Michele Beaconsfield

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 McNemars 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.

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.

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.

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.

Conjunctival epithelial cells maintain stem cell properties after long-term culture and cryopreservation

AIM Transplantation of tissue-engineered conjunctival epithelial cell sheets has proven to be a promising technique for conjunctival reconstruction. The ability to cryopreserve conjunctival epithelial cells and maintain their stem cell population would improve their availability for clinical use. The aim of this study was to evaluate whether cryopreservation and long-term in vitro culture has an effect on the proliferative capacity and the progenitor-like cell characteristics of conjunctival epithelial cells. METHOD Human conjunctival cells from bulbar biopsies were isolated and expanded on a growth arrested 3T3 feeder layer. The cells were evaluated for cytokeratin (CK4/CK19) expression by immunostaining. An aliquot with half of the cells from the initial culture was frozen in liquid nitrogen and stored for 14 days and, in addition, donor cells were cryopreserved for more than 6 months (202.7 +/- 13.0 days). Both cryopreserved and noncryopreserved cells were serially cultivated over four passages. For each passage the colony-forming efficiency and the cell population doubling rates were evaluated, and expression of putative progenitor cell markers, p63alpha and ABCG2, was assessed by immunostaining and reverse transcription PCR. RESULTS Both noncryopreserved and cryopreserved cells demonstrated a high colony-forming capacity that decreased with passage. Cells from both groups underwent approximately 20 cell population doublings before senescence. Immunoreactivity to p63alpha and ABCG2 was found in both groups until passage 4 and their presence was also confirmed by reverse transcription PCR. No difference in cell viability, colony-forming efficiency and immunoreactivity to p63alpha and ABCG2 was observed between cells cryopreserved for 14 days, and more than 6 months (202.7 +/- 13.0 days). CONCLUSION Conjunctival epithelial cells with progenitor cell-like characteristics can be efficiently cryopreserved and can subsequently maintain their function in vitro over several culture passages. The option to cryopreserve conjunctival cells prior to in vitro expansion would be an advantage when cells have to be cultivated for clinical transplantation.

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.

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.

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.

Subspecialty Adnexal Ophthalmological Examination Using Telemedicine

We studied the clinical outcome of examination of a group of patients with adnexal (eyelid and orbit) conditions. Seventeen patients with adnexal problems were assessed by an ophthalmologist at a distance using telemedicine, and then subsequently by an ophthalmologist in a face-to-face consultation. Measurements such as palpebral aperture, levator muscle function and eyelid skin crease position were recorded. The clinical outcomes from both consultations were recorded independently by the consultants and then compared. The study showed that certain adnexal conditions, such as congenital and involutional ptosis, could be accurately assessed using telemedicine, but that other conditions, such as socket problems in patients who had a previous enucleation or those with non-specific ocular pain with less clear-cut features, were better assessed in a face-to-face consultation. Overall, teleconsultations appeared to be suitable for the assessment of uncomplicated ptosis but not for less well defined conditions. Other factors, such as family dynamics and language problems, also limited the usefulness of the technique.