Quantitative Assessment of the Retina Using OCT and Associations with Cognitive Function.

PURPOSE: To determine the association of retinal thickness with cognitive function in Japanese persons. DESIGN: Cross-sectional, population-based survey. PARTICIPANTS: A total of 1293 Japanese persons aged 65 to 86 years who resided in the Saku area in the Japan Public Health Center-Based Prospective Study participated in the eye and mental health screening. METHODS: Participants underwent comprehensive ophthalmic assessment, including fundus photography, measurement of intraocular pressure, and determination of refraction status. We assessed the thickness of the macular retinal nerve fiber layer (mRNFL), ganglion cell-inner plexiform layer (GC-IPL), and ganglion cell complex (GCC, which includes the retinal nerve fiber layer and GC-IPL), and the full thickness in the macula and peripapillary retinal nerve fiber layer (ppRNFL) using spectral-domain (SD) OCT. Cognitive tests consisted of the Mini-Mental State Examination, Wechsler Memory Scale Revised logical memory I/II subtest, clock drawing test, and Clinical Dementia Rating Scale. These were used to designate the participants in the following 3 groups: Normal, those with mild cognitive impairment (MCI), and those with dementia. Multivariable logistic regression models were used to analyze associations between retinal thickness and cognitive function after adjusting potential confounding factors. MAIN OUTCOME MEASURES: Association of retinal thickness with cognitive function. RESULTS: Among the 1293 potential subjects, 114 were excluded for a diagnosis of depression, 64 were excluded for retinal disease, and 140 were excluded for scanning errors or suboptimal OCT images. The remaining 975 participants (mean age, 73.2 years) were included in this analysis. Significant differences were found in the 3 groups in all layers and GCC thickness, but not in ppRNFL thickness. After adjusting for age, sex, educational status, and refraction, full macular thickness and GCC thickness were inversely associated with the presence of dementia, but ppRNFL thickness was not. Furthermore, GC-IPL, GCC, and full macular thicknesses were all associated with the presence of dementia in the inferior sectors. CONCLUSIONS: Macular thickness was associated with the presence of dementia, but ppRNFL was not. Our results suggest that OCT measurements of the macula could be superior to those of the ppRNFL in assessing neurodegenerative changes and a potentially useful diagnostic biomarker of cognitive function.

Macular Impairment in Fabry Disease: A Morpho-functional Assessment by Swept-Source OCT Angiography and Focal Electroretinography.

Purpose: Fabry disease (FD) is a multiorgan X-linked condition characterized by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in a progressive intralysosomal deposit of globotriaosylceramide. The aim of this study was to evaluate the macular ultrastructure of the vascular network using optical coherence tomography angiography (OCTA) and to evaluate macular function using focal electroretinography (fERG) in Fabry patients (FPs). Methods: A total of 20 FPs (38 eyes, mean age 57 ± 2.12 SD, range of 27-80 years) and 17 healthy controls (27 eyes, mean age 45 years ± 20.50 SD, range of 24-65 years) were enrolled in the study. Color fundus photography, swept-source optical coherence tomography (SS-OCT), OCTA and fERG were performed in all subjects. The OCTA foveal avascular zone (FAZ), vasculature structure, superficial and deep retinal plexus densities (images of 4.5 × 4.5 mm) and fERG amplitudes were measured. Group differences were statistically assessed by Student's t-test and ANOVA. Results: In the FP group, the FAZ areas of the superficial and deep plexuses were enlarged (P = 0.036, t = 2.138; P < 0.001, t = -3.889, respectively), the vessel density was increased in the superficial plexus, and the fERG amplitude was reduced (P < 0.001, t = -10.647) compared with those in healthy controls. No significant correlations were found between the structural and functional data. Conclusions: OCTA vascular abnormalities and reduced fERG amplitudes indicate subclinical signs of microangiopathy with early retinal dysfunction in FPs. This study highlights the relevance of OCTA imaging analysis in the identification of abnormal macular vasculature as an ocular hallmark of FD.

Maculopathy from an accidental exposure to welding arc.

Welding light can cause photic retinal injury. We report binocular maculopathy induced by a brief exposure to electric arc welding light in a patient who could not equipped with protective device because of narrow space. A 47-year-old man performed electric arc welding for approximately 10-15 min without wearing protective device because of narrow space and subsequently experienced eye discomfort and decreased visual acuity. At the initial visit, his best corrected visual acuity was 0.5. Fundus examination, optical coherence tomography (OCT) and multifocal electroretinogram (mfERG) were performed. OCT showed disruption in the ellipsoid zone, and mfERG amplitudes in the central 10° were markedly reduced in both eyes. The decrease in visual acuity had been noted for at least 18 months. Using the proper protective device is essential in welding, despite short time periods of work. For patients with welding-induced photokeratitis, doctors should also consider the possibility of photic retinal injury.

Objective assessment of visual acuity: a refined model for analyzing the sweep VEP.

PURPOSE: The aim of this study was to develop a simple and reliable method for the objective assessment of visual acuity by optimizing the stimulus used in commercially available systems and by improving the methods of evaluation using a nonlinear function, the modified Ricker model. METHODS: Subjective visual acuity in the normal subjects was measured with Snellen targets, best-corrected, and in some cases also uncorrected and with plus lenses (+ 1 D, + 2 D, + 3 D). In patients, subjective visual acuity was measured best-corrected using the Freiburg Visual Acuity Test. Sweep VEP recordings to 11 spatial frequencies, with check sizes in logarithmically equidistant steps (0.6, 0.9, 1.4, 2.1, 3.3, 4.9, 7.3, 10.4, 18.2, 24.4, and 36.5 cpd), were obtained from 56 healthy subjects aged between 17 and 69 years (mean 42.5 ± 15.3 SD years) and 20 patients with diseases of the lens (n = 6), retina (n = 8) or optic nerve (n = 6). The results were fit by a multiple linear regression (2nd-order polynomial) or a nonlinear regression (modified Ricker model) and parameters compared (limiting spatial frequency (sflimiting) and the spatial frequency of the vertex (sfvertex) of the parabola for the 2nd-order polynomial fitting, and the maximal spatial frequency (sfmax), and the spatial frequency where the amplitude is 2 dB higher than the level of noise (sfthreshold) for the modified Ricker model. RESULTS: Recording with 11 spatial frequencies allows a more accurate determination of acuities above 1.0 logMAR. Tuning curves fitted to the results show that compared to the normal 2nd-order polynomial analysis, the modified Ricker model is able to describe closely the amplitudes of the sweep VEP in relation to the spatial frequencies of the presented checkerboards. In patients with a visual acuity better than about 0.5 (decimal), the predicted acuities based on the different parameters show a good match of the predicted visual acuities based on the models established in healthy volunteers to the subjective visual acuities. However, for lower visual acuities, both models tend to overestimate the visual acuity (up to ~ 0.4 logMAR), especially in patients suffering from AMD. CONCLUSIONS: Both models, the 2nd-order polynomial and the modified Ricker model performed equally well in the prediction of the visual acuity based on the amplitudes recorded using the sweep VEP. However, the modified Ricker model does not require the exclusion of data points from the fit, as necessary when fitting the 2nd-order polynomial model making it more reliable and robust against outliers, and, in addition, provides a measure for the noise of the recorded results.

Predictive value of spectral-domain optical coherence tomography features in assessment of visual prognosis in eyes with acute welding arc maculopathy.

OBJECTIVE: To observe spectral-domain optical coherence tomography (SD-OCT) features and to determine whether baseline OCT features can be used as predictors of visual acuity outcome in eyes with acute welding arc maculopathy. METHODS: This retrospective study enrolled twenty-two eyes of eleven subjects with acute welding arc maculopathy. All subjects were evaluated by SD-OCT at baseline and final visit. The involved parameters included best-corrected visual acuity (BCVA), central macular thickness (CMT), the length of ellipsoid zone (EZ) defects, the greatest linear dimension (GLD) of outer retinal lesions, EZ reflectivity and relative EZ reflectivity (defined as the ratio of EZ reflectivity to retinal pigment epithelium reflectivity on OCT). RESULTS: Acute welding arc maculopathy was presented as abnormal hyperreflectivity, hyporeflectivity and defects of outer retinal layer in fovea on OCT. Compared with baseline, BCVA improved significantly accompanied by decreased GLD of outer retinal lesions and the length of EZ defects at final visit (P = 0.0004, P < 0.0001 and P < 0.0001, respectively). No significant changes were shown on CMT (P = 0.248). In multivariate regression analysis, final BCVA was associated with baseline BCVA and the length of EZ defects (P = 0.012 and P = 0.045, respectively). However, EZ reflectivity and relative EZ reflectivity were not associated with final BCVA (P > 0.05). CONCLUSION: In conclusion, SD-OCT images clearly reveal morphological changes in outer retinal layer in acute welding arc maculopathy. The baseline BCVA and length of EZ defects are the strongest predictors of final BCVA.

ASSESSMENT OF ANATOMICAL AND FUNCTIONAL OUTCOMES WITH OCRIPLASMIN TREATMENT IN PATIENTS WITH VITREOMACULAR TRACTION WITH OR WITHOUT MACULAR HOLES: Results of OVIID-1 Trial.

PURPOSE: To evaluate the anatomical and functional outcomes with ocriplasmin in patients with vitreomacular traction (VMT) with or without macular hole (MH). METHODS: In a Phase 4, multicenter, single-arm, open-label study, eligible patients (VMT with focal adhesion, without epiretinal membrane, and with MH ≤400 µm [if present]) received a single intravitreal injection of ocriplasmin. Nonsurgical resolution of VMT (Day 28 [primary endpoint]), best-corrected visual acuity, MH closure, vitrectomy rate, and safety were assessed through Day 180. RESULTS: Overall, 466 patients were included in the full analysis set, of whom 47.4% had VMT resolution by Day 28; resolution rates in patients with VMT without MH, VMT with MH ≤250 µm, and VMT with MH >250 to ≤400 µm were 43.4%, 68.6%, and 62.7%, respectively. Macular hole closure was higher in eyes with VMT and MH ≤250 µm (57.1%) than in eyes with VMT and MH >250 to ≤400 µm (27.5%) at Day 28. Overall, 30.8% of patients with VMT resolution gained ≥10 letters in best-corrected visual acuity at Day 180. Adverse events were consistent with the known safety profile of ocriplasmin. CONCLUSION: Ocriplasmin is effective for resolution of VMT without or with MH (≤400 µm); treatment outcomes can be optimized with patient selection.

ASSESSMENT OF MACULAR VASCULATURE OF CHILDREN WITH SICKLE CELL DISEASE COMPARED TO THAT OF HEALTHY CONTROLS USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: This study aims at describing the macular vascular features of the eyes of pediatric patients with the homozygous form of sickle cell disease (SCD) using optical coherence tomography angiography. METHODS: This is a retrospective case series of eyes of pediatric patients with SCD, race- and age-matched to those of healthy individuals. Using optical coherence tomography angiography images of superficial capillary plexus and deep capillary plexus, the nonflow area, vascular density, and foveal avascular zone were measured. The remodeled microvascular foveal architectures obtained on optical coherence tomography angiography and fluorescein angiography were compared. RESULTS: A total of 19 eyes of patients with SCD and 18 eyes of race-matched healthy controls were examined. The best-corrected visual acuity ranged from 75 to 85 letters in all cases. In the SCD series, 8 eyes displayed signs of retinopathy on funduscopy. The foveal avascular zone was significantly enlarged, the foveal vascular density was 8% lower, and there were more perifoveal vascular alterations in the eyes of patients with SCD compared to those of controls. CONCLUSION: The foveal vascular density was significantly reduced and area of the foveal avascular zone was significantly increased in the eyes of patients with SCD. Consistent architectural changes in the perifoveal capillaries were also observed in the pediatric patients with SCD.

Electrophysiological assessment for early detection of retinal dysfunction in ß-thalassemia major patients.

PURPOSE: The purpose of this study was to assess the role of various diagnostic tests in early detection of retinal changes in ß-thalassemia major patients. METHODS: Thirty-eight visually asymptomatic ß-thalassemia major patients receiving regular blood transfusions and iron-chelation therapy with deferoxamine (group A, n = 13), deferasirox (group B, n = 11) or deferoxamine with deferiprone (group C, n = 14) and fourteen age- and sex- matched healthy individuals were included in the study. All participants underwent ophthalmoscopy, full-field electroretinography (ERG), visual evoked potentials (VEP), multifocal electroretinography (mfERG), fundus autofluorescence (FAF) imaging and optical coherence tomography (OCT) scans. RESULTS: Retinal pigment epithelium changes were present in two cases. Scotopic ERG demonstrated decreased a-wave amplitude in groups A, B and C (p = 0.03, p = 0.002 and p = 0.002, respectively) and decreased b-wave amplitude in groups B and C (p = 0.002 and p = 0.01, respectively) compared to controls. Photopic ERG showed delayed b-wave latency in groups A and C (p = 0.03 and p = 0.03, respectively) ERG maximal combined response and VEP response did not differ between groups. MfERG showed reduced retinal response density in ring 1 in groups A, B, C (p < 0.001, p < 0.001, p = 0.001, respectively) and ring 2 in group B (p = 0.02) and delayed latency in ring 5 in groups A and B (p = 0.04 and p = 0.04, respectively). Abnormal FAF images appeared in three cases and OCT abnormalities in one case, whereas no changes were observed in controls (p = 0.55 and p = 1.00, respectively). CONCLUSIONS: Full-field ERG and mfERG are more sensitive tools for detecting early retinal changes in ß-thalassemia patients compared with ophthalmoscopy, VEP, FAF imaging and OCT scans.

The Role of Multifocal Electroretinography in the Assessment of Drug-Induced Retinopathy: A Review of the Literature.

Multifocal electroretinography (mfERG) is an objective, noninvasive examination for the assessment of visual function. It enables the stimulation of multiple retinal areas simultaneously and recording of each response independently, providing a topographic measure of retinal electrophysiological activity in the central 40-50° of the retina. A clinical application of mfERG represents the assessment of retinal toxicity associated with systemic medications. Drug-induced retinopathy represents a disease that, although not common, requires early recognition: if not detected early, it may progress and cause irreversible retinal dysfunction with subsequent visual impairment. This review aims to evaluate the use of mfERG in the assessment of retinal dysfunction associated with various systemic pharmacological agents based on the currently available literature. The most commonly recognized systemic medications affecting retinal function are included, such as chloroquine and hydroxychloroquine, vigabatrin, deferoxamine, ethambutol, interferon-α, tamoxifen, digoxin, sildenafil, canthaxanthin, amiodarone and nefazodone. The role of mfERG in the early diagnosis of retinal toxicity and the evaluation of disease severity is reviewed, as well as its clinical value in monitoring disease progression or recovery after drug cessation.

Ocular toxicity assessment of chronic sildenafil therapy for pulmonary arterial hypertension.

PURPOSE: The aim of this study was to investigate possible functional and structural ocular changes caused by chronic sildenafil therapy to treat pulmonary arterial hypertension (PAH). METHODS: Case-control study included patients with pulmonary arterial hypertension: chronically using sildenafil and without sildenafil treatment. A comprehensive ophthalmologic exam including ectoscopy, extrinsic ocular motility, logMAR visual acuity measurement, contrast sensitivity test, color test, anterior segment biomicroscopy, Schirmer test 1, intraocular pressure, fundus exam under pupil dilation, fundus pictures, time domain and spectral domain optical coherence tomography, ocular Doppler ultrasound were performed. Full-field electroretinography (ERG) was tested for each eye in a subgroup of sildenafil-treated patients. RESULTS: Twenty patients from each group were tested. Bilateral severe keratitis was found in seven (35 %) patients under sildenafil therapy. Lacrimal film break-up time (BUT) was significantly reduced (p = 0.006 respectively) and Doppler ultrasound showed a reduced resistance index of the central retinal artery in the group of sildenafil users (p = 0.019). No diffuse retinal functional abnormalities were found in ERG in treated patients. Visual acuity, contrast sensitivity and color discrimination were normal in both groups. No abnormalities were found in both time-domain and spectral-domain OCT for retinal parameters. CONCLUSIONS: One-third of the treated PAH group showed severe bilateral keratitis. This finding could be related to connective tissue abnormalities usually present in patients with this condition that might be exacerbated with the sildenafil usage. The resistance index of the central retinal artery was diminished in the chronic users group and it could be associated to the vasodilation caused by the medication in the choroidal vessels. An ophthalmic assessment for these patients is recommended to diagnose and treat possible ocular surface and choroidal blood flow abnormalities caused by sildenafil.

The diagnosis and assessment of visual function in Singaporean children with electrophysiology: 10-year results.

PURPOSE: To study the clinical use and efficacy of electrophysiology in children. METHODS: This was a retrospective review of all children aged <16 years, who were referred to the Visual Electrophysiology Laboratory at the Singapore National Eye Center between 2003 and 2013. RESULTS: A total of 586 children, median age 8 years (range 0.15-16), were referred for a variety of reasons including investigation of poor vision (40 %), suspected retinal disease or optic nerve/cortical dysfunction (17 %), nystagmus (13 %) and screening or monitoring of a variety of ocular or neurological conditions (12 %). The number of children with vision 6/15 or worse was 418 (71 %), and 103 (18 %) had vision 6/120 or worse in at least one eye. The most common pathology noted was retinal dystrophy or dysfunction (41 %) or optic nerve/cortical dysfunction (12 %). In 30 %, visual electrophysiology was within normal limits, and in 6 %, a conclusive diagnosis could not be obtained. CONCLUSION: Electrophysiology testing played an important role in the assessment of children and added to the clinical management of the patient.

ASSESSMENT OF THE SIGNIFICANCE OF CYSTIC CHANGES AFTER EPIRETINAL MEMBRANE SURGERY WITH INTERNAL LIMITING MEMBRANE REMOVAL.

PURPOSE: To assess the prevalence and significance of cystic changes after internal limiting membrane peeling during epiretinal membrane surgery. METHODS: A retrospective review was performed on 64 patients who underwent pars plana vitrectomy with membranectomy for idiopathic epiretinal membrane between January 2010 and January 2012 by a single physician. Pars plana vitrectomy alone (Group 1, n = 32) or in combination with phacoemulsification (Group 2, n = 32) was performed. Peeling of the epiretinal membrane was assisted by triamcinolone, and internal limiting membrane was peeled up to the vascular arcades with the aid of brilliant blue dye. RESULTS: In Group 1, best-corrected visual acuity in logMAR (Snellen) improved from 0.53 ± 0.29 (20/68) at baseline to 0.23 ± 0.22 (20/34) at 6-month follow-up (P < 0.001). Two cases (6.3%) developed new cystic changes within the inner nuclear layer; however, there was no significant difference in best-corrected visual acuity at 6 months (P = 0.475). In Group 2, best-corrected visual acuity improved from 0.41 ± 0.17 (20/51) at baseline to 0.18 ± 0.15 (20/30) at 6 months (P < 0.001). Eight cases (25%) developed new inner nuclear layer cystic changes; however, there was no significant difference in best-corrected visual acuity at 6 months (P = 0.894). CONCLUSION: Development of new inner nuclear layer cystic changes after epiretinal membrane surgery may be a frequent finding, but in contrast to cystoid macular edema, it does not seem to affect visual recovery and should be observed. The combination of pars plana vitrectomy with cataract extraction may increase the risk of inner nuclear layer cystic changes.

Assessment of vascular regeneration in the CNS using the mouse retina.

The rodent retina is perhaps the most accessible mammalian system in which to investigate neurovascular interplay within the central nervous system (CNS). It is increasingly being recognized that several neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and amyotrophic lateral sclerosis present elements of vascular compromise. In addition, the most prominent causes of blindness in pediatric and working age populations (retinopathy of prematurity and diabetic retinopathy, respectively) are characterized by vascular degeneration and failure of physiological vascular regrowth. The aim of this technical paper is to provide a detailed protocol to study CNS vascular regeneration in the retina. The method can be employed to elucidate molecular mechanisms that lead to failure of vascular growth after ischemic injury. In addition, potential therapeutic modalities to accelerate and restore healthy vascular plexuses can be explored. Findings obtained using the described approach may provide therapeutic avenues for ischemic retinopathies such as that of diabetes or prematurity and possibly benefit other vascular disorders of the CNS.

Functional and high resolution retinal imaging assessment in a case of ocular siderosis.

PURPOSE: To report new findings in a case of ocular siderosis explored by high resolution angiography and adaptive optics (AO). METHODS: We report data on a 40-year-old man with an intraocular foreign body (IOFB) embedded in the sclera after hammering. RESULTS: Nine months after this accident, the patient presented with full-field electroretinogram (FF-ERG) abnormalities. Subsequent IOFB extraction was performed. One month after the surgery, high resolution angiography showed for the first time small iron particles all over the inner retinal surface. Spreading of these deposits was followed by inflammatory prepapillary new vessels and venous retinal vasculatis, which spontaneously resolved within a few months. ERG responses became slightly electronegative at this time. Clearance of the iron particles was followed over a year with AO and ERG recording. AO revealed an arterial tropism with a decrease in the amount of particles overtime, which may be consistent with macrophagic activity. CONCLUSION: High resolution angiography and AO are new tools, combined with electrophysiology, to better understand ocular siderosis pathophysiology.

The value of clinical electrophysiology in the assessment of the eye and visual system in the era of advanced imaging.

Electrophysiological techniques allow clinical investigations to include a 'dissection' of the visual system. Using suitable electrophysiological techniques, the 'dissection' allows function to be ascribed to the different photoreceptors (rod and cone photoreceptors), retinal layers, retinal location or the visual pathway up to the visual cortex. Combined with advances in genetics, retinal biochemistry, visual fields and ocular imaging, it is now possible to obtain a better understanding of diseases affecting the retina and visual pathways. This paper reviews core electrophysiological principles that can complement other examination techniques, including advanced ocular imaging, and help the interpretation of other clinical data and thus, refine and guide clinical diagnosis.

Association of ideal cardiovascular health metrics and retinal microvascular findings: the Atherosclerosis Risk in Communities Study.

BACKGROUND: This study evaluated the prevalence of ideal cardiovascular (CV) health in the Atherosclerosis Risk in Communities Study and determined its relationship with prevalent retinopathy, wider retinal venular diameters, and narrower arteriolar diameters, which are risk markers for subclinical cerebrovascular disease and are associated with increased stroke and coronary heart disease (CHD) morbidity and mortality. METHODS AND RESULTS: We used gradings of fundus photography measurements from the Atherosclerosis Risk in Communities Study to examine the association of retinopathy and retinal arteriolar and venular calibers to the number of ideal CV health metrics. Prevalent retinopathy showed a graded relationship with the CV health categories and number of ideal CV health metrics present: retinopathy prevalence was 2.1% among those with ≥5 ideal CV health metrics compared with 13.1% among those with zero ideal CV health metrics (odds ratio [CI]), 4.8 [2.5 to 8.9]). Central retinal venule equivalent and central retinal arteriolar equivalent diameters also showed graded relationships with CV health categories and number of ideal CV health metrics: after adjustment for age, race, sex, and education, mean central retinal venular equivalent was 187.8 µm (95% CI, 186.9 to 188.6 µm) among those with ≥5 ideal CV health metrics compared with 201.1 µm (95% CI, 199.1 to 203.1 µm) among those with zero ideal CV health metrics. Mean central retinal arteriolar equivalent was 163.8 µm (95% CI, 163.0 to 164.5 µm) among those with ≥5 ideal CV health metrics compared with 157.9 µm (95% CI, 156.1 to 159.7 µm) among those with zero ideal CV health metrics. CONCLUSIONS: Few adults had ideal cardiovascular health. Those with the best level of health were less likely to have retinopathy signs, wide retinal venules, and narrow retinal arterioles, which are associated with increased stroke and coronary heart disease risk.

[Noninvasive analysis of retinal microstructure and function: challenges and a promising future].

Challenges in the evaluation of the retinal microstructure. To facilitate evaluation of the retinal microstructure we participated in the development of a scanning laser ophthalmoscope (SLO) for 32 years. The 'retro-mode' is the latest developed lateral aperture SLO made in Japan. This instrument enables us to observe the cystoid spaces and retinal microfolds underlying the epiretinal membrane. We investigated the pathogenesis and the mechanism of early development of idiopathic macular holes (MHs) and the vitreomacular interface in idiopathic full-thickness MHs using spectral-domain optical coherence tomography (SD-OCT). We studied the anatomic morphology of stage 1-A impending MHs, characterized by a foveolar yellow spot, using SD-OCT in the fellow eyes of patients diagnosed with a full-thickness MH. SD-OCT showed the reflectivity of the perifoveal posterior vitreous detachment (PVD) with vitreofoveal adhesion in the eyes with a yellow spot; the foveal microstructure had a triangular foveolar detachment of the cone outer segment tip line. The foveolar detachment of the cone outer segment tip line might be responsible for the yellow spot seen in stage 1-A MHs. Using SD-OCT, we also analyzed the vitreomacular interface in idiopathic full-thickness MHs and identified four configurations of the vitreomacular interface in MHs without a complete PVD. The majority, i.e., 92%, of eyes with a MH without a complete PVD are likely due to the anteroposterior vitreofoveal traction exerted by a perifoveal PVD. About 55% of cases with an open roof in the eyes without a complete PVD might be at risk of progression to operculum formation (loss of retinal tissue). 2. Challenges in the evaluation of retinal function SLO microperimetry is used to evaluate the retinal function during observation of the retinal microstructure. We evaluated the retinal sensitivity and the focal visual acuity using our original microperimetry program and clarified the characteristics of the preferred retinal locus (PRL) in macular diseases and the importance of the PRL evaluation. Further refinement of the SLO as an all-in-one instrument with the addition of a treatment feature is planned. We evaluated the retinal blood flow (RBF) using a laser Doppler velocimetry instrument that we developed. In clinical studies, we found that the RBF decreased in patients with type 2 diabetes mellitus with no or mild retinopathy compared with healthy subjects. In in vivo animal studies performed in anesthetized cats, we elucidated the mechanism of RBF regulation in response to physiologic stimuli, i.e., systemic hypoxia, hypercapnia, hyperoxia, hyperglycemia and hypertension. We showed that the retinal vascular endothelium plays an important role in regulating the RBF. In in vitro studies, we examined the effects of laminar shear stress on gene expression in human retinal microvascular endothelial cells (HRMECs) and found that long-term exposure to physiologic shear stress in the retinal arterioles upregulated eNOS and thrombomodulin mRNA expression and down-regulated ET-1 mRNA expression in the HRMECs. In ex vivo studies, we found that simvastatin, pioglitazone, resveratrol and fenofibrate dilated isolated porcine retinal arterioles, suggesting that systemic administration of these drugs may have the therapeutic potential to improve the impaired RBF in patients with type 2 diabetes mellitus. 3. Challenges to the development of a telemedicine support system We established a real-time telemedicine system that can transmit precise retinal images of patients between Asahikawa Medical University Hospital and our branch hospitals. We also developed a method of 3-dimensional high-definition transmission and stereoscopic display for ophthalmology. Moreover, we established a system to share medical information using Peer to Peer technology and network control technology that can transmit urgent information during a disaster. In response to a request from the Chinese Government, which has limited medical facilities in rural areas, we donated our system to four hospitals in Beijing, Shanghai, Sichuan and Shaanxi Provinces. As a result of the development of our unique telemedicine home medical care system, patients can be followed at home even after discharge from a hospital. 4. Conclusions. We believe that ophthalmologists can obtain important information about not only ocular but also systemic diseases by analyzing the retinal microstructure and functions simultaneously and can share this information worldwide via the telemedicine technology that we established, which can be a promising advance in patient care.

An assessment of the ocular safety of excipient maleic acid following intravitreal injection in rabbits.

Maleic acid was formulated in 0.7% saline and injected intravitreally in rabbits in order to evaluate ocular safety and tolerability. Maleic acid was formulated within a narrow pH range (2-3), administered in a fixed volume (100 µl), and concentrations ranged from 0.00 to 2.00 mg/eye (0.00 to 12.30 mM vitreous). Ocular evaluations were conducted at 2, 4, and 8 days post injection. Ocular irritation responses were observed at doses from 0.50 mg/eye (3.07 mM vitreous) to 2.00 mg/eye (12.30 mM vitreous) and included conjunctival redness and scleral swelling. Chemosis was observed at 2.00 mg/eye (12.30 mM vitreous). Funduscopic evaluations revealed enlarged retinal blood vessels and optic disk swelling at doses ≥1.50 mg/eye (9.22 mM vitreous), retinal folds and retinal discoloration at 2.00 mg/eye (12.30 mM vitreous). Histopathologic evaluations on days 4 and 8 post injection revealed retinal degeneration at doses ≥1.0 mg/eye (6.15 mM vitreous), conjunctival inflammation at doses ≥1.5 mg/eye (9.22 mM vitreous), and retinal pigment epithelial hypertrophy, optic nerve demyelination, anterior chamber fluid, and conjunctival fibrosis at 2.00 mg/eye (12.30 mM vitreous) maleic acid. The data suggest that maleic acid formulations at ≥1.00 mg/eye (6.15 mM vitreous) were not suitable for intraocular indications.

Assessment of "non-recordable" electroretinograms by 9 Hz flicker stimulation under scotopic conditions.

To refine methods of electroretinographical (ERG) recording for the analysis of low retinal potentials under scotopic conditions in advanced retinal degenerative diseases. Standard Ganzfeld ERG equipment (Diagnosys LLC, Cambridge, UK) was used in 27 healthy volunteers (mean age 28 ± SD 8.5 years) to define the stimulation protocol. The protocol was then applied in clinical routine and 992 recordings were obtained from patients (mean age 40.6 ± 18.3 years) over a period of 5 years. A blue stimulus with a flicker frequency of 9 Hz was specified under scotopic conditions to preferentially record rod-driven responses. A range of stimulus strengths (0.0000012-6.32 scot. cd s/m² and 6-14 ms flash duration) was tested for maximal amplitudes and interference between rods and cones. Analysis of results was done by standard Fourier Transformation and assessment of signal-to-noise ratio. Optimized stimulus parameters were found to be a time-integrated luminance of 0.012 scot. cd s/m² using a blue (470 nm) flash of 10 ms duration at a repetition frequency of 9 Hz. Characteristic stimulus strength versus amplitude curves and tests with stimuli of red or green wavelength suggest a predominant rod-system response. The 9 Hz response was found statistically distinguishable from noise in 38% of patients with otherwise non-recordable rod responses according to International Society for Clinical Electrophysiology of Vision standards. Thus, we believe this protocol can be used to record ERG potentials in patients with advanced retinal diseases and in the evaluation of potential treatments for these patients. The ease of implementation in clinical routine and of statistical evaluation providing an observer-independent evaluation may further facilitate its employment.