Dry Eye Subtypes in the Dry Eye Assessment and Management (DREAM) Study: A Latent Profile Analysis.

Purpose: Dry eye disease (DED) is a heterogeneous condition with poorly characterized subtypes. The DREAM study was a large multicenter randomized clinical trial that did not find omega-3 to be more effective than placebo in treating symptomatic DED. We performed secondary analysis of DREAM data to characterize DED subtypes and their omega-3 response. Methods: A total of 535 patients with moderate-to-severe DED were randomized to omega-3 or placebo treatment for one year. We used latent profile analysis to identify subtypes based on baseline Ocular Surface Disease Index, tear break-up time (TBUT), anesthetized Schirmer's test, corneal and conjunctival staining, and meibomian gland dysfunction (MGD). We evaluated omega-3's effect for each subtype using generalized linear regression. Results: Five clinically meaningful DED subtypes were identified. They differed significantly in sex (P < 0.001) and race (P = 0.02). Subtype 1 had the most severe DED signs yet milder symptoms and was associated with more Sjögren's syndrome (21%, P < 0.001). Subtype 2 had the mildest DED signs except MGD. Subtype 3 had the most severe symptoms, out of proportion to DED signs. Subtype 4 had relatively milder symptoms and MGD. Subtype 5 had severe MGD and TBUT and was associated with rosacea (29%, P = 0.04). Omega-3 was not significantly more beneficial than placebo for any subtype. Conclusions: Five clinically meaningful DED subtypes differed significantly in demographics, symptoms, signs, and systemic disease associations. Omega-3 was not significantly more effective than placebo for any subtype. Translational Relevance: T3 translational research identifying subtypes in the DREAM study can improve DED clinical classification and targeted management.

Once-Daily Low Inflammatory Foods Everyday (LIFE) Smoothie or the Full LIFE Diet Lowers C-Reactive Protein and Raises Plasma Beta-Carotene in 7 Days.

Serum C-reactive protein (CRP), a marker of systemic inflammation, is associated with increased risk for numerous inflammation-driven chronic diseases. A prior longitudinal study showed that the Low Inflammatory Foods Everyday (LIFE) diet, which is rich in dark green leafy vegetables (DGLV), lowered CRP over a mean follow-up period of 6 months. In this retrospective study, we investigate whether patients who consume the LIFE diet or their regular diet plus one component of the LIFE diet (LIFE smoothie), experience reductions in high-sensitivity CRP (hsCRP) in 7 days. Sixteen patients in a community practice met inclusion criteria. Patient compliance was assessed by patient interviews and measurements of beta-carotene, which is abundant in DGLV. Following the interventions, CRP decreased in both the LIFE diet (-0.47 mg/L, P = .02) and smoothie groups (-1.2 mg/L, P = .04). No statistically significant difference in reduction was observed between groups (P = .18). Plasma beta-carotene increased in both groups (+23.2, P = .02; +20.6, P = .006, respectively). These findings suggest that the LIFE diet or a regular American diet supplemented with the LIFE smoothie may quickly reduce systemic inflammation and the risk of many chronic diseases.

Pediatric glaucoma suspects: characteristics and outcomes.

PURPOSE: To determine the characteristics of children diagnosed with glaucoma suspect (GS) status, their clinical outcomes, and risk factors for progression to a diagnosis of glaucoma. METHODS: This was a retrospective sequential cohort study of children <18 years diagnosed as GS between 2013 and 2019, based on clinical (C-GS) and CGRN (CGRN-GS) criteria. Children with penetrating ocular trauma, steroid-response, treated ocular hypertension, and glaucoma at presentation were excluded. Outcomes included glaucoma, treated ocular hypertension, nonglaucomatous cupping (pseudoglaucomatous or physiologic), or persistent GS. Secondary outcomes were characteristics of children who progressed to glaucoma. RESULTS: A total of 887 children (mean age, 9.3 ± 4.7 years) were diagnosed as C-GS, because of optic nerve appearance (83%), family history (25%), ocular hypertension (15%), periocular lesion (4% [eg, Sturge-Weber]), blunt-trauma history (3%), ocular anomaly (2%), and systemic/genetic syndrome (1.5%). Outcomes among 487 children with one or more follow-up visits (mean, 1.7 ± 1.6 years) included 14 (3%) with glaucoma, 98 (20%) with physiologic cupping, 50 (10%) with prematurity-associated cupping, and 1 (0.2%) with treated ocular hypertension; 324 (67%) remained GS. Of children lost to follow-up, 116 (29%) were suspected physiologic or pseudoglaucomatous. Glaucoma diagnosis occurred at a mean age of 8.4 ± 5.5 years, based on elevated intraocular pressure (IOP; 79%), optical coherence tomography changes (43%), disk changes (21%), or field defects (14%). Risk factors for glaucoma were baseline IOP of ≥24 (P = 0.01) and periocular lesion (P = 0.008). Results from 773 children who met CGRN-GS criteria were similar. CONCLUSIONS: Risk of conversion to glaucoma diagnosis among children with glaucoma suspect status appears low. Baseline cup:disk ratio and family history of glaucoma were not predictive of glaucoma diagnosis. Baseline IOP >24 and presence of a periocular lesion carry higher risk.

Effect of Omega-3 on HLA-DR Expression by Conjunctival Cells and Tear Cytokine Concentrations in the Dry Eye Assessment and Management Study.

OBJECTIVES: To determine effect of omega-3 supplementation on conjunctival cell HLA-DR expression and tear concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-17A, interferon-γ, and tumor necrosis factor-α in dry eye disease patients in the Dry Eye Assessment and Management study. METHODS: Patients were randomized to receive a daily dose of eicosapentaenoic and docosahexaenoic acids (ω3) or refined olive oil (placebo) for 12 months. At baseline, 6 and 12 months, HLA-DR expression in conjunctival total, epithelial, and white blood cells and cytokine concentration in tears were determined. Differences in change from baseline between treatment groups were assessed using generalized estimating equations (HLA-DR) or Wilcoxon rank-sum test (cytokines). RESULTS: No differences were observed in HLA-DR expression in total, epithelial, or white blood cells between ω3 and placebo groups at 6 months (n=435) or 12 months (n=436). The median concentration percent change differed between ω3 and placebo groups at 6 months for IL-6 (-36.6 vs. 24.5%, P =0.02, n=75) and for IL-8 (3.7% vs. 72.6%, P =0.02, n=68); at 12 months, they did not differ ( P ≥0.18). No other differences between the treatment groups were detected. CONCLUSIONS: ω3 supplementation did not consistently affect ocular inflammatory status as measured by the frequency of HLA-DR expressing conjunctival cells or tear cytokines.

Associations Between Systemic Omega-3 Fatty Acid Levels With Moderate-to-Severe Dry Eye Disease Signs and Symptoms at Baseline in the Dry Eye Assessment and Management Study.

PURPOSE: Omega-3 (n-3) fatty acid supplementation is used to treat systemic inflammatory diseases, but the role of n-3 in the pathophysiology and therapy of dry eye disease (DED) is not definitive. We evaluated the relationship of systemic n-3 levels with signs and symptoms at baseline in the Dry Eye Assessment and Management (DREAM) Study. METHODS: Blood samples from participants at baseline were analyzed for n-3 and n-6, measured as relative percentage by weight among all fatty acids in erythrocytes. Symptoms were evaluated using the Ocular Surface Disease Index. Signs including conjunctival staining, corneal staining, tear breakup time (TBUT), and Schirmer's test with anesthesia were also evaluated. RESULTS: There was no correlation between the systemic n-3 levels and DED symptoms. When the associations with signs of DED were assessed, lower DHA levels were associated with higher conjunctival staining, with mean scores of 3.31, 2.96, and 2.82 for low, medium, and high levels of DHA, respectively (linear trend P=0.007). None of the other signs were associated with DHA or the other measures of n-3. CONCLUSION: Previous studies have found varying results on the role of n-3 supplementation with the signs and symptoms of DED. Among patients with DED enrolled in the DREAM Study, lower systemic n-3 levels were not associated with worse symptoms and most signs of DED.

ASSOCIATION BETWEEN ORAL IRON SUPPLEMENTATION AND RETINAL OR SUBRETINAL HEMORRHAGE IN THE COMPARISON OF AGE-RELATED MACULAR DEGENERATION TREATMENT TRIALS.

PURPOSE: Because patients often take iron supplements without medical indication, and iron can accumulate in vascular endothelial cells, the authors evaluated the association of oral iron supplementation with retinal/subretinal hemorrhage in patients with neovascular age-related macular degeneration. METHODS: A post hoc secondary data analysis of comparison of age-related macular degeneration treatments trials was performed. Participants were interviewed for use of oral iron supplements. Trained readers evaluated retinal/subretinal hemorrhage in baseline fundus photographs. Adjusted odds ratios from multivariate logistic regression models assessed the association between iron use and baseline hemorrhage adjusted by age, sex, smoking, hypertension, anemia, and use of antiplatelet/anticoagulant drugs. RESULTS: Among 1,165 participants, baseline retinal/subretinal hemorrhage was present in the study eye in 71% of 181 iron users and in 61% of 984 participants without iron use (adjusted odds ratio = 1.47, P = 0.04), and the association was dose dependent (adjusted linear trend P = 0.048). Iron use was associated with hemorrhage in participants with hypertension (adjusted odds ratio = 1.87, P = 0.006) but not without hypertension. The association of iron use with hemorrhage remained significant among hypertensive participants without anemia (adjusted odds ratio = 1.85, P = 0.02). CONCLUSION: Among participants of comparison of age-related macular degeneration treatments trials, the use of oral iron supplements was associated with retinal/subretinal hemorrhage in a dose-response manner. Unindicated iron supplementation may be detrimental in patients with wet age-related macular degeneration.

n-3 Fatty Acid Supplementation for the Treatment of Dry Eye Disease.

BACKGROUND: Dry eye disease is a common chronic condition that is characterized by ocular discomfort and visual disturbances that decrease quality of life. Many clinicians recommend the use of supplements of n-3 fatty acids (often called omega-3 fatty acids) to relieve symptoms. METHODS: In a multicenter, double-blind clinical trial, we randomly assigned patients with moderate-to-severe dry eye disease to receive a daily oral dose of 3000 mg of fish-derived n-3 eicosapentaenoic and docosahexaenoic acids (active supplement group) or an olive oil placebo (placebo group). The primary outcome was the mean change from baseline in the score on the Ocular Surface Disease Index (OSDI; scores range from 0 to 100, with higher scores indicating greater symptom severity), which was based on the mean of scores obtained at 6 and 12 months. Secondary outcomes included mean changes per eye in the conjunctival staining score (ranging from 0 to 6) and the corneal staining score (ranging from 0 to 15), with higher scores indicating more severe damage to the ocular surface, as well as mean changes in the tear break-up time (seconds between a blink and gaps in the tear film) and the result on Schirmer's test (length of wetting of paper strips placed on the lower eyelid), with lower values indicating more severe signs. RESULTS: A total of 349 patients were assigned to the active supplement group and 186 to the placebo group; the primary analysis included 329 and 170 patients, respectively. The mean change in the OSDI score was not significantly different between the active supplement group and the placebo group (-13.9 points and -12.5 points, respectively; mean difference in change after imputation of missing data, -1.9 points; 95% confidence interval [CI], -5.0 to 1.1; P=0.21). This result was consistent across prespecified subgroups. There were no significant differences between the active supplement group and the placebo group in mean changes from baseline in the conjunctival staining score (mean difference in change, 0.0 points; 95% CI, -0.2 to 0.1), corneal staining score (0.1 point; 95% CI, -0.2 to 0.4), tear break-up time (0.2 seconds; 95% CI, -0.1 to 0.5), and result on Schirmer's test (0.0 mm; 95% CI, -0.8 to 0.9). At 12 months, the rate of adherence to treatment in the active supplement group was 85.2%, according to the level of n-3 fatty acids in red cells. Rates of adverse events were similar in the two trial groups. CONCLUSIONS: Among patients with dry eye disease, those who were randomly assigned to receive supplements containing 3000 mg of n-3 fatty acids for 12 months did not have significantly better outcomes than those who were assigned to receive placebo. (Funded by the National Eye Institute, National Institutes of Health; DREAM ClinicalTrials.gov number, NCT02128763 .).

The Role of the Human Visual Cortex in Assessment of the Long-Term Durability of Retinal Gene Therapy in Follow-on RPE65 Clinical Trial Patients.

PURPOSE: Gene therapy (GT) has offered immense hope to individuals who are visually impaired because of RPE65 mutations. Although GT has shown great success in clinical trials enrolling these individuals, evidence for stability and durability of this treatment over time is still unknown. Herein we explored the value of functional magnetic resonance imaging (fMRI) as an objective measure to assess independently the longevity of retinal GT. DESIGN: Individuals with RPE65 mutations who underwent GT in their worse-seeing eye in a phase 1 clinical trial received a second subretinal injection in their contralateral eye in a follow-on clinical trial. Functional magnetic resonance imaging (MRI) was performed longitudinally to assess brain responses of patients with RPE65 mutations after stimulation of their most recently treated eye before and 1 to 3 years after GT. PARTICIPANTS: Seven participants with RPE65 mutations who were part of the follow-on clinical trial gave informed consent to participate in a longitudinal neuroimaging fMRI study. METHODS: All participants underwent fMRI using a 3-Tesla MRI system and a 32-channel head coil. Participants' cortical activations were assessed using a block design paradigm of contrast reversing checkerboard stimuli delivered using an MRI-compatible video system. MAIN OUTCOME MEASURES: The primary parameters being measured in this study were the qualitative and quantitative fMRI cortical activations produced by our population in response to the visual task. RESULTS: Functional MRI results showed minimal or no cortical responses before GT. Significant increase in cortical activation lasting at least 3 years after GT was observed for all participants. Repeated measures analysis showed significant associations between cortical activations and clinical measures such as full-field light sensitivity threshold for white, red, and blue colors; visual field; and pupillary light reflex. CONCLUSIONS: Participants with RPE65 mutations showed intact visual pathways, which became responsive and strengthened after treatment. Functional MRI results independently revealed the efficacy and durability of a 1-time subretinal injection. The fMRI results paralleled those recently reported during the long-term clinical evaluations of the same patients. Results from this study demonstrated that fMRI may play an important role in providing complementary information to patients' ophthalmic clinical evaluation and has usefulness as an outcome measure for future retinal intervention studies.

Characteristics of incident geographic atrophy in the complications of age-related macular degeneration prevention trial.

OBJECTIVE: To characterize the size, location, conformation, and features of incident geographic atrophy (GA) as detected by annual stereoscopic color photographs and fluorescein angiograms (FAs). DESIGN: Retrospective cohort study within a larger clinical trial. PARTICIPANTS: Patients with bilateral large drusen in whom GA developed during the course of the Complications of Age-related Macular Degeneration Prevention Trial (CAPT). METHODS: Annual stereoscopic color photographs and FAs were reviewed from 114 CAPT patients in whom GA developed in the untreated eye during 5 to 6 years of follow-up. Geographic atrophy was defined according to the Revised GA Criteria for identifying early GA.(23) Color-optimized fundus photographs were viewed concurrently with the FAs during grading. MAIN OUTCOME MEASURES: Size and distance from the fovea of individual GA lesions, number of areas of atrophy, and change in visual acuity (VA) when GA first developed in an eye. RESULTS: At presentation, the median total GA area was 0.26 mm(2) (0.1 disc area). Geographic atrophy presented as a single lesion in 89 (78%) eyes. The median distance from the fovea was 395 µm. Twenty percent of incident GA lesions were subfoveal and an additional 18% were within 250 µm of the foveal center. Development of GA was associated with a mean decrease of 7 letters from the baseline VA level compared with 1 letter among matched early age-related macular degeneration eyes without GA. Geographic atrophy that formed in areas previously occupied by drusenoid pigment epithelial detachments on average were larger (0.53 vs. 0.20 mm(2); P = 0.0001), were more central (50 vs. 500 µm from the center of the fovea; P<0.0001), and were associated with significantly worse visual outcome (20/50 vs. 20/25; P = 0.0003) than GA with other drusen types as precursors. CONCLUSIONS: Incident GA most often appears on color fundus photographs and FAs as a small, singular, parafoveal lesion, although a large minority of lesions are subfoveal or multifocal at initial detection. The characteristics of incident GA vary with precursor drusen types. These data can facilitate design of future clinical trials of therapies for GA. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial.

BACKGROUND: Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. METHODS: We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years. FINDINGS: AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. INTERPRETATION: The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. FUNDING: Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

Evaluation of actual vs expected photodynamic therapy spot size.

PURPOSE: To determine the accuracy of the photodynamic therapy (PDT) laser spot size on the retina as generated by 2 Food and Drug Administration (FDA)-approved lasers. DESIGN: Prospective observational case series. METHODS: Fundus photographs were taken of 1 eye of each of 10 subjects with the WinStation 4000 fundus photography system (OIS; Ophthalmic Imaging Systems, Sacramento, California, USA); disc size was calculated using OIS software. Slit-lamp photographs were taken of the PDT laser spot focused on the retina adjacent to the optic disc, using various spot sizes in combination with 3 different contact lenses and 2 different lasers. Spot size at the retina was determined by measuring the ratio of disc diameter to spot diameter in Adobe Photoshop (San Jose, California, USA) and applying this ratio to the OIS disc measurements. RESULTS: Spot size at the retina averaged 87% of expected spot size for the Coherent Opal laser (Coherent Inc, Santa Clara, California, USA) and 104% of expected spot size for the Zeiss Visulas laser (Carl Zeiss Meditec Inc, Dublin, California, USA)(P = .002). Multivariate analysis demonstrated that percentage of expected spot size decreased with larger spot diameter (P = .01 for Coherent laser; P = .02 for Zeiss laser). CONCLUSIONS: PDT spot size at the retina appears to be consistently smaller than expected for the Coherent laser while the spot size was consistently within 10% of expected size for the Zeiss laser. The deviation from expected size increased with larger spot size using the Coherent laser.

Retinal temperature increase during transpupillary thermotherapy: effects of pigmentation, subretinal blood, and choroidal blood flow.

PURPOSE: To study the risk of adverse events in transpupillary thermotherapy (TTT) for age-related macular degeneration by measuring how laser-induced retinal temperature increase is affected experimentally by subretinal blood, choroidal blood flow, and chorioretinal pigmentation. METHODS: An ultrafine thermocouple technique was developed to measure retinal temperature increase during TTT in albino and pigmented rabbit eyes. TTT was performed with 60-second, 0.78-mm spot size, 810-nm infrared diode laser exposures with power settings ranging from 50 to 950 mW. Intraretinal and subretinal temperature increases were measured in pigmented and albino rabbits, with or without subretinal blood and choroidal blood flow. RESULTS: Threshold power settings for visible lesions in albino and pigmented rabbits were 950 and 90 mW, respectively, corresponding to retinal temperature increases of 11.8 degrees C and 5.28 degrees C, respectively. Power settings required to produce threshold lesions in albino rabbits caused retinal temperature increases in pigmented rabbits that were five times higher than in the albino rabbits. Temperature increases in albino rabbits were 1.5 times higher with subretinal blood than without it. Choroidal blood flow generally did not affect measured retinal temperature increases. CONCLUSIONS: The results confirm prior theoretical recommendations that clinicians should consider decreasing TTT power settings in darkly pigmented eyes and proceed with caution in those with subretinal hemorrhage or pigment clumping.