Factors associated with ocular surface disease and severity in adults with atopic dermatitis: a nationwide survey.

BACKGROUND: Ocular surface diseases (OSDs), including conjunctivitis and blepharitis, are common in atopic dermatitis (AD) patients, but the magnitude and patient characteristics are unclear. OBJECTIVES: To examine the prevalence of OSDs in adults with AD and identify patient characteristics and risk factors. METHODS: We designed a cross-sectional questionnaire-based survey and sent it via a secure public mail to all adult Danes with a hospital diagnosis of AD (ICD-10 code L20.x) registered in the National Patient Register (n = 16 718) between 2000 and 2019 and 7044 (42%) participated. Primary outcomes were OSDs and severity according to Ocular Surface Disease Index (OSDI). Adjusted odds ratios (aOR) were calculated with 95% confidence intervals (CIs) using logistic regression models. RESULTS: Respondents were mostly females and middle-aged (67.4%, mean [SD] age, 39.0 [15.5] years). Based on Patient-Oriented SCORing Atopic Dermatitis 49% had mild AD, 35% moderate, 10% severe and in 6% AD was inactive; 44.3% reported physician-diagnosed asthma bronchiale and 55.8% rhinitis. The lifetime prevalence of OSDs was 66.6% for conjunctivitis, 63.5% for hordeolum, 11.0% for blepharitis, 9.7% for keratitis, 2.0% for pterygium, 1.5% for symblepharon, 1.1% for keratoconus and 12.7% reported current conjunctivitis. Factors associated with lifetime occurrence of conjunctivitis included mild, moderate, and severe AD (aOR = 1.48 [95% CI, 1.02-2.14], aOR = 1.73 [95% CI, 1.19-2.53], aOR = 2.17 [95% CI, 1.42-3.21]), asthma bronchiale and rhinitis (aOR = 1.76 [95% CI, 1.49-2.07]), childhood-onset of AD (aOR = 1.34 [95% CI, 1.16-1.56]) and systemic AD treatment (aOR = 1.27 [95% CI, 1.08-1.50]). Use of soft and hard contact lenses (aOR = 2.15 [95% CI, 1.65-2.80], aOR = 3.35 [95% CI, 1.62-6.92]) were associated with lifetime occurrence of keratitis. Moderate and severe AD, asthma bronchiale and rhinitis were also associated with a higher OSDI level. CONCLUSIONS: This study identified important patient factors associated with OSDs. Clinicians should be attentive of ocular signs and symptoms in AD patients and ask about these.

Management of patients with ocular manifestations in vesiculobullous disorders affecting the mouth.

Pemphigoid and pemphigus diseases as well as Stevens-Johnson syndrome present as vesiculobullous disorders of the skin and may additionally involve both the oral cavity and the ocular surface. Ocular involvement ranges from mild irritation and dry eye disease to chronic conjunctivitis, symblepharon, eyelid malposition, ocular surface scarring and severe visual loss. In addition to diagnostic assessments, ophthalmologists must treat the dry eye and meibomian gland dysfunction components of these diseases using a stepladder approach, including eyelid hygiene and lubricants. Topical anti-inflammatory therapy is used to treat acute inflammatory exacerbations of the ocular surface, but it cannot prevent scarring alone. Intralesional antimetabolite therapy can cause regression of conjunctival pathology in selected cases. Hence, patients with vesiculobullous disorders should be managed by a multidisciplinary team representing ophthalmology, dermatology, otolaryngology, oral medicine and pathology, internal medicine and intensive care. Systemic treatments including corticosteroids, azathioprine, cyclophosphamide, cyclosporine and mycophenolate mofetil help control inflammation. Intravenous immunoglobulins, plasmapheresis and targeted antibody therapy can be used in selected, severe and treatment-resistant cases. Local surgical management may include debridement of pseudomembranes, lysis of symblepharon, amniotic and mucous membrane grafting as well as reconstructive procedures. Prospective, multicentre, international studies are recommended to further support evidence-based practice.

Bilateral oblique facial clefts, rudimentary eyes and hydrocephalus in an aborted equine foetus.

Knowledge of congenital malformations and their causes in horses is generally sparse. Such conditions require more scientific attention to improve their diagnostics and inform prevention strategies. Here, a unique syndrome of bilateral oblique facial clefts (meloschisis), rudimentary eyes and hydrocephalus is reported in an equine foetus spontaneously aborted at gestation day 224. The cause of abortion was considered to be intrauterine death caused by umbilical cord torsions and subsequent compromised blood flow, but the aetiology of the malformation could not be determined. A detailed history, which includes exposure to a range of pharmaceutical compounds during the early stages of pregnancy, is provided and emphasizes the need for accurate recording of treatments in pregnant animals.

A recurrent germline BAP1 mutation and extension of the BAP1 tumor predisposition spectrum to include basal cell carcinoma.

We report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.

Ophidian Spectaculitis and Spectacular Dysecdysis: A Histologic Description.

The histologic features of abnormal spectacles in 60 snakes from the 5 families of Boidae, Colubridae, Elapidae, Pythonidae, and Viperidae are described in a retrospective study conducted on specimens submitted to a private diagnostic service during a period of 15 years. Fifty-two snakes had inflammatory reactions in the spectacle. The stroma and outer epithelium of the spectacle were the layers most often involved in inflammatory disease. Lesions of the outer epithelium included edema, hyperkeratosis, and granulocyte infiltration occasionally with bacterial colonies and fungal elements. The stroma had infectious agents and inflammatory reactions in vessels and between the collagen fibrils. The inner epithelium had varying degrees of hyperplasia and hypertrophy, but no infectious agents were seen. Infectious agents in these cases included mites, bacterial disease, fungal disease, or a combination of bacterial and fungal disease. Special stains identified the bacteria most commonly involved to be Gram-positive cocci. Thirteen snakes had dysecdysis of the spectacle. Of these, 5 displayed a concurrent inflammatory reaction of the spectacle, while the remaining 8 snakes had extra keratin layers on a spectacle with an otherwise normal appearance. These keratin layers were attached to serocellular crusts located on the inner surface of the periocular scales. The cause for dyskeratotic lesions of the spectacle was not always apparent, and concurrent acariasis, other forms of dermatitis, trauma, suboptimal husbandry, and visceral disease were considered possible contributing factors. It was notable that only 4% of the submitted cases were found to have spectaculitis and/or spectacular dysecdysis.

Toxicity profiles of subretinal indocyanine green, Brilliant Blue G, and triamcinolone acetonide: a comparative study.

BACKGROUND: This study introduces a novel porcine model to examine the histopathological and electrophysiological consequences of retinotoxicity exerted by dyes commonly used for internal limiting membrane (ILM) staining. METHODS: Indocyanine green (ICG) 0.5 mg/ml, Brilliant Blue G (BBG) 0.25 mg/ml and triamcinolone acetonide (TA) 13 mg/ml was injected subretinally in 12 vitrectomized pig eyes. At 6 weeks, retinas were examined by multifocal electroretinography (mfERG), ophthalmoscopy, fluorescein angiograpy, histopathology, and apoptosis assay. RESULTS: mfERG responses were significantly lower in ICG-injected eyes than in healthy fellow eyes (p = 0.039). The ratio between injected eyes and healthy fellow eyes was lower in the ICG group than in the BBG (p = 0.009) and TA group (p = 0.025). No difference between BBG and TA existed. All retinas were reattached, and fluorescein angiographies showed a window defect corresponding to the injected areas but no blood-retina barrier break-down. Histopathology confirmed damage to the outer retina after ICG, but not after BBG and TA. No apoptosis was found at 6 weeks. CONCLUSIONS: Subretinal ICG induces histological and functional damage to the retina, suggesting that ICG should be used with caution in macular hole surgery, where subretinal migration can occur. In contrast, BBG and TA appear safe after subretinal injection.

[Beyond esthetics-Regenerative medicine for severe diseases of the adnexa oculi]. / Jenseits von Ästhetik ­ Regenerative Medizin bei schweren Erkrankungen der okulären Adnexe.

BACKGROUND: Restoration of eyelid and lacrimal functions are important steps on the way to an intact ocular surface. Clinically available substitute tissues or therapeutic options for eyelid reconstruction and lacrimal gland regeneration often reach their limits in patients with severe diseases of the adnexa oculi. Several approaches in regenerative medicine have been intensively researched and clinically tested in recent years. These range from reconstructive approaches with novel tissue matrices in the field of eyelid surgery to stem cell therapies to regenerate lacrimal gland function. MATERIAL AND METHODS: The state of the art in the current literature is presented and an overview of clinically applied or currently researched tissues for eyelid reconstruction is given. Furthermore, approaches in stem cell therapy of the lacrimal gland as well as own results are presented. RESULTS: Acellular dermis has been successfully used for eyelid reconstruction and represents a viable option in cases of limited availability of autologous tissue. In vitro grown cellular constructs or tissues with genetically modified cells have already been successfully applied in dermatology for the treatment of burns or severe genodermatoses. First studies on stem cell therapy for severe dry eye in Sjögren syndrome showed a safe and effective application of mesenchymal stem cells by injection into the lacrimal gland. CONCLUSION: Due to the limitations of currently available replacement tissues, there is a clinical need for the development of new materials for adnexa oculi reconstruction. Constructs grown in vitro with allogeneic and/or genetically engineered cells are slowly making their way into clinical practice. The efficacy and mode of action of stem cells in severe dry eye are subject matters of current clinical trials.

Attendance in a national screening program for diabetic retinopathy: a population-based study of 205,970 patients.

AIMS: A nationwide diabetic retinopathy (DR) screening program has been established in Denmark since 2013. We aimed to perform an evaluation of adherence to DR screenings and to examine whether non-adherence was correlated to DR progression. METHODS: The population consisted of a register-based cohort, who participated in the screening program from 2013 to 2018. We analyzed age, gender, marital status, DR level (International Clinical DR severity scale, none, mild-, moderate-, severe non-proliferative DR (NPDR) and proliferative DR (PDR)), comorbidities and socioeconomic factors. The attendance pattern of patients was grouped as either timely (no delays > 33%), delayed (delays > 33%) or one-time attendance (unexplained). RESULTS: We included 205,970 patients with 591,136 screenings. Rates of timely, delayed and one-time attendance were 53.0%, 35.5% and 11.5%, respectively. DR level at baseline was associated with delays (mild-, moderate-, severe NPDR and PDR) and one-time attendance (moderate-, severe NPDR and PDR) with relative risk ratios (RRR) of 1.68, 2.27, 3.14, 2.44 and 1.18, 2.07, 1.26, respectively (P < 0.05). Delays at previous screenings were associated with progression to severe NPDR or PDR (hazard ratio (HR) 2.27, 6.25 and 12.84 for 1, 2 and 3+ delays, respectively). Any given delay doubled the risk of progression (HR 2.28). CONCLUSIONS: In a national cohort of 205,970 patients, almost half of the patients attended DR screening later than scheduled or dropped out after first screening episode. This was, in particular, true for patients with any levels of DR at baseline. DR progression in patients with delayed attendance, increased with the number of missed appointments.

[Visual loss under silicone oil]. / Visusminderung unter Silikon.

Silicone oil is used as intravitreal tamponading agent in surgery for rhegmatogenous retinal detachment (RRD) cases complicated with proliferative vitreoretinopathy (PVR). Recently, a number of case series have appeared where profound central visual loss has been found in eyes after uncomplicated vitrectomy with silicone tamponade for RRD in eyes with seemingly good visual potential. Several reports have demonstrated the migration of silicone oil droplets into the retina and the optic nerve, others the widespread loss of myelinated optic nerve fibres. These reports are reviewed, and it is concluded that caution is warranted when silicone oil is used in eyes with good visual potential. Finally the additional danger of central visual loss should be taken into consideration when deciding to use silicone oil or gas as intravitreal tamponade.

Calcium-independent phospholipase A2 regulates retinal pigment epithelium proliferation and may be important in the pathogenesis of retinal diseases.

Calcium-independent phospholipase A2, group VIA (iPLA2-VIA) is involved in cell proliferation. This study aimed to evaluate the role of iPLA2-VIA in retinal pigment epithelium (RPE) cell proliferation and in retinal diseases involving RPE proliferation. A human RPE cell line (ARPE-19) was used to explore this role in vitro. Proliferating ARPE-19 cells had increased expression and activity of iPLA2-VIA. iPLA2-VIA was found in the nuclei of proliferating ARPE-19 cells, whereas in confluent ARPE-19 cells, with limited proliferation, iPLA2-VIA was primarily found in the cytosol. Inhibition of iPLA2-VIA decreased the rate of proliferation, whereas over expression of iPLA2-VIA increased the rate of proliferation. Using an experimental porcine model of RPE proliferation we demonstrated significant nuclear upregulation of iPLA2-VIA in proliferating RPE cells in vivo. We furthermore evaluated the expression of iPLA2-VIA in proliferative vitreoretinopathy (PVR). PVR membranes revealed nuclear expression of iPLA2-VIA in the RPE cells which had migrated and participated in the formation of the membranes. Overall, the present results point to an important role of iPLA2-VIA in the regulation of RPE proliferation suggesting that iPLA2-VIA may be considered as a possible pharmaceutical target in retinal diseases involving RPE proliferation and migration.

Primary lymphoma of the lacrimal sac: an EORTC ophthalmic oncology task force study.

AIM: To define the clinical and histopathological characteristics of primary lacrimal sac lymphoma in a predominantly white population. METHODS: Specimens of lacrimal sac lymphoma and follow up data were solicited from members of the Ophthalmic Oncology Task Force of the European Organization for Research and Treatment of Cancer (EORTC) and the European Ophthalmic Pathology Society (EOPS). Specimens were stained with haematoxylin and eosin and an immunohistochemical panel against leucocyte antigens was applied. Diagnosis was reached by consensus of five experienced pathologists according to the World Health Organization classification system. The histopathological findings were correlated with the clinical data. RESULTS: Of 15 primary lacrimal sac lymphomas, five (33%) were diffuse large B cell lymphoma (DLBCL), five (33%) were extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma), three were classified as "transitional MALT lymphoma," being in transition from MALT lymphoma to DLBCL, and two were unclassified B cell lymphomas. Nine of the patients were female, and the median age at the time of diagnosis was 71 years (range 45-95 years). The most frequent presenting symptoms were epiphora (85%), swelling in the region of the lacrimal sac (79%), and dacryocystitis (21%). All but one patient presented in stage I. Systemic spread occurred in three of nine patients (33%). The 5 year overall survival was 65%. CONCLUSIONS: DLBCL and MALT lymphoma are equally common in the lacrimal sac in contrast with the remaining periorbital and/or orbital region where MALT lymphoma predominates.

Epstein-Barr positive T-cell lymphoma in the ocular region.

PURPOSE: To present two cases of rapidly growing tumors in the ocular adnexa. Both tumors were Epstein-Barr virus (EBV) positive peripheral T-cell lymphoma. METHODS: Case 1 was a 60-year-old man with a non-tender ulcerating tumor involving the lateral third of both upper and lower right eyelid. Case 2 was a 55-year-old man with a swelling of the left eyelid expanding cranially and dislocating the left eye, resulting in proptosis and diplopia. Both patients underwent incisional biopsy that did not disclose the malignant nature of the tumors. Clinical evaluation resulted in suspicion of malignancy and surgical excision was performed. RESULTS: The tumors were found to be consistent with EBV-positive peripheral T-cell lymphoma. CONCLUSIONS: Peripheral T-cell lymphoma is uncommon but a diagnosis to be considered in a patient with a tumorous lesion in the eye region. Furthermore, peripheral T-cell lymphoma may be EBV-positive.

Uveal and conjunctival malignant melanoma in Denmark, 1943-97: incidence and validation study.

PURPOSE: To study the incidence of malignant melanoma in the ocular region in Denmark during the period 1943-97. METHODS: The patients were mainly identified through the Danish Cancer Registry. Age-period-cohort modelling of the incidence rates was done based on age at diagnosis, calendar period and birth cohort in 5-year groups and for each gender. RESULTS: The age-standardized incidence of malignant melanoma in the ocular region was 0.78 for men (N = 1327) and 0.65 for women (N = 1242) per 100,000 person-years. Calendar period and birth cohort had no effect on the incidence in the ocular region or in the topography subgroups choroid/ciliary body and conjunctiva. However, the incidence increased with birth cohort for iris melanomas. CONCLUSIONS: The incidence of malignant melanoma in the ocular region was stable in contrast to a major increase in cutaneous melanoma in Denmark during the period 1943-97. The incidence of iris melanomas increased substantially, whereas the rate was stable for choroid/ciliary body and conjunctival melanomas.

An unusual retinal vascular morphology in connection with a novel AIPL1 mutation in Leber's congenital amaurosis.

AIMS: To report a case of an unusual retinal vascular morphology in connection with a novel AIPL1 mutation in a patient with Leber's congenital amaurosis (LCA). METHODS: A patient with LCA and no light perception from birth had both eyes enucleated at the age of 22 years because of excruciating pain. Mutation analysis was performed on known LCA genes. The eyes were processed for casts of the vascular tree, routine histopathology, and electron microscopy. RESULTS: A novel H82Y (244C-->T) mutation and a H90D (286G-->C) polymorphism were detected in exon 2 of the AIPL1 gene. Both the cast and the histopathological examination showed dilated retinal vessels, mainly venules, primarily localised in the posterior pole. In the mid-peripheral retina the density of capillaries on the arteriolar side of the microcirculatory units was significantly decreased. The vascular system was seen to gradually attenuate towards the retinal periphery, and to stop at a zone located approximately 4 mm from the ora serrata along the whole circumference. In this zone pigmented aggregates characteristic of retinitis pigmentosa were seen to ensheath the retinal vessels. The photoreceptors were almost totally absent and retinal gliosis was present. A decreased number of ganglion cells and an increased vacuolisation of the nerve fibre layer were observed. The retinal pigment cells and Bruch's membrane appeared normal in all regions. CONCLUSION: An unusual retinal vascular morphology in an LCA patient is presented and possible pathogenic mechanisms of the findings are discussed.

Human papillomavirus in conjunctival papilloma.

AIM: To examine conjunctival papillomas for the presence of human papillomavirus (HPV) and koilocytosis. METHODS: Archival paraffin embedded tissue from 55 conjunctival papillomas was analysed for the presence of HPV by polymerase chain reaction and subsequent filter hybridisation. Histological sections of the 55 papillomas were evaluated for the presence of koilocytosis. RESULTS: HPV was present in 48 of 52 (92%) beta globin positive papillomas. HPV type 6/11 were found in 40 of 47 investigated papillomas and a double infection with HPV 6/11 and 16 was identified in a single papilloma. In six papillomas the HPV type could not be identified. Koilocytosis was present in 22 of 55 papillomas (40%). CONCLUSION: There is a strong association between HPV and conjunctival papillomas. HPV type 6/11 is the most common HPV type in conjunctival papilloma. The sensitivity of koilocytosis as an indicator of HPV in conjunctival papilloma is low.

Establishment and characterization of human uveal malignant melanoma xenografts in nude mice.

The purpose of this study was to develop a suitable animal model for the investigation of the pathogenesis and therapy of uveal malignant melanoma. Eight choroidal malignant melanomas from eight patients were transplanted into nude mice in an attempt to establish a serially transplantable tumour model. Tumour tissue blocks (2 x 2 x 2 mm) from enucleated eyes with choroidal malignant melanoma were transplanted subcutaneously into the flanks of nude mice. The growing tumours were measured and serially transplanted. The tumour samples were investigated by histology, immunohistochemistry and electron microscopy. Only one of the eight transplanted primary tumours (13%) was established as a xenograft in nude mice. Furthermore, the take rate of the transplantable tumour was low (13%). The growth of the tumour fitted a Gompertz function, and the calculated tumour volume doubling time was 54 days. The transplanted tumour cells were epithelioid and slightly larger than the primary tumour cells and had prominent nucleoli. However, the transplanted tumour retained a morphological appearance similar to that of the primary tumour. Immunohistochemical examinations demonstrated that the cells preserved the characteristic properties of malignant melanoma. However, the transplanted cells demonstrated vimentin reactivity, whereas the primary tumour cells were negative for vimentin. It can be concluded that a new experimental model of malignant uveal melanoma with tumours that were easy to observe and access was established in nude mice.

Immunohistochemical diagnosis of malignant melanoma of the conjunctiva and uvea: comparison of the novel antibody against melan-A with S100 protein and HMB-45.

A novel antibody A103, which recognizes melan-A/MART-1, has been found to be more sensitive than the antibody HMB-45, which recognizes gp100, in melanocytic lesions of the skin and might therefore also be useful in the diagnosis of uveal and conjunctival melanocytic lesions. In this study we compared the staining characteristics of anti-melan-A, anti-S100 protein and HMB-45 in 13 conjunctival, 11 iris and 37 ciliary and choroidal malignant melanomas. The ciliary and choroidal melanomas comprised 13 spindle cell (10 spindle B and three spindle A), 14 mixed cell and 10 epithelioid cell tumours. In the conjunctival melanomas the diagnostic sensitivity was 100% for anti-S100 and anti-melan-A and 85% for HMB-45. In the iris melanomas the sensitivity was 100% for anti-S100 and anti-melan-A and 55% for HMB-45. A high staining intensity of anti-melan-A was particularly noticed in iris melanomas. In the choroidal malignant melanomas, the spindle cell and mixed cell types showed a sensitivity of only 69-79% with all three antibodies. In the epithelioid cell type the sensitivity was 80% for anti-S100 and 100% for HMB-45 and anti-melan-A. In conclusion, anti-melan-A was found to be a useful addition to antibody panels for ocular melanocytic lesions. Anti-melan-A has a higher sensitivity than HMB-45 in conjunctival and iris melanomas, but the sensitivity is similar to HMB-45 in choroidal melanomas. Anti-melan-A stains in a very similar pattern to anti-S100, but the staining intensity of anti-melan-A is higher than that of anti-S100 in iris melanoma.

Reflexology and bronchial asthma.

Many asthma patients seek alternative or adjunctive therapies. One such modality is reflexology, whereby finger pressure is applied to certain parts of the body. The aim of the study was to examine the popular claim that reflexology treatment benefits bronchial asthma. Ten weeks of active or simulated (placebo) reflexology given by an experienced reflexologist, were compared in an otherwise blind, controlled trial of 20+20 outpatients with asthma. Objective lung function tests (peak flow morning and evening, and weekly spirometry at the clinic) did not change. Subjective scores (describing symptoms, beta2-inhalations and quality of life) and also bronchial sensitivity to histamine improved on both regimens, but no differences were found between groups receiving active or placebo reflexology. However, a trend in favour of reflexology became significant when a supplementary analysis of symptom diaries was carried out. It was accompanied by a significant pattern compatible with subconscious unblinding, in that patients tended to guess which treatment they had been receiving. No evidence was found that reflexology has a specific effect on asthma beyond placebo influence.

Immunohistochemical investigation of p53 and EGFR expression of oligodendrogliomas.

The biological behavior of oligodendrogliomas is somewhat unpredictable. A supplementing prognostic factor is, therefore, desirable. Thirty-two supratentorial pure oligodendrogliomas were studied immunohistochemically by exposing the tumors to a monoclonal antibody towards the p53 protein, and a polyclonal antibody against the epidermal growth factor receptor (EGFR). A mean p53 labeling index (% of tumor cells stained) of 8.6% and a weak EGFR expression in 18 of the oligodendrogliomas were found. Univariate analysis showed no correlation between p53, EGFR expression and prognosis. Multivariate analysis showed that age was a prognostic factor for survival.