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1.  Ultra-widefield fluorescein angiography of white without pressure 
To describe ultra-widefield fluorescein angiography (UWFA) findings in eyes with white without pressure (WWOP) and in eyes without any obvious peripheral chorioretinal disease, and to determine if a difference exists between these two groups.
A retrospective review of 379 eyes undergoing diagnostic UWFA using the Optos 200Tx imaging system. Eyes were excluded if the quality of the color photograph or UWFA prevented reliable evaluation. Eyes were also excluded if there was any evidence of peripheral retinal or choroidal disease, which was thought to have an effect on UWFA (eg, peripheral background diabetic or hypertensive retinopathy, vein occlusion, or any other peripheral vascular disorder). Eyes were determined to have WWOP, based on a dilated fundus examination and color fundus photography that contained areas of peripheral retinal whitening consistent with the diagnosis. UWFA was evaluated by trained masked graders, and determined to have or not have peripheral vascular leakage and/or staining.
Of the 379 eyes evaluated, 45 eyes were included in the study. Twelve eyes were determined to have peripheral WWOP; 33 eyes did not have WWOP on examination or color fundus photography. Three common UWFA peripheral patterns were visualized. Eyes with and without WWOP were grouped into one of three patterns. The majority of eyes without WWOP demonstrated UWFA pattern one (69.7%), while those in the WWOP group demonstrated pattern three (50%). The distribution of UWFA patterns is statistically different between those with and without WWOP (P = 0.002). In eyes without WWOP, in patients with no documented systemic microvascular disease (diabetes, hypertension), 71.4% of eyes had UWFA pattern one while 14.3% had both patterns two and three.
This study is one of the first to specifically evaluate peripheral vascular leakage/staining in eyes with WWOP as well as in eyes without any obvious peripheral chorioretinal disease. We demonstrate that a significant portion of WWOP eyes exhibit peripheral findings on UWFA (pattern one) compared to eyes without WWOP. Importantly, even in eyes that are apparently unremarkable in the periphery on exam and color photography, UWFA can still show peripheral vascular abnormalities. These results warrant further investigation.
PMCID: PMC3667996  PMID: 23737658
ocular imaging; ptos imaging; retina periphery
2.  Exaggerated relative nasal-temporal asymmetry of macular capillary blood flow in patients with clinically significant diabetic macular oedema 
Aims: To compare the macular capillary blood flow of patients with clinically significant diabetic macular oedema (DMO) with that of non-diabetic subjects and to determine the relation between blood flow and capillary leakage in patients with DMO.
Methods: The sample comprised 45 non-diabetic subjects (mean age 59 years) and 18 type 2 patients with clinically significant DMO (mean age 60 years). Macular capillary blood flow measurements were acquired using the Heidelberg retina flowmeter (HRF) and a 10°×2.5° scan field centred on the fovea. Fluorescein angiography was undertaken on each of the diabetic patients after the completion of HRF measurements.
Results: Temporal macular capillary blood flow was significantly lower for the patients with clinically significant DMO compared with age matched non-diabetic subjects (ANCOVA, p = 0.0011) while relative nasal-temporal asymmetry of macular capillary blood flow was significantly higher (p = 0.0125). Nasal-temporal asymmetry of macular capillary blood flow was significantly higher for the patients with DMO and capillary leakage within the scan area (two tailed t test, p = 0.0071). Macular capillary blood flow was always lower in areas of DMO and capillary leakage.
Conclusion: Capillary blood flow was reduced in areas of DMO and capillary leakage, suggesting the presence of a localised perturbation of capillary blood flow regulation.
PMCID: PMC1772510  PMID: 15665341
diabetic macular oedema; retinal thickening; capillary blood flow
3.  A multicentre phase III randomised controlled single-masked clinical trial evaluating the clinical efficacy and safety of light-masks at preventing dark-adaptation in the treatment of early diabetic macular oedema (CLEOPATRA): study protocol for a randomised controlled trial 
Trials  2014;15(1):458.
This study will evaluate hypoxia, as a novel concept in the pathogenesis of diabetic macular oedema (DMO). As the oxygen demand of the eye is maximum during dark-adaptation, we hypothesize that wearing light-masks during sleep will cause regression and prevent the development and progression of DMO. The study protocol comprises both an efficacy and mechanistic evaluation to test this hypothesis.
This is a phase III randomised controlled single-masked multicentre clinical trial to test the clinical efficacy of light-masks at preventing dark-adaptation in the treatment of non-central DMO. Three hundred patients with non-centre-involving DMO in at least one eye will be randomised 1:1 to light-masks and control masks (with no light) to be used during sleep at night for a period of 24 months. The primary outcome is regression of non-central oedema by assessing change in the zone of maximal retinal thickness at baseline on optical coherence tomography (SD-OCT). Secondary outcomes will evaluate the prevention of development and progression of DMO by assessing changes in retinal thickness in different regions of the macula, macular volume, refracted visual acuity and level of retinopathy. Safety parameters will include sleep disturbance. Adverse events and measures of compliance will be assessed over 24 months. Participants recruited to the mechanistic sub-study will have additional retinal oximetry, multifocal electroretinography (ERG) and microperimetry to evaluate the role of hypoxia by assessing and comparing changes induced by supplemental oxygen and the light-masks at 12 months.
The outcomes of this study will provide insight into the pathogenesis of DMO and provide evidence on whether a simple, non-invasive device in the form of a light-mask can help prevent the progression to centre-involving DMO and visual impairment in people with diabetes.
PMCID: PMC4255925  PMID: 25417120
4.  Comparison of ultra-widefield fluorescein angiography with the Heidelberg Spectralis® noncontact ultra-widefield module versus the Optos® Optomap® 
To compare ultra-widefield fluorescein angiography imaging using the Optos® Optomap® and the Heidelberg Spectralis® noncontact ultra-widefield module.
Five patients (ten eyes) underwent ultra-widefield fluorescein angiography using the Optos® panoramic P200Tx imaging system and the noncontact ultra-widefield module in the Heidelberg Spectralis® HRA+OCT system. The images were obtained as a single, nonsteered shot centered on the macula. The area of imaged retina was outlined and quantified using Adobe® Photoshop® C5 software. The total area and area within each of four visualized quadrants was calculated and compared between the two imaging modalities. Three masked reviewers also evaluated each quadrant per eye (40 total quadrants) to determine which modality imaged the retinal vasculature most peripherally.
Optos® imaging captured a total retinal area averaging 151,362 pixels, ranging from 116,998 to 205,833 pixels, while the area captured using the Heidelberg Spectralis® was 101,786 pixels, ranging from 73,424 to 116,319 (P = 0.0002). The average area per individual quadrant imaged by Optos® versus the Heidelberg Spectralis® superiorly was 32,373 vs 32,789 pixels, respectively (P = 0.91), inferiorly was 24,665 vs 26,117 pixels, respectively (P = 0.71), temporally was 47,948 vs 20,645 pixels, respectively (P = 0.0001), and nasally was 46,374 vs 22,234 pixels, respectively (P = 0.0001). The Heidelberg Spectralis® was able to image the superior and inferior retinal vasculature to a more distal point than was the Optos®, in nine of ten eyes (18 of 20 quadrants). The Optos® was able to image the nasal and temporal retinal vasculature to a more distal point than was the Heidelberg Spectralis®, in ten of ten eyes (20 of 20 quadrants).
The ultra-widefield fluorescein angiography obtained with the Optos® and Heidelberg Spectralis® ultra-widefield imaging systems are both excellent modalities that provide views of the peripheral retina. On a single nonsteered image, the Optos® Optomap® covered a significantly larger total retinal surface area, with greater image variability, than did the Heidelberg Spectralis® ultra-widefield module. The Optos® captured an appreciably wider view of the retina temporally and nasally, albeit with peripheral distortion, while the ultra-widefield Heidelberg Spectralis® module was able to image the superior and inferior retinal vasculature more peripherally. The clinical significance of these findings as well as the area imaged on steered montaged images remains to be determined.
PMCID: PMC3583407  PMID: 23458976
peripheral; retina; wide-angle; widefield; ultra-widefield
5.  Factors predicting outcome of vitrectomy for diabetic macular oedema: results of a prospective study 
To determine preoperative demographic, clinical, and optical coherence tomography (OCT) factors which might predict the visual and anatomical outcome at 1 year in patients undergoing vitrectomy and inner limiting membrane peel for diabetic macular oedema (DMO).
A prospective, interventional case series of 33 patients who completed 1 year follow up. Measurements were taken preoperatively and at 1 year. Outcome measures were logMAR visual acuity (VA) and OCT macular thickness. A priori explanatory variables included baseline presence of clinical and/or OCT signs suggesting macular traction, grade of diabetic maculopathy, posterior vitreous detachment, fluorescein leakage and ischaemia on angiography, presence of subretinal fluid, and peroperative indocyanine green (ICG) use.
33 patients completed 1 year follow up. On average VA deteriorated by 0.035 logMAR (p = 0.40). Macular thickness significantly improved by a mean of 139 μm (95% CI; 211 to 67, p<0.001). Patients with evidence of clinical and/or OCT macular traction significantly improved logMAR acuity (logMAR improvement  = 0.08) compared with patients without traction (logMAR deterioration 0.11, p = 0.01). Presence of subretinal fluid significantly predicted worse postoperative result (p = 0.01)
On average, patients showed a statistically significant improvement in central macular thickness following treatment but a marginal acuity worsening. Presence of subretinal fluid on OCT is hypothesised to be exudative rather than tractional in nature. The visual benefit of vitrectomy for DMO in this study was limited to patients who exhibit signs of macular traction either clinically and/or on OCT.
PMCID: PMC1856901  PMID: 16361663
diabetic macular oedema; vitrectomy; diabetic retinopathy; maculopathy; optical coherence tomography
6.  Effect of a single intravitreal bevacizumab injection on different optical coherence tomographic patterns of diabetic macular oedema 
Eye  2013;27(6):716-721.
The aim of this study is to compare the therapeutic effect of a single intravitreal bevacizumab (IVB) injection in eyes with diabetic macular oedema (DMO) of different patterns determined by optical coherence tomography (OCT).
Medical records of patients who had a single IVB injection for DMO were analysed retrospectively. Eyes with a clinically significant DMO and a central foveal thickness (CFT) of 250 μm or more determined by OCT were included in the analysis. Best-corrected visual acuity (BCVA), CFT and total macular volume values before and after the injection were recorded. Eyes were divided into sponge-like diffuse retinal thickening (DRT), cystoid macular oedema (CMO) and serous retinal detachment (SRD) groups according to the morphology on OCT.
A total of 92 eyes (42 with DRT, 31 with CMO and 19 with SRD) were included in the study. There was no statistically significant variation between three groups regarding the change in BCVA (P=0.695). CMO and SRD groups had greater reductions in their mean CFT, and the amount of reduction showed statistically significant variation between three groups (P=0.048). However, no statistically significant difference was found between groups in terms of percentage of change in CFT (P=0.278).
CMO and SRD subtypes are associated with a greater reduction in the CFT than the DRT subtype. Although the change in BCVA was not significantly different between groups, the DRT group showed markedly better visual improvement in proportion to the decrease in CFT.
PMCID: PMC3682346  PMID: 23470789
diabetic macular oedema; intravitreal bevacizumab; optical coherence tomography
7.  Two-wavelength fundus autofluorescence and macular pigment optical density imaging in diabetic macular oedema 
Eye  2012;26(8):1078-1085.
To evaluate the application of 488 and 514 nm fundus autofluorescence (FAF) and macular pigment optical density (MPOD) imaging in diabetic macular oedema (DMO) and to demonstrate the typical imaging features.
Patients and Methods
A hundred and twenty-five eyes of 71 consecutive patients with diabetic retinopathy who underwent examination at a specialist university clinic employing a modified Heidelberg Retina Angiograph, using two different light sources of 488 and 514 nm wavelength, were retrospectively reviewed. MPOD images were calculated using modified Heidelberg Eye Explorer software. All images were evaluated by two independent masked graders. Features from FAF and MPOD images were correlated with optical coherence tomography (OCT) imaging findings and inter-grader variability, sensitivity and specificity were calculated using OCT as reference.
Sixty-seven eyes had DMO on OCT. The inter-grader variability was 0.84 for 488 nm FAF, 0.63 for 514 nm FAF and 0.79 for MPOD imaging. Sensitivity and specificity for detection of DMO were 80.6 and 89.7% for 488 nm FAF; 55.2 and 94.8% for 514 nm FAF; and 80.6 and 91.4% for MPOD imaging. In 488 nm FAF and MPOD imaging, DMO was better visualised in comparison with 514 nm FAF imaging, P<0.01. MPOD revealed displacement of macular pigment by intraretinal cysts.
MPOD imaging, and particularly its combination with 488 nm and 514 nm FAF, provides a valuable addition to OCT in the evaluation of DMO and is clinically useful in rapid en-face assessment of the central macula.
PMCID: PMC3420036  PMID: 22699976
diabetic macular oedema; fundus autofluorescence; macular pigment
8.  Structural and Functional Measures of Efficacy in Response to Bevacizumab Monotherapy in Diabetic Macular Oedema: Exploratory Analyses of the BOLT Study (Report 4) 
PLoS ONE  2013;8(8):e72755.
To describe structural and functional changes associated with diabetic macular oedema (DMO) treated with intravitreal bevacizumab over 24 months.
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.
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.
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.
PMCID: PMC3754932  PMID: 24013651
9.  Correlation of a scanning laser derived oedema index and visual function following grid laser treatment for diabetic macular oedema 
Aim: To correlate change of an oedema index derived by scanning laser tomography with change of visual function in patients undergoing grid laser photocoagulation for clinically significant diabetic macular oedema (DMO).
Methods: The sample comprised 24 diabetic patients with retinal thickening within 500 μm of the fovea. Inclusion criteria included a logMAR visual acuity of 0.25, or better. Patients were assessed twice before a single session of grid laser treatment and within 1 week of, and at 1, 2, 4, and 12 weeks after, treatment. At each visit, patients underwent logMAR visual acuity, conventional and short wavelength automated perimetry (SWAP), and scanning laser tomography. Each visual function parameter was correlated with the mean oedema index. The mean oedema index represented the z-profile signal width divided by the maximum reflectance intensity (arbitrary units). A Pearson correlation coefficient (Bonferroni corrected) was undertaken on the data set of each patient.
Results: 13 patients exhibited significant correlation of the mean oedema index and at least one measure of visual function for the 10° × 10° scan field while 10 patients correlated for the 20° × 20° scan field. Seven patients demonstrated correlation for both scan fields. Laser photocoagulation typically resulted in an immediate loss of perimetric sensitivity whereas the oedema index changed over a period of weeks. Localised oedema did not impact upon visual acuity or letter contrast sensitivity when situated extrafoveally.
Conclusions: Correlation of change of the oedema index and of visual function following grid laser photocoagulation was not found in all patients. An absence of correlation can be explained by the localised distribution of DMO in this sample of patients, as well as by differences in the time course of change of the oedema index and visual function. The study has objectively documented change in the magnitude and distribution of DMO following grid laser treatment and has established the relation of this change to the change in visual function.
PMCID: PMC1771618  PMID: 12642310
diabetic macular oedema; scanning laser tomography; ocular imaging; visual function; laser photocoagulation
10.  Intraocular pressure rise is predictive of vision improvement after intravitreal triamcinolone acetonide for diabetic macular oedema: a retrospective analysis of data from a randomised controlled trial 
BMC Ophthalmology  2014;14(1):123.
Intravitreal triamcinolone acetonide (IVTA) is an effective treatment for recalcitrant diabetic macular oedema (DMO). It has been shown to improve vision with benefits persisting up to five years. The most common initial side effect of IVTA treatment is rise in intraocular pressure, occurring in approximately 50% of patients within the first 6 months of treatment. We evaluated whether there is a correlation between the development of intraocular pressure rise and improvement in vision.
Analysis of individual data from 33 eyes of 33 participants treated with IVTA for DMO from a prospective, randomised, double-masked, placebo controlled trial. The degree of intraocular pressure (IOP) rise was correlated with improvement in best-corrected visual acuity (BCVA) at 1 and 6 months.
The proportion of eyes gaining 5 or more logMAR letters was higher in eyes with greater IOP rise (p = 0.044). Better absolute improvement in BCVA at 6 months (p = 0.045) was also found in eyes with greater IOP rise. Regression analyses revealed a correlation between IOP rise of 10 or more mmHg and absolute BCVA improvement at 6 months (odds ratio 1.22, 95% confidence interval 1.01-1.48, p = 0.039), but not at 1 month.
IOP rise and vision improvement appear to be correlated following IVTA for DMO, suggesting that the mechanisms that cause both may be linked.
Trial Registration
Clinical NCT00167518, September 5, 2005.
PMCID: PMC4223852  PMID: 25335434
Intravitreal triamcinolone; Diabetic macular oedema; Vision improvement; Intraocular pressure rise; Adverse events; Efficacy
11.  Retinal vessel dilatation and elongation precedes diabetic macular oedema 
AIMS/BACKGROUND—Retinal vessel dilatation is a well known phenomenon in diabetes. In this study, the theory of whether excessive changes in diameter and length of retinal vessels occur in the development of diabetic macular oedema was tested, supporting a hypothesis that the development of diabetic macular oedema may be linked to hydrostatic pressure changes described in Starling's law.
METHODS—From fundus photographs of diabetic patients attending a regular eye screening programme, the diameter and segment length of retinal vessels were measured in three retinopathy groups (12 patients each) with diabetic macular oedema (DMO), background retinopathy and no retinopathy, over a period of approximately 4 years, ending at the time of diagnosis of diabetic macular oedema in the DMO group.
RESULTS—A statistically significant dilatation and elongation of retinal arterioles, venules, and their macular branches was found before the diagnosis of macular oedema in the DMO group. No significant changes were found in the other two groups.
CONCLUSION—It is suggested that Starling's law applies to the formation of oedema in the retina as in other tissues.

PMCID: PMC1722148  PMID: 9215053
12.  Qualitative and quantitative OCT response of diffuse diabetic macular oedema to macular laser photocoagulation 
Eye  2011;25(7):901-908.
To assess the quantitative and morphological changes of the macula in response to macular grid laser for diabetic macular oedema (DMO) using optical coherence tomography (OCT).
Patients and Methods
Cirrus OCT macular cube scans of 30 eyes of 25 patients were retrospectively analysed before and 4 months after macular grid laser for diffuse DMO. The oedema was quantified and response evaluated in the nine early-treatment diabetic retinopathy study (ETDRS) zones of the macula. Post-laser OCT changes were compared with the baseline features, including morphology patterns, changes in both logarithmic transformed (logOCT) and standardised average macular thickness (AMT), total macular volume, number of parafoveal quadrants involved, and the presence of intact 3rd hyper-reflective band (HRB).
The rate of change of retinal thickness in response to laser was maximum in the central (8.17%) and perifoveal inferior quadrants (0.04%). Diffuse retinal thickening on OCT responded best to treatment. The AMT of 300–350 μm had the worst response (+0.94%). Eyes with less than four quadrants of oedema showed good response. Disrupted HRB was associated with poor visual gain (−0.33 ETDRS letters).
The topographic location of oedema on the retinal map and the morphological patterns of the oedema on OCT are useful predictors of treatment response in diffuse DMO.
PMCID: PMC3171792  PMID: 21494279
diabetic macular oedema; diffuse retinal thickening; hyper-reflective band; laser photocoagulation; macular thickness; OCT
13.  Management of retinal vascular diseases: a patient-centric approach 
Eye  2012;26(Suppl 2):S1-S16.
Retinal vascular diseases are a leading cause of blindness in the Western world. Advancement in the clinical management of these diseases has been fast-paced, with new treatments becoming available as well as license extensions of existing treatments. Vascular endothelial growth factor (VEGF) has been implicated in certain retinal vascular diseases, including wet age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vein occlusion (RVO). Treatment of wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO with an anti-VEGF on an as needed basis, rather than a fixed schedule, allows an individualised treatment approach; providing treatment when patients are most likely to benefit from it, while minimising the number of unnecessary intravitreal injections. Thus, an individualised treatment regimen reduces the chances of over-treatment and under-treatment, optimising both the risk/benefit profile of the treatment and the efficient use of NHS resource. Streamlining of treatment for patients with wet AMD and visual impairment due to either DMO or macular oedema secondary to RVO, by using one treatment with similar posology across all three diseases, may help to minimise burden of clinic capacity and complexity and hence optimise patient outcomes. Informed treatment decisions and efficient clinic throughput are important for optimal patient outcomes in the fast-changing field of retinal vascular diseases.
PMCID: PMC3335302  PMID: 22495396
age-related macular degeneration; diabetic retinopathy; retinal vein occlusion; anti-VEGF therapy; individualised medicine
14.  A point prevalence study of 150 patients with idiopathic retinal vasculitis: 1. Diagnostic value of ophthalmological features. 
This paper describes the ophthalmological features of 150 patients with idiopathic retinal vasculitis, 67 of whom had isolated retinal vasculitis (RV) and 83 had RV associated with systemic inflammatory disease (RV + SID). The diagnosis of retinal vasculitis was made by ophthalmoscopy and fluorescein angiography, and patients with any identifiable cause (infection, ischaemia, or malignancy) were excluded from the study. Patients with isolated RV tended to have peripheral vascular sheathing, macular oedema, and diffuse capillary leakage. Those with RV accompanying Behçet's disease often had branch vein retinal occlusions and retinal infiltrates together with macular oedema and diffuse capillary leakage; the retinal infiltrates were pathognomonic for Behçet's disease. In sarcoidosis the retina typically showed features of periphlebitis associated with focal vascular leakage. Patients with uveomeningitis, multiple sclerosis, arthritis, or systemic vasculitis showed diffuse retinal capillary leakage associated with a mixture of the other features. Poor visual function was particularly associated with macular oedema and branch vein retinal occlusion, while the retina appeared to 'withstand' the impact of vascular sheathing, periphlebitis, or neovascularisation alone. Within the limitations of a point prevalence study it was concluded that different patterns of retinal vasculitis occur in different systemic inflammatory diseases, and that in isolated retinal vasculitis there is a particular association between peripheral vascular sheathing, macular oedema, and diffuse capillary leakage. In Part 2 we describe the results of examining the sera of these patients for the presence of antiretinal antibodies and circulating immune complexes.
PMCID: PMC1041865  PMID: 2804027
15.  Five-year visual outcome following laser photocoagulation of diabetic macular oedema 
Eye  2011;25(7):850-859.
To evaluate the 5-year visual outcome associated with laser photocoagulation treatment of diabetic macular oedema (DMO), and to investigate the relationship between systemic factors and visual outcomes in a real-life setting.
The mean annual visual outcomes and systemic parameters of 100 consecutive subjects with type 2 diabetes who underwent the first session of focal/grid macular laser photocoagulation for clinically significant macular oedema between 2003 and 2004 were collected retrospectively and compared with the outcomes of the laser arm of the Diabetic Retinopathy Clinical Research Network (DRCRN trial comparing intravitreal triamcinolone acetonide injection with laser photocoagulation treatment for DMO). The primary outcome measures included the mean change in visual acuity (VA) in 5 years and the influence of systemic factors on final visual outcome.
The mean change in VA at 5 years was −5.23 in a real-life setting for an inner city population. The 3-year outcome was inferior to the clinical trial results with more people gaining vision (≥15 letter gain) in the DRCRN group compared with this cohort (26 vs9%). Furthermore, three times more patients lost vision (>15 letter loss) in the real-life setting of this cohort compared with the clinical trial results of the DRCRN group (27 vs8%, respectively).
The visual outcomes and the control of systemic factors of patients with DMO in this cohort were inferior to those recruited for the clinical trial involving the DRCRN group.
PMCID: PMC3178156  PMID: 21587271
diabetic macular oedema; laser photocoagulation; ethnicity
16.  A randomised controlled feasibility trial of vitrectomy versus laser for diabetic macular oedema 
Aim: (1) To evaluate whether vitrectomy is preferable to further macular laser in improving visual acuity and resolving retinal thickening in patients with diabetic macular oedema (DMO) despite previous laser and no macular traction. (2) To determine the feasibility of further trials in this population in terms of magnitude of comparative clinical effect, rate of recruitment, and loss to follow up.
Methods: A randomised controlled feasibility study. Patients with DMO and a visual acuity of 0.3 logMAR (6/12) or worse after one or more macular laser treatments were randomised on a 1:1 basis to either pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling or further macular laser. Patients with a posterior vitreous detachment, biomicroscopic evidence of retinal traction, or a taut thickened posterior hyaloid (TTPH) were excluded. Primary outcome measures were (1) best corrected logMAR visual acuity, (2) mean central macular thickness on optical coherence tomography, and (3) rate of recruitment and loss to follow up. Analysis was on an intention to treat basis.
Results: 19 patients were randomised to PPV and 21 to further macular laser. The mean baseline logMAR visual acuity was 0.65 (SD 0.28) for the group randomised to PPV and 0.60 (0.23) for the group randomised to laser. The mean change in best corrected visual acuity of the vitrectomy group was deterioration by 0.05 logMAR, while in the control group the mean change was an improvement of 0.03 logMAR. The median (interquartile range) baseline central macular thickness was 403 (337, 492) for the group randomised to PPV and 387 (298, 491) for the controls randomised to laser. The median change in central macular thickness from baseline to review in the vitrectomy group was a thinning by 73 μm (20%) and by 29 μm (10.7%) in the control laser group. This single centre was able to recruit 40 patients in 18 months with follow up of 82% at 1 year.
Conclusion: A randomised controlled trial was found to be potentially feasible in this population, the rate of recruitment was however slow and one in five patients were lost to follow up because of death and ill health. These data provide little evidence in terms of visual acuity and macular thickness of any benefit of vitrectomy over further macular laser in patients with an attached hyaloid, DMO despite previous laser, and no clinically evident macular traction or TTPH.
PMCID: PMC1772459  PMID: 15615752
diabetic macular oedema; vitrectomy; laser
17.  Determination of Olanzapine and N-desmethyl-olanzapine in Plasma Using a Reversed-Phase HPLC Coupled with Coulochemical Detection: Correlation of Olanzapine or N-desmethyl-olanzapine Concentration with Metabolic Parameters 
PLoS ONE  2013;8(5):e65719.
Olanzapine (OLZ) is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N-desmethyl-olanzapine (DMO), one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients.
The chromatographic analysis was carried out with a solvent delivery system coupled to a Coulochem III coulometric detector to determine OLZ and DMO simultaneously in OLZ-treated patients. The correlation between the concentration of OLZ or DMO and the metabolic parameters was analyzed by the Spearman rank order correlation method (rs).
Principal Findings
The established analytical method met proper standards for accuracy and reliability and the lower limitation of quantification for each injection of DMO or OLZ was 0.02 ng. The method was successfully used for the analysis of samples from nonsmoking patients (n = 48) treated with OLZ in the dosage range of 5–20 mg per day. There was no correlation between OLZ concentrations and tested metabolic parameters. DMO concentrations were negatively correlated with glucose (rs = –0.45) and DMO concentrations normalized by doses were also negatively correlated with insulin levels (rs = –0.39); however, there was a marginally positive correlation between DMO and homocysteine levels (rs = +0.38).
The observed negative correlations between levels of DMO and glucose or insulin suggest a metabolic normalization role for DMO regardless of its positive correlation with a known cardiovascular risk factor, homocysteine. Additional studies of the mechanisms underlying DMO’s metabolic effects are warranted.
PMCID: PMC3669135  PMID: 23741510
18.  Intravitreal triamcinolone for the treatment of refractory diabetic macular oedema with hard exudates: an optical coherence tomography study 
The British Journal of Ophthalmology  2004;88(9):1131-1136.
Aim: To investigate the use of intravitreal triamcinolone acetonide (IVTA) for the treatment of diabetic macular oedema (DMO) unresponsive to previous laser photocoagulation.
Method: A retrospective, interventional, non-comparative case series. There were 30 eyes of 22 consecutive patients with refractory DMO. An intravitreal injection of triamcinolone acetonide at the dose of 4 mg in 0.1 ml was administered. Best corrected visual acuity was measured at each examination. In addition the central macular thickness was quantitatively measured by optical coherence tomography (OCT) examination at each visit. The amount of hard exudates deposition in the macula was subjectively evaluated using colour fundus photographs.
Results: 30 eyes of 22 patients completed 6 months or more of follow up and were included in the study. Mean (SD) visual acuity improved from 0.17 (0.12) at baseline to 0.34 (0.18), 0.36 (0.16), and 0.31 (0.17) at the 1, 3, and 6 month follow up respectively. Mean (SD) OCT macular thickness decreased from 476 (98.32) μm at baseline to 277.46 (96.77) μm, 255.33 (95.73) μm, and 331.25 (146.76) μm at the 1, 3, and 6 month follow up period respectively. 18 and seven eyes completed 12 months and 18 months of follow up, respectively. Mean (SD) visual acuity was 0.36 (0.15) and 0.35 (0.16) at the 12 and 18 month follow up period respectively. 12 eyes received two, seven eyes received three, and two eyes received four IVTA injections. The mean (SD) interval between the first and second IVTA injection was 5.7 (2.67) months and between the second and third was 5.7 (3.25) months. Hard exudates were present in the macula at baseline in all eyes. Progressive reduction in the number and size of the hard exudates was noted after IVTA in all cases. Intraocular pressure was raised above 21 mm Hg in 12 (40%) of 30 eyes. Two eyes developed posterior subcapsular cataract and two developed vitreous haemorrhage.
Conclusions: IVTA is a promising treatment for patients with DMO refractory to laser treatment. IVTA is effective in improving vision, reducing macular thickness, and inducing reabsorption of hard exudates. Further investigation is warranted to assess the safety of IVTA for the treatment of DMO.
PMCID: PMC1772301  PMID: 15317702
triamcinolone; diabetic macular oedema; optical coherence tomography
19.  Regression of early diabetic macular oedema is associated with prevention of dark adaptation 
Eye  2011;25(12):1546-1554.
Dark-adapted rods consume oxygen at high rates and light adaptation decreases this oxygen burden and can have therapeutic effects on diabetic macular oedema (DMO).
Patients with mild non-proliferative diabetic retinopathy (DR) and early, untreated non-sight-threatening DMO slept for 6 months wearing masks that illuminated the eyelid of one closed eye by 505 nm light. Exclusion criteria were any concomitant eye disease, DR >ETDRS grade 35, and other systemic diseases. Primary outcome: change of OCT retinal thickness in the local region where oedema was present.
A total of 34 out of 40 patients completed the study. Mean baseline OCT macular cube thickness was equivalent for study and fellow eyes. But study eyes had a greater mean thickness in the central subfield zone 1 (282±53 μm) vs (256±19 μm) the fellow eyes. Twenty-eight study eyes showed intraretinal cysts compared with nine in the fellow eyes. At 6 months, only 19 study eyes had cysts while cysts were seen in 20 fellow eyes. After 6 months, the worst affected ETDRS zone and the central subfield zone 1 reduced in thickness in study eyes only by 12 μm (95% CI 20 to −7, P=0.01). The secondary outcomes of change in visual acuity, achromatic contrast sensitivity, and microperimetric thresholds improved significantly in study eyes and deteriorated in fellow eyes.
Sleeping in dim light that can keep rods light adapted may reverse the changes of DMO.
PMCID: PMC3234487  PMID: 22020171
lightmasks; diabetic macular oedema; hypoxia; dark; adaptation
20.  Macular microcirculation in cystoid maculopathy of diabetic patients. 
BACKGROUND--In patients with diabetic macular oedema and central cysts ischaemia of the retina appears to be an important contributing factor in the pathogenesis of cysts. This study was performed to further elucidate the role of the inner retinal microcirculation in diabetic cystoid macular oedema (CMO). METHODS--Video fluorescein angiography allows visualisation of the macular microvasculature and measurements of the capillary blood velocity (CBV), foveal avascular zone (FAZ), and perifoveal intercapillary area (PIA, characterising capillary density). RESULTS--Twenty three diabetic subjects with CMO, matched diabetic patients without macular oedema (n = 23), and healthy subjects (n = 23) were included. CBV, PIA, and FAZ did not differ significantly among diabetic groups regardless of presence of cystoid changes. CBV was significantly reduced (p < 0.0001) and PIA was more than doubled in both diabetic groups (p < 0.0001) when compared with healthy subjects. Furthermore, FAZ showed a nearly doubled size in diabetic patients without macular oedema (p < 0.01) and a less pronounced enlargement (by 29%) in diabetics with CMO (p < 0.05). CONCLUSION--The results indicate that the retinal microcirculation in diabetic patients is markedly altered when compared with healthy subjects, regardless of CMO presence. In CMO patients the microcirculatory changes are similar to those of diabetic patients without macular oedema. Thus inner retinal perfusion does not contribute to tissue ischaemia leading to cystoid formations in diabetic maculopathy.
PMCID: PMC505186  PMID: 7662623
21.  Relationship between perifoveal capillaries and pathomorphology in macular oedema associated with branch retinal vein occlusion 
Eye  2012;26(6):771-780.
To study the relationship between macular ischaemia on fluorescein angiography (FA) and pathomorphology at the foveal centre delineated by spectral-domain optical coherence tomography (OCT) in macular oedema (MO) associated with branch retinal vein occlusion (BRVO).
One hundred and five consecutive eyes of 105 patients with MO (centre point thickness (CPT) ≥300 μm) associated with BRVO in which FA using Heidelberg Retinal Angiography 2 and Spectralis OCT were performed on the same day were retrospectively reviewed. We evaluated the foveal pathomorphology using OCT images and the association with macular ischaemia.
Within 1 year from symptom onset, 94 eyes were classified with perfused macula (34 eyes) or non-perfused macula (60 eyes). Eyes with perfused macula had better visual acuity and less CPT than those with non-perfused macula (P=0.024 and P<0.001, respectively). Fourteen eyes with perfused macula had serous retinal detachment (SRD) alone at the presumed foveal centre (SRD type); seven, a sponge-like swelling at that area (retinal swelling type); 11, foveal cystoid spaces alone (cystoid MO (CMO) type), and 2, with both SRD and foveal cystoid spaces (SRD+CMO type). However, 58 eyes with non-perfused macula had foveal cystoid spaces (42 of CMO type and 16 of SRD+CMO type), with a significant association between them (P<0.001). Among 11 eyes with symptoms exceeding 1 year, 6 eyes had perfused macula, and none had the SRD type.
Most eyes without foveal cystoid spaces have perfused macula in MO associated with BRVO.
PMCID: PMC3376306  PMID: 22653519
branch retinal vein occlusion; macular oedema; spectral domain optical coherence tomography; fluorescein angiography; macular ischemia; cystoid spaces
22.  Current treatments in diabetic macular oedema: systematic review and meta-analysis 
BMJ Open  2013;3(3):e002269.
The aim of this systematic review is to appraise the evidence for the use of anti-VEGF drugs and steroids in diabetic macular oedema (DMO) as assessed by change in best corrected visual acuity (BCVA), central macular thickness and adverse events
Data source
MEDLINE, EMBASE, Web of Science with Conference Proceedings and the Cochrane Library (inception to July 2012). Certain conference abstracts and drug regulatory web sites were also searched.
Study eligibility criteria, participants and interventions
Randomised controlled trials were used to assess clinical effectiveness and observational trials were used for safety. Trials which assessed triamcinolone, dexamethasone, fluocinolone, bevacizumab, ranibizumab, pegaptanib or aflibercept in patients with DMO were included.
Study appraisal and synthesis methods
Risk of bias was assessed using the Cochrane risk of bias tool. Study results are narratively described and, where appropriate, data were pooled using random effects meta-analysis.
Anti-VEGF drugs are effective compared to both laser and placebo and seem to be more effective than steroids in improving BCVA. They have been shown to be safe in the short term but require frequent injections. Studies assessing steroids (triamcinolone, dexamethasone and fluocinolone) have reported mixed results when compared with laser or placebo. Steroids have been associated with increased incidence of cataracts and intraocular pressure rise but require fewer injections, especially when steroid implants are used.
The quality of included studies varied considerably. Five of 14 meta-analyses had moderate or high statistical heterogeneity.
Conclusions and implications of key findings
The anti-VEGFs ranibizumab and bevacizumab have consistently shown good clinical effectiveness without major unwanted side effects. Steroid results have been mixed and are usually associated with cataract formation and  intraocular pressure increase. Despite the current wider spectrum of treatments for DMO, only a small proportion of patients recover good vision (≥20/40), and thus the search for new therapies needs to continue.
PMCID: PMC3612765  PMID: 23457327
23.  Decreasing efficacy of repeated intravitreal triamcinolone injections in diabetic macular oedema 
The British Journal of Ophthalmology  2006;90(9):1137-1141.
Intravitreal triamcinolone (IVTA) results in transient improvements in diabetic macular oedema (DMO), necessitating repeated injections. The authors report a case series of 10 eyes of 10 patients with DMO, who received a repeat injection of 4 mg IVTA, at least 26 weeks after the first injection of the same dose.
Pre‐injection and at 2, 4, 9, and 17 weeks post‐injection, best corrected visual acuity (BCVA) and central foveal thickness (CFT) on optical coherence tomography, after the first and repeat injections, were compared using paired t test. Side effects were monitored.
BCVA, CFT, intraocular pressure (IOP), and cataract scores were not significantly different before initial and repeat injections (given at 32.5 (SD 3.5) weeks after the first injection). Transient improvements of BCVA and CFT were achieved after both injections. However, after the repeat injection, the BCVA was significantly worse at all time points (p<0.05) and so were the best achieved CFT and the CFT at 4 weeks post‐injection (p = 0.034 and 0.011 respectively), compared with the initial injection. Post‐injection maximum IOPs and increase in cataract scores were not significantly different between the two injections.
A repeat injection of 4 mg of IVTA may not be as effective as an initial injection for the treatment of DMO.
PMCID: PMC1857409  PMID: 16707525
diabetic macular oedema; triamcinolone acetonide; dose‐response relation
24.  Validation of Diabetic Retinopathy and Maculopathy Diagnoses Recorded in a U.K. Primary Care Database 
Diabetes Care  2012;35(4):762-767.
To describe the validity of recorded diabetic retinopathy (DR) and diabetic maculopathy (DMP) diagnoses, including edema (DMO) in The Health Improvement Network (THIN) database.
In two independent computer searches, we detected 20,838 patients with diabetes aged 1–84 years with a first DR computer Read entry in 2000–2008 and 4,064 with a first DMP entry. A two-step strategy was used to validate both outcomes as follows: 1) review of patient profiles including free-text comments from primary care practitioners (PCPs) (containing referral information and test results) of a random sample of 500 DR and all DMP computer-detected patients. We classified them in probable, possible, and noncase according to the diagnosis plausibility based on the manual review of the computerized information; and 2) review of questionnaires sent by PCPs and medical records in a random sample (N = 200 for each outcome including 36 diabetic macular edema [DMO]). Gold standard was PCPs’ confirmation.
After profiles review, we categorized 418 as probable/possible DR. In addition, 3,676 DMP were categorized as probable/possible (including 711 DMO). After review of information sent by PCPs, confirmation rates were 87.3 and 87.2%, respectively (90.3% for DMO). When we applied them to the whole sample of computer-detected patients, the weighted confirmation rate was 78.0% for DR and 78.8% for DMP (86.2% for DMO).
Read codes for DR, DM, and DMO are moderately accurate in identifying incident case subjects of these ophthalmologic complications. The validity improved when incorporating PCPs’ text comments to the patient’s profile. THIN database proved to be a valuable resource to study ophthalmological diabetes complications.
PMCID: PMC3308315  PMID: 22357184
25.  Quantitative assessment of macular thickness in normal subjects and patients with diabetic retinopathy by scanning retinal thickness analyser 
AIMS—To evaluate the scanning retinal thickness analyser (RTA), a novel non-invasive imaging instrument, in diagnosing and quantitatively characterising diabetic macular oedema, and to investigate the relation between central macula thickness measured by RTA and other clinical examinations.
METHODS—Central macular thickness was measured using the RTA in 40 normal subjects and 60 patients with diabetic retinopathy. The reproducibility of the retinal thickness measurements was evaluated by calculating the mean of the inter- and intrasession variations. Central macular thickness was correlated with the results of visual acuity measurements, biomicroscopy, and fluorescein angiography.
RESULTS—Intra- and intersession reproducibility of the RTA in normal subjects was plus or minus 5.2% (16 µm) and plus or minus 6.1% (19 µm), respectively. The mean central macular thickness was 182 (SD 16) µm in normal subjects, 283 (116) µm in diabetic eyes without clinically significant macular oedema (CSMO), and 564 (168) µm in diabetic eyes with CSMO. Central macular thickness was significantly greater (p<0.001) in eyes with diabetic retinopathy than in normal subjects, even when macular thickening did not meet the standard for CSMO (p=0.019) measured by biomicroscopy. Although greater fluorescein leakage at the macula results in greater central macular thickness, only eyes with diffuse leakage had statistically significant macular thickening compared with normal subjects (p=0.022). Central macular thickness measured with the RTA was significantly correlated with the logarithmic converted visual acuity (r2= 0.76) in diabetic eyes.
CONCLUSION—Scanning RTA, which has good reproducibility, might be useful to quantitatively detect and monitor macular thickening in diabetic retinopathy. Central macular thickness was highly correlated with logarithmic converted visual acuity in diabetic macular oedema.

 Keywords: scanning retinal thickness analyser; macular thickness; diabetic retinopathy; macular oedema
PMCID: PMC1722802  PMID: 10209436

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