Changes in cone-driven functions after intravitreal aflibercept injections in patients with age-related macular degeneration.

PURPOSE: To determine the changes in the cone-driven functions in patients with age-related macular degeneration (AMD) treated with intravitreal aflibercept. METHODS: We studied 44 eyes of 44 patients diagnosed with AMD whose mean age was 75 years. The contralateral unaffected eyes served as controls. All patients were initially treated with 3 consecutive monthly intravitreal aflibercept injections and thereafter with bimonthly injections for 12 months. Full-field cone electroretinograms (cone ERGs) were recorded at the baseline and at 3, 6, and 12 months after beginning the intravitreal aflibercept injections. The cone ERGs were elicited by red stimuli on a blue background. The focal macular ERGs (fmERGs) were elicited by 15 degrees white stimulus spot centered on the fovea. The amplitudes of the a- and b-waves, photopic negative response (PhNR), and sum of the oscillatory potentials (ΣOPs, sum of OP1-3 amplitudes) were analyzed. In addition, the implicit times of the a- and b-waves were also analyzed. RESULTS: The amplitudes and implicit times of all components of the fmERGs were significantly improved compared to the baseline at 3 months after beginning the intravitreal aflibercept injections (P < 0.0005-0.05). The amplitudes of the a-waves and PhNRs were further increased during the maintenance phase (P < 0.005-0.01). On the other hand, the amplitudes of the full-field a-waves and PhNR of the cone ERGs were significantly reduced at 6 and 12 months compared to the baseline. CONCLUSIONS: The macular function improved continuously during the maintenance phase of the intravitreal aflibercept injections. In contrast, the cone-driven functions of the more peripheral retina decreased with repeated injections suggesting adverse effects of the intravitreal aflibercept injections on the function of the more peripheral normal retina.

Changes of focal macular and full-field electroretinograms after intravitreal aflibercept in patients with central retinal vein occlusion.

PURPOSE: To evaluate the physiology of the macular and whole retina after intravitreal aflibercept (IVAs) injections in patients with macular edema associated with a central retinal vein occlusion (CRVO) by electroretinography (ERG). METHODS: We studied 20 eyes of 20 patients with non-ischemic CRVO (72.0 ± 9.2 years). All patients were treated with monthly injections of IVA for the initial 3 months and then treated by the treat-and-extend (TAE) regimen for 12 months. The best-corrected visual acuity (BCVA), optical coherence tomographic images, focal macular ERGs (fmERGs), and full-field ERGs recorded before and after the treatment were compared. The fmERGs were elicited by a 15° white stimulus spot centered on the fovea. The full-field ERGs were recorded by a protocol recommended by International Society for Clinical Electrophysiology of Vision. The amplitudes and implicit times determined before and after the IVA were compared. RESULTS: The foveal thickness was significantly reduced accompanied by improvement of the BCVA after the treatments, and the improvements were maintained for at least 12 months. The amplitudes and implicit times of the fmERGs improved continuously for the 12 months. On the other hand, the reduced amplitudes of the full-field ERG, summed oscillatory potentials, and the photopic negative responses remained unchanged for the 12-month period. However, the implicit times of the maximum and cone responses were significantly shortened after the IVA. CONCLUSIONS: IVA injections by the TAE regimen led to a continuous improvement of the macular function in patients with ME associated with a CRVO. However, the function of the whole retina changed differently than the macula after the treatment.

Macular function following intravitreal ranibizumab for macular edema associated with branch retinal vein occlusion: 12-month results.

PURPOSE: To evaluate the 12-month effects of intravitral ranibizumab (IVR) injections on the physiology and morphology of the macula in eyes with a branch retinal vein occlusion with macular edema (BRVOME). METHODS: We studied 13 eyes of 13 patients with a BRVOME. All patients were initially treated with IVR injections at 3 consecutive monthly intervals, the initiation phase. Additional treatments were done according to the pro re nata (PRN) regimen. The physiology of the macula was assessed by the focal macular electroretinograms (fmERGs) and the best-corrected visual acuity (BCVA). The morphology of the macular area was determined by spectral-domain optical coherence tomography. The retina was assessed at the baseline, and at 3, 6, and 12 months after beginning the IVR injections. The fmERGs were elicited by a 15° circular stimulus, and also by 15° semicircular stimuli placed on the occluded or non-occluded side of the macula. The amplitudes of the a- and b-waves, photopic negative response (PhNR), and sums of the oscillatory potentials (ΣOPs) were measured. In addition, the implicit times of the a- and b-waves were measured. RESULTS: The BCVA was improved significantly relative to the baseline after the initiation phase (P < 0.01), and it was maintained with the PRN regimen for the 12-month experimental period. The foveal thickness was also significantly decreased after the initiation phase (P < 0.005) but was then worse at 12 months during the maintenance phase (P < 0.05). The fmERGs on the occluded side were significantly reduced at the baseline, and the b-waves and ΣOPs amplitudes improved after the initiation phase. However, they decreased during the PRN period. On the non-occluded side, the amplitudes and implicit times of the a- and b-waves remained unchanged after the initiation phase, the PhNR and ΣOPs amplitudes significantly increased at 3 months compared to the baseline (PhNR, P < 0.005; ΣOPs, P < 0.005), which was maintained throughout the 12 month study period. CONCLUSIONS: The deterioration of the macular function on the occluded side during the maintenance phase suggests that there is a progression of the disease process during the PRN period in eyes with BRVOME.

Retinal dysfunction of syphilitic outer retinopathy.

PURPOSE: We present our findings in two cases of retinal dysfunction caused by syphilitic outer retinopathy. CASE 1: A 59-year-old man visited our clinic complaining of blurred vision in his left eye. Optical coherence tomography (OCT) demonstrated an absence of the ellipsoid zone (EZ) in the left eye. A round yellowish-white lesion was observed in the posterior pole of the left fundus. Fundus autofluorescence (FAF) showed hyperfluorescent areas in the posterior pole of both fundi although no specific ophthalmoscopic findings were seen in the right eye. The amplitudes of the LA 3.0 1 Hz and LA 3.0 30 Hz ERG responses were reduced with better preservation of the rod responses. Based on a strong positivity to the rapid plasma reagin (RPR) assay and the Treponema pallidum hemagglutination (TPHA) test, he was diagnosed with syphilitic outer retinopathy and treated with systemic antibiotics. The treatment resulted in a restoration of the retinal structures and cone function. CASE 2: A 47-year-old man was referred to our clinic complaining of reduced vision in both eyes. Although the ocular fundus appeared normal, FAF showed a diffuse hyperfluorescent area in the posterior pole and multiple hyperfluorescent spots. Indocyanine green angiography showed multiple confluent areas of hypofluorescence. OCT demonstrated irregular EZs in both eyes. The amplitudes of the LA 3.0 1 Hz and LA 3.0 30 Hz ERG responses were slightly reduced with prolonged implicit times. These findings are comparable to the findings in patients with multiple evanescent white dot syndrome. However, the strong positivity to the RPR and TPHA tests led us to diagnose the patient with outer retinopathy caused by syphilis. Systemic administration of antibiotics resulted in the restoration of the retinal structures and retinal function. CONCLUSIONS: Syphilitic outer retinopathy affected the retinal structures and function that can be restored by antibiotic treatments.

Macular function following intravitreal ranibizumab for macular edema associated with branch retinal vein occlusion.

PURPOSE: To determine the physiology of the macula by the focal macular electroretinograms (fmERGs) in patients with branch retinal vein occlusion with macular edema (BRVOME) treated by intravitreal injections of ranibizumab (IVR). METHODS: We studied 17 eyes of 17 patients with BRVOME. The contralateral unaffected eyes served as controls. All patients were treated with an IVR at monthly intervals for 3 consecutive months. The baseline best-corrected visual acuity (BCVA), optical coherence tomographic (OCT) findings, and fmERGs were compared to the post-treatment values. The fmERGs were elicited by a 15° circular spot or a superior or inferior semicircular spot. The center of the spot was placed on the fovea. The amplitudes of the a- and b-waves, photopic negative response (PhNR), and sum of the oscillatory potentials (ΣOPs: sum of OP1, OP2, and OP3 amplitudes) were measured. In addition, the implicit times of the a- and b-waves were also measured. RESULTS: The BCVA improved significantly from 0.39 ± 0.28 logMAR units to 0.17 ± 0.18 logMAR units after the resolution of the central macular edema (P < 0.01). All components of the fmERGs elicited by the semicircular stimulus spot placed on the occluded side were smaller than that elicited from the corresponding area of the control eyes. The b-wave amplitudes increased significantly from 0.49 ± 0.25 to 0.75 ± 0.36 µV following the IVR injections, but the amplitudes of the a-wave and PhNR remained reduced (P < 0.05). The amplitudes of the PhNR and ΣOPs elicited by stimulating the non-occluded side were reduced with relative preservation of the a- and b-waves (P < 0.05). They recovered after the treatment from 0.27 ± 0.15 to 0.50 ± 0.30 and 0.33 ± 0.15 to 0.53 ± 0.19 µV, respectively. CONCLUSIONS: IVRs improved the macular function not only on the occluded side but also on the non-occluded side. On the occluded side, the BRVOME affects the function of all retinal layers of the macula. Even after the IVR, the function of the photoreceptors and retinal ganglion cells remained abnormal. On the non-occluded side, the inner retinal function improved after the IVR.

Comparisons of focal macular electroretinograms after indocyanine green-, brilliant blue G-, or triamcinolone acetonide-assisted macular hole surgery.

PURPOSE: To compare the effects of indocyanine green (ICG)-, brilliant blue G (BBG)-, or triamcinolone acetonide (TA)-assisted internal limiting membrane (ILM) peeling during macular hole (MH) surgery on the different components of the focal macular electroretinograms (fmERGs). METHODS: Forty-eight eyes of 48 patients with a macular hole were randomly divided into those undergoing ICG-, BBG-, or TA-assisted vitrectomy (n = 16 for each group). All patients had combined cataract and macular hole surgery with ILM peeling. The fmERGs were recorded before, and 1, 3, 6, 9, and 12 months postoperatively. The amplitudes and implicit times of the a- and b-waves, the amplitudes of the sum of the oscillatory potentials (ΣOPs), and the photopic negative responses (PhNRs) were analyzed. RESULTS: The amplitudes of all of the components of the fmERGs gradually increased with time after surgery (P < 0.005). The implicit times of the a- and b-waves were significantly prolonged at 1 month (P < 0.01) and then gradually returned to the baseline times. No significant differences were found in these changes among the groups. In pooled data from the 48 patients, the PhNR amplitude increased more than the a- and b-waves and the ΣOPs amplitudes at every time point after 3 months (P < 0.005). CONCLUSIONS: The lack of significant differences on the different components of the fmERGs indicates that none of the three agents was toxic to the macula. After closure of a MH, the function of the retinal ganglion cells may recover more than that of the other neural elements in the macular area.

Structures affecting recovery of macular function in patients with age-related macular degeneration after intravitreal ranibizumab.

PURPOSE: To determine the retinal structures affecting the recovery of macular function in patients with exudative age-related macular degeneration (AMD) treated with intravitreal ranibizumab (IVR). METHOD: Thirty eyes of 30 patients with exudative AMD who were treated with IVR at monthly intervals for 3 months were studied. Focal macular electroretinograms (fmERGs) and spectral-domain optical coherence tomography (SD-OCT) were performed before and 3 months after beginning the IVR injections. The fmERGs were elicited by a 15° white stimulus spot centered on the fovea. The thickness of different retinal layers, presence of a serous retinal detachment (SRD), and presence of a pigment epithelial detachment (PED) at the fovea was determined in the SD-OCT images. Measurements were made of the inner, middle, and outer layers of the retina and also of the SRD and PED in the horizontal and vertical meridians at 1.2 mm from the fovea (parafoveal regions). The significance of the correlations between these structural parameters and the a-wave amplitude of the fmERG was determined. RESULTS: There was no significant correlation between the structural parameters of the fovea and the a-wave amplitude. In the parafoveal regions, the thickness of the outer retinal layer was significantly correlated with an increase of the a-wave amplitude (R = 0.56, P = 0.001). In addition, the SRD thickness was negatively and significantly correlated with the a-wave amplitude (R = -0.54, P = 0.002). The change in the parafoveal SRD thickness after IVRs was the only independent determinant of recovery of the a-wave amplitude after the treatments (P < 0.05). CONCLUSIONS: The macular function measured by the fmERGs was determined by the parafoveal outer layer and SRD thickness in patients with exudative AMD. Of these, changes in the SRD thickness by IVRs most strongly affected the recovery of macular function.

Comparisons of cone electroretinograms after indocyanine green-, brilliant blue G-, or triamcinolone acetonide-assisted macular hole surgery.

PURPOSE: To compare the function of retinal ganglion cells (RGCs) using the photopic negative response (PhNR) in patients who had undergone indocyaine green (ICG)-assisted, brilliant blue G (BBG)-assisted, or triamcinolone acetonide (TA)-assisted internal limiting membrane (ILM) peeling during macular hole (MH) surgery. METHODS: Forty-eight eyes of 48 patients with a macular hole were randomly divided into those undergoing ICG-assisted, BBG-assisted, or TA-assisted vitrectomy (n = 16 for each group). Full-field cone ERGs were recorded before and 1, 3, 6, 9, and 12 months postoperatively. The amplitudes and implicit times of the a-waves and b-waves and the amplitudes of the oscillatory potentials (OPs) and PhNRs were measured. The mean deviations (MDs) of standard automated perimetry and the best-corrected visual acuity (BCVA) were measured. The circumferential retinal nerve fiber layer (RNFL) thickness was evaluated by SD-OCT. RESULTS: All macular holes were closed with a significant improvement of the BCVA and MD without differences among the groups. There was no significant difference between the preoperative and postoperative RNFL thickness. The implicit times of the a-waves and b-waves were significantly prolonged, and the ΣOPs amplitude was significantly decreased postoperatively in all groups. These ERG changes were not significantly different among the groups. The postoperative PhNR amplitudes were significantly lower in the ICG group than in the BBG or TA group. CONCLUSIONS: The results indicate that the PhNR may detect subclinical impairments of RGCs caused by the possible toxic effect of ICG. This finding adds to the data that BBG and TA may be safer than ICG for use during MH surgery.

Conformation of Horizontal Extraocular Muscle Insertions in Acute Acquired Concomitant Esotropia Induced by Excessive Digital Device Usage.

Purpose: Acute acquired concomitant esotropia induced by excessive digital device usage, especially smartphones (SAACE), has been increasing over the past few years. Convergence spasm induced by excessive near work has been suggested as a mechanism. Anatomical differences could also potentially contribute to SAACE onset. The present study investigated the conformation of horizontal recti between SAACE patients and normal subjects. Patients and Methods: In 15 SAACE patients (SAACE group), the distances between the limbus and insertion of the horizontal recti (LI distance) and the widths of horizontal recti on the insertion (insertion width) were measured. The control group consisted of 30 patients who underwent retinal detachment surgery. Differences in LI distances and insertion widths were compared between SAACE and control groups. Results: While there were no differences between the two groups for LI distances and insertion widths of lateral recti, there were significantly shorter LI distances for the medial recti in the SAACE group (P<0.05). Moreover, the SAACE group tended to exhibit larger insertion widths of the medial recti. Medial/lateral ratio of LI distances were significantly lower and insertion widths were significantly higher in the SAACE compared to the control group (P<0.05). Conclusion: Based on the observations of more anterior insertion and larger muscle widths, this suggests there are stronger forces of medial recti in SAACE. In addition to excessive accommodation followed by increases in medial recti tonus, the results also suggest that an anatomical imbalance between lateral and medial recti contributes to esotropia onset following excessive near work.

Contribution of N-methyl-DL-aspartic acid (NMDA)-sensitive neurons to generating oscillatory potentials in Royal College of Surgeons rats.

PURPOSE: We investigated how the N-methyl-DL-aspartic acid (NMDA) receptor contributes to generating oscillatory potentials (OPs) of the electroretinogram (ERG) in the Royal College of Surgeons (RCS) rat. METHODS: Scotopic ERGs were recorded from dystrophic and wild-type congenic (WT) RCS rats (n = 20 of each) at 25, 30, 35, and 40 days of age. The stimulus intensity was increased from -2.82 to 0.71 log cd-s/m(2) to obtain intensity-response function. NMDA was injected into the vitreous cavity of the right eyes. The left eyes were injected with saline as controls. The P3 obtained by a-wave fitting was digitally subtracted from the scotopic ERG to isolate the P2. For the OPs, the P2 was digitally filtered between 65 and 500 Hz. The amplitudes of OP1, OP2, OP3, and OP4 were then measured and summed and designated as ΣOPs. The implicit times of OP1, OP2, and OP3 were also measured. The frequency spectra of the OPs were analyzed using fast Fourier transform (FFT). RESULTS: The maximum ERG a- and b-waves as well as ΣOPs amplitudes reduced with age in dystrophic rats. Compared with intravitreal saline injection, administration of NMDA decreased ΣOPs amplitudes from 30 days of age in dystrophic rats, while it did not attenuate ΣOPs amplitudes in WT rats. The implicit times of the OPs of the maximum ERG were prolonged by NMDA injections in WT and dystrophic rats. NMDA/saline ratios of ΣOPs amplitudes area under the FFT curves were significantly lower in dystrophic rats from 30 days of age than that in WT rats. CONCLUSION: In the early stage of photoreceptor degeneration, intravitreal NMDA injection attenuated OPs amplitudes in dystrophic rats. This indicates that NMDA receptors play a significant role in generating OPs amplitudes with advancing photoreceptor degeneration.

Effect of hydroxychloroquine or chloroquine and short wavelength light on in vivo retinal function and structure in mouse eyes.

CLINICAL RELEVANCE: The use of chloroquine or hydroxychloroquine can lead to both acute and chronic changes to both retinal structure and function. BACKGROUND: Chloroquine (CQ) and hydroxychloroquine (HCQ) have the potential for retina toxicity. The acute impact of short-term drug exposure (2-4 weeks) on in vivo retinal structure and function and assess whether short wavelength light exposure further exacerbates any structural and functional changes was assessed in a murine model. METHODS: Adult C57BL/6 J mice received intraperitoneal injection of vehicle or hydroxychloroquine (10 mg/kg) 3 times per week for 2 or 4 weeks, or chloroquine for 4 weeks (10 mg/kg). Over this period, animals were exposed to room light (8 hours) or short-wavelength light 4 hours per day (4 hours of normal room light) for 5 days each week. Retinal changes were assessed using electroretinography (ERG), in vivo optical coherence tomography (OCT) imaging. RESULTS: Short-term low-dose HCQ and CQ treatment led to RPE thickening and elongation of photoreceptors. These structural changes were associated with a no dysfunction in the case of HCQ treatments and widespread functional changes (photoreceptor sensitivity, bipolar cell amplitude and oscillatory potential amplitude) in the case of CQ treatment. Exposure to low intensity short-wavelength light does not appear to alter the effect of HCQ or CQ. CONCLUSIONS: HCQ and CQ treatment has acute effects on both retinal structure and function, effects that were not exacerbated by short wavelength light exposure. Whether chronic short wavelength light exposure exacerbates these changes require further study.

Retinal Assessment Using In Vivo Electroretinography and Optical Coherence Tomography in Rodent Models of Diabetes.

Electroretinography and optical coherence tomography imaging allow for non-invasive quantitative assessment of the retina. These approaches have become mainstays for identifying the very earliest impact of hyperglycemia on retinal function and structure in animal models of diabetic eye disease. Moreover, they are essential for assessing the safety and efficacy of novel treatment approaches for diabetic retinopathy. Here, we describe approaches for in vivo electroretinography and optical coherence tomography imaging in rodent models of diabetes.

Macular function evaluated by focal macular electroretinograms after reduced fluence photodynamic therapy in eyes with polypoidal choroidal vasculopathy.

The purpose of this study was to evaluate the macular function by measuring the focal macular electroretinograms (ERGs) recorded before and after reduced fluence photodynamic therapy (RFPDT) in patients with polypoidal choroidal vasculopathy (PCV). Eleven eyes of 11 patients with PCV were studied. Their ages ranged from 62 to 85 years with a mean of 74.7 ± 6.9 years. The exposure time for the RFPDT was reduced to 42 s, so that the total energy of the laser was approximately one-half that of the standard PDT. We measured the visual acuity, foveal thickness, and focal macular ERGs before and after the RFPDT. The follow-up period ranged from 13 to 34 months with a mean of 26 months after the treatment. A significant recovery of vision was seen even at 1 week after the RFPDT (P < 0.005), and the visual acuities improved gradually thereafter (P < 0.0005). The foveal thickness was significantly reduced at 1 week after the treatment (P < 0.005) and then continued to become significantly thinner with time (P < 0.0001). A slight recovery of the a- and b-wave amplitudes was seen postoperatively without a transient reduction in the amplitudes. The b-wave amplitude was significantly larger at 3 months after the treatment than at baseline (P < 0.05). Choroidal hypoperfusion did not develop 3 months postoperatively in the indocyanine green angiograms. Exudative changes recurred in 4 (27%) eyes after 1 year and in 9 (82%) eyes during the follow-up period. RFPDT provided short-term benefits in selected patients with PCV with small lesions. The macular function was retained after RFPDT without a transient decrease in visual function. Further study is needed to determine the long-term efficacy of RFPDT for eyes with PCV.

Significant correlations between focal photopic negative response and focal visual sensitivity and ganglion cell complex thickness in glaucomatous eyes.

PURPOSE: To determine whether there are significant correlations between the focal photopic negative response (PhNR), the focal visual sensitivity and the ganglion cell complex (GCC) thickness in glaucomatous eyes. STUDY DESIGN: Single-center observational study. METHODS: Fifty-two eyes of 52 patients (71.4 ± 9.42 years) with clinically diagnosed open angle glaucoma were studied. Thirty-six age-matched normal subjects served as controls. The focal PhNR of the focal macular electroretinograms (fmERGs) were elicited by a 15° circular, a superior semicircular or an inferior semicircular stimulus centered on the fovea. The thickness of the GCC was measured in the corresponding retinal areas in the spectral-domain optical coherence tomographic images. The visual sensitivities (dB) were measured by microperimetry at the retinal area where the fmERGs were elicited and were converted to liner values (1/Lambert). RESULTS: The focal PhNR amplitudes were significantly correlated with the visual sensitivities of the full-circle (R = 0.532), the superior (R = 0.530) and inferior (R = 0.526) semicircular responses (P < 0.0001). The GCC thickness was correlated with the visual sensitivities in the same areas with stronger correlations (R = 0.700, 0.759 and 0.650, respectively; P < 0.0001). The focal PhNR amplitudes were proportionally reduced with the thinning of the GCC thickness (R = 0.494, 0.518 and 0.511, respectively; P < 0.0001). CONCLUSIONS: The significant correlations between the focal PhNR amplitudes, the focal visual sensitivities and the GCC thickness indicate that these may be good biomarkers to track the changes in the physiology and anatomy of the macular area in glaucomatous eyes.

Optimizing Retinal Thermofusion in Retinal Detachment Repair: Achieving Instant Adhesion without Air Tamponade.

Purpose: Rhegmatogenous retinal detachment repair by intraoperative sealing of the tear without a tamponade agent should enable faster restoration of vision and resumption of normal activities. It avoids the need for further surgery in the case of silicone oil endotamponade. This study evaluated the retinal thermofusion (RTF) retinopexy method of subretinal space dehydration before photocoagulation to create an instantaneous intraoperative retina reattachment in a preclinical model. Design: Preclinical study. Participants: Twenty Dutch Belt, pigmented rabbits that underwent RTF repair after experimental retinal detachment. Methods: This ex vivo model quantified adhesion force between the retina and underlying retinal pigment epithelium and choroid after treatment of 1 retinal edge using postmortem porcine or human retina (6 × 12 mm). We compared (1) control, (2) laser photocoagulation alone, (3) dehydration alone, and (4) dehydration followed by photocoagulation (RTF). Optimized parameters for RTF were then applied in the in vivo rabbit model of retinal detachment. Animals were followed up for 14 days. Main Outcome Measures: For this ex vivo model, we measured adhesion force and related this to tissue temperature. For the in vivo study, we assessed retinal attachment using funduscopy and histologic analysis. Results: The ex vivo model showed that RTF repair produced significantly higher adhesion force than photocoagulation alone independent of dehydration method: warm (60° C) high airflow (50-70 ml/minute) or using laser wavelengths targeting water absorption peaks (1470 or 1940 nm) with coaxial low airflow (10-20 ml/minute). The latter approach produced a smaller footprint of dehydration. Application of RTF (1940-nm laser with coaxial airflow) in an in vivo retinal detachment model in rabbit eyes resulted in immediate retinal adhesion, achieving forces similar to those in the ex vivo experiments. Retinal thermofusion repair resulted in stable reattachment of the retina over the 2-week follow-up period. Conclusions: We showed that a short preliminary dehydrating laser treatment of a retinal tear margin before traditional laser photocoagulation creates an immediate intraoperative waterproof retinopexy adhesion independent of tamponade and a wound-healing response. This approach potentially will allow rapid postoperative recovery regardless of the tear location and improved vision.

Relationships between the vascular structure and neural function of the macula in patients with diabetes mellitus.

PURPOSE: To determine the significance of the correlation between the vascular structure and neural function of the macula in patients with diabetes mellitus. STUDY DESIGN: Single-center observational study. PATIENTS AND METHODS: Ninety eyes of 90 diabetic patients with an average (SD) age of 63.5 (3.8) years were studied. Fifty of the eyes had no clinically apparent diabetic retinopathy (non-DR), and 40 eyes had mild-to-moderate nonproliferative DR (NPDR). Thirty age-matched healthy individuals were also studied in the same way. Swept-source optical coherence tomography angiography (OCTA) was performed to obtain 3 × 3-mm en face images of the posterior pole of the eye. The vascular densities (VDs) of the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) were determined. The focal macular electroretinograms (ERGs) elicited by a 15° circular stimulus centered on the fovea were recorded. The amplitudes of the a- and b-waves, sum of the oscillatory potentials (ΣOPs), photopic negative response (PhNR), and implicit times of the individual OPs (OP1-OP3) were measured. RESULTS: The VDs of the SCP and DCP were reduced in eyes with advanced DR (P < .01 for SCP). The implicit times of OP1-OP3 were significantly prolonged in eyes with a lower VD of the SCP and DCP in the non-DR group (P < .05). The amplitudes of the ΣOPs were significantly smaller in eyes with a reduced VD of the SCP and DCP in the NPDR group (P < .05). The correlation coefficients were higher for the OP implicit times than for the ΣOP amplitudes in the non-DR group. CONCLUSIONS: The OPs of the focal macular ERG are smaller with prolonged implicit times in association with capillary loss in the macula of diabetic patients. The implicit times are the most sensitive functional parameter that reflects the early changes of the microvasculature in the macula caused by diabetes.

Targeted delivery of LM22A-4 by cubosomes protects retinal ganglion cells in an experimental glaucoma model.

Glaucoma, a major cause of irreversible blindness worldwide, is associated with elevated intraocular pressure (IOP) and progressive loss of retinal ganglion cells (RGCs) that undergo apoptosis. A mechanism for RGCs injury involves impairment of neurotrophic support and exogenous supply of neurotrophic factors has been shown to be beneficial. However, neurotrophic factors can have widespread effects on neuronal tissues, thus targeting neurotrophic support to injured neurons may be a better neuroprotective strategy. In this study, we have encapsulated LM22A-4, a small neurotrophic factor mimetic, into Annexin V-conjugated cubosomes (L4-ACs) for targeted delivery to injured RGCs in a model of acute IOP elevation, which is induced by acute IOP elevation. We have tested cubosomes formulations that encapsulate from 9% to 33% LM22A-4. Our data indicated that cubosomes encapsulating 9% and 17% LM22A-4 exhibited a mixture of Pn3m/Im3m cubic phase, whereas 23% and 33% showed a pure Im3m cubic phase. We found that 17% L4-ACs with Pn3m/Im3m symmetries showed better in-situ and in-vitro lipid membrane interactions than the 23% and 33% L4-ACs with Im3m symmetry. In vivo experiments showed that 17% L4-ACs targeted the posterior retina and the optic nerve head, which prevented RGCs loss and improved functional outcomes in a mouse model of acute IOP elevation. These results provide evidence that Annexin V-conjugated cubosomes-based LM22A-4 delivery may be a useful targeted approach to prevent the progression of RGCs loss in glaucoma. STATEMENT OF SIGNIFICANCE: Recent studies suggest that the therapy of effectively delivering neurotrophic factors to the injured retinal ganglion cells (RGCs) could promote the survival of RGCs in glaucoma. Our present work has for the first time used cubosomes as an active targeted delivery system and have successfully delivered a neuroprotective drug to the damaged RGCs in vivo. Our new cubosomal formulation can protect apoptotic cell death in vitro and in vivo, showing that cubosomes are a promising drug carrier system for ocular drug delivery and glaucoma treatment. We have further found that by controlling cubosomes in Pn3m phase we can facilitate delivery of neuroprotective drug through apoptotic membranes. This data, we believe, has important implications for future design and formulation of cubosomes for therapeutic applications.

Comparisons of photopic negative responses elicited by different conditions from glaucomatous eyes.

PURPOSE: To compare the clinical significance of the photopic negative response (PhNRs) elicited by different stimuli from glaucomatous eyes. STUDY DESIGN: Single-center observational study METHOD: Eighty-four eyes of 84 patients with open angle glaucoma (OAG) and 40 eyes of 40 normal subjects were studied. Cone electroretinograms (ERGs) were elicited by white stimuli on a white background (W/W) or red stimuli on a blue background (R/B). The luminance of the stimuli was 0.5, 1.0, 2.0 or 3.0 cd-s/m2, and of the background light was 10 cd/m2. The first and second troughs of the ERGs that appeared following the b-wave were designated as PhNR1 and PhNR2, respectively. The thickness of the circumpapillary retinal nerve fiber layer (cpRNFL) was measured by spectral-domain optical coherence tomography. The mean deviation (MD) was determined by standard automated perimetry. The area under the receiver operating characteristic curves (AUCs) was created to determine the diagnostic ability of the PhNRs elicited by the different stimulus conditions. RESULTS: The correlation coefficients of the amplitudes of the PhNR1 elicited by W/W stimuli to the MDs and cpRNFL thickness were generally stronger, and the regression lines steeper than for the amplitudes of the PhNR1 elicited by R/B stimuli. In contrast, the correlation coefficients of the amplitudes of the PhNR2 elicited by R/B stimuli to the MDs and cpRNFL thickness were generally stronger, and the regression lines were steeper than the amplitudes of the PhNR2 elicited by W/W stimuli. With both types of stimuli, the slopes of the regression lines became steeper when the ERG recorded with higher stimulus intensities. The AUCs were significantly larger for the PhNR2 elicited by the R/B stimuli at 3.0 cd-s/m2 than for PhNR1 and PhNR2 elicited by W/W stimuli at the same intensity when the PhNRs were used for diagnosing advanced glaucoma. CONCLUSION: The PhNR1 and PhNR2 elicited by the W/W and R/B stimuli are suitable measures to assess the function of the RGCs in eyes with OAG. The PhNR2 elicited by R/B stimuli at higher stimulus intensities is most effective in detecting functional and structural changes of the RGCs with the highest diagnostic capacity in discriminating advanced glaucoma.

Correlation between macular structure and function in patients with age-related macular degeneration treated with intravitreal ranibizumab: 12-month-results.

PURPOSE: To determine the significance of the correlation between optical coherence tomographic (OCT) findings and focal macular electroretinograms (fmERG) at 12 months after beginning intravitreal injections of ranibizumab (IVR) in eyes with age-related macular degeneration (AMD). STUDY DESIGN: Prospective, clinical study. METHOD: We studied 28 eyes of 28 patients with AMD treated with IVR at monthly intervals for the initial three months. Additional IVR was given according to a pro re nata (PRN) regimen. OCT and fmERGs were performed preoperatively and at 3 and 12 months postoperatively. The fmERGs were elicited by a 15° white stimulus spot centered on the fovea. The thickness of the inner, middle, and outer layers of the retina and also of the serous retinal detachment (SRD) and pigment epithelial detachment (PED) in the horizontal and vertical meridians at 1.2 mm from the fovea (parafoveal) were measured in the OCT images. RESULTS: The b-wave amplitude at 12 months was significantly correlated with the thicknesses of the outer retinal layer, SRD, and PED (P=0.001-0.02). Multiple regression analyses showed that the outer retinal layer thickness was an independent determinant (P= 0.0001). The changes in the b-wave amplitude between the baseline and 12 months were significantly correlated with the changes in the SRD thickness (P=0.006). The changes in the b-wave amplitude during the PRN period were significantly correlated with the changes in the PED thickness (P=0.02). CONCLUSIONS: At 12 months after beginning treatment, the reduction in the SRD thickness affects macular function recovery. As recurrences of the PED can occur during the PRN period, control of the PED is necessary to obtain good macular function for the long term.

Identification of eyes at risk of acute primary angle-closure in elderly Japanese patients.

Purpose: To identify from the anterior segment the structural variables of the eyes that can be used to distinguish acute primary angle-closure (APAC) eyes or primary angle-closure suspect (PACS) eyes from normal eyes. Patients and methods: We used a Pentacam scanner to measure participants' anterior eye segments. We assessed each anterior segment structure variable on the basis of receiver operating characteristic curves using the area under the curve (AUC). Results: AUCs for eyes in men with APAC were 1.000 for central anterior chamber depth (ACD), 0.982 for peripheral ACD, 0.916 for anterior chamber angle (ACA), and 0.992 for anterior chamber volume (ACV). AUCs for eyes in women with APAC were 0.997 for central ACD, 0.942 for peripheral ACD, 0.922 for ACA, and 0.946 for ACV. AUCs for eyes in men with PACS were 0.933 for central ACD, 0.930 for peripheral ACD, 0.887 for ACA, and 0.937 for ACV. AUCs for eyes in women with PACS were 0.960 for central ACD, 0.957 for peripheral ACD, 0.937 for ACA, and 0.937 for ACV. The negative predictive values (%) in men with APAC were 100 for all the four variables (central ACD, peripheral ACD, ACA, and ACV). The negative predictive values (%) in women with APAC were 100 for central ACD, 98.7 for peripheral ACD, 97.1 for ACA, and 97.9 for ACV. The negative predictive values (%) in men with PACS were 98.6 for central ACD, 100 for peripheral ACD, 98.5 for ACA, and 99.4 for ACV. The negative predictive values (%) in women with PACS were 100 for central ACD, 98.7 for peripheral ACD, 97.1 for ACA, and 97.9 for ACV. Conclusions: The central ACD, peripheral ACD, ACA, and ACV measurements seem to be excellent markers to identify eyes without APAC or PACS.