Ophthalmology Resident Oculofacial Surgery Case Exposure: An ACGME Case Log Analysis.

PURPOSE: The authors quantified trends in resident oculofacial surgery exposure between 2009 and 2018, reviewed specific procedure volume, and correlated procedure volume with program characteristics. METHODS: The authors requested de-identified case logs of residents graduating US ophthalmology residency programs in 2018 from all 118 programs. Current Procedural Terminology codes of all oculofacial procedures were analyzed. Current Procedural Terminology codes were grouped into 25 unique categories that the authors created in addition to the 11 Accreditation Council for Graduate Medical Education categories. RESULTS: One hundred and sixty-six of 488 (34%) US ophthalmology residents graduating in 2018 provided case logs (32.2% of programs). According to Accreditation Council for Graduate Medical Education case logs, residents graduating in 2018 completed significantly fewer eye removal/implant procedures, lacrimal surgeries, "other orbital" procedures, entropion/ectropion repairs, and temporal artery biopsies as primary surgeon than residents graduating in 2009, yet significantly more eyelid laceration repairs, chalazion excisions, tarsorrhaphies, ptosis repairs, and blepharoplasty/reconstruction procedures ( p < 0.05). No difference was found between the total number of oculofacial cases between 2009 and 2018 ( p = 0.051). The most frequently logged procedure per resident in the sample was blepharoplasty/reconstruction (17.2 ± 15) followed by "other oculoplastic" (12.7 ± 10.6). The least commonly performed procedures included temporal artery biopsy (1.5 ± 2.2) and "other orbital" (1.9 ± 3.1). Program size, location, and presence of oculofacial fellowship program all impacted case volume. CONCLUSIONS: Oculofacial surgery has the second highest case number requirement for residents per Accreditation Council for Graduate Medical Education guidelines. However, resident exposure to oculofacial surgery cases greatly varies in each ophthalmology residency program.

Epidemiologic Trends in Oculoplastics-Related Emergency Department Visits in the United States, 2006-2015.

PURPOSE: To characterize demographics and trends in oculoplastics-related emergency department (ED) visits. METHODS: The authors conducted a retrospective, multiyear study of the nationwide ED sample database. The nationwide ED sample was queried for oculoplastics-related International Classification of Disease-ninth revision codes identified from a comprehensive list and categorized based on anatomic location, urgency, and trauma status. Demographics, clinical characteristics, procedure requirement, and cost data were analyzed. Variables associated with inpatient admission were assessed using univariate and multivariate logistic regression. RESULTS: The authors identified an estimated 4.2 million ED visits in the United States with oculoplastics-related primary diagnoses, of which pathology was 80.8% eyelid/adnexal, 17.4% orbital, and 1.74% lacrimal. Overall, 31.3% of the visits were deemed to be nonurgent. Orbital pathology was more likely to be caused by trauma (70.6%), to be urgent (98.0%), and to require a procedure (45.6%) (p < 0.001). While less than 5% of all patients required hospitalization, predictors for inpatient admission were urgent diagnoses (odds ratio, 14.9; CI, 13.7-16.1), presentation to a level 1 trauma center (odds ratio, 3.19; CI, 2.7-3.79), and presence of orbital pathology (odds ratio, 6.09; CI 5.73-6.47). Incidence of ED visits decreased in all categories; however, total inflation-adjusted charges increased. CONCLUSIONS: Over half of oculoplastics-related ED visits are for trauma, with orbital pathology being less common but requiring a high level of care. Although trends show a potentially decreasing incidence of oculoplastics-related ED visits, increasing costs and high proportion of nonurgent visits pose an opportunity for mitigating periocular trauma and increasing outpatient access to care, respectively.

Intralesional Rituximab for the Treatment of Recurrent Ocular Adnexal Lymphoma.

A 41-year-old female with Sjogren syndrome presented with a 5-month history of bilateral upper eyelid swelling. Incisional biopsy of the left lacrimal gland revealed mucosa-associated lymphoid tissue lymphoma. Due to bilateral severe dry eyes, the patient declined external beam radiotherapy and systemic rituximab was initiated. The patient responded well to intravenous rituximab and the follow-up CT revealed decrease in size of both lacrimal glands. Eleven months after systemic rituximab, the patient developed bilateral lacrimal gland recurrence. The patient declined external beam radiotherapy. Intralesional rituximab (50 mg/1 ml) was injected into the left lacrimal gland, followed by injection in the right lacrimal gland 7 months later. Twenty-three months follow-up after the injection into the right lacrimal gland, there was significant decrease in size of bilateral lacrimal glands and subjective improvement of dry eye symptoms. This case highlights the intralesional rituximab as an alternative therapy for recurrent orbital mucosa-associated lymphoid tissue lymphoma in selected cases.

Etiology and Characteristics of Patients Presenting with Eyelid Lacerations at a Level 1 Trauma Center.

Purpose: To investigate the etiology and demographic associations of patients presenting with eyelid lacerations to a US level 1 trauma center emergency department (ED). Patient and Methods: A retrospective chart review of all patients with eyelid lacerations presenting to the ED at a single level 1 trauma center was performed. Eyelid lacerations were categorized as simple eyelid lacerations, eyelid lacerations with eyelid margin involvement, and eyelid lacerations with nasolacrimal system involvement. Data on demographics and clinical characteristics were analyzed. Results: A total of 303 eyelid laceration cases were identified, 56% were simple eyelid lacerations, followed by 24% with nasolacrimal involvement and 20% involving the eyelid margin. Sixty percent of animal bites/scratches resulted in a nasolacrimal system involving laceration, most commonly affecting children. Falls were the most common etiology in children and patients over the age of 60. Black patients, patients presenting with concomitant ophthalmic injuries, and those with Medicaid insurance were more likely to have an assault etiology (p < 0.05 for all). Conclusion: Falls were the most common etiology for eyelid lacerations in children and the elderly, while assault was the most common in adults. Identifying the most common etiology by demographic factors can help raise awareness regarding targeted prevention strategies for high-risk populations.

Incidence, Characteristics, and Cost of Eyelid Lacerations in the United States from 2006 to 2014.

INTRODUCTION: To report the incidence, demographics, and cost of eyelid lacerations (ELs) in the USA. METHODS: The Nationwide Emergency Department Sample is the largest publicly available emergency department database in the US. We conducted a retrospective longitudinal analysis to identify all emergency department (ED) visits in the sample from 2006 to 2014 with a primary or secondary diagnosis of EL. Descriptive statistics were calculated for hospital characteristics, patient demographics, and inflation-adjusted patient ED and in-patient (IP) charges. RESULTS: The incidence of primary and total ELs from 2006 to 2014 decreased by 50 per million and 7.1 per million, respectively. In the same period, the total ED and average ED charge, corrected for inflation, increased by almost $37 million and $1600 per person, respectively. Motor vehicle accidents (MVAs) were the mechanism of injury (MOI) associated with the highest average ED and IP costs at $5391 and $42,677, respectively. However, object- (42.2%) and fall-related (28.8%) were the most reported MOI overall. Peak months of EL presentations were seen in May and July, and > 90% of primary ELs were classified as periocular. Most ELs occurred in men and children, representing 69% and 44% of all primary EL cases, respectively. CONCLUSION: The incidence of ELs declined from 2006 to 2014. ELs occurred most frequently in children and young adults. The high proportion of object and fall-related injuries in this population highlights an area to develop strategies to reduce the frequency of preventable eye injuries.

Cost and Prescriber and Patient Characteristics of Cenegermin Use in the Medicare Population.

PURPOSE: To assess the cost and prescriber and patient characteristics associated with the early use of cenegermin (OXERVATE) after its approval among Medicare beneficiaries to better define resource use and areas for improvement in the treatment of neurotrophic keratopathy. DESIGN: Retrospective, cross-sectional study. METHODS: Medicare Part D claims data of all cenegermin prescriptions from January 1, 2019, to December 31, 2020, were identified using its National Drug Code. Patients younger than 65 years and those with missing demographic characteristics were excluded. Information on patient and prescriber demographic characteristics, quantity of cenegermin prescription, gross drug costs, and patient out-of-pocket costs were extracted from each claim. RESULTS: In 2019-2020, a total of 2410 Medicare beneficiaries aged 65 years or older were prescribed cenegermin. The mean (standard deviation [SD]) age of these patients was 77.3 (7.6) years. Most patients were female (63.6%), White (87.3%), and lived in urban areas (86.9%). The majority (72%) received a standard 8-week course. A total of 1025 clinicians prescribed cenegermin. Most were male (68.2%), in an urban setting (90.8%). The median (interquartile range [IQR]) duration of cenegermin therapy prescribed per patient by each clinician was 8 (7.5-8) weeks. Total gross drug cost of all cenegermin therapy over the study period was $287 million. Median (IQR) out-of-pocket patient cost was $5791 (180-7179). CONCLUSIONS: Despite the clinical benefits of cenegermin therapy, the associated significant cost warrants further analysis of its cost-effectiveness in patient care, especially in comparison with alternative novel management options.

Utility of diffusion-weighted imaging to differentiate benign and malignant solid orbital tumours.

OBJECTIVE: We assessed the utility of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging to differentiate benign and malignant orbital tumours by oculoplastic surgeons in the clinical setting and sought to validate observed ADC cut-off values. DESIGN AND PARTICIPANTS: Retrospective review of patients with benign or malignant biopsy-confirmed orbital tumours. METHODS: Blinded graders including 2 oculoplastic surgeons, 1 neuroradiologist, and 1 medical student located and measured orbital tumour ADCs (10-6 mm2/s) using the Region of Interest tool. OUTCOME MEASURES: Nonradiologist measurements were compared with each other to assess reliability and with an expert neuroradiologist measurement and final pathology to assess accuracy. RESULTS: Twenty-nine orbital tumours met inclusion criteria, consisting of 6 benign tumours and 23 malignant tumours. Mean ADC values for benign orbital tumours were 1430.59 ± 254.81 and 798.68 ± 309.12 mm2/s for malignant tumours. Our calculated optimized ADC cut-off to differentiate benign from malignant orbital tumours was 1120.84 × 10-6 mm2/s (sensitivity 1, specificity 0.9). Inter-rater reliability was excellent (intraclass correlation coefficient = 0.92; 95% CI, 0.86-0.96). Our 3 graders had a combined accuracy of 84.5% (92.3%, 92.3%, and 65.4%). CONCLUSIONS: Our ADC cut-off of 1120.84 × 10-6 mm2/s for benign and malignant orbital tumours agrees with previously established values in literature. Without priming with instructions, training, or access to patient characteristics, most tumours were correctly classified using rapid ADC measurements. Surgeons without radiologic expertise can use the ADC tool to quickly risk stratify orbital tumours during clinic visits to guide patient expectations and further work-up.

Ophthalmology Resident Ophthalmic Trauma Case Exposure: Trends Over Time and an ACGME Case Log Analysis.

Purpose: To describe ophthalmology resident experience with ophthalmic trauma cases in the U.S. . Methods: We analyzed Accreditation Council for Graduate Medical Education (ACGME) case log data and de-identified case logs from US ophthalmology residency programs for residents graduating in 2018.  Current Procedural Terminology (CPT) codes documented as "Globe Trauma" and  trauma-related "Oculoplastic and Orbit" codes including lid lacerations and lateral canthotomies were analyzed. Results: 38 residency programs provided case logs (response rate: 32.2%). Residents performed an average of 7.24±4.37 open globe repairs, 8.66±6.94 lid laceration repairs, 0.49±1.4 orbital fracture repairs, 1.22±1.81 lateral canthotomies, and 0.28±0.69 anterior chamber washouts as primary surgeon. On average, the most logged "Globe Trauma" procedure was open globe repair as primary surgeon. The more common trauma-related "Oculoplastic and Orbit" procedure was lid laceration repair as primary surgeon.  42.8% of residents did not log any lateral canthotomy procedures. Medium programs performed significantly more canthotomies than large programs (F(2166) = 6.35, p = 0.002), and large programs performed significantly more orbital fracture repairs than small and medium programs (F(2166) = 4.45, p = 0.013). Conclusion: Significant variation in globe trauma volume exists across programs. ACGME guidelines require a minimum of four globe trauma procedures for graduation, but procedures like anterior chamber paracentesis count towards this requirement. Open globe repairs, simple lid lacerations, and lateral canthotomies are basic skills every graduating resident should be competent in. Updating ACGME case log requirements for ophthalmic trauma and increasing opportunities for wet lab simulations may assist in ensuring graduating ophthalmology residents' competency in performing these procedures.

Incidence and Characteristics of Orbital Hemorrhages in the United States from 2006 to 2018.

Purpose: To determine the incidence, characteristics, and costs associated with orbital hemorrhages presenting to US EDs. Patients and Methods: This was a retrospective, longitudinal study of the Nationwide Emergency Department Sample, 2006 to 2018. Medical records from patients presenting to participating hospital-owned EDs and diagnosed with primary or secondary orbital hemorrhage were examined to determine incidence, demographics, clinical characteristics, mechanism, disposition and related risk factors, and costs. Results: From 2006 to 2018, an estimated 20,762 US ED visits included an orbital hemorrhage diagnosis. Most primary diagnosis patients were elderly (35%) and male (51%), and incidence increased from 1.1 (95% CI: 0.8-1.4) to 3.1 per million (95% CI: 2.5-3.7, p < 0.0001). Fall was the most common mechanism (21.6%), particularly among the elderly (39.9%). Fall-related diagnoses increased from 0.03 (95% CI: -0.01-0.07) to 1.0 per million (95% CI: 0.7-1.3, p < 0.0001), while overall falls increased by only 7%. Assault-related orbital hemorrhage increased from 0.1 (95% CI: 0.0-0.2) to 0.6 per million (95% CI: 0.4-0.7, p < 0.0001), while overall assaults decreased by 22%. Annual total ED costs increased from $463,220 (95% CI: 233,993-692,446) to $6,117,320 (95% CI: 4,665,403-7,569,237, p < 0.001). Inpatient admission was uncommon (9.0%), but related costs totaled $18.9 million (95% CI: 13.3-24.5). Odds of admission were lower in fall- and objects-related injuries and higher with certain concurrent injuries. Conclusion: Orbital hemorrhages are becoming more frequent and costly. A disproportionately large increase in fall- and assault-related diagnoses highlights the need for targeted injury prevention strategies to reduce cost and morbidity.

Cell-specific regulation of gene expression using splicing-dependent frameshifting.

Precise and reliable cell-specific gene delivery remains technically challenging. Here we report a splicing-based approach for controlling gene expression whereby separate translational reading frames are coupled to the inclusion or exclusion of mutated, frameshifting cell-specific alternative exons. Candidate exons are identified by analyzing thousands of publicly available RNA sequencing datasets and filtering by cell specificity, conservation, and local intron length. This method, which we denote splicing-linked expression design (SLED), can be combined in a Boolean manner with existing techniques such as minipromoters and viral capsids. SLED can use strong constitutive promoters, without sacrificing precision, by decoupling the tradeoff between promoter strength and selectivity. AAV-packaged SLED vectors can selectively deliver fluorescent reporters and calcium indicators to various neuronal subtypes in vivo. We also demonstrate gene therapy utility by creating SLED vectors that can target PRPH2 and SF3B1 mutations. The flexibility of SLED technology enables creative avenues for basic and translational research.

Temperature and species-dependent regulation of browning in retrobulbar fat.

Retrobulbar fat deposits surround the posterior retina and optic nerve head, but their function and origin are obscure. We report that mouse retrobulbar fat is a neural crest-derived tissue histologically and transcriptionally resembles interscapular brown fat. In contrast, human retrobulbar fat closely resembles white adipose tissue. Retrobulbar fat is also brown in other rodents, which are typically housed at temperatures below thermoneutrality, but is white in larger animals. We show that retrobulbar fat in mice housed at thermoneutral temperature show reduced expression of the brown fat marker Ucp1, and histological properties intermediate between white and brown fat. We conclude that retrobulbar fat can potentially serve as a site of active thermogenesis, that this capability is both temperature and species-dependent, and that this may facilitate regulation of intraocular temperature.

Transcriptomic Profiling of Control and Thyroid-Associated Orbitopathy (TAO) Orbital Fat and TAO Orbital Fibroblasts Undergoing Adipogenesis.

Purpose: Orbital fat hyperplasia commonly occurs in thyroid-associated orbitopathy (TAO). To understand molecular mechanisms underlying orbital adipogenesis, we used transcriptomics to compare gene expression in controls and patients with TAO, as well as in orbital fibroblasts (OFs) undergoing adipogenic differentiation. Methods: We performed bulk RNA sequencing (RNA-Seq) on intraconal orbital fat from controls and patients with TAO. We treated cultured OFs derived from patients with TAO with adipogenic media to induce adipogenesis. We used single nucleus RNA-Seq (snRNA-Seq) to profile treated and control OFs, identifying genes that are dynamically expressed during orbital adipogenesis in vitro, and compared these results to data from control and TAO orbital fat. Results: Gene expression profiles in control and TAO orbital fat are distinct. Signaling pathways including PI3K-Akt signaling, cAMP signaling, AGE-RAGE signaling, regulation of lipolysis, and thyroid hormone signaling are enriched in orbital fat isolated from patients with TAO. SnRNA-Seq of orbital fibroblasts undergoing adipogenesis reveals differential expression of the adipocyte-specific genes FABP4/5, APOE, PPARG, and ADIPOQ during adipogenic differentiation. The insulin-like growth factor-1 receptor and Wnt signaling pathways appear to be enriched early in adipogenesis. Gene modules that are enriched in TAO orbital fat are upregulated in orbital adipocytes during differentiation in vitro, whereas genes that are enriched in control orbital fat are enriched in undifferentiated OFs. Conclusions: We identified pathways enriched in TAO orbital fat, and dynamic changes in gene expression that occur during adipogenic differentiation of orbital fibroblasts. These findings may help guide functional studies of genes and pathways critical for orbital adipogenesis.

Current Understanding of the Progression and Management of Thyroid Associated Orbitopathy: A Systematic Review.

Thyroid associated orbitopathy (TAO) is a common diagnosis encountered by ophthalmologists and oculoplastic surgeons. TAO has a varying clinical presentation that can include upper eyelid retraction, restrictive strabismus, proptosis, exposure keratopathy, and optic neuropathy. In this review, we discuss the most recent literature on and the current understanding of the pathophysiology of TAO. We also review available and potential future treatment options for the management of TAO.

Bicanalicular Intubation with the Kaneka Lacriflow for Proximal Lacrimal Drainage System Stenosis.

PURPOSE: The Kaneka Lacriflow CL (Lacriflow) bicanalicular lacrimal intubation system was evaluated as a self-retaining alternative to traditional modalities for stenting and dilation of the lacrimal drainage system in proximal lacrimal drainage system stenosis. PATIENTS AND METHODS: A retrospective chart review was conducted to assess the use of the Lacriflow system for treatment of patients with punctal and canalicular stenosis. Anesthesia type, operative time, and complications were assessed. RESULTS: In the time period evaluated, a total of 72 Lacriflow stents were placed in 45 patients, most commonly under intravenous sedation. Stents were left in place for a mean of 145 days, with 9 stents left in place for more than 1 year, and a mean follow-up time of 263 days. Early complications within 90 days included prolapse in 1 stent, symptomatic colonization for 2 stents, and corneal abrasion in 1 stent in a patient with anterior basement membrane dystrophy. Five additional stents developed colonization in the late postoperative period (four of which were more than 1 year after stent placement). The overall complication rate (per stent) at 3 months after surgery was 5.6% and at all follow-up time points was 13.9%. Operative times were significantly shorter for a cohort of patients undergoing bicanalicular intubation with the Ritleng system (P = 0.015). CONCLUSION: The Lacriflow bicanalicular stent can be easily placed without general anesthesia. Complication rates are comparable to other bicanalicular intubation systems, but increase with longer time that stents are left in place.

Gene regulatory networks controlling vertebrate retinal regeneration.

Injury induces retinal Müller glia of certain cold-blooded vertebrates, but not those of mammals, to regenerate neurons. To identify gene regulatory networks that reprogram Müller glia into progenitor cells, we profiled changes in gene expression and chromatin accessibility in Müller glia from zebrafish, chick, and mice in response to different stimuli. We identified evolutionarily conserved and species-specific gene networks controlling glial quiescence, reactivity, and neurogenesis. In zebrafish and chick, the transition from quiescence to reactivity is essential for retinal regeneration, whereas in mice, a dedicated network suppresses neurogenic competence and restores quiescence. Disruption of nuclear factor I transcription factors, which maintain and restore quiescence, induces Müller glia to proliferate and generate neurons in adult mice after injury. These findings may aid in designing therapies to restore retinal neurons lost to degenerative diseases.

Expression of the dominant negative retinoid receptor, RAR403, alters telencephalic progenitor proliferation, survival, and cell fate specification.

Retinoic acid (RA) signaling plays critical roles in diverse cellular processes during nervous system development. In mouse models, the roles for RA signals in telencephalic development remain unclear, partly because of the ambiguity of RA telencephalic sources after E8.75. Here, we have developed a genetic approach that utilizes Cre-lox technology to conditionally express a potent dominant negative retinoid receptor, RAR403, in vivo. This approach blocks RA signaling pathways at the receptor level, enabling the disruption of RA signals in contexts in which the RA source is unknown. RAR403 expression throughout the developing telencephalon causes pronounced hypoplasia resulting from defective proliferation in dorsal telencephalic progenitors and extensive cell death. Furthermore, Nkx2.1(+) progenitors in the medial ganglionic eminence (MGE) are misspecified such that they acquire a subset of lateral ganglionic eminence (LGE)-specific properties at the expense of MGE fates. This genetic approach reveals new roles for RA signaling in telencephalic proliferation, survival and fate specification, and underscores its utility in investigating the function of retinoid signaling pathways throughout peri- and postnatal development.

Practice Patterns in Orbital Decompression Surgery Among American Society of Ophthalmic Plastic and Reconstructive Surgery Members.

INTRODUCTION: Orbital decompression surgery for thyroid-associated orbitopathy (TAO) has evolved greatly over the past decades with the development of new surgical techniques and strategies for patient management. However, randomized controlled trials comparing surgical approaches are lacking. The goal of this study was to report the current preferred practices among American Society of Ophthalmic Plastic Surgeons (ASOPRS) members for orbital decompression surgery for TAO, including surgical techniques and perioperative patient management. METHODS: An anonymous electronic survey consisting of 21 questions was sent to the current membership of the ASOPRS, leading to 170 responses in total (response rate: 23.7%). Questions regarding preoperative and postoperative care as well as surgical technique were included. RESULTS: 54.2% of the respondents prefer two-wall surgery as their initial procedure of choice. Of these, 53.8% prefer balanced lateral and medial decompression as the two-walled procedure of choice, and 44.0% prefer the orbital floor and medial wall. Steroids are routinely used preoperatively by 35.9% and postoperatively by 69.2%. Antibiotics are used preoperatively by 32.9% and postoperatively by 56.4% of respondents. CONCLUSION: Practice patterns for orbital decompression surgery continue to vary widely among ASOPRS members, but balanced medial and lateral wall decompression has gained in popularity as compared to prior studies. Postoperative steroids are preferred by a majority of members.

Delayed Orbital Emphysema Mimicking Orbital Cellulitis: An Uncommon Complication of Dental Surgery.

A 79-year-old man presented to the ophthalmology clinic with acute-onset left orbital and periorbital swelling, 6 days following surgery to revise a zygomatic implant to anchor his dentures. On evaluation, there was left eye proptosis with ipsilateral facial crepitus. Emphysema was confirmed on computed tomography. With visual function and motility remaining intact, he was observed without intervention. Within 2 weeks, his evaluation returned to baseline. Periorbital emphysema is a rare complication of dental procedures. Awareness of this potential complication enables timely diagnosis and avoidance of unnecessary therapy.

Single-Cell RNA-Seq Analysis of Retinal Development Identifies NFI Factors as Regulating Mitotic Exit and Late-Born Cell Specification.

Precise temporal control of gene expression in neuronal progenitors is necessary for correct regulation of neurogenesis and cell fate specification. However, the cellular heterogeneity of the developing CNS has posed a major obstacle to identifying the gene regulatory networks that control these processes. To address this, we used single-cell RNA sequencing to profile ten developmental stages encompassing the full course of retinal neurogenesis. This allowed us to comprehensively characterize changes in gene expression that occur during initiation of neurogenesis, changes in developmental competence, and specification and differentiation of each major retinal cell type. We identify the NFI transcription factors (Nfia, Nfib, and Nfix) as selectively expressed in late retinal progenitor cells and show that they control bipolar interneuron and Müller glia cell fate specification and promote proliferative quiescence.