Psychological aspects of living with an artificial eye.

PURPOSE: Artificial eye clinics address physical and aesthetic aspects of orbital prostheses, but psychological effects may not be formally addressed. In general, without effective coping mechanisms, stress can lead to anxiety and depression. This study aims to determine, in the context of having an artificial eye, whether coping strategies, as well as perception of illness and other demographic and clinical variables are associated with anxiety or depression. METHODS: Consecutive patients attending two artificial eye clinics were invited to participate in this audit. Participants completed questionnaires: HADS, Brief IPQ and Brief COPE. Variables with a correlation coefficient of ≥0.2 with anxiety or depression were included in regression modeling. The extent to which the participants' emotional and cognitive representations of their artificial eye related to feelings of anxiety and depression was determined. RESULTS: In the cohort of 208, clinically significant anxiety was present in 29.5% and clinically significant depression was present in 8.4%. Perceptions of the impact of the artificial eye and self-blame as a coping strategy were correlated with anxiety. Depression levels were higher when participants believed that their artificial eye had a greater impact on their life, when they lived alone, and when they used substances as a coping strategy. CONCLUSION: Significant levels of anxiety exist in those living with artificial eyes, with various coping strategies used. Addressing this and offering alternative coping strategies may improve patient well being and overall satisfaction.

MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma.

Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa-miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets.

Analysis of hedgehog signaling in periocular sebaceous carcinoma.

PURPOSE: Sebaceous carcinoma (SC) is a clinical masquerader of benign conditions resulting in significant eye morbidity, sometimes leading to extensive surgical treatment including exenteration, and even mortality. Little is known about the genetic or molecular basis of SC. This study identifies the involvement of Hedgehog (Hh) signaling in periocular SC. METHODS: Fifteen patients with periocular SC patients were compared to 15 patients with eyelid nodular basal cell carcinoma (nBCC; a known Hh tumor), alongside four normal individuals as a control for physiological Hh expression. Expression of Patched 1 (PTCH1), Smoothened (SMO), and glioma-associated zinc transcription factors (Gli1 and Gli2) were assessed in histological sections using immunohistochemistry and immunofluorescence (IF) techniques. Antibody specificity was verified using Western-blot analysis of a Gli1 over-expressed cancer cell line, LNCaP-Gli1. Semi-quantification compared tumors and control tissue using IF analysis by ImageJ software. RESULTS: Expression of the Hh pathway was observed in SC for all four major components of the pathway. PTCH1, SMO, and Gli2 were more significantly upregulated in SC (P < 0.01) compared to nBCC. Stromal expression of PTCH1 and Gli2 was observed in SC (P < 0.01). In contrast, stromal expression of these proteins in nBCC was similar or down-regulated compared to physiological Hh controls. CONCLUSIONS: The Hh signaling pathway is significantly more upregulated in periocular SC compared to nBCC, a known aberrant Hh pathway tumor. Furthermore, the stroma of the SC demonstrated Hh upregulation, in particular Gli2, compared to nBCC. Targeting of this pathway may be a potential treatment strategy for SC.

Merkel cell carcinoma of the eyelid: management and prognosis.

IMPORTANCE: The literature on Merkel cell carcinoma (MCC) of the eyelid remains scarce, and there has yet to be a study using the most up-to-date TNM staging system for this rare but aggressive tumor. OBJECTIVE: To analyze the TNM stage, management, and outcomes of patients with MCC of the eyelid. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series of 21 patients from 5 tertiary referral centers in the United Kingdom and Australia with primary MCC of the eyelid presenting at a median age of 77 years, with median follow-up of 54 months. Tumors were staged according to the American Joint Committee on Cancer, 7th edition, TNM criteria for eyelid carcinoma and MCC. MAIN OUTCOMES AND MEASURES: TNM stage, treatment modalities, and clinical outcome. RESULTS: The eyelid carcinoma TNM stages were T2aN0M0 for 5 patients, T2bN0M0 for 7 patients, T3aN0M0 for 4 patients, T3bN0M0 for 3 patients, T2bN1M0 for 1 patient, and T3aN1M0 for 1 patient. The MCC TNM stages were T1N0M0 for 12 patients, T2N0M0 for 7 patients, T1N1M0 for 1 patient, and T2N1M0 for 1 patient. One patient had a sentinel lymph node biopsy, and 8 patients underwent head/neck imaging. Eighteen patients underwent a wide local excision, 12 with a paraffin section and 6 with a frozen section. Two patients underwent Mohs surgery, 1 of whom required an orbital exenteration. Twelve patients (57%) received adjuvant radiotherapy, and 2 patients received chemotherapy. The local recurrence rate was 10%, the regional nodal recurrence rate was 10%, and the distant metastatic recurrence rate was 19%. The lowest T category tumor metastasizing to both regional nodes and distant locations was a T2a (eyelid TNM)/T1 (Merkel TNM) tumor measuring 8 mm. Two patients with T3a (eyelid TNM)/T2 (Merkel TNM) tumors died of metastatic MCC. CONCLUSIONS AND RELEVANCE: The majority of patients with MCC of the eyelid present with localized eyelid disease of T category T2 (eyelid TNM)/T1 (Merkel TNM). A wide local excision with margin control remains the mainstay of treatment, whereas the use of radiotherapy is institution specific. Tumors with a low T category are associated with regional nodal and distant metastatic disease. It may therefore be reasonable to consider a sentinel lymph node biopsy or strict regional lymph node surveillance for all MCCs of the eyelid, regardless of T category or size.

Evaluation of human MRC-5 cells as a feeder layer in a xenobiotic-free culture system for conjunctival epithelial progenitor cells.

PURPOSE: Aim of this study was to evaluate the efficiency of human MRC-5 cells to act as a feeder layer for conjunctival epithelial cells in order to develop a complete xenobiotic-free culture system for the expansion of conjunctival epithelial progenitor cells for clinical applications. METHODS: Human conjunctival epithelial cells were expanded from a bulbar biopsy, in a completely xenobiotic-free culture system using growth arrested MRC-5 cells as a feeder layer, without (MRC-5/No Serum) and in the presence of 5% (MRC-5/HS 5%) or 10% (MRC-5/HS 10%) human serum. The total cell count, the surface area as well as the total colony-forming efficiency (CFE), the percentage of aborted colonies and the expression of putative progenitor cell markers p63α, ABCG2, CK15 was compared to the gold standard culture system (GS) in which growth arrested 3T3 feeder cells and feotal calf serum were used. RESULTS: The epithelial cell count revealed significantly less proliferation in the MRC-5/No Serum group compared to the GS conditions. All groups showed immunoreactivity to CK19; however, more differentiated epithelial cells were observed in the MRC-5/No Serum- and MRC-5/HS 10%-group and less immunoreactivity to p63 α and ABCG2 was found in these groups compared to GS and MRC-5/HS 5% conditions. This was in accordance with CFE results, were the MRC-5/HS 5% group showed similar CFE results compared to the GS group, while in the MRC-5/No Serum- and MRC-5/HS 10%-group significantly lower CFE's were observed. CONCLUSIONS: Our results indicate that a completely xenobiotic-free culture system using MRC-5 cells as a feeder layer in combination with human serum can be successfully used to expand conjunctival epithelial cells with progenitor cell characteristics and might be a useful tool for the safe expansion of these cells for clinical use.

Changes in tarsal plate fibrillar collagens and elastic fibre phenotype in floppy eyelid syndrome.

BACKGROUND: The aims of this study are to investigate the expression of the main structural components of the tarsal extracellular matrix (ECM) in floppy eyelid syndrome (FES) focusing on elastic fibres and collagen types I and III, and also to identify possible cell-mediated inflammatory mechanisms in the pathogenesis of this condition. METHODS: A histopathological case control study was conducted using 30 upper lid specimens from patients with FES and 15 undiseased upper lid control specimens. Structural ECM components were assessed using a combination of immunctorial ataining ohistochemical and techniques including antibodies to collagens I and III, Verhöeff's iron haematoxylin, Gomori's aldehyde fuchsin and Lillie's oxidised aldehyde fuchsin. The contribution of different cellular components of the inflammatory response was investigated by immunohistochemical techniques using antibodies to CD3, CD20, CD68. Slide scoring was performed using a semiquantitative technique on an ordinal scale. Statistical analysis was performed using matched ordinal regression analysis. RESULTS: FES tarsal plate tissue demonstrated a decreased abundance of mature elastic fibres (P ≤ 0.001) and an increased abundance of oxytalan fibres (P = 0.006). Intensity of staining for collagens I (P = 0.012) and III (P < 0.001) was increased. No significant difference in the abundance of CD3, CD20 and CD68 expressing cells was identified. CONCLUSIONS: The findings of altered elastic fibre phenotype and collagen accumulation are consistent with an adaptive response to cyclic mechanical loading of the tarsal plate, rather than an aetiological feature. These findings are important in understanding how the tarsal ECM responds to mechanical loading.

Surgical technique: modified lateral tarsorrhaphy.

PURPOSE: The signs of thyroid eye disease include proptosis, eyelid retraction, and exposure of the ocular surface, resulting in a symptomatic and unsatisfactory aesthetic appearance. A number of surgical techniques have been proposed to treat the eyelid sequelae of thyroid eye disease, which vary in both complexity and potential complications; the authors propose a novel technique for correcting inferolateral scleral show. This technique is proposed for cases of mild inferior scleral show (2 mm or less). METHODS: This retrospective consecutive case series includes 7 eyes of 5 patients from 2003 to 2006. All patients underwent surgery by a single surgeon at Moorfields Eye Hospital, London, UK. The surgical technique is composed of 3 principal steps: 1) marking of intended lateral tarsorrhaphy, 2) gray line split and anterior lamella excision, and 3) suturing of upper and lower limbs of lateral canthal tendon/lateral ends of tarsal pates) and canthal angle reformation. RESULTS: Seven eyes of 5 patients underwent the procedure; all patients were women, and their mean age was 49.6 years (range 29-67). Mean inferior scleral show was reduced from 2.0 mm preoperatively (range 1.5-2.5) to 0.3 mm postoperatively (range 0.0-0.5) at 49-month follow up. There were no complications related to the surgical technique, and all patients were satisfied with the postoperative result. One patient with proptosis measuring 24 mm required 2-wall orbital decompression 20 months later. CONCLUSIONS: Patient selection is important for the effective use of the modified tarsorrhaphy technique and should be reserved for those with 2 mm or less of inferior scleral show. Two principal factors to be considered before this eyelid surgery and the use of a box suture in reformation of the lateral canthal angle are discussed. Although a number of surgical procedures are available to manage eyelid malposition secondary to thyroid eye disease, they vary in complexity and severity of complications. The modified tarsorrhaphy technique was effective in the treatment of a specific group of patients who had undergone previous orbital and eyelid surgery for thyroid eye disease.

Scleral contact lens usage in patients with complex blepharoptosis.

PURPOSE: To evaluate the efficacy of scleral contact lenses (ScCLs) as an alternative or as an adjunct to surgical correction for the management of complex ptosis. METHODS: A retrospective case-note review was used to determine the subjective function and cosmetic acceptability of the lenses. Digital photographs were taken, both with and without the lens in place; analytic software was used to assess the vertical height of the palpebral aperture (PA) and the upper margin-reflex distance. Three masked observers independently graded the photographs for cosmesis as "good," "moderate," or "poor." RESULTS: Ten patients (6 male) had been wearing ScCLs in 14 treated eyes for between 1 and 40 years (mean, 10.3 years; median, 3 years). Without a lens, the mean PA was 4.9 mm (median, 5.1 mm; range, 1.7-7.1 mm), increasing to 9.5 mm (median, 8.9 mm; range, 5.8-14.8 mm) with the lens in place (p < 0.005). Likewise, the upper margin-reflex distance increased from 0.39 mm (median, 0.03 mm; range, 0-2.4 mm) without a lens in place to 3.1 mm (median, 2.7 mm; range, 1.5-5.8 mm) with lens wear (p < 0.005). In 6 patients with unilateral ScCL wear, mean PA was 10.4 mm in the treated eye and 8.4 mm in the eye without a lens (p = 0.22). All patients who were wearing ScCLs long term found them to be both comfortable and cosmetically acceptable. On subjective grading of photographs, however, the cosmesis was judged as "good" in 22%, "moderate" in 64%, and "poor" in 14%. CONCLUSION: In some patients, ScCLs provide a well-tolerated and practical long-term solution to safely elevating the upper eyelid in which complex ptosis is present. The patients in our cohort seem to be satisfied with the cosmesis, although there are some limitations to this aspect when viewed subjectively.

Simulation of an in vitro niche environment that preserves conjunctival progenitor cells.

AIM: To evaluate a serum-free system where mitotically active subconjunctival fibroblasts were co-cultured with conjunctival epithelial cells to mimic a niche environment for conjunctival progenitor cells. METHODS: Human conjunctival epithelial cells were expanded in vitro and evaluated for their colony-forming efficiency and clonal ability. The cells were then transferred to a serum-free co-culture system and cultured in the presence of mitotically active subconjunctival fibroblasts (human conjunctival epithelial cells and human bulbar subconjunctival fibroblasts [HCEC-HCF]). Cells were evaluated by Ki67 staining, total colony-forming efficiency and the number of colonies with a surface area of more than 10 mm(2). The expression of putative progenitor cell markers p63α, ABCG2 and CK15, and the presence of MUC5AC- and periodic acid-Schiff-positive cells was compared with standard culture conditions (HCEC-3T3). RESULTS: Conjunctival epithelial cells cultured under HCEC-HCF and HCEC-3T3 conditions demonstrated strong immunoreactivity to p63α and ABCG2. Co-localization of CK15 and p63α revealed a subpopulation of CK15-positive cells under HCEC-3T3 conditions compared with only a few CK15-positive cells found under HCEC-HCF conditions. MUC5AC- and periodic acid-Schiff-positive cells were much more common under HCEC-3T3 conditions than under HCEC-HCF conditions. These results were confirmed by reverse transcription-PCR. Cells in HCEC-HCF conditions demonstrated a significantly higher total colony-forming efficiency and a significantly higher percentage of colonies with holoclone-like morphology. CONCLUSIONS: The simulation of a niche environment in vitro by co-culturing mitotically active subconjunctival fibroblasts with conjunctival epithelial cells supports the maintenance of conjunctival cells with progenitor cell characteristics and therefore might be a useful tool to expand conjunctival epithelial progenitor cells in vitro for clinical use.

Changes in fibroblast mechanostat set point and mechanosensitivity: an adaptive response to mechanical stress in floppy eyelid syndrome.

PURPOSE: Floppy eyelid syndrome (FES) is an acquired hyperelasticity disorder affecting the upper eyelid. The tarsal plate becomes hyperelastic with a loss of intrinsic rigidity. As a result, the eyelid is subjected to cyclic mechanical stress. This condition was used as a model to investigate changes in dynamic fibroblast contractility in the context of chronic cyclic mechanical stress. METHODS: Contractile efficiency was investigated in a free-floating, three-dimensional collagen matrix model. Intrinsic cellular force measurements and responses to changes in gel tension were explored using a tensioning culture force monitor (t-CFM). Gene expression differences between cell lines exhibiting differences in contractile phenotype were explored with a genome level microarray platform and RT-PCR. RESULTS: FES tarsal plate fibroblasts (TFs) showed an increased contractile efficiency compared with the control, and t-CFM measurements confirmed a higher intrinsic cellular force at plateau levels. Cyclic stretch/relaxation experiments determined that TFs in FES maintained a functional tensional homeostasis response but with an altered sensitivity, operating around a higher mechanostat set point. Gene expression array and RT-PCR analysis identified V-CAM1 and PPP1R3C as being upregulated in FES TFs. CONCLUSIONS: These changes may represent an adaptive response that allows tensional homeostasis to be maintained at the high levels of tissue stress experienced in FES. Gene expression studies point to a role for V-CAM1 and PPP1R3C in mediating changes in the dynamic range of mechanosensitivity of TFs. This work identifies FES as a useful model for the study of adaptive physiological responses to mechanical stress.

Long-term outcomes of surgical approaches to the treatment of floppy eyelid syndrome.

OBJECTIVE: To identify and describe the different procedures used in the treatment of floppy eyelid syndrome (FES) at Moorfields Eye Hospital and to evaluate their effectiveness. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 71 patients who had undergone surgery for FES over a 13-year period since 1995 at Moorfields Eye Hospital were recruited. Retrospective data from 7 patients were also included, providing data for 78 patients. METHODS: Patients underwent a full ocular examination. A survival analysis was determined by plotting Kaplan-Meier curves for each type of procedure encountered. Comparison of survival trends was made using a log-rank test. The possible effects of bias arising from bilaterality of the condition were investigated using a sensitivity analysis and a Cox regression analysis allowing for clusters. Tests for surgeon bias were made using the Fisher exact test. MAIN OUTCOME MEASURES: Recurrence of the condition. An assessment of recurrence was made clinically by 2 independent observers who were masked to the type of surgery the patient had undergone. RESULTS: Four different forms of surgical treatment were encountered: (1) Full-thickness wedge excision (FTWE) (26 patients, 33 procedures); (2) Upper lid lateral tarsal strip (LTS) (31 patients, 43 procedures); (3) Medial canthal (MC) and lateral canthal (LC) plication (15 patients, 19 procedures); (4) Medial tarsal strip (6 patients, 6 procedures). A total of 44 of 101 procedures had failed. Superior long-term survival outcomes of both LC/MC plication (P = 0.003) and upper lid LTS (P = 0.001) procedures over FTWE was demonstrated. However, survival comparison between the LC/MC plication and LTS groups did not achieve significance (P = 0.37). No significant difference in outcome between surgeon groups of equivalent experience was demonstrated (P = 0.18). No bias arising from bilaterality of the condition was identified. CONCLUSIONS: These data provide strong evidence of better survival outcomes in FES using the MC/LC plication and LTS procedures in comparison with the FTWE procedure. On the basis of experience from our unit, we recommend that the FTWE procedure be avoided as a form of treatment for FES in favor of the MC/LC plication, LTS, or medial tarsal strip procedure. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The associations of floppy eyelid syndrome: a case control study.

OBJECTIVE: To describe the demographic features of a large series of patients with floppy eyelid syndrome (FES) and to investigate the associations of the condition with keratoconus, obstructive sleep apnea-hypopnea syndrome (OSAHS), and a variety of upper and lower eyelid features. DESIGN: Case control study. PARTICIPANTS: The test group comprised 102 patients with FES. A control group of 102 patients were recruited from a diabetic retinopathy clinic and matched on a 1:1 basis on age, gender, and body mass index (BMI). METHODS: A full medical and ophthalmic history was taken. Patients also underwent a full ocular examination, including an assessment of upper and lower lid laxity and upper lid levator function. Keratoconus grading was made using the Oculus Instruments Pentacam imaging system (Oculus Optikgerate GmbH, Wetzlar, Germany). Patients were screened for OSAHS using the Epworth daytime somnolence score. Matched statistical analysis of dichotomous data was made using Mantel-Haenszel methods for odds ratios and McNemar's test. Analysis of continuous data was performed using a matched t test and tests for symmetry of larger tables were made using the McNemar-Bowker test. MAIN OUTCOME MEASURES: The significance of association of FES with keratoconus, OSAHS, smoking history, medial and lateral canthal laxity of the upper and lower lids, levator function, lash ptosis, and dermatochalasis. RESULTS: Significant associations were found between FES and OSAHS (P = 0.0008), keratoconus (P<0.0001), lash ptosis (P<0.0001), dermatochalasis (P = 0.02), upper lid medial canthal laxity (P = 0.02), upper lid distraction (P = 0.001), palpebral aperture (P = 0.004), and levator function (P = 0.005). CONCLUSIONS: Floppy eyelid syndrome seems to be a condition strongly associated with OSAHS and keratoconus. As well as providing a platform for an etiologic hypothesis for the condition, these findings should also encourage clinicians to be aware of these associations and to direct further treatment. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Floppy eyelid syndrome: stretching the limits.

Floppy eyelid syndrome is a distressing condition that can cause significant morbidity and vision loss. Many systemic and ocular associations have been proposed, most notably keratoconus and obstructive sleep apnea-hypopnea syndrome. Although conservative treatments can sometimes be effective, a wide variety of surgical treatments to tighten the upper eyelid have been described. The underlying pathogenesis remains elusive, although progress has been made in the identification of extracellular matrix changes in the tarsal plate. This systematic review discusses the issues surrounding ambiguities in the definition of floppy eyelid syndrome as well as what is currently known about its clinical features, ocular and systemic associations, pathological changes, and proposed theories of pathogenesis. In addition a critical discussion of the proposed surgical treatments and their reported success rates and follow-up times is provided.

Tissue engineering for conjunctival reconstruction: established methods and future outlooks.

Reconstruction of the conjunctiva is an essential part of ocular surface regeneration, especially if an extensive area or the whole ocular surface is affected, such as in patients with ocular cicatricial pemphigoid, Stevens-Johnson syndrome, toxic epidermal necrolysis, or chemical/thermal burns. In these situations, corneal reconstruction almost inevitably fails unless the conjunctival surface is first repaired and a deep fornix is restored. The growing field of tissue engineering and advances in stem cell research offer promising new alternatives for these challenges. This article reviews the present approaches for reconstruction of the conjunctival surface, considering the established strategies and new potential methodologies.

Pleomorphic lipoma of the orbit: a case series and review of literature.

OBJECTIVE: Pleomorphic lipomas are rare benign tumors that can resemble a variety of malignant soft tissue tumors on histologic examination. Six cases of patients with orbital pleomorphic lipoma, one of which was proven to be bilateral, are presented. DESIGN: Retrospective, noncomparative, interventional case series with clinicopathologic correlation. METHODS: Clinical and histologic review of 6 patients with pleomorphic lipomas of the orbit and histologic review of fat from 22 exenteration specimens and 20 other orbital procedures. MAIN OUTCOME MEASURES: Evidence of histologic abnormalities in histologic specimens. RESULTS: Pleomorphic spindle cells and multinucleated cells with nuclei arranged in a floret-like pattern were present in 7 specimens from 6 patients presenting with a clinical diagnosis of orbital fat prolapse, but there were no similar cell types present in the adipose tissue of 22 exenteration or 20 other orbital specimens. CONCLUSION: Pleomorphic lipoma may arise in the orbit, presenting as what was hitherto considered to be age-related epibulbar prolapse of orbital fat.