Aqueous Humor Cytokine Levels and Anatomic Response to Intravitreal Ranibizumab in Diabetic Macular Edema.

Importance: Variability in response to anti-vascular endothelial growth factor (VEGF) treatment in diabetic macular edema (DME) remains a significant clinical challenge. Biomarkers could help anticipate responses to anti-VEGF therapy. Objectives: To investigate aqueous humor cytokine level changes in response to intravitreal ranibizumab therapy for the management of DME, and to determine the association between baseline aqueous levels and anatomic response. Design, Setting, and Participants: In this prospective multicenter cohort study, 49 participants with diabetes mellitus complicated by center-involving DME, with a central subfield thickness of 310 µm or greater on spectral-domain optical coherence tomography (SD-OCT), were recruited from December 22, 2011, to June 13, 2013 and statistical analysis were performed from March 1, 2017, to June 1, 2017. A total of 48 participants proceeded to follow-up. Interventions: Participants received monthly injections of ranibizumab, 0.5 mg, for 3 months. Aqueous fluid for cytokine analysis was obtained at baseline and repeated at the 2-month visit. Multiplex immunoassay was carried out in duplicate for VEGF, placental growth factor, transforming growth factor beta 2, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), IL-8, IL-10, vascular intercellular adhesion molecule, and monocyte chemoattractant protein 1. Main Outcomes and Measures: Baseline and 2-month change in aqueous cytokine levels, 3-month change in SD-OCT central subfield thickness and macular volume (MV), and the statistical association between baseline aqueous cytokine levels and these measures of anatomic response to ranibizumab in center-involving DME. Results: Among the 48 participants, the mean (SD) age was 61.9 (7.1) years and 36 participants (75.0%) were men. The following cytokines were lower at month 2 vs baseline: ICAM-1 (median change, -190.88; interquartile range [IQR], -634.20 to -26.54; P < .001), VEGF (median change, -639.45; IQR, -1040.61 to -502.61; P < .001), placental growth factor (median change, -1.31; IQR, -5.99 to -0.01; P < .001), IL-6 (median change, -38.61; IQR, -166.72 to -2.80; P < .001), and monocyte chemoattractant protein 1 (median change, -90.13; IQR, -382.74 to 109.47; P = .01). When controlling for age, foveal avascular zone size, and severity of retinopathy, multiple linear regression determined that increasing baseline aqueous ICAM-1 was associated with a favorable anatomic response, in terms of reduced SD-OCT MV at 3 months (every additional 100 pg/mL of baseline ICAM-1 was associated with a reduction of 0.0379 mm3; P = .01). Conversely, increasing baseline aqueous VEGF was associated with a less favorable SD-OCT MV response at 3 months (every additional 100 pg/mL of baseline VEGF was associated with an increase of 0.0731 mm3; P = .02) and was associated with lower odds of being a central subfield thickness responder (odds ratio, 0.868; 95% CI, 0.755-0.998). Conclusions and Relevance: Elevated aqueous ICAM-1 and reduced VEGF levels at baseline are associated with a favorable anatomic response to ranibizumab in DME, although there is not always direct correlation between anatomic and visual acuity response.

AQUEOUS HUMOR CYTOKINE LEVELS AS BIOMARKERS OF DISEASE SEVERITY IN DIABETIC MACULAR EDEMA.

PURPOSE: To determine whether aqueous cytokine levels correlate with disease severity in diabetic macular edema. METHODS: A prospective cross-sectional study of 49 adults with diabetes mellitus, centre-involving diabetic macular edema and central subfield macular thickness ≥310 µm on spectral domain optical coherence tomography. Clinical examination and aqueous sampling were carried out before an initial injection of ranibizumab. Multiplex immunoassay of sample was carried out for vascular endothelial growth factor, placental growth factor, transforming growth factor beta, intercellular adhesion molecule-1, interleukin (IL)-2, IL-3, IL-6, IL-8, IL-10, IL-17, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and epidermal growth factor. Multivariate robust regression models were constructed, and adjusted for age, lens status, or severity of retinopathy, and size of foveal avascular zone. RESULTS: Spectral domain optical coherence tomography macular volume was an excellent measure of disease severity, correlating strongly with central subfield macular thickness (P < 0.001), best-corrected Snellen visual acuity (P < 0.001), and baseline diabetic retinopathy severity (P = 0.01). Elevated aqueous intercellular adhesion molecule-1 correlated with greater macular volume (P = 0.002). No aqueous cytokine, including VEGF, correlated with central subfield macular thickness. There was an association between IL-10 levels and best-corrected Snellen visual acuity (P = 0.03). CONCLUSION: Aqueous intercellular adhesion molecule-1 correlates with disease severity as measured by macular volume on spectral domain optical coherence tomography, and IL-10 is associated with BCVA. Intercellular adhesion molecule-1 may be a clinically useful biomarker for diabetic macular edema severity.

Vogt-Koyanagi-Harada disease, diabetes mellitus, and psoriasis in a child.

PURPOSE: To report a case of a child with near-simultaneous onset of Vogt Koyanagi Harada disease (VKH) and insulin-dependent diabetes mellitus (IDDM). DESIGN: Interventional case report. METHODS: An 11-year-old child with known psoriasis presented with headache and bilateral granulomatous panuveitis. Nine weeks later, he presented with diabetic ketoacidosis and IDDM. Diffuse choroidal depigmentation followed within months. HLA was positive for DRB1*0405. Despite aggressive local and systemic therapy, the ocular disease was complicated by bilateral cataracts, angle closure glaucoma, and choroidal neovascularization. RESULTS: The patient is currently pseudophakic in one eye and aphakic in the other, with best-corrected visual acuity of 6/24 and 6/5, respectively. CONCLUSIONS: VKH may present in children with panuveitis in the setting of other autoimmune disorders. Treating such patients is complicated by the need to minimize systemic corticosteroid use. A combination of local therapy and systemic steroid-sparing agents should be the mainstay of treatment.

Retinopathy signs in people without diabetes: the multi-ethnic study of atherosclerosis.

OBJECTIVE: To describe the prevalence of retinopathy and associations with cardiovascular risk factors in persons without diabetes in 4 racial/ethnic groups (white, black, Hispanic, and Chinese). DESIGN: Population-based, cross-sectional study. PARTICIPANTS: We included 6176 subjects aged 45-84 years without diabetes, selected from 6 United States communities. METHODS: Fundus images were taken using 45° digital camera through dark-adapted pupils and were graded for retinopathy as defined by the Early Treatment Diabetic Retinopathy Study severity scale: microaneurysms, hemorrhages, cotton wool spots, intraretinal microvascular abnormalities, hard exudates, venous beading, and new vessels. MAIN OUTCOME MEASURES: Retinopathy and the association with cardiovascular risk factors. RESULTS: Prevalence rates of retinopathy in persons without diabetes were 12.5% overall, varying from 11.9% (white), 13.9% (black), 12.6% (Hispanic), to 17.2% (Chinese). Hypertension was strongly associated with retinopathy (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.23-1.75). After adjusting for age, gender, race, and other parameters, smoking (OR, 1.50; 95% CI, 1.09-2.06) and increased internal carotid intima media thickness (OR, 1.22; 95% CI, 1.05-1.41) were associated with retinopathy. A range of serum inflammatory factors were examined, but none were found to be significant. CONCLUSIONS: Retinopathy in persons without diabetes is common, varies with race/ethnicity, and associated with cardiovascular risk factors, including hypertension, smoking, and carotid artery intima media thickness.

Intravitreal methotrexate as adjunctive, palliative therapy in intraocular T-cell lymphoma.

PURPOSE: To report on the rapid and sustained effect following injection of intravitreal methotrexate (IVTMTX) in intraocular T-cell lymphoma. DESIGN: Report of 2 cases. METHODS: A young male with natural killer/T-cell lymphoma presented with infiltrative nodular iridocyclitis and received a single IVTMTX. An elderly female with peripheral T-cell lymphoma presented with a hypopyon, infiltrative iridocyclitis, and choroidal effusions and received 3 IVTMTX over 4 months. RESULTS: Both patients responded well after the first injection, with resolution of signs within 1 week and improvement in vision. CONCLUSIONS: IVTMTX may be effective as a palliative, vision-restoring measure in patients with systemic T-cell lymphoma.

In vivo confocal microscopy and polarizing microscopy of the cornea in a patient with nephropathic cystinosis.

The clinicopathological and in vivo confocal microscopic characteristics of the corneas from a patient with infantile cystinosis is reported. Crystals were demonstrated in the epithelium and stroma of this patient.

Assessment of vision-related quality of life in an older population subsample: The Blue Mountains Eye Study.

PURPOSE: To assess visual functioning and vision-specific health-related quality of life (HRQOL) in an older, community-dwelling-based population subsample, using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). METHODS: Three-quarters (76%, n = 892) of Extension Blue Mountains Eye Study participants (aged > or = 50 years, mean 60.8 years) completed the self-administered NEI-VFQ-25, an instrument consisting of 12 dimensions and one summary composite score, and comprehensive eye examinations, including monocular distance visual acuity. Visual impairment was defined as visual acuity < 6/12. Unilateral and bilateral visual impairment was defined by the worse eye and better eye, respectively. Correctable visual impairment was defined as that which improved, and non-correctable visual impairment as that which persisted after subjective refraction. Mild visual impairment was defined as visual acuity < 6/12 but > or = 6/24, moderate as < 6/24 but > or = 6/60, and severe as < 6/60. RESULTS: There were no significant differences in age, sex, or vision status between NEI-VFQ-25 responders and non-responders. Men had significantly better scores in three subscales than women but there were no significant differences in their overall composite scores (men 88.5+/- 0.5; women 88.1+/- 0.4). Persons aged 60-69 years had the best NEI-VFQ-25 profiles (mean composite score +/- standard error, 90.2 +/- 0.5; 50-59 years, 88.5 +/- 0.4; > or =70 years, 86.2 +/- 0.8). Presenting bilateral visual impairment (77.1 +/- 1.4) was associated with significantly poorer functioning than unilateral (87.5 +/- 0.8) or no visual impairment (89.4 +/- 0.3). Increasing levels of impairment were associated with poorer levels of visual functioning. The impact of impairment was principally from non-correctable (49.2 +/- 2.6) rather than refractive impairments (85.3 +/- 1.4), although the latter accounted for over three-quarters (77.5%) of presenting bilateral impairment. Non-correctable unilateral impairment (85.3 +/- 1.1) was associated with poorer functioning than no impairment. CONCLUSIONS: The findings from this community-dwelling older population show that the NEI-VFQ-25 differentiates well between various levels of visual impairment with regard to the magnitude of their impact on vision-specific quality of life. Greater impacts were noted among persons with bilateral compared to unilateral impairment, with increasing impacts at greater severities of visual impairment. Visual impairment from refractive errors is more frequent than from underlying pathologic disorders, but the impact of correctable visual impairment was considerably milder than the impact of non-correctable visual impairment.

Causes and associations of amblyopia in a population-based sample of 6-year-old Australian children.

OBJECTIVES: To describe the prevalence of amblyopia and associated factors in a representative sample of 6-year-old Australian children. METHODS: Logarithm of minimum angle of resolution visual acuity (VA) was measured in both eyes before and after pinhole correction, correcting cylindrical refractive components greater than 0.50 diopter (D), and with spectacles (if worn) in a population-based sample of 1741 schoolchildren. Retinal pathological abnormalities were excluded based on photographs. Amblyopia was defined using various best-available corrected VA measures in the absence of significant organic pathological abnormalities. RESULTS: Using the criteria of corrected VA less than 20/40 and at least a 2-line difference between eyes, amblyopia was diagnosed in 13 children (0.7%). The inclusion of children with amblyopia who had been successfully treated (n = 19) increased the amblyopia prevalence to 1.8%. Strabismus or strabismus surgery history was present in 37.5% of the children with amblyopia, anisometropia in 34.4%, both conditions in 18.8%, and isoametropia in 6.3%. Mean corrected VA in amblyopic eyes was 37.7 logarithm of minimum angle of resolution letters (Snellen VA equivalent < 20/40), ranging from 0 to 48 logarithm of minimum angle of resolution letters (Snellen VA equivalent < 20/200-20/25). Most amblyopic eyes (58.7%) were significantly hyperopic (spherical equivalent > or = +3.00 D); 8.7% were myopic. CONCLUSIONS: A relatively low prevalence of amblyopia in a sample of 6-year-old children is documented. The majority of these children had already been diagnosed and treated for this condition.

Accuracy of the Lang II stereotest in screening for binocular disorders in 6-year-old children.

PURPOSE: To assess the accuracy of the Lang II stereotest in screening for strabismus, amblyopia, and anisometropia in 6-year-old children. DESIGN: Cross-sectional population-based study. METHODS: The Sydney Myopia Study examined 1765 6-year-old children (78.9% of eligible) who were identified by random cluster sampling of 34 schools in Sydney, Australia. Sensitivity and specificity of the Lang II stereotest was determined by best stereoacuity. Cycloplegic autorefraction, assessment of visual acuity, and ocular motility were conducted. RESULTS: Test sensitivity ranged from 21.4% for anisometropia (> or =1.0 diopter) to 31.3% for amblyopia. The detection rate for new cases of amblyopia ranged from 20% to 40%; the detection rate for new cases of strabismus was 30%. Specificity was >98% in all three conditions. Children with false-negative results included newly diagnosed cases of strabismus (14 of 25 children) or amblyopia (5 of 12 children). CONCLUSION: The Lang II stereotest, when used alone, has very limited value as a screening test of binocular dysfunction.

Effect of stature and other anthropometric parameters on eye size and refraction in a population-based study of Australian children.

PURPOSE: To determine the effect of anthropometric parameters on refraction and ocular biometry. METHODS: Noncontact methods were used to examine ocular dimensions and cycloplegic refraction in a stratified random cluster sample of year-1 Sydney school students (mean age, 6 years; n = 1765). Height, body weight, and waist circumference were measured according to a standardized protocol. Body mass index (BMI) was subsequently calculated. The percentage of body fat was measured with leg-leg bioelectrical impedance analysis. Associations between parameters were analyzed by multiple linear regression. RESULTS: After adjustment for age in weeks, height was found to be strongly associated with axial length and corneal radius. Children in the 1st quintile for height had axial length of 22.39 +/- 0.04 mm compared with 22.76 +/- 0.04 mm in children in the 5th quintile. Other anthropometric parameters were not associated with axial length or corneal radius. Height was not associated with anterior chamber depth after adjustment for weight. Increases in weight, BMI, and waist circumference were associated with a deeper anterior chamber after adjustment for height. No associations were found between the measured anthropometric parameters and refraction or axial length-corneal radius ratio. CONCLUSIONS: This study found a strong association between height and axial length and corneal radius, but not spherical equivalent refraction. The findings may demonstrate the effectiveness of emmetropization in the presence of normal physiological influences.

Impact of birth parameters on eye size in a population-based study of 6-year-old Australian children.

PURPOSE: To study the effect of birth parameters, including birth weight, birth length, and birth head circumference on ocular dimensions in 6-year-old children. DESIGN: Cross-sectional study. METHODS: A stratified random cluster sample of 6-year-old Sydney school-students (n = 1765) were participants in this study. Children had ocular dimensions measured with non-contact methods (Zeiss IOLMaster, Zeiss, Meditec-AG, Jena, Germany). Information on birth weight, height, and head circumference was derived from a questionnaire. RESULTS: After adjusting for cluster, age, and gender, children with birth weight <2500 g had mean axial length 22.46 mm (95% confidence interval [CI], 22.20-22.72) and mean corneal radius 7.70 mm (CI 7.61-7.79). This compared with axial length 22.80 mm (CI 22.70-22.90) and mean corneal radius 7.85 mm (CI 7.81-7.89) for children with birth weight > or =4000 g. Axial length and corneal radius were also related to birth length and head circumference. Refraction, however, was unrelated to birth size. CONCLUSION: Birth parameters have a lasting effect on eye size but not on spherical equivalent refraction.

Distribution of ocular biometric parameters and refraction in a population-based study of Australian children.

PURPOSE: To study the distribution of spherical equivalent refraction and ocular biometric parameters in a young Australian population. METHODS: Noncontact methods were used to examine ocular dimensions and cycloplegic autorefraction in a stratified random cluster sample of year 1 Sydney school students (n = 1765), mean age 6.7 years (range, 5.5-8.4 years). Repeated measures of axial length, anterior chamber depth, and greatest and least corneal radius of curvature (CR1, CR2, respectively) were taken in each eye. Refraction was measured as the spherical equivalent. RESULTS: Mean spherical equivalent refraction in right eyes was +1.26 +/- 0.03 D (SEM; range, -4.88 to +8.58). The distribution was peaked (kurtosis 14.4) and slightly skewed to the right (skewness, 1.7). Prevalence of myopia, defined as spherical equivalent refraction < or = -0.5 D, was 1.43% (95% CI, 0.94-2.18) in the overall population. Axial length, anterior chamber depth, and corneal radii of curvature were normally distributed. The mean axial length in right eyes was 22.61 +/- 0.02 mm (SEM; range, 19.64-25.35). The mean anterior chamber depth was 3.34 +/- 0.01 mm (SEM; range, 2.14-4.06). Mean CR1 was 7.85 +/- 0.01 mm (SEM) and mean CR2 was 7.71 +/- 0.01 mm (SEM). The distribution of axial length/mean corneal radius ratio was peaked (leptokurtic) with a mean of 2.906. Mean axial length was longer, anterior chambers were deeper, and corneas were flatter in the boys. CONCLUSIONS: A peaked (leptokurtic) distribution of spherical equivalent refraction was present in this predominantly hyperopic 6-year-old population. The results also showed that ocular biometric measures were normally distributed, with statistically significant gender differences found in measurements.

Visual acuity and the causes of visual loss in a population-based sample of 6-year-old Australian children.

PURPOSE: To describe the distribution of visual acuity and causes of visual loss in a representative sample of Australian schoolchildren. DESIGN: Population-based cross-sectional study. PARTICIPANTS: One thousand seven hundred thirty-eight predominantly 6-year old children examined during 2003 to 2004. METHODS: Logarithm of the minimum angle of resolution (logMAR) visual acuity was measured in both eyes before and after pinhole correction and with spectacles if worn. Cycloplegic autorefraction (cyclopentolate) and detailed dilated fundus examination were performed. MAIN OUTCOME MEASURES: Visual impairment was defined as any (visual acuity <20/40; <40 letters) or severe (visual acuity < or =20/200; 0-5 letters) for both better and worse eyes. Myopia was defined as spherical equivalent (SE) refraction < or =-0.50 diopters (D), and hyperopia as SE refraction > or =+2.0 D, deemed significant when > or =+3.0 D. Astigmatism was defined as cylinder > or =1.0 D and anisometropia as SE refraction difference between eyes at least 1.0 D. Amblyopia was defined as corrected visual acuity <0.3 logMAR units (<20/40; <40 letters) in the affected eye not attributable to any underlying structural abnormality of the eye or visual pathway, together with a 2-logMAR line difference between the eyes and presence of an amblyogenic risk factor. RESULTS: The mean visual acuity of this sample was 20/25 (49.3 letters). Uncorrected visual impairment was found in the better eye of 23 children (1.3%) and in the worse eye of 71 children (4.1%). The prevalence was higher in girls than boys and among children of lower socioeconomic status. Refractive error was the most frequent cause, accounting for 69.0%, followed by amblyopia (22.5%). Astigmatism was the principle refractive error causing visual impairment and was frequently uncorrected. Presenting visual impairment (using current glasses if worn) was found in the better and worse eyes of 15 children (0.9%) and 54 children (2.8%), respectively. This was mainly due to under corrected or uncorrected refractive error. CONCLUSIONS: This study has documented a relatively low prevalence of visual impairment in a population of Australian children. Uncorrected astigmatism and amblyopia were the most frequent causes.

Methods for a population-based study of myopia and other eye conditions in school children: the Sydney Myopia Study.

PURPOSE: The Sydney Myopia Study will establish the prevalence of myopia and other eye diseases in a large representative sample of Sydney school children. It will also examine the relationship between myopia and potential modifiable risk factors and will assess potential gene-environment interactions by examining parents and siblings. METHODS: The target population is a stratified random cluster sample of 1750 Year 1 (age 6 years) and 1500 Year 7 (age 12 years) students from Sydney metropolitan schools. Procedures (comprehensive parent-administered questionnaire and examination) involve standardized protocols to allow for comparison with international population-based data. Examinations include a detailed assessment of visual acuity, cover testing for strabismus, identification of amblyopia, slit-lamp examination, non-contact ocular biometry and cycloplegia (cyclopentolate) followed by autorefraction, optical coherence tomography, retinal thickness measurement, digital mydriatic retinal photography and aberrometry. CONCLUSIONS: The Sydney Myopia Study design and methodology will ensure valid findings on ocular development and health in a large representative sample of Sydney school children, for comparison with other population-based refraction data.

Anterior uveitis in a child with Takayasu's arteritis.

Takayasu's arteritis is a rare idiopathic arteriopathy that produces narrowing and eventually closure of affected blood vessels. Ocular symptoms typically occur late in the disease process in those individuals who have severe involvement of the aortic arch and the carotid arteries. Visual loss typically occurs as a result of either systemic hypertension or concomitant ocular hypo-perfusion. We describe an unusual case of Takayasu's arteritis presenting in a child who complained of painful blurred vision. In this individual, no carotid artery disease was identified on vascular imaging and no evidence of impairment of ocular perfusion was demonstrable. Vision loss in this instance was due to anterior uveitis and cystoid maculopathy. These are atypical and rarely described features of Takayasu's arteritis. The patient responded well to anti-inflammatory treatment and his symptoms resolved. The clinical significance of these findings are discussed and the relevant literature reviewed.