United States

Purpose: 
The 13-lined ground squirrel (13-LGS), a cone-dominant hibernator, has emerged as an accessible animal model for vision research. Induction of cone degeneration through exposure to cytotoxic chemicals has revealed variable effectiveness in the 13-LGS. Here, we sought to examine how the time of year (relative to hibernation emergence) influenced the degree of cone damage in 13-LGS following intravitreal injection of adenosine triphosphate (ATP).

Methods: 
Eighteen (9M,9F) 13-LGS were placed into three active season experimental groups, early-season (N=6), mid-season (N=6), and late-season (N=6), to determine the time of intravitreal ATP injection. Each animal underwent baseline imaging OU using near-infrared reflectance and short wavelength autofluorescence scanning light ophthalmoscopy (SLO) as well as optical coherence tomography (OCT). Animals then received a 10µL intravitreal injection of 0.723M ATP in one eye, followed by OCT and SLO imaging at 1, 3, 10, and 21 days post-injection. Among mid-season and late-season animals where no retinal damage was observed in follow-up imaging, adaptive optics SLO (AOSLO) was performed. Retinal thickness and cone density measures from the late-season cohort were compared to values from a control group of wild-type animals (N=12 eyes, OCT; N=6 eyes, AOSLO).

Results: 
Five animals showed retinal damage following ATP injection, including 4/6 early-season, 0/6 mid-season, &amp; 1/6 late-season (Fisher’s exact test, p= 0.065). A two-way ANOVA showed significant differences in axial length between early-season &amp; mid/late season cohorts (p = 0.029; p = 0.035). All animals with retinal damage displayed lesions on SLO and disrupted retinal lamination on OCT. Follow-up imaging with AOSLO on mid-season and late-season animals without observed retinal damage showed no evidence of photoreceptor disruption at any of the 97 ROIs analyzed. In late-season animals, 518 of 528 eccentricity matched locations imaged by OCT were within the normative range (mean +/- 2SD) from the control group, consistent with no ATP-induced damage.

Conclusions:
The 13-LGS retina may be more susceptible to retinal damage by intravitreal ATP injection during the early season. However, differences in both axial length and vitreous volume between groups may impact the effective dose. Future studies adjusting dose based on ocular biometry may help elucidate the impact of time of year on chemical response.

AMA Research Challenge 2022

ATP-induced retinal damage in cone-dominant 13-lined ground squirrel throughout euthermia

Purpose: 
The 13-lined ground squirrel (13-LGS), a cone-dominant hibernator, has emerged as an accessible animal model for vision research. Induction of cone degeneration through exposure to cytotoxic chemicals has revealed variable effectiveness in the 13-LGS. Here, we sought to examine how the time of year (relative to hibernation emergence) influenced the degree of cone damage in 13-LGS following intravitreal injection of adenosine triphosphate (ATP).

Methods: 
Eighteen (9M,9F) 13-LGS were placed into three active season experimental groups, early-season (N=6), mid-season (N=6), and late-season (N=6), to determine the time of intravitreal ATP injection. Each animal underwent baseline imaging OU using near-infrared reflectance and short wavelength autofluorescence scanning light ophthalmoscopy (SLO) as well as optical coherence tomography (OCT). Animals then received a 10µL intravitreal injection of 0.723M ATP in one eye, followed by OCT and SLO imaging at 1, 3, 10, and 21 days post-injection. Among mid-season and late-season animals where no retinal damage was observed in follow-up imaging, adaptive optics SLO (AOSLO) was performed. Retinal thickness and cone density measures from the late-season cohort were compared to values from a control group of wild-type animals (N=12 eyes, OCT; N=6 eyes, AOSLO).

Results: 
Five animals showed retinal damage following ATP injection, including 4/6 early-season, 0/6 mid-season, & 1/6 late-season (Fisher’s exact test, p= 0.065). A two-way ANOVA showed significant differences in axial length between early-season & mid/late season cohorts (p = 0.029; p = 0.035). All animals with retinal damage displayed lesions on SLO and disrupted retinal lamination on OCT. Follow-up imaging with AOSLO on mid-season and late-season animals without observed retinal damage showed no evidence of photoreceptor disruption at any of the 97 ROIs analyzed. In late-season animals, 518 of 528 eccentricity matched locations imaged by OCT were within the normative range (mean +/- 2SD) from the control group, consistent with no ATP-induced damage.

Conclusions:
The 13-LGS retina may be more susceptible to retinal damage by intravitreal ATP injection during the early season. However, differences in both axial length and vitreous volume between groups may impact the effective dose. Future studies adjusting dose based on ocular biometry may help elucidate the impact of time of year on chemical response.

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Charles Lopresto, DO

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Background
Photophobia in the pediatric population is an uncommon complaint in the ophthalmology office, but one that can be debilitating for the patient and a cause of much consternation for the provider. In a prior retrospective review of 36 pediatric patients presenting with a primary complaint of photophobia, 25 of these children (69.4%) left the clinic without a diagnosis.1 In this study, we seek to better understand why so many children leave the office without a specific cause.

Methods
We performed a new retrospective study of patients less than eighteen years old presenting with a primary complaint of photophobia between July 1, 2016 and August 6, 2021. We documented the demographics, pertinent past medical history, diagnoses, and treatments of this population.

Results
Three hundred four pediatric charts from the University of Utah Ophthalmology and Optometry clinics were identified, and one hundred twenty-five unique patients were included for analysis. Migraine headache was the most common identified cause of pediatric photophobia (29.6%) followed by eyelid inflammation/abnormality (7.2%), but frequently a cause is not identified (30.4%). High morbidity and vision threatening conditions including pediatric glaucoma, inherited retinal disease, and intracranial masses were occasionally implicated (3.2%). Treatment is generally symptomatic with tinted lenses (47.2%), but often no treatment is proffered (21.6%) and the patient was simply observed.

Conclusion
Although many neurologists and headache specialists may be aware of the most common causes of photophobia in children and adults, many ophthalmologists remain unaware of these causes. Migraine is the most common cause of photophobia identified (29.6%), but approximately one-third remains without an identifiable cause (30.4%), and the remainder has an alternative identifiable cause (40.0%). Because of this significant knowledge gap, we are developing a curriculum to teach providers how to address photophobia in their patients.

Causes of Photophobia in Children Evaluated at a Tertiary Eye Center

New technology has allowed for infrared imaging of the meibomian glands, but a standardized method of image analysis has not been uniformly adopted. This is a verification study and comparison of two commonly-utilized analysis methods, the Meiboscore method and Line Tracing (LT) method, applied to images taken using the TearScience® LipiView® II Ocular Surface Interferometer (Johnson & Johnson Vision Care, Inc., New Brunswick).

Challenges and drawbacks of meibography analysis: Meiboscore versus Line Tracing method

Comparing FA and OCTA evaluation of retinal vascularity of murine eyes with diabetic retinopathy with Contrast-Limited Adaptive Histogram Equalization (CLAHE) and Matched Filter Image Processing Technique

Background: 
Dry Eye Syndrome (DES) is a multifactorial disorder of the ocular surface, characterized by inadequate moisture and subsequent discomfort, pain, or visual disturbances. DES is associated with increased corneal dendritic cell (DC) density, a marker of inflammation. Treatments proposed to decrease inflammation in DES currently lack quantitative evidence. This study investigated the effects of cyclosporine eye drops on corneal DC density using in vivo confocal microscopy (IVCM). Our hypothesis is that topical cyclosporine treatment will reduce inflammation as demonstrated by decreased DC density.

Methods:
In this prospective study, central cornea images for DES patients were obtained with IVCM (HRT III RCM). Images were taken prior to and three months after treatment with either cyclosporine 0.05% or 0.09% twice daily in both eyes. A semi-automated cell count software was used to analyze dendritic cells (DCs) in the sub-basal nerve plexus. A student t-test was conducted to compare DC density before and after treatment.

Results:
20 eyes of 10 patients (7 women; mean age 56 ± 22 years) completed the study. 16 eyes and 4 eyes were treated with cyclosporine 0.05% and 0.09% respectively. One eye was excluded due to poor image quality. Mean DC density was 64.63 ± 81.48 cells/mm2 at baseline and 50.36 ± 61.86 cells/mm2 after three months of treatment. There was an average DC density decrease of 14.26 ± 44.95 cells/mm2 after treatment. 12 eyes showed decreased corneal DC density and 7 eyes showed either no detectable change or increased DC density. For eyes treated with cyclosporine 0.05% and 0.09%, the mean difference between baseline and post-intervention was a non-statistically significant decrease of 3.00 ± 25.56 cells/mm2 (p=0.92) and 56.50 ± 77.87 cells/mm2 (p=0.24) respectively.

Conclusion: 
Topical cyclosporine is known to be effective in treating DES, but its microstructural effects on ocular surface inflammation have not been quantified. In this study, IVCM was used to quantify cyclosporine’s effects on reducing corneal DC density in dry eyes. Further investigation is necessary to elucidate this potentially dose-related effect.

Effect of Topical Cyclosporine on Dendritic Cell Density in Patients with Dry Eye Syndrome Using In Vivo Confocal Microscopy

Abstract Title: Morphological and Vascular Features of the Optic Nerve in Healthy Asians

Background: Glaucoma is the second leading cause of blindness worldwide, impacting nearly 3 million patients in the US and 80 million globally. Glaucoma is characterized by progressive optic neuropathy, which leads to structural and vascular damage to the optic nerve (ON) and retina. A novel technology, known as optical coherence tomography angiography (OCTA), captures both the structure and vascular features of the retina and ON. Previous studies have indicated that blacks with large optic discs (ODs) experience a more severe form of glaucoma. Information about OD size and glaucoma in Asians is not well documented. Therefore, the aim of our study was to evaluate morphological and vascular features of the OD in healthy South Asian (SA India), East Asian (EA- China), and Southeast Asian (SEA- Vietnam) patients using OCTA scans.

Methods: In this IRB approved, retrospective, age-matched study conducted at an academic center, we reviewed OCTA scans from 76 healthy subjects who were self-identified as SA, SEA, or EA. Exclusion criteria included high myopia/hyperopia, poor scan quality and vitreoretinal disorders. We measured mean disc area, rim area, cup/disc ratio, and vessel densities on the ON. Data was analyzed with pairwise Student’s two-tailed t-tests.

Results: After exclusions, 46 patients [33 (62 eyes) SA, 4 (8 eyes) EA, 9 (16 eyes) SEA] were included. The mean disc vertical size of SEA was higher than SA (1.84mm vs. 1.73mm, p=0.016). The mean disc area in SEA was higher than that in SA (2.49mm² vs. 2.25mm², p=0.024). There were no differences in measurements between SA and EA or EA and SEA. Peripapillary vessel density was significantly higher in SA than in EA (52.2% vs. 50.2%, p=0.036). All other measurements were not significant.

Conclusion: Our pilot study has shown that disc area and disc vertical size are greater in SEA than SA, potentially making them more prone to glaucomatous damage. We believe that these OD ethnic differences, if further investigated, could serve as early markers of glaucoma in healthy Asian eyes.

Morphological and Vascular Features of the Optic Nerve in Healthy Asians

Purpose: To describe OCT findings in pediatric uveitis patients and analyze visual acuity changes over time.

Methods: A retrospective chart review of pediatric patients (0 to 18 years old) seen at the Emory Eye Center between 2008 and June 2020 with a diagnosis of uveitis and OCT imaging available was conducted. Data collected included demographic data, uveitis etiology, anatomical uveitis location, best-corrected visual acuity (BCVA), findings on OCT, and treatment.

Results: There were 204 patients and 327 eyes with a diagnosis of pediatric uveitis and at least one OCT on record. The average age was 11.5 years with 57% females (116), 43% Black (87) and 33% Caucasian (68). 137 (67%) patients had bilateral uveitis with the majority, 194 (95%), with a non-infectious etiology. Anatomical location of uveitis was anterior, intermediate, anterior/intermediate, posterior, or panuveitis in 42%, 24%, 9%, 10%, and 15% respectively. At baseline on OCT, there were 222 normal eyes, 19 eyes with an epiretinal membrane (ERM), 53 eyes with macular edema, 14 eyes with both macular edema and ERM, and 19 eyes with subretinal fibrosis. On mixed model analysis controlling for the correlation that exists between eyes of the same subject, the worst initial BCVA was seen in eyes with epiretinal membrane and macular edema, followed by macular edema eyes, subretinal fibrosis, and eyes with an ERM with a logMAR BCVA of 0.95, 0.75, 0.73, and 0.50 respectively (p<0.0001). Notably, with most abnormal OCT findings, BCVA improved over 24 months except for ERM eyes, which showed a logMAR BCVA change of 0.50 to 0.60 (p<0.0001). In a sub-analysis of patients with macular edema with or without subretinal fluid (SRF), there was no difference between baseline clinical characteristics or BCVA in patients who had SRF.

Conclusions: OCT imaging in pediatric uveitis is important for diagnosis and monitoring progression of sight- threatening complications. Pediatric uveitis cases show a high proportion of bilateral involvement and prevalence of complications leading to worse BCVA, which demonstrates that prompt treatment and continued monitoring via OCT imaging can prevent ocular sequelae leading to blindness.

Optical coherence tomography (OCT) findings in a pediatric uveitis cohort

Purpose: Orbital exenteration involves removal of the entire orbital contents including the globe. It is typically reserved for orbital malignancies, the incidence of which have increased. This study aims to evaluate the demographics of patients undergoing orbital exenteration, as well as survival based on disease, status of surgical margins, and surgical technique. 

Methods: Retrospective chart review.

Results: Patients undergoing exenteration were on average 62.7 years old, and the majority were male (63.8%). The most common diagnoses were squamous (41.8%), basal (15.4%), and sebaceous cell carcinoma (11.0%). Total exenteration (59.8%) was the most common surgical technique, and reconstruction was most often performed with a skin graft (60.0%). 20.7% of patients demonstrated tumor recurrence and 17.7% showed metastasis. Additionally, 25.3% of patients demonstrated surgical complications on an average of 12.6 months after the procedure. Most patients were treated with adjuvant therapy (57.1%), most of whom underwent radiation therapy (56.3%). Survival was significantly higher amongst basal cell carcinoma and adenoid cystic carcinoma patients than those with mucormycosis (40.4 and 28.5 vs. 1.8 months) (p=.05). Patients with positive surgical margins (39.4%) showed significantly higher tumor recurrence than those without (35.7% vs 9.5%, p<.01). There was no significant difference in survival based on surgical margins or techniques (p>0.5). 

Conclusion: With an aging population, the incidence of invasive orbital and adnexal tumors has increased over time. Our results support prior literature by suggesting that survival is highly dependent on the predisposing disease, and positive surgical margins significantly increase the risk for tumor recurrence and/or metastasis. There was no statistically significant difference in survival based on surgical or reconstruction technique, which suggests we can successfully perform partial exenterations, including lid-sparing surgery, without affecting disease course and survival. Many patients presenting with advanced disease may have a wider range of treatment options in favor of radical surgery.

Orbital Exenteration at Bascom Palmer Eye Institute: 2002-2021

The use of silicone oil (SO) during rhegmatogenous retinal detachment (RRD) surgery allows for prolonged retinal tamponade. While SO removal (SOR) is performed to optimize visual function, there are incompletely defined risks such as re-detachment (re- RD) associated with SOR. The current study characterizes rates of re-RD and functional outcomes following SOR.
Data was retrospectively collected from an urban retina practice with 14 physicians. Inclusion criteria were SO placement (SOP) during an RRD repair followed by SOR from 2016-2021. Exclusion criteria were vitreoretinal surgery performed outside the current practice and post-operative follow-up periods of <3 months. Analyzed parameters included epidemiological data, intraoperative variables, and post-operative outcomes. Statistical analysis included one-way ANOVA with Tukey HSD testing (significance defined as p<0.05).
89 eyes of 88 patients underwent SOR following 31 RRD repair with SOP. 77 of 89 eyes (86.5%) did not undergo further RRD surgery following SOR; of this group, 2 eyes did not achieve reattachment due to persistent subretinal fluid (SRF) and 1 eye underwent enucleation due to Proteus spp. panophthalmitis. Additional RRD repairs were required by 12 of 89 eyes (13.5%); of this group, 2 eyes received gas tamponade while 10 eyes received SOP in re-surgeries. 9 of 10 eyes receiving SOP a second time did not undergo further SOR, while 1 eye proceeded successfully with a second SOR. Only 1 of 12 eyes experiencing an additional RRD repair remained unattached due to persistent SRF. Visual acuity (VA) among eyes without additional RRD repairs following SOR improved by 0.32logMAR from SOR (baseline VA) to final follow-up (p<0.05), while VA among eyes undergoing 31 additional RRD repair minimally improved or worsened from baseline.
This study characterized re-RD rates and visual outcomes among eyes undergoing SOR after RRD repair. VA improvement was observed among eyes that did not undergo additional surgeries following SOR. Further work comparing the risks of re-RD with the functional benefits following SOR may help guide clinical management.

Outcomes of Eyes Undergoing Silicone Oil Removal Following ComplexRhegmatogenous Retinal Detachment Repair

Background: Glaucoma is the second leading cause of blindness affecting over 3 million Americans and 80 million worldwide. Glaucoma is a progressive optic neuropathy affecting both the structure and vascular supply of the optic nerve and retina. Optical Coherence Tomography Angiography (OCTA) is a new non-invasive imaging technique which provides 3D volumetric information on the structure and vascular networks of the optic nerve and retina. However, OCTA artifacts can reduce the quality of scans, and their prevalence is not well known. Therefore, the aim of our study was to investigate the prevalence and severity of OCTA artifacts in healthy (H), ocular hypertension (OHT), glaucoma suspect (GS), primary open angle glaucoma (POAG), and moderate/severe myopia (M) patients.

Methods: In this IRB-approved, retrospective, age-matched study conducted at an academic center, we selected consecutive single-eye OCTA scans in 292 patients (50 H, 30 OHT, 32 GS, 90 POAG, 90 M) between January-June 2021. Patients with severe retinal disease, dementia, tremors, and secondary angle closure glaucoma were excluded. We classified artifacts as either patient-related motion artifacts (MA) or operator/machine-related image artifacts (IA). The artifacts were scored as 1, 0, -1 (none, some, & severe, respectively) and sub-classified within MA (eye movement, blinking, crisscross, and refraction error) and IA (decentration, defocus, projection, segmentation, cropping, and shadow). Chi-square and Cramer's V analysis were utilized to assess differences between groups.

Results: Essentially every patient (99.3%) had at least 1 artifact, and severe artifacts were found in 25.8% of scans. Compared to H, severe artifacts were seen in patients with POAG and M (18% vs. 32.8% and 31.1%, respectively; p < 0.001). The most prevalent artifacts overall were eye movement (66.1%), defocus (64.7%), projection (48.6%), and shadow (40.1%).

Conclusion: Our study is among the first to report prevalence of OCTA artifacts in those with glaucoma or myopia. Although OCTA is a powerful tool in diagnosis and management of glaucoma, a high prevalence of artifacts can limit clinical interpretation. Further research to minimize both patient-related and machine-related artifacts must be conducted.

Prevalence of Artifacts in Optical Coherence Tomography Angiography in Glaucoma and Myopia

Background: Retinal vein occlusion (RVO) is the second most common cause of blindness among retinal vascular diseases. It consists of central retinal artery occlusion (CRAO), central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). While the regional prevalence of RVO in the U.S. is 0.5 to 2 %, the national rate is still unknown. Therefore, we utilized a nationally representative sample collected by the National Health and Nutrition Examination Survey (NHANES) to better estimate the national prevalence and risk factors for
RVO.
Methods: The NHANES is a multi-ethnic study, which surveyed individuals from 30 different counties across the U.S. between 2005-2008. Besides demographic and medical diseases survey, participants underwent 45 degrees non-mydriatic retinal photography of both eyes. Out of 7081 cases, 1552 were excluded due to missing and ungradable images. For the remaining 5559 participants (2771 men and 2788 women), retinal scans were masked and evaluated by graders for the presence of RVO. We performed weighted analysis to estimate national prevalence rates and multivariate analysis to examine associated risk factors. 
Results: Out of 5559 subjects, 33 (20 men and 13 women, 0.59%) had RVO [27 (0.48%) BRVO, and 6 (0.11%) CRVO]. The overall national prevalence of BRVO, CRVO, and any RVO was 0.42% (95% CI = 0.23—0.60), 0.08% (95% CI = 0—0.18), and 0.50% (95% CI = 0.30—0.71), respectively. Multivariate analysis found that age, per 10-year increase (OR, 1.93; 95% CI = 1.31—2.92, P = 0.001) and elevated diastolic blood pressure, per 10 mm Hg increase (OR, 1.47; 95% CI = 1.10—2.12, P = 0.032) were significant risk factors for the prevalence of RVO. Race, gender, history of diabetes, stroke, and cardiovascular disease were not found to be significant risk factors. In univariate analysis glaucoma (P = 0.009) and total cholesterol (P =0.021) were significantly associated with RVO.
Conclusion: Our study found that the overall national prevalence of RVO was 0.50%. In addition, older age and elevated diastolic BP were strongly associated with RVO. We recommend that patients with these characteristics undergo regular comprehensive ocular examination.

Next from AMA Research Challenge 2022

Causes of Photophobia in Children Evaluated at a Tertiary Eye Center

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