Downregulation of collagen XI during late postnatal corneal development is followed by upregulation after injury.

Collagen XI plays a role in nucleating collagen fibrils and in controlling fibril diameter. The aim of this research was to elucidate the role that collagen XI plays in corneal fibrillogenesis during development and following injury. The temporal and spatial expression of collagen XI was evaluated in C57BL/6 wild-type mice. For wound-healing studies in adult mice, stromal injuries were created using techniques that avoid caustic chemicals. The temporal expression and spatial localization of collagen XI was studied following injury in a Col11a1 inducible knockout mouse model. We found that collagen XI expression occurs during early maturation and is upregulated after stromal injury in areas of regeneration and remodeling. Abnormal fibrillogenesis with new fibrils of heterogeneous size and shape occurs after injury in a decreased collagen XI matrix. In conclusion, collagen XI is expressed in the stroma during development and following injury in adults, and is a regulator of collagen fibrillogenesis in regenerating corneal tissue.

Collagen XII regulates stromal wound closure.

The role of collagen XII in regulating injury repair and reestablishment of corneal function is unknown. This manuscript aims to investigate the role(s) of collagen XII in the repair of incisional and debridement injuries in an adult mouse model. Two different types of injury in wild type and Col12a1-/- corneas were created to investigate the effects of collagen XII -in wound repair and scar formation-by using clinical photographs, immunohistology, second harmonic generation imaging and electron microscopy. Results showed that collagen XII is a regulator of wound closure after incisional injuries. Absence of collagen XII retarded wound closure and the wound healing process. These findings show that collagen XII regulates fibrillogenesis, CD68 cell lineage infiltration, and myofibroblast survival following injury. In vitro studies suggest that collagen XII regulates deposition of an early and provisional matrix by interacting with two proteins regulating early matrix deposition: fibronectin and LTBP1(latent transforming growth factor ß binding protein 1). In conclusion, collagen XII regulates tissue repair in corneal incisional wounds. Understanding the function of collagen XII during wound healing has significant translational value.

Conjunctivitis: A Primer on Conjunctival Biopsy and Approach to Histopathologic Diagnosis.

Conjunctivitis, or inflammation of the mucosal covering the anterior third of sclera and inner eyelid, is a common clinical condition of varied causation. Most cases are self-limited due to infection or allergy and rarely necessitate biopsy. Inflammation of the conjunctiva, however, is one of the most common principal histopathologic diagnoses rendered when the tissue is biopsied. In the context of conjunctivitis, biopsy is usually performed when inflammation is chronic and recalcitrant to therapy, has clinically atypical features, or requires an etiologic diagnosis when one cannot be reached through other laboratory methods. The exclusion of ocular surface neoplasia in a chronically inflamed conjunctiva is a common justification for biopsy. When inflammation is the principal histopathology finding, it is desirable-whenever feasible-to establish the cause. This brief review provides a guide in how histologic findings of an inflamed conjunctiva can direct the clinical evaluation towards an etiologic diagnosis.

Collagen XIV Is an Intrinsic Regulator of Corneal Stromal Structure and Function.

Collagen XIV is poorly characterized in the body, and the current knowledge of its function in the cornea is limited. The aim of the current study was to elucidate the role(s) of collagen XIV in regulating corneal stromal structure and function. Analysis of collagen XIV expression, temporal and spatial, was performed at different postnatal days (Ps) in wild-type C57BL/6 mouse corneal stromas and after injury. Conventional collagen XIV null mice were used to inquire the roles that collagen XIV plays in fibrillogenesis, fibril packing, and tissue mechanics. Fibril assembly and packing as well as stromal organization were evaluated using transmission electron microscopy and second harmonic generation microscopy. Atomic force microscopy was used to assess stromal stiffness. Col14a1 mRNA expression was present at P4 to P10 and decreased at P30. No immunoreactivity was noted at P150. Abnormal collagen fibril assembly with a shift toward larger-diameter fibrils and increased interfibrillar spacing in the absence of collagen XIV was found. Second harmonic generation microscopy showed impaired fibrillogenesis in the collagen XIV null stroma. Mechanical testing suggested that collagen XIV confers stiffness to stromal tissue. Expression of collagen XIV is up-regulated following injury. This study indicates that collagen XIV plays a regulatory role in corneal development and in the function of the adult cornea. The expression of collagen XIV is recapitulated during wound healing.

Ocular Paraneoplastic Syndromes: A Critical Review of Diffuse Uveal Melanocytic Proliferation and Autoimmune Retinopathy.

Background: Dozens of paraneoplastic syndromes affect the visual system ranging from conjunctival pemphigoid to encephalopathy of the occipital cortex. The most profiled ocular syndromes are bilateral diffuse uveal melanocytic proliferation (BDUMP) and the autoimmune retinopathies.Purpose: To review the critical features of these 2 entities then concentrate on advancements in treatment made within the last 10 years.Study Design: Literature review with structured data abstraction.Results: Major insights into pathogenesis have been wanting. Plasmapheresis appears to improve vision in a substantial proportion of patients with BDUMP. The number of clinical variables that influence visual outcome in paraneoplastic retinopathies combined with the variety of local and systemic treatment options makes interpretation of clinical effectiveness difficult.Conclusions: The rarity of these disorders makes randomized clinical trials unlikely. It may be time for a clinical professional organization to use a modified Delphi method to establish a consensus algorithm for the diagnosis and management of retinal paraneoplastic syndromes to augment clinical communications and clinical trials.

Gliomas of the Optic Nerve: A SEER-Based Epidemiologic Study.

BACKGROUND: To determine whether patients with biopsy-confirmed optic nerve glioma differ in clinical features and outcomes from those diagnosed by neuroradiologic imaging alone. METHODS: Retrospective comparative analysis. Pilocytic astrocytomas (PAs) and gliomas of the optic nerve were identified through ICD-O codes in the Surveillance, Epidemiology, and End Results (SEER) cancer registry from 1975 through 2017. Demographics, clinical features, and outcomes were compared according to the method of diagnosis (biopsy-confirmed and radiologic only) and by age (birth through 19 years and 20 years of age and older). Differences in proportions were tested with the chi-square test. Associations with tumor-related death were evaluated with logistic regression. Statistical significance: α < 0.01. RESULTS: Over 42 years, 313 PAs and 720 gliomas of the optic nerve were identified. The young age distributions were similar between the 2 groups. PAs were biopsied more often than gliomas (54% vs 13.2% [ P < 0.001]). Tumor-attributable death occurred more often among PAs and gliomas that were biopsied than those that were not (7.1% vs 0.7% [ P < 0.01]; 7.4% vs 1.1% [ P < 0.01], respectively). Roughly 15% of both PAs and gliomas were diagnosed in persons 20 years and older. CONCLUSIONS: Biopsy-confirmed cases of PA and glioma of the optic nerve were associated with more therapeutic interventions and worse outcomes compared with patients who were diagnosed radiologically. Clinical variables relevant to clinical decision-making not captured by SEER likely explain the inability to meaningfully interpret outcome from the registry database. Cancer registries should avoid coding specific histopathologic diagnoses when tissue is not obtained.

Bell's Palsy and the Peril of Eponyms.

The seemingly mundane management of a Bell's palsy can have devastating consequences if the diagnosis of nonidiopathic cranial nerve palsy is not kept in perspective. The case of an elderly man mislabeled by a primary care physician as having a Bell's palsy illustrates how eye physicians can prevent an adverse outcome. Unilateral incomplete eyelid exposure and ipsilateral progressive pain were this patient's main problems for roughly 18 months during which time ophthalmologists managed his corneal exposure but failed to appreciate a parotid gland tumor. Eye physicians are in a unique position to recognized if a nonidiopathic cause of seventh cranial nerve palsy exists because they manage problems with corneal exposure. Replacing Bell's palsy with the term idiopathic facial nerve palsy may heighten awareness that other causes of seventh cranial nerve palsy must be considered, but recounting an adverse outcome may also be a valuable learning experience.

Diseases of the corneal endothelium.

The corneal endothelial monolayer and associated Descemet's membrane (DM) complex is a unique structure that plays an essential role in corneal function. Endothelial cells are neural crest derived cells that rest on a special extracellular matrix and play a major role in maintaining stromal hydration within a narrow physiologic range necessary for clear vision. A number of diseases affect the endothelial cells and DM complex and can impair corneal function and vision. This review addresses different human corneal endothelial diseases characterized by loss of endothelial function including: Fuchs endothelial corneal dystrophy (FECD), posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial dystrophy (CHED), bullous keratopathy, iridocorneal endothelial (ICE) syndrome, post-traumatic fibrous downgrowth, glaucoma and diabetes mellitus.

IgG4-rich reactive lymphoid hyperplasia of the lacrimal gland.

We describe an otherwise healthy 24-year-old woman with reactive lymphoid hyperplasia of one lacrimal gland. She was found to have modest elevation of serum IgG4 and high density of IgG4+ plasma cells in her lacrimal gland, ranging from 40% to 60% of IgG+ plasma cells. The patient transiently responded to systemic corticosteroids before treatment with rituximab. IgG4-rich reactive lymphoid hyperplasia of the lacrimal gland is neither an established part of IgG4-related disease spectrum nor a known precursor lesion to lymphoma. Although there is a plausible risk of transforming to IgG4-related disease or to lymphoma, the biological potential and natural history of IgG4-rich reactive lymphoid hyperplasia remains to be determined.

Inflammatory Reaction to Decellularized Porcine-Derived Xenograft for Lower Eyelid Retraction.

A 54-year-old woman underwent uncomplicated bilateral lower eyelid surgery for eyelid retraction using porcine decellularized membrane graft (TarSys). Left lower eyelid pain began several months after surgery and persisted until the graft was removed 15 months after implantation. The opposite eyelid graft caused no symptoms. Histologically, the lesion consisted of acellular collagen surrounded by florid granulomatous inflammation. Although the inflammatory reaction suggested a cell-mediated immune response, this pathway of injury is difficult to reconcile given the asymptomatic opposite eyelid. The literature reflects limited experience with porcine decellularized membranes of the eyelid. Complications and long-term tolerance remain to be determined.

Epithelial downgrowth. Report of 2 cases diagnosed by ocular biopsy.

Epithelial downgrowth is an uncommon complication of ocular surgery or adverse consequence of accidental trauma, caused by surface squamous epithelium that has gained access to the inner compartments of the eye. Once embedded in the eye, squamous epithelium spreads over contiguous structures, interfering with normal aqueous outflow and vision. The pursuit of improved therapies is ongoing, but the greatest chance of preventing blindness is with early recognition. Two cases of epithelial downgrowth diagnosed from a corneal button and an iris biopsy are presented to familiarize pathologists with this disorder. In the appropriate clinical setting, the presence of stratified squamous epithelium, with or without goblet cells, is diagnostic of epithelial downgrowth. Other than congenital epithelial inclusion cyst (choristoma), stratified squamous epithelium is not found inside the eye. Surface epithelium introduced surgically or traumatically needs to be differentiated histologically from ectopic corneal endothelium and metastatic carcinoma.

Role of Vismodegib in the Management of Advanced Periocular Basal Cell Carcinoma.

BACKGROUND: Vismodegib is the first selective hedgehog pathway inhibitor approved to treat locally advanced and metastatic basal cell carcinoma (BCC). Limited information is available concerning its role in managing advanced BCC around the eye. METHODS: The medical literature was searched for cases of nonsyndromic periocular BCC treated with vismodegib. Clinical information was abstracted and analyzed. In addition, a review of the pharmacology of vismodegib, including general effectiveness and safety, was conducted. RESULTS: Thirty study patients with nonsyndromic periocular BCC treated with vismodegib were found in the literature. Vismodegib was used in 3 ways: medical therapy, adjuvant therapy prior to surgery or radiotherapy, and treatment of positive surgical margins. Complete regression was reported in 9 study patients (30%), with follow-up visits after therapy averaging fewer than 5 months. Four study participants developed squamous cell carcinoma while receiving treatment. CONCLUSIONS: Too few cases exist to draw any conclusions on the role that vismodegib might play in the management of periocular BCC. In addition, long-term follow-up data are not yet available. Although the objective response rate of advanced BCC is impressive in study patients receiving vismodegib, well-controlled clinical studies are needed to determine whether vismodegib has any impact on survival or quality of life.

Extranodal Marginal Zone B-cell Lymphoma of the Ocular Adnexa.

BACKGROUND: Low-grade B-cell lymphomas located around the eye present unique challenges in diagnosis and treatment. Extranodal marginal zone B-cell lymphoma is the most common lymphoma of the ocular adnexa (conjunctiva, orbit, lacrimal gland, and eyelid). METHODS: A systematic search of the relevant literature was performed. Material pertinent to the diagnosis, prognosis, pathogenesis, and treatment of extranodal marginal zone B-cell lymphoma of the ocular adnexa was identified, reviewed, and analyzed, focusing on management strategies for primary localized disease. RESULTS: The primary cause of extranodal marginal zone B-cell lymphoma of the ocular adnexa remains elusive, although an infectious agent is suspected. Radiotherapy is the most common initial treatment for localized disease. Initial treatment with chemotherapy, immunotherapy, and antibiotics has shown promising results, but the number of series is limited and controlled trials do not exist. CONCLUSIONS: Although the long-term outcome of localized extranodal marginal zone B-cell lymphoma of the ocular adnexa is good, optimal treatment remains a goal. The variation in rates of local and systemic relapse among treated stage 1E tumors suggests that critical factors affecting outcomes are not fully understood. Radiotherapy is the standard of care; at this time, the evidence is insufficient to recommend chemotherapy, immunotherapy, or antibiotics for initial treatment of extranodal marginal zone B-cell lymphoma localized to the ocular adnexa. Well-controlled comparative studies are needed.

Volume of Cataract Surgery and Surgeon Gender: The Florida Ambulatory Surgery Center Experience 2005 Through 2012.

Cataract is the most common surgically reversible cause of vision loss and the most common major surgical procedure performed in the United States. To understand how gender composition might affect differences in health services, we examined the surgeon gender-specific rates of routine cataract surgery performed in ambulatory surgical centers in Florida. Routine cataract surgeries were identified through the Florida Agency for Health Care Administration (AHCA) ambulatory surgery center dataset. The background of individual surgeons was determined by linking license numbers in the dataset to physician profiles publicly available from AHCA. From 2005 through 2012, women ophthalmologists in Florida performed roughly half the annual rate of cataract surgery as their male counterparts. This difference is not explained by greater time in clinical practice for men. Further investigation into the causes of this gender-volume disparity is warranted to determine what roles choice and barriers may play.

The remarkable life of Erwin Schrödinger's What Is Life?

In the seven decades since Schrödinger's book was published, it has gone through stages of differing appraisal, starting with guarded approbation in the 1940s. When several luminaries in molecular biology described the work as influencing their careers, the book's renown increased. In What Is Life?, Schrödinger examined genetics from the perspective of a theoretical physicist, and conjured up ideas that dilettantes admired and experts slighted. Schrödinger sowed his most important ideas in terms of metaphors, allowing readers considerable latitude for interpretation. Some found nothing worthwhile in the book, only chemical naivete and ignorance of work that had already been done. Others found deep inspiration and a desire to understand biological reproduction, even if it required new paradigms of physical science. What Is Life?--like the ancient parable of the blind men and an elephant--is an example of the ineffable nature of truth, pitting subjective experience against the totality of the reality. The legacy of What Is Life? may ultimately be respect for different opinions.

Uveitis: the collaborative diagnostic evaluation.

Uveitis, or inflammation of the uveal tract (i.e., iris, ciliary body, and choroid), results from a heterogeneous collection of disorders of varying etiologies and pathogenic mechanisms. Uveitis is caused by a systemic disease in 30% to 45% of patients. Primary care physicians may be asked to evaluate patients with uveitis when an underlying systemic diagnosis is suspected but not apparent from eye examination or history. If the history, physical examination, and basic laboratory studies do not suggest an underlying cause, serologic tests for syphilis and chest radiography for sarcoidosis and tuberculosis are recommended. Typing for human leukocyte antigen-B27 is appropriate for patients with recurrent anterior uveitis. Because the prevalence of many rheumatologic and infectious diseases is low among persons with uveitis, Lyme serology, antinuclear antibody tests, serum angiotensin-converting enzyme tests, serum lysozyme tests, and tuberculin skin tests can result in false-positive results and are not routinely recommended. Drug-induced uveitis is rare and can occur from days to months after the time of initial exposure. Primary ocular lymphoma should be considered in persons older than 50 years with persistent intermediate or posterior uveitis that does not respond to anti-inflammatory therapy.

Jonas Friedenwald, Eugene Wolff, and the Two Books That Helped Bridge the Specialty Gap.

Background: Eugene Wolff (1896-1954) and Jonas S. Friedenwald (1897-1955) were life-long students and educators of anatomic pathology and ophthalmology. Both contributed toward narrowing the gap between the two rapidly diverging specialties of pathology and ophthalmology. Friedenwald in 1929 and Wolff in 1934 each published textbooks of ophthalmic pathology that influenced medical education for decades to come. Summary: Friedenwald's The Pathology of the Eye and Wolff's A Pathology of the Eye introduced ophthalmologists in training and practice to anatomic pathology, while familiarizing pathologists with the nature of ocular disease. Both books appeared at the time when anatomic pathology was departing from its mostly academic roles in education and research to assume more active participation in clinical care by establishing diagnoses through biopsy. Key Messages: Wolff and Friedenwald dedicated their careers to teaching the art and science of anatomic pathology to clinical ophthalmologists. Their efforts helped anchor ophthalmology to the traditions of mainstream medicine.

Self-Reported Visual Disability and Unemployment: Findings from the National Health Interview Survey.

PURPOSE: To investigate the association between visual impairment and employment status due to disability, utilizing data from the 2022 National Health Interview Survey (NHIS). METHODS: Adults 18 years of age and older were extracted from the 2022 NHIS dataset. A multivariable logistic regression model was created to evaluate the odds of unemployment ("laid off" and "looking for work"). Persons over the age of 65, as well as persons retired, going to school, self-employed, seasonal, or contract workers were excluded. Independent variables for the model included gender, race, Hispanic ethnicity, urban residency, level of education, citizenship, and self-reported vision. The latter variable was categorized as seeing with "some" difficulty, with "severe" difficulty, "can't see at all," and "a lot of difficulty." Outcomes were reported as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Associations with unemployment included education less than high school (OR 6.05, 95% CI: 3.98-9.18) and high school (OR 3.80, 95% CI 2.78-5.21); severe vision difficulty (OR 3.68 95% CI 1.73-7.86); Asian race (OR 2.53, 95% CI 1.64-3.89); and Black race (OR 1.78, 95% CI 1.31-2.41). The odds of unemployment were marginally elevated for those living in large metropolitan areas, while being born in the United States had a modest protective effect (OR 0.53, 95% CI 0.42-0.66). CONCLUSION: The degree of visual impairment in this post-COVID-19 pandemic survey substantially affects employment, which is consistent with historical studies. Education among those with impaired vision is an important and modifiable variable that can positively influence the chances of employment.