genetic deletion or pharmacological inhibition of IKK2 significantly reduces laser-induced choroid neovascularization (CNV). To achieve a sustained and controlled intraocular release of a selective and potent IKK2 inhibitor, 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) (MW: 279.29), we developed a biodegradable poly-lactide-co-glycolide (PLGA) polymer-delivery system to further investigate the anti-neovascularization effects of IKK2 inhibition and in vivo biosafety using laser-induced CNV mouse model. The solvent-evaporation method produced spherical TPCA-1-loaded PLGA microparticles characterized with a mean diameter of 2.4 ¼m and loading efficiency of 80%. Retrobulbar administration of the TPCA-1-loaded PLGA microparticles maintained a sustained drug level in the retina during the study period. No detectable TPCA-1 level was observed in the untreated contralateral eye. The anti-CNV effect of retrobulbarly administrated TPCA-1-loaded PLGA microparticles was assessed by retinal fluorescein leakage and isolectin staining methods, showing significantly reduced CNV development on day 7 after laser injury. Macrophage infiltration into the laser lesion was attenuated as assayed by choroid/RPE flat-mount staining with anti-F4/80 antibody. Consistently, laser induced expressions of Vegfa and Ccl2 were inhibited by the TPCA-1-loaded PLGA treatment. This TPCA-1 delivery system did not cause any noticeable cellular or functional toxicity to the treated eyes as evaluated by histology and optokinetic reflex (OKR) tests; and no systemic toxicity was observed. We conclude that retrobulbar injection of the small-molecule IKK2 inhibitor TPCA-1, delivered by biodegradable PLGA microparticles, can achieve a sustained and controllable drug release into choroid/retina and attenuate laser-induced CNV development without causing apparent systemic toxicity. Our results suggest a potential clinical application of TPCA-1 delivered by microparticles in treatment of CNV in the patients with age-related macular degeneration and other retinal neovascularization diseases.

Intraocular Pressure Elevation in the Contralateral Untreated Eye Following Selective Laser Trabeculoplasty in Rabbit Eyes

Our study aimed at evaluating if a single session of unilateral selective laser trabeculoplasty would affect the intraocular pressure of the fellow untreated eye in rabbits. Eleven rabbits were involved. 360° selective laser trabeculoplasty with 532 nm frequency-doubled green Nd:YAG laser was performed over the right eyes. The mean intraocular pressure of both eyes at baseline, 3 hours, 24 hours, 3 days and 7 days after laser were measured. The baseline mean intraocular pressure of the right eye and the left eye were 8.07 ± 1.72 mmHg and 8.27 ± 1.56 mmHg respectively (p=0.78). The mean intraocular pressure of the treated eye was lower than the baseline from 3 hours through 3 days after laser, with a maximum mean decrease of 1.36 mmHg on Day 3. On the contrary, the mean intraocular pressures of the untreated eyes were higher than the baseline throughout the study, particularly at later course (1.91 mmHg on Day 3 and 1.85 mmHg on Day 7). This suggests the change of intraocular pressure in one eye after selective laser trabeculoplasty, leads to a change in the pressure of the fellow eye. It is thought that a neuronal and humoral response is triggered centrally after unilateral intraocular pressure change. The detailed mechanisms would require further studies to evaluate. The rising intraocular pressure trend in the contralateral untreated eye suggests that response may continue to exert its action for some time after the initial laser. This is the first reported study of intraocular pressure elevation of the untreated eye following contralateral selective laser trabeculoplasty.