Association between macrophage-like cell density and ischemia metrics in diabetic eyes.

We previously showed that macrophage-like cells (MLCs) are increased in eyes with advanced diabetic retinopathy (DR). Here, we hypothesized that MLC density was correlated with ischemia using optical coherence tomography angiography (OCTA) and ultra-widefield fluorescein angiography (UWF-FA). Treatment-naïve diabetic eyes were prospectively imaged with repeated OCTA (average 5.3 scans per eye) and UWF-FA imaging. OCTA images were registered and averaged to generate a superficial capillary plexus (SCP), deep capillary plexus (DCP), and MLC slab. We calculated geometric perfusion deficit (GPD), vessel length density, and vessel density for the SCP and DCP. MLC density was quantified by two masked graders and averaged. Ischemia on UWF-FA was measured to generate a non-perfusion area (NPA) and index (NPI). Since MLC density was non-parametrically distributed, MLC density was correlated with ischemia metrics using Spearman correlations. Forty-five treatment-naïve eyes of 45 patients (59 ± 12 years of age; 56% female) were imaged. We included 6 eyes with no DR, 7 eyes with mild non-proliferative DR (NPDR), 22 moderate NPDR, 4 severe NPDR, and 6 PDR eyes. MLC density between graders was highly correlated (r = 0.9592, p < 0.0001). MLC density was correlated with DCP GPD (r = 0.296, p = 0.049), but no other OCTA ischemia metrics. MLC density was also correlated with UWF-FA NPA (r = 0.330, p = 0.035) and NPI (r = 0.332, p = 0.034). MLC density was correlated with total ischemia on UWF-FA and local DCP GPD. Since both UWF-FA and DCP non-perfusion are associated with higher risk for DR progression, MLC density could be another potential biomarker for DR progression.

Direct Injection of 5-Fluorouracil Improves Outcomes in Cicatrizing Conjunctival Disorders Secondary to Systemic Disease.

PURPOSE: Conjunctival cicatrizing conditions are vision threatening, with poor outcomes despite aggressive systemic therapy. This study tests the utility of serial injections of 5-fluorouracil (5-FU) into the fornices to treat conjunctival scarring in patients with ocular cicatricial pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis. METHODS: Retrospective cohort study. Fisher exact test and multivariable logistic regression analyses were used to compare clinical outcomes of patients who were administered 5-FU injections versus patients who were not injected. Model fit was examined for multivariable regression. RESULTS: One hundred twelve eyes (56 patients) met the inclusion criteria. Thirty-eight eyes (34%) had Stevens-Johnson syndrome/toxic epidermal necrolysis, and 74 eyes (66%) were diagnosed with ocular cicatricial pemphigoid. Twenty-five eyes received ≥1 injection of 5-FU. Sixteen eyes received 1-4 injections, while 9 received ≥5. Median follow-up until last encounter was 18 months. Analysis of each disease entity alone and in combination revealed that 5-FU injections were associated with improvement in final visual acuity, corneal scarring, trichiasis, need for/number of mucous membrane graft surgeries, and severity of symblephara. CONCLUSIONS: Serial injection of 5-FU in the affected fornices is a promising treatment for severe vision-threatening conjunctival scarring from ocular cicatricial pemphigoid and Stevens-Johnson syndrome/toxic epidermal necrolysis. Given the excellent safety profile of 5-FU around the eye, the solid biologic foundation for using 5-FU in this setting, and the severe risk of vision loss from these disorders, the authors suggest that serial 5-FU injections be adopted as therapy for conjunctival scarring from ocular cicatricial pemphigoid or Stevens-Johnson syndrome/toxic epidermal necrolysis despite the limitations of this retrospective study.

Serum Vitamin D Deficiency Is an Independent Risk Factor for Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) is an inflammatory orbitopathy with significant impact on visual function and quality of life. Although studies have shown that patients who are deficient in vitamin D are more likely to develop autoimmune conditions, there are no studies demonstrating a definitive correlation between serum 25-hydroxyvitamin D (25(OH)D) deficiency and an increased risk of TED. METHODS: This retrospective case-control study compared serum 25(OH)D levels among 4 groups: 1) Graves disease (GD) patients with TED (n = 89); 2) GD patients without TED (n = 89); and healthy control patients matched to 3) the TED group (n = 356); and 4) the GD group (n = 356). The authors compared 25(OH)D level in the TED group measured within 1 year of TED diagnosis to the most recently measured 25(OH)D level in the GD group using Student t test of the log transformation of serum levels. Linear regression was used to control for other risk factors. Thyroid eye disease patients and GD patients were compared separately to their matched healthy control patients with linear mixed models. RESULTS: Thyroid eye disease patients displayed significantly lower serum 25(OH)D levels than GD patients (24.8 ± 13.2 ng/ml vs. 29.4 ± 13.3 ng/ml; p = 0.006). Controlling for smoking status and previous radioactive iodine treatment did not affect this statistically significant difference. CONCLUSIONS: Low serum vitamin D is associated with TED diagnosis. Assessing and supplementing vitamin D levels may be an important addition to the early management of GD patients. Future research should include longitudinal studies and prospective clinical trials to further explore the mechanism responsible for the observed association.Thyroid eye disease is an inflammatory orbitopathy associated with Graves disease. Vitamin D is a known immune system regulator. The authors show that vitamin D deficiency is associated with the development of thyroid eye disease.

Stereotactic Navigation Improves Outcomes of Orbital Decompression Surgery for Thyroid Associated Orbitopathy.

PURPOSE: To test whether intraoperative stereotactic navigation during orbital decompression surgery resulted in quantifiable surgical benefit. METHODS: This retrospective cohort study examined all consecutive patients who underwent primary orbital decompression surgery for thyroid associated orbitopathy performed by a single surgeon (A.K.) during the periods of 2012-2014 (non-navigated), and 2017-2018 (navigated). The study was HIPAA-compliant, was approved by the Institutional Review Board, and adhered to the tenets of the Helsinki declaration. Recorded parameters included patient age, sex, race, decompression technique (side of operation and walls decompressed), estimated blood loss (EBL), intraoperative complications, times that patient entered and exited the operating room (OR), times of surgical incision and dressing completion, pre- and postoperative best corrected visual acuity (BCVA), proptosis, diplopia, postoperative change in strabismus deviation, and need for subsequent strabismus surgery. Recorded times were used to calculate operating time (initial incision to dressing) and maintenance time (time between OR entry and initial incision and time between dressings and OR exit). The total maintenance time was averaged over total number of operations. Student t test was used to compare surgical times, maintenance times, EBL, and proptosis reduction. Fisher exact test was used to compare BCVA change, strabismus deviation change, resolution or onset of diplopia, and need for corrective strabismus surgery. RESULTS: Twenty-two patients underwent primary orbital decompression surgery without navigation, and 23 patients underwent navigation-guided primary orbital decompression surgery. There were no intraoperative complications in either group. The average operative time was shorter in the navigated group for a unilateral balanced decompression (n = 10 vs. 19; 125.8 ± 13.6 vs. 141.3 ± 19.4 min; p-value = 0.019), and a unilateral lateral wall only decompression (n = 13 vs. 3; 80.5 ± 12.8 vs. 93.0 ± 6.1 min; p-value = 0.041). The average maintenance time per surgery was not significantly different between the non-navigated group (51.3 ± 12.7 min) and the navigated group (50.5 ± 6.4 min). There was no significant difference between the navigated and non-navigated groups in average EBL per surgery. There was no significant difference in BCVA change. Average proptosis reduction was larger in the navigated group, but this was not significant. There was a significantly lower proportion of patients who required corrective strabismus surgery following decompression in the navigated group than in the non-navigated group (39.1% vs. 77.3%, p-value = 0.012). CONCLUSIONS: Intraoperative stereotactic navigation during orbital decompression surgery has the potential to provide the surgeon with superior spatial awareness to improve patient outcomes. This study found that use of intraoperative navigation reduced operative time (even without factoring in a resident teaching component) while also reducing the need for subsequent strabismus surgery. This study is limited by its size but illustrates that use of intraoperative navigation guidance has substantive benefits in orbital decompression surgery.

Normative Exophthalmometry Measurements Vary Among Ethiopian Adults and the Major Ethiopian Ethnic Groups.

PURPOSE: Periocular and orbital anthropometric values vary among races. No studies have established normative exophthalmometry values for Ethiopians or the many Ethiopian ethnic groups. This study established a set of normative anthropometric values for exophthalmometry, and further evaluated whether these measurements differed based on sex or ethnic group. METHODS: A cross-sectional study was performed in the ophthalmology department at St. Paul's Hospital in Addis Ababa, Ethiopia. Two hundred ninety-six participants were recruited for the study. Sex, primary Ethiopian ethnic subgroup, and exophthalmometry measurements were recorded. Differences between ethnicities and sexes were evaluated using independent samples t test. RESULTS: Average proptosis for the total cohort was 15.88 ± 2.49 mm, with 582 eyes measured. Females (15.87 ± 2.53, n = 286) and males (15.89 ± 2.49, n = 296) were not significantly different in their proptosis measurements. Within the 3 largest ethnic groups measured, Amhara (16.12 ± 2.67, n = 204), Oromo (15.43 ± 2.51, n = 172), and Gurage (16.23 ± 2.59, n = 98), the difference in proptosis measurement was significant between the Amhara and Oromo groups (p = 0.01), and the Oromo and Gurage groups (p = 0.01). The only ethnic group that was significantly different between sexes was Gurage, of which average female proptosis was 15.51 ± 2.74 (n = 54), while male proptosis was 17.13 ± 2.11 (n = 44) (p < 0.01). CONCLUSIONS: Mean Ethiopian proptosis values vary across ethnicities, are similar to those measured in other African populations, but are lower than those established in African-American populations. This study provides an important resource that Ethiopian ophthalmologists can use when evaluating patients with suspected ophthalmic and orbital disease.

Orbital Septum Fibrosis in Congenital Ptosis Correlates With Eyelid Function: A Clinicopathologic Study.

PURPOSE: Congenital ptosis can threaten visual function and is usually treated with surgical correction. This study tests the hypothesis that congenital ptosis involves not only the levator muscle but also the orbital septum, which may tether the eyelid in the primary position. METHODS: A retrospective chart review was performed on 30 patients (41 eyelids) with congenital ptosis who underwent surgical correction that included partial septum excision. Histologic analysis was performed by a masked pediatric pathologist, with grading of septal tissue disorganization and fibrosis based on standard histologic criteria. An independent comparison of histologic grading with clinical ptosis measures was then performed. RESULTS: Fifteen eyelids demonstrated significant septal fibrosis, 19 were mild, and 7 were not fibrotic. Thirty-six eyelids demonstrated histologic disorganization. Mildly fibrotic eyelids were found to have reduced preoperative levator function than those that were not fibrotic (2.84 ± 1.92 vs. 9.57 ± 4.76 mm; p < 0.0001). Samples that demonstrated significant fibrosis were also found to have reduced preoperative levator function (4.67 ± 2.12 vs. 9.57 ± 4.76 mm; p = 0.0007). Histologically disorganized samples were also found to have a lower preoperative levator function (9.50 ± 6.04 vs. 3.99 ± 2.49; p = 0.0052). CONCLUSIONS: Orbital septae in patients with congenital ptosis demonstrate histologic disorganization and fibrosis. When decreased levator function is observed clinically, septal fibrosis and/or disorganization is likely present. These observations suggest that debulking the fibrotic septum during congenital ptosis surgery may improve outcomes by releasing the eyelid from its congenitally tethered position, improving eyelid elasticity.

Vitreoretinal Abnormalities during Macular Hole Repair in Alport Syndrome.

PURPOSE: To describe abnormal vitreoretinal findings during macular hole repair in Alport syndrome (AS). METHODS: Case report of preoperative, intraoperative, and postoperative findings related to macular hole surgery in a patient with AS. OBSERVATIONS: A 50-year-old woman with Alport syndrome was found to have bilateral full-thickness macular holes. Surgery was recommended for her left eye given recent onset of vision loss and smaller hole size (313 um). Intraoperatively, the vitreous was found to have fine fibrillar strands and to be abnormally adherent to the retinal surface. There was little to no internal limiting membrane (ILM) present. Vitrectomy was performed with posterior cortical hyaloid peeling and 15% C3F8 gas tamponade. Two months after surgery, the macular hole was successfully closed. CONCLUSIONS: Abnormal vitreous composition and adherence to the retinal surface may contribute to macular hole formation in AS patients. Standard surgical approaches including ILM peeling may not be feasible, though thorough removal of the posterior cortical hyaloid may be sufficient to achieve macular hole closure.

Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition: Follow up to the VISORB trial.

Basal cell carcinoma (BCC) is a common skin cancer caused by deregulated hedgehog signaling. BCC is often curable surgically; however, for orbital and periocular BCCs (opBCC), surgical excision may put visual function at risk. Our recent clinical trial highlighted the utility of vismodegib for preserving visual organs in opBCC patients: 67% of patients displayed a complete response histologically. However, further analysis of excision samples uncovered keratin positive, hedgehog active (Gli1 positive), proliferative micro-tumors. Sequencing of pre-treatment tumors revealed resistance conferring mutations present at low frequency. In addition, one patient with a low-frequency SMO W535L mutation recurred two years post study despite no clinical evidence of residual disease. Sequencing of this recurrent tumor revealed an enrichment for the SMO W535L mutation, revealing that vismodegib treatment enriched for resistant cells undetectable by traditional histology. In the age of targeted therapies, linking molecular genetic analysis to prospective clinical trials may be necessary to provide mechanistic understanding of clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02436408.

Glaucoma Awareness and Knowledge Among Ethiopians in a Tertiary Eye Care Center.

INTRODUCTION: Glaucoma outcomes are closely associated with patients' awareness of the disease. However, little is known about glaucoma awareness and knowledge in Addis Ababa, a densely populated and ethnolinguistically diverse capital city in Ethiopia, the second largest country in Africa. METHODS: We performed a cross-sectional survey in the ophthalmology waiting room at St. Paul's Hospital, a tertiary care center in Addis Ababa. Respondents included patients, patient family members, and non-clinical staff. Participants were asked if they had read or heard about glaucoma to gauge basic awareness of the disease; those with awareness were asked to take a quiz to measure their objective glaucoma knowledge. We performed multivariable regression to identify factors associated with glaucoma awareness, quiz performance, and self-rated ability to use eye drops. RESULTS: Of 298 respondents, 145 (48.7%) were female, and the average age was 44.9 ± 17.2 years. A majority (167; 56.0%) had primary school or less than primary school education. Only 131 (44.0%) had basic glaucoma awareness. Of these, 95 (72.5%) knew that glaucoma causes permanent vision loss, 103 (78.6%) knew glaucoma is often asymptomatic in early stages, 62 (47.3%) identified elevated intraocular pressure as a glaucoma risk factor, and 124 (94.7%) knew glaucoma was treatable. A majority of this subset (126; 96.2%) said they would be willing to use medicated eye drops, and 130 (99.2%) indicated a willingness to undergo surgery if recommended. Education level was independently associated with glaucoma awareness (p < 0.001) and glaucoma quiz performance (p = 0.03). CONCLUSION: In a population sample from an ophthalmology waiting room in Addis Ababa, glaucoma awareness was poor and most strongly associated with education level. Educational interventions at public health and provider-patient levels are warranted. Our results suggest high receptiveness to both medical and surgical treatment.

Use of 3D Printed Models to Create Molds for Shaping Implants for Surgical Repair of Orbital Fractures.

RATIONALE AND OBJECTIVES: Surgical repair of an isolated orbital fracture requires anatomically accurate implant shape and placement. We describe a three-dimensional (3D) printing technique to customize the shape of commercially available absorbable implants. MATERIALS AND METHODS: We reviewed our early experience with three cases in which 3D printed molds were utilized for fracture repair. The institution's medical records were reviewed to assess operative time for orbital floor blow-out fracture repairs. Thin section computed tomography (CT) images were loaded into a clinical 3D visualization software, and stereolithography models were created. The models were loaded into stereolithography editing software in which the nonfractured side was mirrored and overlaid with the fractured side. Sterilizable 3D printed molds were created using the fracture images as well as the virtual mirrored images. The molds were taken to the operating room and used to shape a customized orbital implant for fracture repair, using off-the-shelf bioabsorbable implants. RESULTS: The three patients treated using 3D printed molds had excellent outcomes, with decreased postoperative edema and rapid resolution of ocular misalignment/strabismus. Surgical times were decreased from an average of 93.3 minutes using standard implants to 48.3 minutes following adoption of 3D printed molds. CONCLUSION: Three-dimensional printed models can be used to create molds for shaping bioabsorbable implants for customized surgical repair, improving fit, reducing tissue handling and postoperative edema, and reducing surgical times.

Retinoic Acid Potentiates Orbital Tissues for Inflammation Through NF-κB and MCP-1.

Purpose: The orbit displays unique vulnerability to inflammatory conditions. The most prevalent of these conditions, thyroid eye disease (TED), occurs in up to 50% of patients with Graves' disease (GD). Whereas the pathology of both TED and GD is driven by autoantibodies, it is unclear why symptoms manifest specifically in the orbit. Methods: We performed retinoic acid treatment on both normal and TED patient-derived orbital fibroblasts (OFs) followed by mRNA and protein isolation, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, RNA sequencing, and Western blot analyses. Results: Both normal and TED patient-derived OFs display robust induction of monocyte chemoattractant protein 1 (MCP-1) upon retinoid treatment; TED OFs secrete significantly more MCP-1 than normal OFs. In addition, pretreatment of OFs with thiophenecarboxamide (TPCA-1) inhibits retinoid-induced MCP-1 induction, suggesting an NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)-dependent mechanism. We also found that treatment with cholecalciferol (vitamin D3) mitigates MCP-1 induction, likely because of competition between retinoic acid receptors (RARs) and vitamin D receptors (VDR) for their common binding partner retinoid nuclear receptors (RXRs). Conclusions: Retinoids that naturally accumulate in orbital adipose tissue can act on orbital fibroblasts to induce the expression of inflammation-associated genes. These data suggest a potential role for retinoids in sensitizing the orbit to inflammation.

Twist3 is required for dedifferentiation during extraocular muscle regeneration in adult zebrafish.

Severely damaged adult zebrafish extraocular muscles (EOMs) regenerate through dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. Members of the Twist family of basic helix-loop-helix transcription factors (TFs) are key regulators of the epithelial-mesenchymal transition (EMT) and are also involved in craniofacial development in humans and animal models. During zebrafish embryogenesis, twist family members (twist1a, twist1b, twist2, and twist3) function to regulate craniofacial skeletal development. Because of their roles as master regulators of stem cell biology, we hypothesized that twist TFs regulate adult EOM repair and regeneration. In this study, utilizing an adult zebrafish EOM regeneration model, we demonstrate that inhibiting twist3 function using translation-blocking morpholino oligonucleotides (MOs) impairs muscle regeneration by reducing myocyte dedifferentiation and proliferation in the regenerating muscle. This supports our hypothesis that twist TFs are involved in the early steps of dedifferentiation and highlights the importance of twist3 during EOM regeneration.

Non-Therapeutic Laser Retinal Injury.

BACKGROUND: As lasers have become an increasingly important component of commercial, industrial, military, and medical applications, reported incidents of non-therapeutic laser eye injuries have increased. The retina is particularly vulnerable due to the focusing power and optical transparency of the eye. Continued innovations in laser technology will likely mean that lasers will play an increasingly important and ubiquitous role throughout the world. Critical evaluation should thus be paid to ensure that non-therapeutic injuries are minimized, recognized, and treated appropriately. METHODS: A comprehensive literature review on the PubMed database was conducted to present case reports and case series representative of the variety of laser eye injuries in different injury circumstances, tissue types, and biological damage mechanisms. RESULTS: A general summary of non-therapeutic laser retina injuries is presented, including information about growth of the industry, increasingly accessible online markets, inconsistent international regulation, laser classifications, laser wavelengths, and laser power, mechanisms of tissue injury, and a demonstration of the variety of settings in which injury may occur. Finally, 68 cases found in the literature are summarized to illustrate the presentations and outcomes of these patients. CONCLUSIONS: As non-therapeutic laser eye injuries increase in frequency, there is a greater need for public health, policy, diagnosis, and treatment of these types of injuries.

Student Factors That Influence Clerkship Grades and Matching Into a Surgical Residency.

OBJECTIVE: Evaluate the relationship between medical school factors (including preclinical mentorship, order of clerkships, and clerkship grades) and matching into surgical specialties. DESIGN: Clerkship information, match data, and data on structured preclinical research obtained from 2010 to 2015 for a single institution was obtained and analyzed using multivariate analysis. SETTING: University of Michigan Medical School. PARTICIPANTS: Seven hundred and forty-six students who took both the Internal Medicine and Surgery clerkships between 2010 and 2015 and have since participated in the match. RESULTS: Among 740 students studied, 243 matched into a surgical field. Higher Shelf scores were associated with higher clerkship grades in Surgery and Internal Medicine. Honors or High Pass in Surgery were associated with matching into a surgical field. Structured preclinical research in Surgery and order of clerkship were not associated with matching into a surgical field. CONCLUSIONS: Students who went into surgery were more likely to receive Honors or High Pass. Preclinical choices geared toward a surgical specialty (e.g., order of clerkship and structured research) were not associated with matching into a surgical field. These data may help guide school specific advice for students.

Paradoxical Changes Underscore Epigenetic Reprogramming During Adult Zebrafish Extraocular Muscle Regeneration.

Purpose: Genomic reprogramming and cellular dedifferentiation are critical to the success of de novo tissue regeneration in lower vertebrates such as zebrafish and axolotl. In tissue regeneration following injury or disease, differentiated cells must retain lineage while assuming a progenitor-like identity in order to repopulate the damaged tissue. Understanding the epigenetic regulation of programmed cellular dedifferentiation provides unique insights into the biology of stem cells and cancer and may lead to novel approaches for treating human degenerative conditions. Methods: Using a zebrafish in vivo model of adult muscle regeneration, we utilized chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) to characterize early changes in epigenetic signals, focusing on three well-studied histone modifications-histone H3 trimethylated at lysine 4 (H3K4me3), and histone H3 trimethylated or acetylated at lysine 27 (H3K27me3 and H3K27Ac, respectively). Results: We discovered that zebrafish myocytes undergo a global, rapid, and transient program to drive genomic remodeling. The timing of these epigenetic changes suggests that genomic reprogramming itself represents a distinct sequence of events, with predetermined checkpoints, to generate cells capable of de novo regeneration. Importantly, we uncovered subsets of genes that maintain epigenetic marks paradoxical to changes in expression, underscoring the complexity of epigenetic reprogramming. Conclusions: Within our model, histone modifications previously associated with gene expression act for the most part as expected, with exceptions suggesting that zebrafish chromatin maintains an easily editable state with a number of genes paradoxically marked for transcriptional activity despite downregulation.

Persistent macular puckering following excision of causative orbital tumor.

PURPOSE: To describe the clinical course of a patient with a retrobulbar orbital tumor causing myopic shift and macular pucker. OBSERVATION: Following complete surgical removal of a retrobulbar orbital cavernous hemangioma, the myopic shift improved but the macular pucker persisted even 3 years after orbital surgery, with no sign of tumor recurrence. CONCLUSION AND IMPORTANCE: Chorioretinal folds secondary to chronic mechanical force from an orbital tumor may persist long after the tumor is removed. This case may assist ophthalmologists in their discussions with, and counseling of, patients regarding visual prognosis following excision of orbital tumors that are causing retinal changes.