Ranjan Rajendram

A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema (BOLT Study): 12-Month Data: Report 2

PURPOSE To report the findings at 1 year of a study comparing repeated intravitreal bevacizumab (ivB) and modified Early Treatment of Diabetic Retinopathy Study (ETDRS) macular laser therapy (MLT) in patients with persistent clinically significant diabetic macular edema (CSME). DESIGN Prospective, randomized, masked, single-center, 2-year, 2-arm clinical trial. PARTICIPANTS A total of 80 eyes of 80 patients with center-involving CSME and at least 1 prior MLT. METHODS Subjects were randomized to either ivB (6 weekly; minimum of 3 injections and maximum of 9 injections in the first 12 months) or MLT (4 monthly; minimum of 1 treatment and maximum of 4 treatments in the first 12 months). MAIN OUTCOME MEASURES The primary end point was the difference in ETDRS best-corrected visual acuity (BCVA) at 12 months between the bevacizumab and laser arms. RESULTS The baseline mean ETDRS BCVA was 55.7+/-9.7 (range 34-69) in the bevacizumab group and 54.6+/-8.6 (range 36-68) in the laser arm. The mean ETDRS BCVA at 12 months was 61.3+/-10.4 (range 34-79) in the bevacizumab group and 50.0+/-16.6 (range 8-76) in the laser arm (P = 0.0006). Furthermore, the bevacizumab group gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (P = 0.0002). The odds of gaining > or =10 ETDRS letters over 12 months were 5.1 times greater in the bevacizumab group than in the laser group (adjusted odds ratio, 5.1; 95% confidence interval, 1.3-19.7; P = 0.019). At 12 months, central macular thickness decreased from 507+/-145 microm (range 281-900 microm) at baseline to 378+/-134 microm (range 167-699 microm) (P<0.001) in the ivB group, whereas it decreased to a lesser extent in the laser group, from 481+/-121 microm (range 279-844 microm) to 413+/-135 microm (range 170-708 microm) (P = 0.02). The median number of injections was 9 (interquartile range [IQR] 8-9) in the ivB group, and the median number of laser treatments was 3 (IQR 2-4) in the MLT group. CONCLUSIONS The study provides evidence to support the use of bevacizumab in patients with center-involving CSME without advanced macular ischemia.

Photoreceptor mitochondrial oxidative stress in early experimental autoimmune uveoretinitis

Aims: In early S-antigen induced experimental uveitis (EAU), photoreceptor mitochondrial proteins are nitrated prior to macrophage infiltration of the retina, suggesting that oxidative stress is an initial event in the development of EAU. We attempted to detect the oxidative stress and localise it in the EAU retina. Methods: Lewis rats were immunised with S-antigen in complete Freund’s adjuvant (CFA). Animals were injected with CFA alone and non-immunised animals served as controls. Immunised and non-immunised animals were killed on day 5 and subsequent days. Isolated retinas were processed for inducible nitric oxide synthase (iNOS), tumour necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)Iα and CD28 expression by real time polymerase chain reaction. In addition, iNOS was colocalised with cytochrome c oxidase on day 5 of EAU. Oxidative stress was detected by 2′, 7′-dichlorodihydrofluorescein diacetate and localised by a mitochondrial specific marker. Leucocyte and T cell infiltration in the retina/choroid was evaluated by immunohistochemistry. Results: The iNOS, TNFα, IFNγ, IL1α and CD28 transcripts were significantly upregulated on day 5 in EAU, and iNOS was colocalised with cytochrome c oxidase in the photoreceptor mitochondria. Oxidative stress was seen primarily in the photoreceptor mitochondria. Occasional T cells were present in the retina at this stage. Conclusions: During early EAU, mitochondrial oxidative stress is selectively noted in the photoreceptor inner segments. The oxidative stress appears to result from iNOS upregulation in the photoreceptor mitochondria and cytokine generation in the retina by a few antigen specific infiltrating T cells.

Patterns of peripheral retinal and central macula ischemia in diabetic retinopathy as evaluated by ultra-widefield fluorescein angiography

PURPOSE To investigate the association between peripheral and central ischemia in diabetic retinopathy. DESIGN Retrospective, cross-sectional. METHODS Consecutive ultra-widefield fluorescein angiography images were collected from patients with diabetes over a 12-month period. Parameters quantified include the foveal avascular zone (FAZ) area, peripheral ischemic index, peripheral leakage index, and central retinal thickness measurements, as well as visual acuity. The peripheral ischemia or leakage index was calculated as the area of capillary nonperfusion or leakage, expressed as a percentage of the total retinal area. RESULTS Forty-seven eyes of 47 patients were included. A moderate correlation was observed between the peripheral ischemia index and FAZ area (r = 0.49, P = .0001). A moderate correlation was also observed between the peripheral leakage index and FAZ area, but only in eyes that were laser naïve (r = 0.44, P = .02). A thinner retina was observed in eyes with macular ischemia (217 ± 81.8 μm vs 272 ± 36.0 μm) (P = .02), but not peripheral ischemia (258 ± 76.3 μm vs 276 ± 68.0 μm) (P = .24). The relationships between different patterns of peripheral and central macular pathology and visual acuity were evaluated in a step-wise multivariable regression model, and the variables that remained independently associated were age (r = 0.33, P = .03), FAZ area (r = 0.45, P = .02), and central retinal thickness (r = 0.38, P = .01), (R(2)-adjusted = 0.36). CONCLUSIONS Ultra-widefield fluorescein angiography provides an insight into the relationships between diabetic vascular complications in the retinal periphery and central macula. Although we observed relationships between ischemia and vascular leakage in the macula and periphery, it was only macular ischemia and retinal thinning that was independently associated with a reduced visual function.

Vogt-koyanagi-harada disease

Vogt-Koyanagi-Harada (VKH) disease affects primarily persons who are Asian, Latino, Native American, or Asian Indian. Women appear to be affected more commonly than men, and VKH disease may occur at all ages, including childhood. Experimental data continue to support an autoimmune etiology for VKH disease, directed most probably against an antigenic component of the melanocyte, possibly tyrosinase or a tyrosinase-related protein. The clinical diagnosis of VKH disease continues to be based on physical findings. Newer imaging modalities such as magnetic resonance imaging, indocyanine green angiography, and digital image analysis have not added appreciably to our understanding of the condition. First-line therapy consists of high-dose corticosteroids, with use of corticosteroid-sparing agents for resistant or recalcitrant disease. Complications are the main cause of reversible and irreversible vision loss, with subretinal fibrosis and choroidal neovascular membranes having particularly poor prognoses.

Neuroglobin in normal retina and retina from eyes with advanced glaucoma

Background: Neuroglobin is a neurone specific respiratory protein that reversibly binds oxygen. Neuroglobin was discovered in 2000, initially in brain and later, at a 100 times greater concentration, in mouse retina. This protein may be involved in oxygen transport, and/or protection against oxidative stress or premature apoptosis. Aim: To examine the expression of neuroglobin in normal human retina and also in retina from eyes with advanced glaucoma, where hypoxia and ischaemia may be pathological factors. Methods: Immunofluorescence and electron microscopy were used to examine sections of normal human retina and retina from eyes with end-stage glaucoma. Results: Staining for neuroglobin was present in the plexiform layers and the photoreceptor inner segments in human retina, and increased expression was found to occur in these areas, as well as in the nuclear layers in advanced glaucoma. Much less staining for neuroglobin was present in the other retinal layers. Conclusion: Neuroglobin is found in those layers of the human retina that are rich in mitochondria and/or synapses, and consume the highest amount of oxygen. Neuroglobin may be involved in oxygen supply to mitochondria, or in protection from oxidative stress or apoptosis. Neuroglobin expression is increased in advanced glaucoma, and it may protect against hypoxic, ischaemic or oxidative stress, which are thought to be pathological factors that affect the retina in glaucoma.

Vogt–Koyanagi–Harada disease presenting as optic neuritis

Vogt–Koyanagi–Harada (VKH) disease is a granulomatous multisystem inflammatory disorder that classically affects the uvea, inner ear, meninges, and skin. We report three patients who presented with initial findings suggestive of bilateral optic neuritis requiring CSF analysis and brain images. None of these patients had extraocular changes. Fluorescein angiography of the retina led to the diagnosis of VKH disease in all patients. Vogt–Koyanagi–Harada disease should be included in differential diagnosis of bilateral optic neuritis, even when extraocular manifestations of the disease are absent. In such cases, fluorescein angiography will aid diagnosis.

Structural and Functional Measures of Efficacy in Response to Bevacizumab Monotherapy in Diabetic Macular Oedema: Exploratory Analyses of the BOLT Study (Report 4)

Background To describe structural and functional changes associated with diabetic macular oedema (DMO) treated with intravitreal bevacizumab over 24 months. Methods A post-hoc analysis of the data of 34 patients that completed 24 months follow-up in the intravitreal bevacizumab arm of a prospective, randomized controlled trial (BOLT study) was performed. The outcome measures previously used in clinical trials of intravitreal ranibizumab in DMO were employed to describe the visual acuity and macular thickness changes at 12 and 24 months. Results The standard outcomes of mean change in best corrected visual acuity (BCVA) and central macular thickness (CMT) in participants treated with bevacizumab were comparable to those reported in association with ranibizumab. However, exploratory analyses showed that thick maculae at baseline defined as CMT of ≥400 µm, remained significantly thicker than those <400 µm with intensive bevacizumab therapy, despite a comparable gain in visual acuity at both 12 and 24 months. The proportion of subjects that attained a dry macula doubled in both CMT groups between the 12 and 24-month time-points. Conclusions These findings provide valuable information both for clinical practice and trials. Further studies are required to investigate the impact of intravitreal bevacizumab on retinal thickness profiles in DMO.

Gabor fusion master slave optical coherence tomography

This paper describes the application of the Gabor filtering protocol to a Master/Slave (MS) swept source optical coherence tomography (SS)-OCT system at 1300 nm. The MS-OCT system delivers information from selected depths, a property that allows operation similar to that of a time domain OCT system, where dynamic focusing is possible. The Gabor filtering processing following collection of multiple data from different focus positions is different from that utilized by a conventional swept source OCT system using a Fast Fourier transform (FFT) to produce an A-scan. Instead of selecting the bright parts of A-scans for each focus position, to be placed in a final B-scan image (or in a final volume), and discarding the rest, the MS principle can be employed to advantageously deliver signal from the depths within each focus range only. The MS procedure is illustrated on creating volumes of data of constant transversal resolution from a cucumber and from an insect by repeating data acquisition for 4 different focus positions. In addition, advantage is taken from the tolerance to dispersion of the MS principle that allows automatic compensation for dispersion created by layers above the object of interest. By combining the two techniques, Gabor filtering and Master/Slave, a powerful imaging instrument is demonstrated. The master/slave technique allows simultaneous display of three categories of images in one frame: multiple depth en-face OCT images, two cross-sectional OCT images and a confocal like image obtained by averaging the en-face ones. We also demonstrate the superiority of MS-OCT over its FFT based counterpart when used with a Gabor filtering OCT instrument in terms of the speed of assembling the fused volume. For our case, we show that when more than 4 focus positions are required to produce the final volume, MS is faster than the conventional FFT based procedure.

Implementation of medical retina virtual clinics in a tertiary eye care referral centre

Background The increasing incidence of medical retinal diseases has created capacity issues across UK. In this study, we describe the implementation and outcomes of virtual medical retina clinics (VMRCs) at Moorfields Eye Hospital, South Division, London. It represents a promising solution to ensure that patients are seen and treated in a timely fashion Methods First attendances in the VMRC (September 2016–May 2017) were included. It was open to non-urgent external referrals and to existing patients in a face-to-face clinic (F2FC). All patients received visual acuity testing, dilated fundus photography and optical coherence tomography scans. Grading was performed by consultants, fellows and allied healthcare professionals. Outcomes of these virtual consultations and reasons for F2FC referrals were assessed. Results A total number of 1729 patients were included (1543 were internal and 186 external referrals). The majority were diagnosed with diabetic retinopathy (75.1% of internal and 46.8% of external referrals). Of the internal referrals, 14.6% were discharged, 54.5% continued in VMRC and 30.9% were brought to a F2FC. Of the external referrals, 45.5% were discharged, 37.1% continued in VMRC and 17.4% were brought to a F2FC. The main reason for F2FC referrals was image quality (34.7%), followed by detection of potentially treatable disease (20.2%). Conclusion VMRC can be implemented successfully using existing resources within a hospital eye service. It may also serve as a first-line rapid-access clinic for low-risk referrals. This would enable medical retinal services to cope with increasing demand and efficiently allocate resources to those who require treatment.

Simultaneous Measurement of Flow at Several Depths Using Multiple Active Paths in a Low-Coherence Interferometer

We present a multiple-path scalable configuration that allows the interrogation of an intralipid flow in a vessel at five multiple depths separated by a spatial interval that could be easily adjusted from zero to values less, larger, or much larger than the coherence length of the optical source. The range of flow values measured is accommodated by modifying the difference between the frequencies of signals driving two frequency shifters, each being a part of an active loop placed in each arm of a Mach-Zehnder interferometer.