Elevated aqueous TNF-α levels are associated with more severe functional and anatomic findings in eyes with diabetic macular oedema.

BACKGROUND: Intravitreal ranibizumab for diabetic macular oedema (DMO) has been recently shown to modulate levels of aqueous cytokines. This study investigates the associations between changes in aqueous cytokine levels following intravitreal ranibizumab therapy and the corresponding anatomical and functional changes in the eye. METHODS: Twenty-five patients comprising 30 eyes diagnosed with DMO were prospectively recruited. All eyes received three loading dose ranibizumab injections at baseline, week 4 and week 8, followed by pro re nata treatment based on best-corrected visual acuity (BCVA) and central macular thickness (CMT) up to week 48. Prior to ranibizumab administration, aqueous samples were collected from all eyes, and subsequent sampling was performed at week 8. Levels of 32 cytokines were assessed at baseline and at week 8. RESULTS: At baseline, higher aqueous TNF-α levels were associated with poorer BCVA (p = 0.033), greater macular volume (p = 0.017) and worse diabetic retinopathy (p = 0.047). Higher levels of IL-7 were associated with poorer BCVA and greater macular volume (MV). Following treatment with ranibizumab there was a significant correlation with reduction of aqueous TNF-α and improvements in BCVA and MV, both at 6 months (BCVA [r = -0.558, p = 0.001], MV [r = 0.410, p = 0.024]) and 12-months (BCVA [r = -0.413, p = 0.023], MV [r = 0.482, p = 0.008]). The change in VEGF concentration following ranibizumab treatment did not correlate with either BCVA or MV improvements (p > 0.05). CONCLUSIONS: Higher levels of aqueous TNF-α and IL-7 correlated with worse DMO, both anatomically and functionally. Reductions in levels of aqueous TNF-α, but not VEGF, post ranibizumab treatment were associated with improvement in BCVA and MV.

Obstructive sleep apnea, chronic obstructive pulmonary disease and hypertensive microvascular disease: a cross-sectional observational cohort study.

Hypertensive microvascular disease is associated with an increased risk of diastolic heart failure, vascular dementia and progressive renal impairment. This study examined whether individuals with obstructive sleep apnoea (OSA) had more retinal hypertensive microvascular disease than those with chronic obstructive pulmonary disease (COPD) and hospital controls. This was a single-centre, cross-sectional, observational study of participants recruited consecutively from a general respiratory clinic and a general medical clinic. OSA was diagnosed on overnight polysomnography study (apnoea:hypopnoea index ≥ 5), and controls with COPD had a forced expiratory volume/forced vital capacity (forced expiratory ratio) < 70%. Individuals with both OSA and COPD were excluded. Hospital controls had no COPD on respiratory function testing and no OSA on specialist physician questioning. Study participants completed a medical questionnaire, and underwent resting BP measurement, and retinal photography with a non-mydriatic camera. Images were deidentified and graded for microvascular retinopathy (Wong and Mitchell classification), and arteriole and venular calibre using a semiautomated method at a grading centre. Individuals with OSA (n = 79) demonstrated a trend to a higher mean arterial pressure than other hospital patients (n = 143) (89.2 ± 8.9 mmHg, p = 0.02), and more microvascular retinopathy (p < 0.001), and narrower retinal arterioles (134.2 ± 15.9 µm and 148.0 ± 16.2 µm respectively, p < 0.01). Microvascular retinopathy and arteriolar narrowing were still more common in OSA than hospital controls, after adjusting for age, BMI, mean arterial pressure, smoking history and dyslipidaemia (p < 0.01, p < 0.01, respectively). Individuals with OSA demonstrated a trend to a higher mean arterial pressure than those with COPD (n = 132, 93.2 ± 12.2 mmHg and 89.7 ± 12.8 mmHg respectively, p = 0.07), and more microvascular retinopathy (p = 0.0001) and narrower arterioles (134.2 ± 15.9 and 152.3 ± 16.8, p < 0.01). Individuals with OSA alone had more systemic microvascular disease than those with COPD alone or other hospital patients without OSA and COPD, despite being younger in age.

Quantitative Analysis of the Ellipsoid Zone Intensity in Phenotypic Variations of Intermediate Age-Related Macular Degeneration.

Purpose: Reduction of the ellipsoid zone (EZ) intensity has been reported in eyes with age-related macular degeneration (AMD). This study determined whether overall EZ intensity, in retinal locations undisturbed by pathologic features, is associated with the presence of clinical features, which are known important phenotypic risk factors for disease progression, large drusen, reticular pseudodrusen (RPD), and pigmentary abnormalities. Methods: A horizontal B-scan through the foveola on spectral-domain optical coherence tomography (SD-OCT) was performed in both eyes of 75 participants with bilateral intermediate AMD and 10 age-similar control participants. Eyes with AMD were classified as per the presence of large drusen, RPD, and hyperpigmentary changes. The relative EZ intensity profile, up to an eccentricity of 3400 µm, was averaged over seven 1000-µm retinal segments. The association between relative EZ intensity profile over seven retinal segments and AMD pathologic features was analyzed. Results: The average relative EZ intensities were significantly reduced in eyes with intermediate AMD compared to normal eyes (P ≤ 0.025) and with increasing age (P ≤ 0.020). On multivariate analyses, only the presence of hyperpigmentary changes and increasing age were significantly associated with reduced overall relative intensities (P ≤ 0.024), but not the presence of large drusen or RPD (P ≥ 0.115). Conclusions: The presence of hyperpigmentary change in the macula in association with large drusen, not large drusen alone, nor large drusen with RPD, was significantly associated with a generalised reduction in EZ intensity. Quantitative assessment of the relative EZ intensity may serve as an effective biomarker of disease severity and progression.

Long-term Outcomes of Limited Vogt-Koyanagi-Harada Syndrome.

PURPOSE: To describe the long-term outcomes of patients with limited Vogt-Koyanagi Harada syndrome (VKH), characterized by steroid-responsive serous retinal detachments without other signs of intraocular inflammation. DESIGN: Retrospective case series. METHODS: Consecutive patients from the Royal Victorian Eye and Ear Hospital with acute bilateral serous retinal detachments without anterior chamber inflammation, with no previous ocular history or trauma, and with negative screening for vasculitis and other systemic autoimmune disease were included. Serous retinal detachment was confirmed on optical coherence tomography (OCT) and fundus fluorescein angiography. Visual acuity, treatment regimen, complications, and duration of follow-up were recorded. RESULTS: Nine patients (6 male, median age 29 years [interquartile range (IQR) 27-36 years]) from January 2010 through May 2014 were studied. Median presenting logMAR visual acuity (VA) was 0.48 (IQR -0.1 to 3.0). Six patients were initially commenced on intravenous methylprednisolone for 3 days, followed by oral prednisolone. All received a course of tapering oral prednisolone (1 mg/kg prior to taper). Median duration of treatment was 9 weeks (IQR 8-14 weeks). Median time to complete resolution of subretinal fluid on OCT was 3.7 weeks (range, 2-12 weeks), with a corresponding improvement in VA (median logMAR 0.00; range, -0.08 to 0.04). There was no recurrence after a mean follow-up of 145.2 weeks (95% confidence interval 72.5-217.9). CONCLUSION: In contrast to typical VKH, patients with limited VKH in our series appear to have good outcomes with systemic corticosteroid treatment. They have a marked improvement of VA and no episodes of relapse after cessation of corticosteroid treatment.

Hypertensive/Microvascular Disease and COPD: a Case Control Study.

BACKGROUND/AIMS: This study tested the hypothesis that individuals with chronic obstructive pulmonary disease (COPD) have more small vessel disease and more severe disease than an age- and gender- matched hospital patient comparison group. METHODS: This was a single centre, case-control study of 151 individuals with COPD (FEV1/VC) < 0.7 recruited consecutively immediately after respiratory function tests at a Melbourne teaching hospital over a 4 month period in 2010. Controls were individuals with normal respiratory function tests recruited contemporaneously from the same centre. Retinal images were obtained with a nonmydriatic camera (KOWA or Canon CR5-45NM), deidentiifed and graded by two trained graders for microvascular retinopathy (Wong and Mitchell classification), and vessel calibre using a computer-assisted method and Knudtson's modification of the Parr-Hubbard formula. Differences in microvascular retinopathy and vessel calibre between COPD patients and the comparison group were examined using Fisher's exact test or the t test (StataCorp, Texas). RESULTS: Patients with COPD had more microvascular retinopathy (121, 80% and 76, 50%; OR 3.98, 95%CI 2.39 to 6.64) and more severe disease (42, 28% and 18, 12%; OR 2.85, 95% CI 1.55 to 5.23) than other hospital patients. COPD remained an independent determinant of microvascular retinopathy (OR 4.56, 95%CI 2.49 to 8.36) after adjusting for gender, hypertension, smoking, and diabetes duration. Retinal arterioles and venules were wider in patients with COPD than other hospital patients (mean difference +6.5 µm, 95% confidence interval 1.4 to 11.6; and +17.4 µm, 95%CI 9.4 to 25.5, respectively). Larger venules were more common in younger individuals (+0.6 µm, 0.1 to 1.17) with more cigarette exposure (+0.3 µm, 0.2 to 0.5) or a lower serum albumin (+23.0 µm, 6.0 to 40.0). Venular calibre was not different in current and former smokers (p=0.77). There were trends for venules to be larger with more severe COPD (lower FEV1/VC, p=0.09) and with CT-demonstrated emphysema (p=0.06). CONCLUSIONS: Hypertensive/microvascular disease is more common and more severe in patients with COPD. This is likely to contribute to the associated increase in cardiac risk.

Retinoic acid and the ocular surface.

Retinoic acid is known to improve cutaneous wound healing and, in recent years, its application in ophthalmology has been investigated. This review looks at the role of retinoic acid on the ocular surface. Retinoic acid can be produced synthetically, and its mechanism of action includes both nuclear and non-nuclear receptor mediated pathways. It has been shown to improve full and partial thickness corneal lacerations as well as corneal epithelial defects. Retinoic acid plays a critical role in cell differentiation at the cornea, conjunctiva, and limbus, and may have an anti-tumor role. Its positive effect is only achieved at the correct concentration, however; excess concentrations of retinoic acid have a deleterious effect. The main limiting factor of retinoic acid use is its detrimental effect on meibomian glands, resulting in cell death, atrophy of acini, hyposecretion of oils, and altered gene expression, eventually resulting in dry eye symptoms. This effect is reversible on discontinuation of the drug.

Brinzolamide plus brimonidine for the treatment of glaucoma: an update.

INTRODUCTION: Glaucoma is a common sight-threatening condition that is primarily treated by lowering intraocular pressure (IOP). Today the mainstay of treatment is topical ocular hypotensive medications; many patients require more than one agent to achieve target IOP. For such patients, fixed combination formulations have several advantages including simplicity of treatment regimen, adherence to the treatment regimen, efficacy, improved ocular surface comfort and reduced cost. All currently available fixed combinations contain a ß-blocker, which is contraindicated in some patients. Hence there is a clinical need for fixed-combination preparations without a ß-blocker. This paper reviews the current literature on a new fixed-combination drug containing brinzolamide 1% and brimonidine 0.2% (BBFC). AREAS COVERED: A PubMed, Embase and ClinicalTrials.gov registry search was performed to identify all relevant studies. Four published clinical papers pertaining to three randomized controlled trials were identified for review. All studies demonstrated a significant reduction (p < 0.01) in mean IOP in patients administered with BBFC compared with its individual components, brinzolamide 1% or brimonidine 0.2%. Adverse effects from BBFC were no different from each of the individual components, the most common being blurred vision, eye irritation and dysgeusia (abnormal taste sensation). Although BBFC use was associated with more adverse effects compared with the individual components used as monotherapy (p < 0.001), the cumulative adverse effect profile from BBFC did not appear greater than one would expect from the simultaneous use of the two components. EXPERT OPINION: BBFC is a potential alternative to other fixed-combination medications and is especially useful when topical ß-blockers are contraindicated. Longer-term experience will determine if additional adverse effects occur or if efficacy is maintained over longer periods.

The relationship of retinal vessel caliber with erectile dysfunction in patients with type 2 diabetes.

PURPOSE: To investigate the relationship of retinal vessel caliber with erectile dysfunction (ED) in males with type 2 diabetes. METHODS: A hospital-based cross-sectional study. Male patients with type 2 diabetes were recruited from the Diabetic Management Project. All underwent a complete eye examination, a comprehensive interview, and blood and urine tests. Retinal vessel diameter was measured from retinal photographs by trained graders using semiautomated software. ED was defined as problems achieving or maintaining an erection and was assessed using a self-reported questionnaire. RESULTS: A total of 289 male patients with a mean (±SD) age of 65.3 years (±11.2) were assessed. After adjusting for age, diastolic blood pressure, duration of diabetes, HbA1c, total cholesterol, presence of diabetic retinopathy, and any diabetic complication, narrower retinal arteriolar diameter (odds ratio [OR] 1.66; 95% confidence interval [CI] 1.09-2.54; P = 0.019) and wider venular diameter (OR 1.58; 95% CI 1.03-2.44; P = 0.038) were associated with ED. CONCLUSIONS: Narrower retinal arteriolar and wider venular diameter are independently associated with an increased risk of self-reported ED. These results suggest a microvascular component in the pathogenesis of this condition.

Relationship between diabetic retinopathy, diabetic macular oedema and erectile dysfunction in type 2 diabetics.

BACKGROUND: To investigate the relationship of diabetic retinopathy and diabetic macular oedema with erectile dysfunction in patients with type 2 diabetes. DESIGN: Hospital-based, cross-sectional study. PARTICIPANTS: Three hundred twenty-four men with diabetes from the Diabetic Management Project were recruited. METHODS: Participants underwent a comprehensive interview, a complete eye examination, fasting blood tests, and had retinal and macula assessments using fundus images and optical coherence tomography, respectively. Diabetic retinopathy was categorized as none, mild, moderate, severe non-proliferative and proliferative, and diabetic macular oedema as none, mild, moderate and severe. Erectile dysfunction was defined as problems achieving or maintaining an erection and was assessed using a self-reported questionnaire. MAIN OUTCOME MEASURES: Erectile dysfunction. RESULTS: The mean ± standard deviation age of 324 men with type 2 diabetes was 65.2 ± 11.1 years. Compared with patients without diabetic retinopathy, those with any retinopathy (odds ratio 2.06, 95% confidence interval 1.22-3.48, P = 0.007) had a twofold increased odds of having erectile dysfunction. Patients with severe non-proliferative diabetic retinopathy (odds ratio 4.39, 95% confidence interval 1.48-13.0, P = 0.008) and proliferative diabetic retinopathy (odds ratio 2.74, 95% confidence interval 1.44-5.19, P = 0.002) had fourfold and threefold increased odds of having erectile dysfunction, respectively, compared with those without diabetic retinopathy. Diabetic macular oedema, irrespective of presence or severity, was not independently associated with erectile dysfunction. CONCLUSION: The presence and severity of diabetic retinopathy but not diabetic macular oedema are independently associated with self-reported erectile dysfunction.

Retinal arteriolar diameter and the prevalence and incidence of hypertension: a systematic review and meta-analysis of their association.

Hypertension is a leading risk factor for increased mortality and morbidity. One pathogenesis mechanism, increased peripheral vascular resistance, relates to arteriolar diameter. Retinal arterioles, visualized and measured through retinal images, provide an insight into the microvascular structure and hints of peripheral vascular resistance. Multiple studies have demonstrated an inverse association between increasing blood pressure and narrowing retinal arteriolar diameter. This systematic review summarizes the currently available evidence from cross-sectional and longitudinal population-based studies that have investigated this association. A meta-analysis of five cross-sectional studies (19,633 adults) provided an averaged regression coefficient of -3.07 µm (95% CI, -3.73, -2.40) narrowing in retinal arteriolar diameter for every 10 mm Hg increase in mean arterial blood pressure. Four longitudinal studies (6,247 adults) with follow-up periods ranging from 3 to 7 years consistently showed that generalized retinal arteriolar narrowing (defined as the lowest tertile, quartile, or quintile in the population) was associated with an increased risk of incident hypertension (meta-analysis odds ratio 1.91; 95% CI, 1.56-2.34).

Vision-threatening retinal abnormalities in chronic kidney disease stages 3 to 5.

BACKGROUND AND OBJECTIVES: Retinal abnormalities are common in inherited and acquired renal disease. This study determined the prevalence of retinal abnormalities in chronic kidney disease (CKD) stages 3 to 5. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: One hundred fifty patients with CKD stages 3 to 5 and 150 age- and gender-matched hospital patients with CKD stages 1 to 2 underwent bilateral retinal photography. These images were reviewed for incidental abnormalities, microvascular (Wong and Mitchell classification) and diabetic retinopathy (Airlie House criteria), and macular degeneration (Seddon classification). RESULTS: Three (2%) patients with CKD stages 3 to 5 had retinal features characteristic of inherited renal disease (atrophy in Myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes [MELAS] syndrome; and 2 with drusen in dense deposit disease). Fifty-nine (39%) patients had moderate-severe microvascular retinopathy (hemorrhages, exudates, etc.) compared with 19 (13%) with CKD stages 1 to 2. Forty-one (28%) had moderate-severe diabetic retinopathy (microaneurysms, exudates, etc.) compared with 16 (11%) with CKD stages 1 to 2. Ten (7%) had severe macular degeneration (geographic atrophy, hemorrhage, exudates, membranes) compared with one (1%) with CKD stages 1 to 2. Renal failure was an independent risk factor for microvascular retinopathy, diabetic retinopathy, and macular degeneration. Eleven (7.3%) patients with renal failure and one (0.7%) with CKD stages 1 to 2 had previously unrecognized vision-threatening retinal abnormalities that required immediate ophthalmologic attention. CONCLUSIONS: Retinal abnormalities are common in CKD stages 3 to 5, and are more severe and more likely to threaten vision than in hospital patients with CKD stages 1 to 2.