Histopathological Changes in Corneal Ectasia. / Histopathologische Veränderungen bei kornealen Ektasien.

Corneal ectasia comprises keratoconus, keratoglobus, pellucid marginal degeneration, and iatrogenic keratectasia. In all forms of corneal ectasia, there is a thinning of the cornea, usually accompanied by steepening of the cornea, leading to irregular astigmatism. Here, we provide an overview of histopathologic alterations of the various corneal ectasias. Furthermore, histologic changes after surgical procedures that are performed in severe cases of corneal ectasia, such as corneal cross-linking and penetrating keratoplasty (pKPL), as well as refractive surgical procedures that may lead to postsurgical ectasia are presented. In addition to a literature review, histopathologic archival material was reviewed and examined to illustrate the specific histologic changes.

On the Current Care Situation and Treatment of Ocular Mucous Membrane Pemphigoid in Germany. / Zur Versorgungssituation und konservativen Therapie des okulären vernarbenden Schleimhautpemphigoids in Deutschland.

BACKGROUND: Ocular involvement in mucous membrane pemphigoid (MMP) is relatively rare, with a prevalence of 25 cases per million population, equating to approx. 2,100 patients throughout Germany. Diagnosis can be difficult - especially in cases of isolated ocular involvement - and treatment can be complex and lengthy. Immunosuppressants or immunomodulatory drugs are often used. Due to the complexity of diagnosis and treatment, MMP patients are usually referred to specialized centers. The aim of this project was to evaluate the current care situation of patients with ocular MMP in Germany. METHODS: A paper-based survey was designed and sent to all university eye clinics and other specialized centers in Germany in April 2020. The survey asked about the existence of a specialized outpatient service, the total annual number of patients with MMP, the annual number of newly diagnosed patients, any interdisciplinary collaboration for diagnostic or therapeutic purposes, as well as the local and systemic therapy used. RESULTS: Of a total of 44 clinics, 28 (64%) responded, reporting a total average of 27 ± 42 (0 - 200) patients and 3.6 ± 2.2 (0 - 10) new cases per year. This corresponds to a total of 741 patients. Only nine (32%) of the responding clinics offer specialized MMP clinics. 93% of the centers collaborate with the local dermatology department. 79% perform serological and histological diagnostics in-house. About half of the centers (n = 16) apply a standardized treatment regime. Systemic glucocorticoids (66.7%) are most commonly used, followed by mycophenolate mofetil and dapsone (57.1%), rituximab (33.3%), azathioprine and cyclophosphamide (28.6%), as well as methotrexate (19.0%). The least frequently used treatment is intravenous immunoglobulin (14.3%). CONCLUSION: This survey of German ophthalmology departments obtained data from about one third of the estimated total cohort of all patients with MMP in Germany. These are presumed to be exclusively patients with at least one ocular involvement. The complex care of these patients is usually provided in collaboration with a dermatologist and with the use of systemic anti-inflammatory medication. Currently, an ophthalmological MMP register is being established to better record the epidemiology and care situation of this rare disease in Germany and to improve it in the long term.

[Ophthalmopathologic Aspects of Endophthalmitis]. / Endophthalmitis aus ophthalmopathologischer Sicht.

Endophthalmitis is one of the most severe ophthalmic emergencies. Most patients experience a permanent decrease in visual acuity after the event, but the eye can be preserved in most cases. However, when the eye is enucleated after endophthalmitis, ophthalmopathologic investigation of the globe with respect to the clinical history can provide valuable information regarding the ultimately frustrating course of the disease that can be helpful for the treatment of future patients. Often, valuable aspects also emerge with regard to the therapeutic approach. For example, in therapy-resistant fungal endophthalmitis the necessity of penetrating keratoplasty with a large graft diameter and possibly even removal of the lens including the capsular bag should be stressed. In the following, five enucleated eyes with a different spectrum of endophthalmitis, as well as different potential pathways of exogenous and endogenous endophthalmitis, are illustrated clinically and ophthalmopathologically. In summary, endophthalmitis requires urgent intervention; however, various differential diagnoses must be excluded. Histopathologic examination of enucleated eyes is helpful for understanding the course of the disease and may also have forensic significance.

Validation of the Newly Proposed World Health Organization Classification System for Conjunctival Melanocytic Intraepithelial Lesions: A Comparison with the C-MIN and PAM Classification Schemes.

PURPOSE: We sought to compare the sensitivity, specificity, accuracy, and interobserver agreement of the two most commonly used classification systems for conjunctival melanocytic intraepithelial lesions with the new World Health Organization (WHO) classification. DESIGN: Retrospective case series and evaluation of classification systems. METHODS: We reviewed the pathology and medical records of all patients who underwent a primary biopsy procedure for conjunctival primary acquired melanosis (PAM) at Wills Eye Hospital between 1974 and 2002 who had ≥36 months of follow-up. Data collected included age, sex, clinical findings, recurrence, and progression to melanoma. Twelve ophthalmic pathologists analyzed scanned hematoxylin and eosin-stained virtual microscopic slides using 3 classification systems: PAM, conjunctival melanocytic intraepithelial neoplasia, and the WHO 4th edition classification of conjunctival melanocytic intraepithelial lesions. Observer agreement, sensitivity, specificity, and diagnostic accuracy of each classification system were assessed. RESULTS: There were 64 patients who underwent 83 primary excisions with cryotherapy for conjunctival PAM who had adequate tissue for histopathologic evaluation. The interobserver agreement in distinction between the low- and high-grade lesions was 76% for PAM, 67% for conjunctival melanocytic intraepithelial neoplasia, and 81% for WHO classification system. Low-grade lesions provided the greatest interpretative challenge with all 3 classification systems. The 3 classification systems had comparable accuracy of 81%-83% in their ability to identify lesions with potential for recurrence. CONCLUSIONS: This study highlights the comparable strengths and limitations of the 3 classification systems for conjunctival melanocytic intraepithelial lesions and suggests that the simplified WHO classification scheme is appropriate for evaluation of these lesions.

The Willingness of Patients to Participate in an Eye Donation Registry for Research.

INTRODUCTION: For ophthalmologic research, the systematic correlation of clinical data with data obtained from postmortem tissue donation is of great benefit. In this respect, the establishment of an eye donation registry represents a prerequisite for the acquisition of such data. METHODS: A total of 300 patients were interviewed at a tertiary referral center in Germany by means of a standardized questionnaire. Binary questions were evaluated by percentage; Likert-scaled questions (1 = does apply; 5 = does not apply) were analyzed by the median and 25th (Q25) and 75th (Q75) percentiles. RESULTS: The majority of patients (77.0%) would agree to donate their eyes for research purposes. When asked about reasons against an eye donation, 60.9% of all patients only stated reasons in the category "addressable" (e.g., not enough awareness of the topic). The vast majority of patients considered it appropriate for an ophthalmologist to approach them on the issue of postmortem eye donation (median 1, Q25 1, Q75 1). CONCLUSION: Overall, patients had a positive attitude towards postmortem eye donation for research purposes. Importantly, reasons given against postmortem eye donation were often related to misconceptions and were potentially addressable. These results underline the fundamental willingness of ophthalmological patients in Germany to donate their eyes postmortem for research purposes.

[The history of an eye-Investigation of enucleated eyes]. / Die Geschichte eines Auges ­ Untersuchung enukleierter Bulbi.

BACKGROUND: A variety of findings can be obtained from enucleated eyes, which provide the ophthalmologist with information with respect to the effectiveness, improvement options and of course also the possible complications of surgical interventions. Representative for many important findings, relevant clinical and ophthalmopathological findings are presented and discussed on the basis of three enucleated eyeballs. METHODS: Clinical histopathological correlation of three enucleated eyeballs. RESULTS: Enucleated eyeballs typically exhibit advanced changes in different tissues making it sometimes difficult to draw direct conclusions about the original surgical interventions. Nevertheless, many findings on the pathophysiology of different diseases, on wound healing and also on the surgical procedures can be deduced, as shown here in three different cases of epithelial invasion, historical retinal surgery and an endogenous fungal endophthalmitis. CONCLUSION: Each enucleated eye should be histopathologically examined and under consideration of the clinical history in order to understand the course of the disease and to use the knowledge gained for the treatment of future patients.

[Ophthalmic Pathology - Still the Gold Standard?] / Goldstandard Ophthalmopathologie ­ noch zeitgemäß?

Ophthalmic pathology has a long tradition in Germany. And, like in general pathology, there is continuous progress due to new technologies and the improvement of molecular biology techniques. Ophthalmic pathology cannot be disregarded, particularly in the context of basic research but also as a medium for understanding pathophysiologic interrelationships and evaluating innovative surgical techniques. By means of various examples, the "four columns" of ophthalmic pathology shall be illustrated: diagnostics, clinicopathologic correlation, evaluation of new surgical and medical techniques and finally research. Ophthalmic pathology is not a discipline of the past but is rather one of the future. It develops and improves together with medical and ophthalmological progress and serves, at the same time, as a critical evaluation tool. Clinicopathologic correlations are of paramount importance for a lasting quality in ophthalmology, and we should not risk depriving ourselves of this instrument by carelessly saving at the wrong end and closing our laboratories. Ophthalmic pathology was, is and will further be the gold standard in many aspects of ophthalmology.

[Eyelid Tumors: Clinical Aspects of Ophthalmic Pathology]. / Lidtumoren: Klinische Aspekte der Ophthalmopathologie.

BACKGROUND: Lid tumors show a heterogenous clinical spectrum. Tumors which display some criteria of malignancy may histologically be diagnosed as inflammatory lesions without any neoplastic component. In contrast, malignant tumors can induce changes on the lid margin mimicking inflammatory changes. MATERIAL AND METHODS/RESULTS: Certain examples of lid tumors are shown to illustrate potential pitfalls as well as clinical unequivocal cases. The clinical appearance of the lesions is correlated with the histologic findings. CONCLUSION: Lid tumors can develop from different structures of the eyelid and, therefore, show a wide spectrum of clinical findings. If a malignant process is suspected or the clinical diagnosis cannot be unequivocally determined, a biopsy (incisional vs. excisional) is necessary followed by histologic evaluation. Furthermore, inadequately treated benign lesions, such as an incomplete excised nevus or a molluscum contagiosum, can lead to serious problems.

[Therapy Resistant Fusarium Keratitis with Intraocular Involvement - Potential Sources of a Persisting Infection]. / Therapieresistente Fusarienkeratitis mit intraokularer Beteiligung ­ potenzielle Quellen für eine persistierende Infektion.

BACKGROUND: Fungal keratitis shows a variable clinical picture and is therefore often diagnosed only late. Fungi in general are quite resistant organisms, and in addition treatment is difficult due to limited and specially manufactured medications. MATERIAL AND METHODS/RESULTS: We describe the unfavourable outcome in a young female patient with keratitis due to fusarium that ended - despite extensive medical and surgical treatment - in enucleation. Histologic examnination of the enucleated globe revealed massive (post-)inflammatory changes throughout the anterior segment but only few persistent fungal elements that were found in the lens capsule (after phacoemulsification) and the peripheral Descemet's membrane. CONCLUSION: Fungus as the pathogenic agent in therapy-resistent keratitis should be included in the differential diagnosis as early as possible. Should surgical interventions become necessary, a keratoplasty as large as possible and removal of the lens capsule should be considered in order to eliminate potential reservoirs for the causative organism.

Assessment of the integrin alpha5beta1 antagonist JSM6427 in proliferative vitreoretinopathy using in vitro assays and a rabbit model of retinal detachment.

PURPOSE: To explore the role of integrin alpha5beta1 in proliferative vitreoretinopathy (PVR) pathogenesis by evaluating the expression alpha5beta1 on ARPE-19 cells and patient proliferative membranes, quantifying the inhibitory effects of JSM6427 (a small molecule alpha5beta1 inhibitor) on ARPE-19 cell adhesion and migration, and assessing the therapeutic potential of JSM6427 in a rabbit retinal detachment model. METHODS: Expression of alpha5beta1 was evaluated on activated ARPE-19 cells by flow cytometry and on PVR membranes by immunohistochemistry. ARPE-19 cells were used in fibronectin-dependent adhesion and migration assays with various concentrations of JSM6427; IC(50) was calculated. In the rabbit model, eyes were intravitreally injected with vehicle or JSM6427 on day 0 or 1 after retinal detachment; BrdU was administered intravitreally on day 3, and retinal tissues were harvested on day 3 (4 hours later) or 7. Retinal scarring, cellular proliferation, and inflammatory responses were quantified, and retinal morphology was analyzed in retinal sections. RESULTS: Activated ARPE-19 cells and PVR membranes expressed high levels of alpha5beta1; expression was low in control eyes. JSM6427 provided a dose-dependent blockade of ARPE-19 cell adhesion to fibronectin (IC(50), 7.1 +/- 2.5 microM) and inhibition of migration (IC(50), 6.0 +/- 4.5 microM). In the rabbit model, intravitreal injection of JSM6427 provided significant inhibition of proliferation of retinal cells (Müller cells, microglia, and macrophages) on days 3 and 7 after detachment and inhibition of inflammatory response and retinal scarring on day 7 after detachment. CONCLUSIONS: JSM6427 is a promising treatment for PVR, with data suggesting that inhibition of alpha5beta1-fibronectin interactions addresses multiple pathways involving retinal pigment epithelial, glial, and inflammatory cells.

Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit models of choroidal neovascularization.

OBJECTIVE: To evaluate the pharmacologic activity and tolerability of JSM6427, a potent and first selective small-molecule inhibitor of integrin alpha5beta1, in monkey and rabbit models of choroidal neovascularization (CNV). METHODS: JSM6427 selectivity for alpha5beta1 was evaluated by in vitro binding assays while the ability of JSM6427 to inhibit CNV was investigated in a laser-induced monkey model and a growth factor-induced rabbit model. Intravitreal injections of JSM6427 (100, 300, or 1000 microg) or vehicle were administered immediately after the CNV induction procedure and at weekly intervals for 4 weeks. Fluorescein angiography was performed weekly. Ocular tolerability was evaluated ophthalmoscopically and histologically in both models; additional assessments in monkeys included electroretinography, biomicroscopy, pathological examination, and analysis of JSM6427 pharmacokinetics. RESULTS: JSM6427 was highly selective for the alpha5beta1-fibronectin interaction. Weekly intravitreal injections of JSM6427 resulted in a statistically significant dose-dependent inhibition of CNV in laser-induced and growth factor-induced models without any ocular JSM6427-related adverse effects. JSM6427 was cleared through the systemic circulation with no evidence of systemic accumulation. CONCLUSIONS: Intravitreal JSM6427 provided dose-dependent inhibition of CNV in monkey and rabbit experimental models. CLINICAL RELEVANCE: JSM6427 may provide a new approach for the treatment of ocular neovascular diseases such as age-related macular degeneration in humans.

Immunohistochemical localization of angiotensin-converting enzyme, angiotensin II and AT1 receptor in human ocular tissues.

We investigated the immunohistochemical distribution of 3 components of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE), angiotensin II (AngII) and AT1 receptor (AT1), in the human eye. ACE and AngII were localized to nonpigmented epithelial cells of the ciliary body, to endothelial and epithelial cells of the cornea, to epithelial cells of the conjunctiva and to trabecular meshwork cells in the anterior part of the eye. In the posterior part of the eye, ACE and AngII were localized to ganglion cells, some cells in the inner nuclear layer, photoreceptor cells and to endothelial cells of the retinal and choroidal vessels. The overall intensity of AT1 immunoreactivity was weak in all ocular tissues, but the main localization was in ganglion cells. As a preliminary investigation, we were able to include 2 Alzheimer's disease (AD) cases. In AD, no differences from controls were found in the cellular distribution and staining intensity of all 3 antigens. The manifold localization sites of the observed antigens point to rather generalized functions of the RAS in human ocular tissues, such as regulatory effects on neuronal cells, vessels and vitreous humor homeostasis.

[Histopathology of herpetic corneal endotheliitis - a case report]. / Histopathologische Befunde bei herpetischer Endotheliitis corneae - eine Kasuistik.

BACKGROUND: Clinically, corneal endotheliitis is characterized by endothelial cell edema associated with immune precipitates. It is supposed to be triggered by a humoral or cellular immunologic reaction against antigens of the corneal endothelium. As yet, only few histopathologic studies of this disease have been performed. PATIENT: A 42-years-old patient developed a complete corneal nebula with neovascularizations due to relapsing herpetic keratitis. He underwent perforating keratoplasty. The inflammatory infiltrate lining Descemet's membrane and the corneal endothelium consisted mostly of CD 45 R0-positive T-lymphocytes with only few neutrophils, macrophages and CD 20-positive B-lymphocytes. We could not demonstrate any viral particles in the removed corneal tissue by either electron microscopy or using antibodies against Herpes simplex type I or II. CONCLUSIONS: Histologically, herpetic endotheliitis appears to correspond to corneal endotheliitis due to graft rejection. Complete virus particles are not necessarily required in case of long-standing inflammation and corneal neovascularizations.