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Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.

Purpose: Current management of submacular hemorrhage (SMH) favors vitrectomy and gas with subretinal administration of recombinant tissue plasminogen activator (rtPA) over mere intravitreal rtPA injections and gas. In this study, we aimed to compare the effectiveness of both treatment modalities to displace submacular blood., Methods: Twenty-four patients with SMH secondary to age-related macular degeneration were included. The SMH had to exist ≤14 days at time of surgery and SMH thickness had to be between 250 μm and 1,250 μm. Patients were randomized to either intravitreal injections of rtPA, perfluoropropane (C3F8) gas, and bevacizumab (n = 12) or vitrectomy with subretinal rtPA administration, intravitreal C3F8 gas, and bevacizumab (n = 12). The SMH volume change was measured on spectral domain optical coherence tomography postoperatively within a 2.5-mm cylinder centered at the fovea., Results: Median relative volume reduction of subretinal blood at 6 weeks postoperatively was 97% (95% confidence interval: 91-99%) in the intravitreal rtPA group and 100% (95-100%) in the subretinal rtPA group and did not differ significantly between groups (P = 0.56)., Conclusion: Both treatment modalities effectively displaced SMH in this exploratory clinical trial. To more definitely study the noninferiority of intravitreal rtPA with gas to subretinal rtPA, vitrectomy with gas, a larger clinical trial would be necessary.

Purpose: To study patients diagnosed with retinal angiomatous proliferation (RAP) based on conventional imaging techniques with phase-resolved Doppler optical coherence tomography (OCT) to detect and localize blood flow in RAP lesions; and to compare these findings to conventional imaging, which are mostly invasive and give limited information concerning intra- and transretinal blood flow., Design: Single-center, consecutive observational case series., Methods: Twelve treatment-naïve patients diagnosed with RAP based on fundus examination, fluorescein angiography, and indocyanine green angiography were included. Median age was 79 years (range 65-90). Patients were imaged with an experimental 1040 nm swept-source phase-resolved Doppler OCT instrument. Abnormal flow was defined as intraretinal neovascularization or retinal choroidal anastomosis., Results: In 11 patients adequate phase-resolved Doppler OCT images were obtained showing abnormal blood flow in the RAP lesion. In 4 patients a retinal choroidal anastomosis was found, 3 patients showed intraretinal neovascularization connected with a pigment epithelial detachment, 2 patients showed only intraretinal neovascularization, and in 2 patients flow was limited to the subretinal or sub-retinal pigment epithelial space., Conclusions: Phase-resolved Doppler OCT is able to detect and localize abnormal blood flow within RAP lesions. Blood flow was mostly confined to the intraretinal structures with or without a connecting pigment epithelial detachment; in one-third of patients a retinal choroidal anastomosis was detected. The potential of angiography with phase-resolved Doppler OCT to accurately distinguish between normal and pathologic blood flow in addition to structural OCT data without invasive procedures will help to further elucidate both retinal and choroidal vascular pathologies like RAP., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To evaluate clinical manifestations of patients with uveitis and scleritis of unknown origin and positive QuantiFERON-TB Gold In-Tube test (quantiferon) in a country not endemic for tuberculosis., Design: Multicenter retrospective cohort study., Methods: Retrospective review of the clinical, laboratory, and imaging data of 77 patients. Main outcome measures consisted of ocular and systemic features as well as results of laboratory examinations., Results: Out of all, 60 of 71 (85%) were living for at least 6 months in tuberculosis-endemic regions. Location of uveitis was variable; posterior uveitis (29/77; 38%) was the most frequent. Two clinical entities were commonly noted: retinal occlusive vasculitis (21/77; 27%) and serpiginoid choroiditis (11/77; 14%). Antituberculosis treatment was completed in 32 patients; 29 of them (91%) achieved complete remission. Mean quantiferon level was 7.5 U/mL; 71% had values above 2 U/mL and 41% above 10 U/mL. We observed no associations between quantiferon levels and clinical and/or imaging features. Previous tuberculosis infection was diagnosed in 5 of 77 patients (6.5%), while hilar/mediastinal lymphadenopathy was found in 25 of 76 patients (33%). Of these, 12 were consistent with the diagnosis of sarcoidosis, 9 were typical for (prior) tuberculosis, and 4 were compatible with both diagnoses., Conclusions: Ocular features of patients with idiopathic uveitis and positive quantiferon were diverse, but retinal occlusive vasculitis and serpiginoid choroiditis were common. The quantiferon levels were usually highly elevated and 33% of patients exhibited lymphadenopathy, suggesting frequently the diagnosis of sarcoidosis. Ocular inflammation reacted favorably to antituberculosis treatment, although only a small minority had documented (prior) tuberculosis., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Rationale: Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement of B cells in the pathogenesis of sarcoidosis., Objectives: To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease., Methods: Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, and serum immunoglobulin levels. Vaccination responses in patients with sarcoidosis to influenza virus and encapsulated bacteria and molecular analysis of immunoglobulin heavy chain transcripts were studied for functional analysis of immunoglobulin responses., Measurements and Main Results: Perigranuloma localization of IgA-producing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD27(+) memory B cells were significantly reduced, and CD27(-)IgA(+) B cells were significantly increased; the results are normalized in patients treated with TNF-α blockers. Despite this, patients had normal serum immunoglobulin levels and normal antigen-specific immunoglobulin responses. IgA and IgG transcripts, however, showed high frequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses., Conclusions: The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.

Visual symptoms due to uveitis involve a wide range of possible causes. Familiarity with its clinical manifestations, referral indications and treatment strategies is required for the optimal use of current therapeutic options. Uveitis can be caused by infectious and non-infectious factors, resulting in differing prognoses and treatments. The treatment of chronic, non-infectious uveitis has profoundly changed in the last years due to the advent of biological therapies. In severe uveitis, treatment of the underlying cause is required for the prevention of the loss of vision; multidisciplinary team collaboration is therefore important.

Aim: To provide age and gender-specific reference values for orbital fat and muscle volumes (MV) in Caucasian adults., Patients and Methods: Computed tomographic scans of 160 orbits from 52 men and 55 women, aged 20-80 years, not affected by orbital disease were evaluated. Orbital bony cavity volume (OV), fat volume (FV) and MV were calculated by a previously validated method using the software program Mimics. Ratios of FV to OV and of MV to OV were determined., Results: OV, FV and MV were all significantly larger in men than in women (p<0.001), but FV/OV and MV/OV were similar in both sexes. OV and MV did not change with age, but FV increased with advancing age in both women (p<0.001) and men (p<0.001). Linear regression analysis with FV/OV and MV/OV ratios as dependent variables and age and gender as independent variables showed a significant correlation between age and FV/OV (r=0.52, p<0.0001) and age and MV/OV (r=-0.26, p=0.001)., Conclusions: Advancing age is associated with an increase of FV/OV and a minor decrease of MV/OV. Gender-specific differences in orbital FV and MV disappear once FV and MV are related to OV, by calculating the ratios FV/OV and MV/OV. Age-specific gender-neutral reference ranges (2.5 and 97.5 percentiles) of FV/OV and MV/OV are presented.

PURPOSE. To determine which retinal layers are most affected by diabetes and contribute to thinning of the inner retina and to investigate the relationship between retinal layer thickness (LT) and diabetes duration, diabetic retinopathy (DR) status, age, glycosylated hemoglobin (HbA1c), and the sex of the individual, in patients with type 1 diabetes who have no or minimal DR. METHODS. Mean LT was calculated for the individual retinal layers after automated segmentation of spectral domain-optical coherence tomography scans of patients with diabetes and compared with that in control subjects. Multiple linear regression analysis was used to determine the relationship between LT and HbA1c, age, sex, diabetes duration, and DR status. RESULTS. In patients with minimal DR, the mean ganglion cell layer (GCL) in the pericentral area was 5.1 mum thinner (95% confidence interval [CI], 1.1-9.1 mum), and in the peripheral macula, the mean retinal nerve fiber layer (RNFL) was 3.7 mum thinner (95% CI, 1.3-6.1 mum) than in the control subjects. There was a significant linear correlation (R = 0.53, P < 0.01) between GCL thickness and diabetes duration in the pooled group of patients. Multiple linear regression analysis (R = 0.62, P < 0.01) showed that DR status was the most important explanatory variable. CONCLUSIONS. This study demonstrates GCL thinning in the pericentral area and corresponding loss of RNFL thickness in the peripheral macula in patients with type 1 diabetes and no or minimal DR compared with control subjects. These results support the concept that diabetes has an early neurodegenerative effect on the retina, which occurs even though the vascular component of DR is minimal.

Purpose: To determine whether type 1 diabetes preferentially affects the inner retinal layers by comparing the thickness of six retinal layers in type 1 diabetic patients who have no or minimal diabetic retinopathy (DR) with those of age- and sex-matched healthy controls., Methods: Fifty-seven patients with type 1 diabetes with no (n = 32) or minimal (n = 25) DR underwent full ophthalmic examination, stereoscopic fundus photography, and optical coherence tomography (OCT). After automated segmentation of intraretinal layers of the OCT images, mean thickness was calculated for six layers of the retina in the fovea, the pericentral area, and the peripheral area of the central macula and were compared with those of an age- and sex-matched control group., Results: In patients with minimal DR, the mean ganglion cell/inner plexiform layer was 2.7 microm thinner (95% confidence interval [CI], 2.1-4.3 microm) and the mean inner nuclear layer was 1.1 microm thinner (95% CI, 0.1-2.1 microm) in the pericentral area of the central macula compared to those of age-matched controls. In the peripheral area, the mean ganglion cell/inner plexiform layer remained significantly thinner. No other layers showed a significant difference., Conclusions: Thinning of the total retina in type 1 diabetic patients with minimal retinopathy compared with healthy controls is attributed to a selective thinning of inner retinal layers and supports the concept that early DR includes a neurodegenerative component.

Purpose: To evaluate donor posterior disk thickness measured with anterior segment optical coherence tomography after Descemet stripping endothelial keratoplasty., Methods: Fifteen patients (17 eyes) after Descemet stripping endothelial keratoplasty, using manually dissected donor posterior disks, were measured with the Visante anterior segment optical coherence tomography (Carl Zeiss Meditec Inc, Dublin, CA). Optical coherence tomography scans were made in a radial pattern, 45 degrees apart, starting in the horizontal axis. Thickness measurements of the donor posterior disks were taken centrally and at fixed radii toward the periphery and were correlated to postoperative change in spherical equivalent (SE), best-corrected visual acuity (BCVA, in Snellen), and improvement in BCVA., Results: Median BCVA was 20/30 (range 20/60-20/20) postoperatively. Median postoperative improvement in BCVA was 4 lines (range 1-11). Median follow-up time was 15.5 months (range 6-32 months). Median postoperative change in SE was -0.25 diopters (range -4.25 to +3.00 diopters). Median central disk thickness was 128.3 microm (range 55-181 microm) and increased significantly toward the periphery: median disk thickness at the 1.5 mm radius was 140.8 microm (range 72-199 microm) and at the 3.0 mm radius was 161.5 microm (range 102-245 microm). No correlation was found between (central) donor disk thickness and postoperative BCVA or change in SE. A nonstatistically significant trend was seen toward more improvement in BCVA with thinner donor disks., Conclusions: Optical coherence tomography measurements of the manually dissected donor posterior disk showed significant variation in thickness, without a statistically significant effect on postoperative BCVA or improvement thereof. Central thickness varied significantly from the peripheral thickness within donor posterior disk.

Aim: A comparison of retinal thickness (RT) measurements with optical coherence tomography (OCT) in patients with type 1 diabetes mellitus (DM) and no or minimal diabetic retinopathy (DR) versus healthy controls., Methods: Fifty-three patients with type 1 DM with no or minimal DR underwent full ophthalmic examination, fundus photography and OCT. Mean RT measured by OCT was calculated for the central fovea, the fovea, the pericentral and the peripheral area of the macula, and compared to healthy controls., Results: Mean RT in the pericentral area was lower in patients with minimal DR (267 microm +/- 20 microm; n = 23) compared to healthy controls (281 microm +/-13 microm; p = 0.005; n = 28). Mean pericentral RT in patients without DR (276 microm +/-14 microm; n = 30) was less than pericentral RT in healthy controls, but higher than in patients with minimal DR, without being statistically significant. None of the other regions showed a significant change., Conclusion: In this study a significantly decreased pericentral RT was measured in patients with minimal DR compared to healthy controls. This could be explained by a loss of intraretinal neural tissue in the earliest stage of DR.

Optical coherence tomography (OCT) was introduced in ophthalmology a decade ago. Within a few years in vivo imaging of the healthy retina and optic nerve head and of retinal diseases was a fact. In particular the ease with which these images can be acquired considerably changed the diagnostic strategy used by ophthalmologists. The OCT technique currently available in clinical practice is referred to as time-domain OCT, because the depth information of the retina is acquired as a sequence of samples, over time. This can be done either in longitudinal cross-sections perpendicular to, or in the coronal plane parallel to the retinal surface. Only recently, major advances have been made as to image resolution with the introduction of ultrahigh resolution OCT and in imaging speed, signal-to-noise ratio and sensitivity with the introduction of spectral-domain OCT. Functional OCT is the next frontier in OCT imaging. For example, polarization-sensitive OCT uses the birefringent characteristics of the retinal nerve fibre layer to better assess its thickness. Blood flow information from retinal vessels as well as the oxygenation state of retinal tissue can be extracted from the OCT signal. Very promising are the developments in contrast-enhanced molecular optical imaging, for example with the use of scattering tuneable nanoparticles targeted at specific tissue or cell structures. This review will provide an overview of these most recent developments in the field of OCT imaging focussing on applications for the retina.

Background: As optical coherence tomography (OCT) is widely used for diagnosis and monitoring of ocular pathology, especially in the elderly people, the influence of cataract on image quality and macular retinal thickness was studied., Methods: In 29 patients scheduled for cataract surgery, preoperative and postoperative OCT scans were obtained. Cataracts were categorised as nuclear, posterior or cortical. Parameters for image quality (signal-to-noise ratio (SNR)) and signal strength and macular thickness were compared. A three-level expert grading scale was used to evaluate the discriminative abilities of SNR and signal strength., Results: Nuclear cataracts (n = 12) provided better preoperative scans (higher SNR/signal strength) than posterior (n = 7) and cortical (n = 10) cataracts (p<0.004). Postoperatively SNR and signal strength increased significantly in all patients (p<0.001). The SNR was better at discriminating poor from acceptable and good scans than signal strength (area under the receiver operating curve: 0.879 and 0.810, respectively). Postoperative macular thickness overall showed a significant increase (p = 0.005), most evident in patients with posterior cataracts (p = 0.028)., Conclusions: OCT imaging is influenced by cataract; image quality is reduced preoperatively and macular thickness measurements are slightly increased postoperatively. In individual patients, OCT scans remain reliable for gross clinical interpretation, even in the presence of cataract.

Background: Evaluating the presence of leakage on fluorescein angiography (FA) in patients with age-related macular degeneration (AMD) retreated with photodynamic therapy (PDT) can be difficult. New diagnostic tools such as optical coherence tomography (OCT) might help to optimize PDT management., Methods: Thirty AMD patients scheduled for regular follow-up FA in conjunction with PDT treatment were also scanned with OCT. Follow-up data at 9 months were retrieved from the patients' medical records. Inter-observer agreement [kappa coefficient] for the presence of leakage on FA, for OCT parameters for leakage, and agreement between FA and OCT evaluations were calculated. The indication for retreatment was evaluated using the leakage analysis based on FA alone, OCT alone, and both examinations combined, and compared to the actual follow-up of the patients at 9 months., Results: Agreement between the two observers for the presence of leakage on FA was moderate (kappa=0.51). OCT agreement between the two observers for the presence of leakage was good (kappa=0.85). Agreement between FA and OCT for the presence of leakage was poor (kappa=0.16). Follow-up data at 9 months on all patients were analyzed. Seven out of 30 patients were not retreated at the time of examination, and four of these patients (57%) remained stable without further treatment. Twenty-three patients did receive a PDT treatment at the time of examination; and eight of these patients did not show leakage on OCT, and five of these patients (62%) remained stable without additional treatment. In contrast, only three out of 15 patients (20%) with leakage on both FA and OCT remained stable during this 9 month follow-up period., Conclusions: Inter-observer agreement for the presence of leakage was moderate for FA and good for OCT. There was considerable disagreement between leakage as judged by OCT and by FA. OCT could be of help in the decision regarding PDT retreatment. Assuming that 57% of the patients without leakage either on FA or OCT would remain stable without retreatment, the rate of probable ineffective retreatment could be reduced from 35% to 20%.

Purpose: To describe retinal changes in active multifocal and serpiginous chorioretinitis seen with en-face optical coherence tomography (OCT)., Design: Observational case report., Methods: Two patients, presenting with active multifocal chorioretinitis (MFC) and serpiginous chorioretinitis (SC), respectively, were scanned with a prototype en face OCT ophthalmoscope., Results: The OCT scan in the patient with the active MFC lesion showed a transretinal hyperreflectivity at the site of lesion. The OCT scan in the patient with the active SC lesion showed hyper-reflectivity in the outer retina at the site of the lesion., Conclusions: OCT allows for better evaluation of intraretinal changes in patients with white dot syndromes. In these two cases, OCT showed different morphologic changes in active lesions. OCT may be helpful in identifying the location of involvement in various white dot syndromes. This may have prognostic and therapeutic significance.

Purpose: To present the possibilities of a new system that combines optical coherence tomography (OCT) and confocal ophthalmoscopy, producing en face OCT images in patients with retinal diseases., Methods: A prototype OCT Ophthalmoscope (OTI, Toronto, Canada) was used to scan patients with retinal conditions. The system uses a super luminescent diode (lambda = 820 nm; Deltalambda = 20 nm) and currently scans at a rate of 2 frames per second. In each frame, the OCT Ophthalmoscope simultaneously produces a transversal OCT scan and a confocal image in the X/Y plane. Both images correspond pixel to pixel., Results: Between January 2002 and August 2003, >800 patients with various retinal diseases were scanned with the OCT Ophthalmoscope. Illustrative cases with regularly seen macular diseases are presented, such as macular hole and central serous retinopathy., Conclusion: Current difficulties as well as future possibilities of this new en face OCT ophthalmoscope are discussed. By presenting normal and pathologic transversal OCT images made by a prototype OCT Ophthalmoscope, we show that it can provide information not available using conventional OCT imaging.

Background: The diagnosis of idiopathic central serous retinopathy (CSR) is usually based on biomicroscopy and fluorescein angiography (FA). The optical coherence tomography (OCT) ophthalmoscope produces en face OCT scans (OCT C-scans) and provides additional information not readily available by conventional imaging techniques. The authors describe the characteristic features observed in patients with a clinical diagnosis of CSR using the OCT ophthalmoscope., Methods: 38 eyes with a clinical diagnosis of CSR, seen at the Academic Medical Centre (Amsterdam, Netherlands) and the New York Eye and Ear Infirmary (New York, USA) between August 2002 and March 2004, were evaluated with standard digital FA and scanned with the OCT ophthalmoscope., Results: Nine of 38 eyes had no serous neurosensory detachment (inactive CSR) when scanned with the OCT ophthalmoscope. Characteristics for active CSR (n=29) were large neurosensory detachment (23/29), subretinal hyper-reflective depoits (20/29), and pigment epithelial detachment (15/29). One third of the patients, either active or inactive, had multiple small pigment epithelial detachments located both within and outside the neurosensory detachment., Conclusion: The OCT ophthalmoscope provides complementary morphological information on patients with CSR. The presence of more diffuse retinal pigment epithelium (RPE) changes lends further support to the concept that CSR is a diffuse rather than localised RPE anomaly.

Background: Combining characteristic morphological and functional information in one image increases pathophysiologic understanding as well as diagnostic accuracy in most clinical settings. En-face optical coherence tomography (OCT) provides a high resolution, transversal OCT image of the macular area combined with a confocal image of the same area (OCT C-scans). Creating an overlay image of a conventional angiographic image onto an OCT image, using the confocal part to facilitate transformation, combines structural and functional information of the retinal area of interest. This paper describes the construction of such overlay images and their aid in improving the interpretation of OCT C-scans., Methods: In various patients, en-face OCT C-scans (made with a prototype OCT-Ophthalmoscope (OTI, Canada) in use at the Department of Ophthalmology (Academic Medical Centre, Amsterdam, The Netherlands)) and conventional fluorescein angiography (FA) were performed. ImagePro, with a custom made plug-in, was used to make an overlay-image. The confocal part of the OCT C-scan was used to spatially transform the FA image onto the OCT C-scan, using the vascular arcades as a reference. To facilitate visualization the transformed angiographic image and the OCT C-scan were combined in an RGB image., Results: The confocal part of the OCT C-scan could easily be fused with angiographic images. Overlay showed a direct correspondence between retinal thickening and FA leakage in Birdshot retinochoroiditis, localized the subretinal neovascular membrane and correlated anatomic and vascular leakage features in myopia, and showed the extent of retinal and pigment epithelial detachment in retinal angiomatous proliferation as FA leakage was subject to blocked fluorescence. The overlay mode provided additional insight not readily available in either mode alone., Conclusion: Combining conventional angiographic images and en-face OCT C-scans assists in the interpretation of both imaging modalities. By combining the physiopathological information in the angiograms with the structural information in the OCT scan, zones of leakage can be correlated to structural changes in the retina or pigment epithelium. This strategy could be used in the evaluation and monitoring of patients with complex central macular pathology.

Objective: To assess the results of lacrimal duct probing in young children with epiphora, due to a congenital nasolacrimal duct obstruction., Design: Retrospective, descriptive., Method: Data were collected from medical dossiers on the results of lacrimal duct probing in children (0-48 months) with epiphora that was done in the period from January 1, 1997 to December 31, 2001 at the University Medical Centre in Utrecht, the Netherlands. The percentage of eyes that showed complete resolution of symptoms three months after the final probing was calculated., Results: Of the 89 children who had undergone lacrimal duct probing, seven were excluded and in three children (six eyes) the data could not be retrieved. In 96 of the remaining 116 eyes (83%), the symptoms disappeared: this included 96% of the age group 0-12 months (n = 25), 85% of the 13-24 months-olds (n = 55), 77% of the 25-36 months-olds (n = 22) and 57% of the 37-48 months-olds (n = 14). No complications of probing were seen., Conclusion: In most children in the various age groups, epiphora disappeared. Thus, children do not need to be probed in the first year of life out of fear of failure at an older age. Whether or not probing shortens the duration of epiphora cannot be determined on the basis of either this study or the literature.