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Thyroid stimulating antibodies (TSAB) cause Graves’ disease and contribute to Graves’ Orbitopathy (GO) pathogenesis. We hypothesise that the presence of TSH binding proteins (truncated TSHR variants (TSHRv)) and/or nonclassical ligands such as thyrostimulin (α2β5) might provide a mechanism to protect against or exacerbate GO. We analysed primary human orbital preadipocyte-fibroblasts (OF) from GO patients and people free of GO (non-GO). Transcript (QPCR) and protein (western blot) expression levels of TSHRv were measured through an adipogenesis differentiation process. Cyclic-AMP production by TSHR activation was studied using luciferase-reporter and RIA assays. After differentiation, TSHRv levels in OF from GO were significantly higher than non-GO (p = 0.039), and confirmed in ex vivo analysis of orbital adipose samples. TSHRv western blot revealed a positive signal at 46 kDa in cell lysates and culture media (CM) from non-GO and GO-OF. Cyclic-AMP decreased from basal levels when OF were stimulated with TSH or Monoclonal TSAB (M22) before differentiation protocol, but increased in differentiated cells, and was inversely correlated with the TSHRv:TSHR ratio (Spearman correlation: TSH r = −0.55, p = 0.23, M22 r = 0.87, p = 0.03). In the bioassay, TSH/M22 induced luciferase-light was lower in CM from differentiated GO-OF than non-GO, suggesting that secreted TSHRv had neutralised their effects. α2 transcripts were present but reduced during adipogenesis (p &lt, 0.005) with no difference observed between non-GO and GO. β5 transcripts were at the limit of detection. Our work demonstrated that TSHRv transcripts are expressed as protein, are more abundant in GO than non-GO OF and have the capacity to regulate signalling via the TSHR.

Background: Previous in vitro experiments have demonstrated that prostaglandin F2-alpha (PF 2α ) reduced proliferation and adipogenesis in a murine cell line and human orbital fibroblasts derived from subjects with inactive Graves' orbitopathy (GO). The objective of this study was to determine if the PGF 2α analogue bimatoprost is effective at reducing proptosis in this population. Methods: A randomized controlled double-masked crossover trial was conducted in a single tertiary care academic medical center. Patients with long-standing, inactive GO but persistent proptosis (>20 mm in at least one eye) were recruited. Allowing for a 15% dropout rate, 31 patients (26 females) were randomized in order to identify a treatment effect of 2.0 mm (p = 0.05; power 0.88). Following informed consent, participants were randomized to receive bimatoprost or placebo for three months, after which they underwent a two-month washout before switching to the opposite treatment. The primary outcome was the change in exophthalmometry readings over the two three-month treatment periods. Results: The mean exophthalmometer at baseline was 23.6 mm (range 20.0-30.5 mm), and the mean age of the patients was 55 years (range 28-74 years). The median duration of GO was 7.6 years (interquartile range 3.6-12.3 years). The majority were still suffering from diplopia (61.3%) with bilateral involvement (61.3%). Using multi-level modeling adjusted for baseline, period, and carry-over, bimatoprost resulted in a -0.17 mm (reduction) exophthalmometry change ([confidence interval -0.67 to +0.32]; p = 0.490). There was a mean change in intraocular pressure of -2.7 mmHg ([confidence interval -4.0 to -1.4]; p = 0.0070). One patient showed periorbital fat atrophy on treatment, which resolved on stopping treatment. Independent analysis of proptosis by photographic images (all subjects) and subgroup analysis on monocular disease (n = 12) did not show any apparent benefit. Conclusions: In inactive GO, bimatoprost treatment over a three-month period does not result in an improvement in proptosis.

Background: Standard treatment for thyroid eye disease is with systemic corticosteroids. We aimed to establish whether orbital radiotherapy or antiproliferative immunosuppression would confer any additional benefit. Methods: CIRTED was a multicentre, double-blind, randomised controlled trial with a 2 × 2 factorial design done at six centres in the UK. Adults with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were recruited to the trial. Patients all received a 24 week course of oral prednisolone (80 mg per day, reduced to 20 mg per day by 6 weeks, 10 mg per day by 15 weeks, and 5 mg per day by 21 weeks) and were randomly assigned via remote computerised randomisation to receive either radiotherapy or sham radiotherapy and azathioprine or placebo in a 2 × 2 factorial design. Randomisation included minimisation to reduce baseline disparities in potential confounding variables between trial interventions. Patients and data analysts were masked to assignment, whereas trial coordinators (who monitored blood results), pharmacists, and radiographers were not. The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in ten to 12 fractions over 2 to 3 weeks. Azathioprine treatment was provided for 48 weeks at 100–200 mg per day (dispensed as 50 mg tablets), depending on bodyweight (100 mg for interaction=0·86). The adjusted odds ratio (ORadj) for improvement in the binary clinical composite outcome measure was 2·56 (95% CI 0·98–6·66, p=0·054) for azathioprine and 0·89 (0·36–2·23, p=0·80) for radiotherapy. In a post-hoc analysis of patients who completed their allocated therapy the ORadj for improvement was 6·83 (1·66–28·1, p=0·008) for azathioprine and 1·32 (0·30–4·84, p=0·67) for radiotherapy. The ophthalmopathy index, clinical activity score, and numbers of adverse events (161 with azathioprine and 156 with radiotherapy) did not differ between treatment groups. In both groups, the most common adverse events were mild infections. No patients died during the study. Interpretation: In patients receiving oral prednisolone for 24 weeks, radiotherapy did not have added benefit. We also did not find added benefit for addition of azathioprine in the primary analysis; however, our conclusions are limited by the high number of patients who withdrew from treatment. Results of post-hoc analysis of those who completed the assigned treatment suggest improved clinical outcome at 48 weeks with azathioprine treatment. Funding: National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity.

Graves' orbitopathy (GO) is a disfiguring/distressing, inflammatory autoimmune condition. This intractable problem is caused by expansion of the orbital contents around the eye by excessive fat generation (adipogenesis) and overproduction of extracellular matrix components, especially hyaluronan (HA) from preadipocytes/fibroblasts (PFs). Current immunosuppressive/antiinflammatory treatments are largely ineffective and have unpleasant side effects, and a better therapeutic strategy through understanding GO-associated pathological features is needed.Previously we identified depot-specific HA synthase 2 regulation (HAS2; major source of HA), which facilitates orbit-specific HA accumulation during adipogenesis, and targeting phosphatidylinositol-3-kinase/mechanistic target of rapamycin-complex-1 pathways blocked both pathological features. The current study revealed low expression levels of Forkhead box O (FOXOs; critical downstream effectors of phosphatidylinositol-3-kinase) in orbital PFs through adipogenesis compared with sc levels. We aimed to dissect the role of FOXOs in GO pathogenesis to identify nonimmunosuppressive targets for GO treatment.Human orbital and sc primary PFs were treated with small interfering RNA/chemical inhibitor (AS1842856) of FOXOs or FOXO enhancer trifluoperazine hydrochloride (TFP; Food and Drug Administration approved drug), in serum-free medium for 24 hours, or TFP treatment in adipogenic medium for 15 days.Quantitative PCR was used to measure HAS2 transcripts and the terminal adipogenesis differentiation marker lipoprotein lipase. HA accumulation in the medium was measured by an ELISA.Substantially increased or decreased HAS2/HA production was observed by inhibiting (small interfering RNA or chemical inhibitor) or enhancing (TFP) FOXO expression, respectively. TFP treatment is also sufficient to counteract thyrotropin receptor-activated HAS2/HA production and block adipogenesis in orbital PFs.FOXOs play a crucial repressor role in the regulation of HAS2/HA production and adipogenesis in orbital PFs. Our data reveal for the first time that resetting GO-associated pathological features through drug-targeted activation of FOXOs could provide a feasible nonimmunosuppressive therapeutic strategy for GO.

BACKGROUND/AIMS: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time.METHODS: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000.RESULTS: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, pCONCLUSIONS: These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.

Context: Graves' orbitopathy (GO) is caused by expansion of the orbital contents by excess adipogenesis and overproduction of hyaluronan (HA). Immunosuppressive and antiinflammatory treatments of GO are not always effective and can have side effects, whereas targeting GO-associated tissue remodeling might be a more logical therapeutic strategy. Previously we reported that signaling cascades through IGF1 receptor and thyrotropin receptor within orbital preadipocytes/fibroblasts drove adipogenesis and HA production. Our current study combined the stimulation of IGF1 receptor and thyrotropin receptor increase of HA accumulation, which we hypothesize is by activation of phosphatidylinositol 3-kinase (PI3K)-1A/PI3K1B, respectively. The central aim of this study was to investigate whether PI3K/mammalian target of rapamycin complex 1 (mTORC1) inhibitors affected adipogenesis and/or HA production within orbital preadipocyte/fibroblasts. Methods: Human orbital preadipocytes were treated with/without inhibitors, LY294002 (PI3K1A/mTORC1), AS-605240 (PI3K1B), or PI103 (PI3K1A/mTORC1) in serum-free medium for 24 hours or cultured in adipogenic medium for 15 days. Quantitative PCR was used to measure hyaluronan synthases (HAS2) transcripts and the terminal adipogenesis differentiation marker lipoprotein lipase. HA accumulation in the medium was measured by an ELISA. Results: Unlike AS-605240, both LY294002 (10 μM) and PI-103 (5 μM) significantly decreased HAS2 transcripts/HA accumulation and adipogenesis. Because PI-103 and LY294002 are dual PI3K/mTOR inhibitors, we investigated the inhibition of mTORC1 (rapamycin 100 nM), which significantly decreased adipogenesis but had no effect on HAS2 transcripts/HA, implicating PI3K-1A in the latter. Conclusions: The combined inhibition of PI3K1A and mTORC1 signaling in vitro decreased both HA accumulation and adipogenesis. Because PI3K and mTOR inhibitors are clinically used to treat other conditions, they have the potential to be repositioned to be used as an alternative nonimmunosuppressive therapy of GO.

Lacrimal gland lesions have diverse pathologies. Bone remodelling on imaging may suggest a benign lacrimal gland pleomorphic adenoma (LGPA) rather than a malignant process. The authors report a case of malignant pleomorphic adenocarcinoma, which was misdiagnosed clinico-radiologically as a benign LGPA. Lesions with bone remodelling on CT imaging were subsequently analysed amongst a cohort of 31 lacrimal gland lesions from a single tertiary centre. 31 lacrimal gland lesions biopsied over a ten-year period featured bone remodeling on CT scan, typical of LGPA. Three diagnoses were of pleomorphic adenocarcinoma. Two of these cases presented classically with unilateral painful eyelid swelling and bone destruction or bone erosion on CT scan. Seven patients (23%) in this ten-year period had bone remodeling on CT scan, typical of LGPA. Of these seven cases, three were LGPA, but the other four cases were a mixture of other diagnoses. Clinical and radiological suspicion of LGPA may be inaccurate and requires prompt histological diagnosis to facilitate appropriate further treatment and prognosis.

High-dose cytosine arabinoside (Ara-C) is known to cause keratoconjunctivitis in a large proportion of patients. Topical steroids are a popular choice of prophylactic treatment. The objective of this survey was to evaluate the type, dose, frequency and duration of drops used in all centres (n = 117) participating in the acute myeloid leukaemia trial 15 (AML 15), and to assess adherence to the trial protocol prescribed guidelines. All centres used prophylactic treatment; however, the dose of Ara-C at which it was initiated varied from 100 to 6000 mg/m(2)/day. All centres used some form of steroid prophylaxis with prednisolone 0.5% being the most commonly used (98/117), but only 6 of the 117 centres initiated treatment at doses recommended in the trial protocol. Ten centres used lubricants in addition to steroids. No centre reported the use of non-steroidal anti-inflammatory drops. The duration of treatment ranged from 2 days prior to commencing Ara-C to 28 days post-treatment. Twenty-two centres reported complications of which preservative allergy was the commonest. There is a large variation in prophylactic treatment practice in the UK. Clear guidance on the use of prophylaxis and further studies are required to ascertain the most effective prophylactic treatment and regimen.

Apart from evaluating orbital inflammation in Graves’ ophthalmopathy (GO), somatostatin (SST) analogs have been proposed as a therapy, but recent trials were disappointing. We aimed to measure somatostatin receptor (SSTR) expression in orbital tissues ex vivo and determine whether the new broad-affinity analog SOM230 might be of therapeutic use. Orbital adipose/connective tissues from 29 GO patients and 10 normal individuals were analyzed. Transcripts were quantified using SYBR Green and a light cycler. In vitro models were used to investigate whether thyrotropin receptor activation (as occurs via thyroid stimulating antibodies) or adipogenesis affected SSTR expression in primary preadipocytes and to compare the biological activity of octreotide and SOM230 in their modulation. The expression of SSTR1 was significantly higher in GO patients than normal controls ( P = 0.024). Although differences in the expression of SSTR2 were not significant, 39% of GO samples had levels above the 97th percentile of the controls. SSTR3, -4, and -5 were at or below the limit of detection (LOD). The lymphocyte contribution was minimal, since CD3α transcripts were at the LOD. TSH receptor activation did not modulate SSTR expression. An in vitro model of adipogenesis indicated upregulation of SSTR1 and SSTR2 during differentiation. SOM230 produced significantly greater inhibition of orbital preadipocyte proliferation than octreotide. Ex vivo analysis of orbital tissues reveals upregulation of SSTR1 and -2 in a group of GO patients. Adipogenesis, a process occurring in GO orbits, provides one possible explanation for some of the observed increase.

Introduction.Inverted papilloma (IP) is an uncommon, benign yet aggressive neoplasm characterised by high recurrence rates and tendency towards malignant transformation. The majority of IP cases originate in the ethmoid region, lateral wall of the nasal fossa, and maxillary sinus. The authors report a case of an IP originating primarily from the nasolacrimal duct (NLD).Case.A 69-year-old Caucasian gentleman presented with a lump in his right medial canthal region, epiphora, and discharge bilaterally. Radiological investigation revealed a well-defined, heterogeneous mass within the proximal NLD eroding the bony canal, protruding into the middle meatus and into the right orbit. The tumour was excised en bloc utilizing a combined external and endoscopic approach based on its location. Histology revealed hyperplastic ribbons of basement membrane-enclosed epithelium growing endophytically into the underlying stroma with no evidence of invasive malignancy. The patient made an uneventful recovery with unchanged visual acuity and normal extraocular movements.Conclusion.The case demonstrates variability within the sinonasal tract that IP can develop and the individuality of each case necessitating tailored operative techniques for complete excision whilst minimising recurrence rates. We also present a combined endoscopic approach for the en bloc resection of a NLD IP with no clinical recurrence at 15-month follow-up.

Purpose Current indications for orbital surgery primarily aimed at improving cosmesis are considered in the context of subspecialist orbital practice by an ophthalmologist. Scope Thyroid eye disease, orbital vascular anomalies, and dermolipomas are common orbital diseases in which the symptoms can be purely cosmetic. Accurate anatomical awareness, preoperative scanning, control of medical factors including smoking and thyroid status, and endoscopic techniques have all contributed to the aesthetic outcome of orbital surgery. The threshold for performing reconstructive orbital surgery has also been lowered by public demand. Conclusions Orbital surgeons can therefore offer the familiar techniques, such as orbital decompression, for pure cosmesis. Sensitive history taking and awareness of the psychological element are of paramount importance for the orbital surgeon who develops a cosmetic practice.

PURPOSE To describe a simple technique for involutional entropion correction and to present the findings of a pilot study. METHODS Consecutive case series of 42 procedures. Patients presenting with involutional entropion in the absence of lateral canthal tendon laxity (lateral canthus could be distracted 1 cm or more medially) underwent a modified full-thickness eyelid shortening combined with retractor plication. Main outcome measures were correction of entropion and cosmesis of the surgical site at final follow up. RESULTS At final follow up, 92% of patients had a satisfactory eyelid position with no recurrence of entropion and a cosmetically satisfactory scar. CONCLUSIONS This is a useful technique with a higher success rate than everting sutures and is particularly suitable for patients for whom rapid surgery is needed or a lateral canthotomy is best avoided.

The authors describe 3 patients with Graves orbitopathy who all have accessory orbital structures on orbital imaging. These structures are isodense on CT and isointense on MRI to the extraocular muscles and have a similar anatomical appearance to accessory extraocular muscles previously described in the literature. The authors propose that Graves orbitopathy involves these accessory muscles and makes them visible on imaging.

Orbital cellulitis due to presumed gas-producing organisms has been associated with poor visual prognosis. We report successful visual recovery in a 14-year-old boy with orbital cellulitis and gas in the orbit on CT scan. The patient was treated with intravenous antibiotics and prompt orbital decompression. Pus from the sinus aspirate and orbital drain grew H. influenzae and Gram-negative bacilli. Repeat orbital surgery with drainage of residual abscess was performed and the patient made a complete recovery.

To highlight the long-lasting benefit of 2–0 Prolene brow suspension for congenital ptosis. Retrospective case review of 38 paediatric cases at two centres in the United Kingdom. Six cases continue to have a successful functional and cosmetic result ranging from 6 to 10 years. Brow suspension with 2–0 Prolene can be long-lasting in some patients.

Context: Graves' orbitopathy (GO) is associated with Graves' disease, in which anti-TSH receptor (TSHR) autoantibodies (thyroid-stimulating antibodies) increase cAMP causing hyperthyroidism. Excess adipogenesis and hyaluronan (HA) overproduction [HA synthase 2 (HAS2) is the major source] expand the orbital contents causing GO. TSHR activation participates in both processes but an anti-TSHR monoclonal without TSAB activity also increased HA, suggesting the involvement of other cascades. Objective and Patients Studied: We investigated using in vitro models in which preadipocytes/fibroblasts from human orbital (n = 12) and sc (n = 10) adipose tissues were treated with IGF-I (to probe the pAkt pathway, recently identified as a positive regulator of HAS2), TSH, and/or various inhibitors. Changes in HA during in vitro-induced adipogenesis were also evaluated. Main Outcome and Results: Adipogenesis in orbital preadipocytes was accompanied by significantly increased HAS2 transcripts and HA accumulation in contrast to sc cells in which differentiation significantly decreased HAS2 mRNA and secreted HA. Surprisingly, IGF-I alone did not increase HAS2 levels, despite significantly increasing the ratio of phosphorylated to total Akt; furthermore, an Akt inhibitor increased orbital (but not sc) HAS2 transcripts. A stimulatory effect of IGF-I on HAS2 transcripts was revealed by addition of rapamycin in sc but by a MAPK kinase inhibitor in orbital fibroblasts. Conclusions: The results have several possible explanations including a phosphorylation-dependent repressor of HAS2 transcript accumulation, exclusively in the orbit. The difference in control of HAS2 expression allows the activation of one of the mechanisms underlying GO, adipogenesis, to be linked biologically with the second, HA overproduction.

The procedure of dacryocystectomy is described in a patient with Wegener's granulomatosis where bone preservation is essential for future reconstructive procedures. With the aid of canalicular clamps, viscoelastic substance is used to distend the lacrimal sac thereby facilitating easier dissection. We describe the use of canalicular clamping and injection of a viscoelastic substance into the lacrimal sac to facilitate easier dissection during dacryocystectomy.

Mohs’ micrographic surgery (MMS) is an effective means of margin control in the management of periocular basal cell carcinomas (BCC). We describe three cases of recurrent BCC that presented with progressive eyelid contracture after MMS. They illustrate high-risk factors for recurrence, namely large tumor size, medial canthal location, previous treatment, and aggressive histological features. Careful long-term surveillance with serial photography may identify early eyelid contracture and thus assist in the detection of recurrent BCC after MMS and improve patient outcome.

Luigi Bartalena, Lelio Baldeschi, Alison J. Dickinson, Anja Eckstein, Pat Kendall-Taylor, Claudio Marcocci, Maarten P. Mourits, Petros Perros, Kostas Boboridis, Antonella Boschi, Nicola Curro, Chantal Daumerie, George J. Kahaly, Gerasimos Krassas, Carol M. Lane, John H. Lazarus, Michele Marino, Marco Nardi, Christopher Neoh, Jacques Orgiazzi, Simon Pearce, Aldo Pinchera, Susanne Pitz, Mario Salvi, Paolo Sivelli, Matthias Stahl, Georg von Arx, and Wilmar M. Wiersinga

Laser photocoagulation of pig retina induced breakdown of the blood-retinal barrier, with the appearance of serum proteins in the vitreous as determined by sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting techniques. Vitreous from lasered eyes inhibited the proliferation of cultured retinal microvascular endothelial cells in comparison with vitreous from non-lasered control eyes, and the inhibitory effect in the lasered eyes persisted for at least seven days. Inhibition was specific for endothelial cells, since no effect was observed when retinal pericytes or Tenon's fibroblasts were the target cells. These results suggest that indirect scatter photocoagulation may induce regression of neovascularisation by causing breakdown of the blood-retinal barrier and thus releasing into the vitreous serum components which result in inhibition of retinal microvascular endothelial cell growth.

Aims: To report a new technique of tissue preparation, employing a marginal strip, following excision of eye-lid basal cell carcinomas (BCC) and to report the long-term results of BCCs excised using this technique. Method: Following excision of eye-lid BCC with a safety margin of 4 mm, a 1mm strip was excised along the whole perimeter from the margin of the freshly excised specimen. This marginal strip had intact conjunctival mucosa along one edge and skin along the other. The marginal strip and the central tumour mass were then fixed immediately in formal saline and subjected to conventional histopathology. Results: Of the 61 patients who completed a 5 years follow-up, the results of 28 eye-lid BCCs that were within 4mm of the lid margin are reported. The marginal strip was clear in 22 specimens and had presence of residual tumour in its margin in 6 specimens. The 6 cases were further managed by observation (2), further surgical excision using marginal strip (2) and by Mohs9 surgery (2). Conclusion: Marginal strip examines the entire resection margins analogous to Mohs9 technique and we recommend its use in lid margin where tarsus is present throughout the specimen and more than 4mm from the lid margin.

To improve management of patients with Graves’ orbitopathy, a multi-center collaborative approach is necessary in order to have large enough sample sizes for meaningful randomized clinical trials. This is hampered by a lack of consensus on how to investigate the eye condition. The European Group on Graves’ Orbitopathy aims to overcome this and has designed a preliminary case record form (CRF) to assess Graves’ orbitopathy patients. This form was used in this first multi-center study. Aim: To investigate patient characteristics and treatment strategies in 152 new consecutively referred patients with thyroid eye disease seen in nine large European referral centers. Methods: Newly referred patients with Graves’ orbitopathy were included who were seen between September and December 2000. Demographic data and a complete ophthalmological assessment were recorded. Results: One-hundred and fifty-two patients (77% females) were included. Diabetes was present in 9%, and glaucoma or cataract in 14% of patients. Forty percent were current smokers, 9% also had dermopathy, and only 33% reported a positive family history of thyroid disease. Mild eye disease was seen in 40%, moderately severe eye disease was seen in 33% and severe eye disease was seen in 28% of patients. Soft tissue involvement was the most frequent abnormality (seen in 75%), proptosis $ 21 mm was found in 63%, eye motility dysfunction in 49%, keratopathy in 16% and optic nerve involvement was found in 21% of patients. According to the clinical impression, 60% had active eye disease. Immunosuppressive treatment was planned more frequently in active patients (57/86; 66%) than in inactive patients (5/57, 9%; Chi-square 46.16; P , 0:02). There were no important differences among the eight centers regarding the severity and the activity of their patients. Conclusions: In view of the large number of patients recruited in only 4 months, multi-center studies in the eight EUGOGO centers appear to be feasible. European Journal of Endocrinology 148 491–495

Appropriate management of ocular surface exposure depends on understanding the pathogenesis in terms of the adnexal tissues, epithelial surfaces, motor and sensory innervation, tear film and sometimes the treatment. A primary aim of the oculoplastic surgeon is to protect the ocular surface and preserve vision. Proptosis, eyelid defects or immobility, eyelid malposition, impaired lacrimal gland secretion or drainage, meibomian gland dysfunction and reduced corneal sensation all compromise the ocular surface. Static and dynamic assessment of the eyelids is a vital part of the anterior segment examination. A simple examination routine for all patients should include comparison of orbital symmetry, infrequency of blink, excluding the presence of lagophthalmos on blink as well as gentle and forced eyelid closure with a check for orbicularis weakness. A test for the presence, direction and extent of the Bell's phenomenon followed by slit lamp examination for eyelid margin entropion or other malpositions, trichiasis, punctal patency and meibomian gland disease helps identify vulnerable corneal zones for exposure or staining. ### Static exposure Static eyelid defects may be congenital, such as coloboma, or acquired, as in surgical sequelae, facial palsy, periocular burns and ocular cicatricial pemphigoid. The detail of eyelid structure is important. Workshops on meibomian gland dysfunction have produced a series of reports, indicating a wide range of types of meibomian gland size, position and secretion; the report of the diagnosis subcommittee is particularly informative.1 …

Introduction The clinical diagnosis of dry-eye is confirmed by a suitable test of tear production and the technique commonly used today to diagnose dry eye is the Schirmer’s test (ST). Although the ST is easy to perform it gives variable results, poor reproducibility and low sensitivity for detecting dry eyes. Another test, the tear break up time (TBUT) is used to assess the stability of tears which if abnormal may also cause symptomatic dry-eye. We present the results of both these tests and a new test, which shows greater sensitivity than the ST in detecting aqueous tear deficiency. The fluorescein meniscus time (FMT) is a new test developed in conjunction with one of the authors (CL) and the Department of Ophthalmology at the University Hospital of Wales. The FMT is a measure of the rate at which a fluorescent tear meniscus is formed using 2% sodium fluorescein, a stopwatch and suitable illumination with a slit lamp. Method An open controlled study in 62 patients and 51 controls was conducted to compare the ability of ST, FMT and TBUT to detect dry-eye in a group of patients diagnosed with rheumatoid arthritis and symptomatic dry eyes for a minimum period of 6 months. A separate control group of 15 subjects was tested on three separate occasions to assess the reproducibility of the FMT test. Results All three tests showed a statistically significant difference between the patient and control populations; Mann–Whitney P < 0.001. There was a correlation between the right and left eye for all three tests in the control group (ST r2 = 0.77, FMT r2 = 0.98, TBUT r2 = 0.94). This correlation was markedly reduced for FMT and TBUT in the patient population and was in keeping with the symptoms reported as being worse on one side in a proportion of the patients (FMT r2 = 0.52, TBUT r2 = 0.54, ST r2 = 0.75). A correlation with age was also observed for all the three tests in the control group (ST r2 = 0.74, FMT r2= 0.92, TBUT r2 = 0.51), but not in the patient population (ST r2 = 0.06, FMT r2 = 0.18, TBUT r2 = 0.03). A significant correlation was observed between the ST and FMT in both the control (ST vs FMT r2 = 0.65) and patient population (ST vs FMT r2 = 0.44). There was no value greater than 200 seconds for FMT recorded in the control group. Using this value to define an abnormal FMT, 85% of the patients (72% of the eyes tested) had an abnormal result. This was in contrast to 35% of patients (26% of the eyes tested) with abnormal results detected by ST. Using ANOVA and Student’s paired t-test, there were no significant differences between the three sets of values recorded serially over 3 months to assess the reproducibility of the FMT. The average standard error of the mean was 2.72% and the average co-efficient of variation 4.07%. Conclusion Our study suggests that the FMT is a more sensitive test with good reproducibility compared to the Schirmer’s test. The FMT correlates with the ST and suggests that both tests measure aqueous tear deficiency. The FMT therefore is a better alternative to ST currently being used to test aqueous tear deficiency.

Purpose To evaluate the effects of steroid injections for periocular capillary hemangioma on adrenal function and body composition. Design Noncomparative, interventional case series. Participants Four patients with periocular hemangioma. Methods Four white female infants with sight-threatening periocular hemangiomata received a combination of steroid injections of triamcinolone and betamethasone. In the first 2 cases, injections were perilesional and in the other 2, intralesional. Main outcome measures The infants were monitored by serial measurements of basal serum cortisol concentrations, responses to the Synacthen stimulation test, measurement of growth and of weight gain, and, in one case, more detailed anthropometric measures of body composition. Results Prolonged suppression of circulating serum cortisol concentrations and cortisol responses to the Synacthen stimulation test were noted in 3 cases, and marked failure to thrive was noted in all 4 cases. Conclusions Adrenal suppression after steroid injection for periocular capillary hemangioma is a potentially life-threatening complication. Failure to thrive is also a frequent side effect of treatment. Ophthalmologists should undertake the above treatment in consultation with a pediatric endocrinologist.

Orbital cellulitis due to presumed gas-producing organisms has been associated with poor visual prognosis. We report successful visual recovery in a 14-year-old boy with orbital cellulitis and gas in the orbit on CT scan. The patient was treated with intravenous antibiotics and prompt orbital decompression. Pus from the sinus aspirate and orbital drain grew H. influenzae and Gram-negative bacilli. Repeat orbital surgery with drainage of residual abscess was performed and the patient made a complete recovery.

Stickler syndrome is a dominantly inherited disorder characterized by arthropathy, midline clefting, hearing loss, midfacial hypoplasia, myopia, and retinal detachment. These features are highly variable both between and within families. Mutations causing the disorder have been found in the COL2A1 and COL11A1 genes. Premature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding. These produce a characteristic congenital “membranous” anomaly of the vitreous of all affected individuals. Experience has shown that vitreous slit-lamp biomicroscopy can distinguish between patients with COL2A1 mutations and those with dominant negative mutations in COL11A1, who produce a different “beaded” vitreous phenotype. Here we characterize novel dominant negative mutations in COL2A1 that result in Stickler syndrome. Both alter amino acids in the X position of the Gly-X-Y triple-helical region. A recurrent R365C mutation occurred in two unrelated sporadic cases and resulted in the membranous vitreous anomaly associated with haploinsufficiency. In a large family with linkage to COL2A1, with a LOD score of 2.8, a unique L467F mutation produced a novel “afibrillar” vitreous gel devoid of all normal lamella structure. These data extend the mutation spectrum of the COL2A1 gene and help explain the basis for the different vitreous phenotypes seen in Stickler syndrome.

Thyroid eye disease (TED) has an autoimmune etiology, but the nature of the autoantigen that is the target of the initiating event remains unknown. A number of candidates have been proposed based on Western blotting, library screening, and deduction from sequence similarity. A strong favorite is the thyrotropin receptor (TSHR), which is the target of the thyroid stimulating antibodies (TSAB) of Graves' disease (GD). We have recently demonstrated TSHR transcripts in orbital adipose tissue from a patient with TED by Northern blot, transcripts in normal adipose tissue being at the limit of detection. We have shown that the transcripts are translated into protein by immunohistochemical analysis using two monoclonal antibodies to the TSHR generated by genetic immunization. TSHR immunoreactivity is associated with elongated cells with the appearance of a fibroblast, often adjacent to clusters of adipocytes, in orbital biopsies from patients with TED but not in strabismus or pseudotumor biopsies. In animal studies, we have transferred thyroiditis to naive BALBc and NOD mice, using T cells primed to the human TSHR, either using the receptor expressed as a bacterial fusion protein or by genetic immunization. The BALBc develop a Th2-type response to the receptor, but the NOD a Th1-type with thyrocyte destruction. Orbital pathology, edema, infiltration by mast cells and lymphocytes, and adipose accumulation was also induced in 68% of the BALBc but none of the NOD mice. Together these data indicate that the preadipocyte expresses the TSHR and that a Th2 autoimmune response to the receptor may be an initiating event in TED.

Thyroid associated ophthalmopathy (TAO) is generally considered to have an autoimmune pathogenesis but the target antigen has yet to be identified. It is most frequently associated with Graves’ disease and there is some logic in assuming that the same antigen, the thyrotropin receptor (TSHR), is the common link. Previous studies, mostly PCR based, aimed at investigating TSHR transcripts in the orbit, have yielded conflicting results, although there is circumstantial evidence for their presence in orbital fat. In this study, we have examined adult human adipose and muscle tissues from various locations, initially by PCR and subsequently by northern blot. We obtained the expected 610bp product in normal intestinal and orbital fat but not skeletal muscle, following two rounds of PCR amplification but only when reverse transcription used a TSHR specific primer. In northern blots, despite loading all of the RNA obtained from total normal orbital fat contents, TSHR transcripts were at the limit of detection and similarly for large samples of intestinal fat. The exception was RNA obtained from TAO orbital fat, in which TSHR transcripts of 4.6 and 1.7kb were clearly visible, as in the thyroid. We conclude that normal adult adipose tissues contain low levels of TSHR transcripts. In TAO, TSHR transcripts are elevated probably due to an increased number of cells, in particular of preadipocytes in orbital adipose tissue.

Angioid streaks with congenital hypertrophy of the retinal pigment epithelium: an association or a mere coincidence?

Cutaneous involvement from primary orbital lymphoma is uncommon. We report a patient with follicular lymphoma of the orbit who presented initially with cutaneous lesions clinically resembling lymphocytoma cutis which subsequently proved to be metastasis from the orbit. A 75 year old woman presented to the dermatologist with a 6–7 month history of lumps on the right and left ears. Examination revealed two soft erythematous nodules, 2–3 cm in diameter behind the right ear and similar symmetrical lesions in both conchal bowls (Fig 1⇓). There was no lymphadenopathy or hepatosplenomegaly. Full clinical examination, chest x ray, full blood counts, erythrocyte sedimentation rate, U&E, and liver function tests were normal. A biopsy was performed. The clinical impression was that of lymphocytoma cutis and the lesions were treated with intralesional steroids resulting in prompt resolution leaving behind only flat discoloured areas. However, histology showed a nodular dermal lymphoid infiltrate of centrocyte-like cells with only scanty scattered blasts. Immunophenotypically, the lesional cells were of B cell phenotype (CD20+, CD79a+, CD10+, bcl6+, CD5−, CD43−, CD23−), overall …

A retrospective study of 58 thyroid patients undergoing eyelid surgery for thyroid related lid malposition is reported. A treatment strategy is suggested, based on the results of this experience. The following points are stressed: (1) The importance of recognising and relieving the inferior rectus tethering component of upper lid retraction when present. (2) The usefulness of a scleral graft in lower lid retractor recession. (3) The inadequacy of lateral tarsorrhaphy in relieving lid retraction but its value in camouflage.

Over a thirteen year period forty patients underwent surgery to remove an orbital dermoid cyst. Cysts which became manifest after the age of three years were deeper and larger than most that were noted before that age. Three out of four epidermoid cysts appeared after the age of 17 years and had an intracranial component. The majority of cysts showed histological evidence of leakage and associated inflammation. It is our view that dermoid cysts should be totally excised because they gradually enlarge and cause inflammation and scarring in adjacent structures.

We describe a pars plana approach for transplantation of autologous retinal pigment epithelial cells from a peripheral chorioretinal biopsy to prepared Bruch's membrane at the posterior pole of the same eye. The technique has potential application in research and could be clinically applicable in the treatment of senile macular degeneration.

Orbital liposarcoma is a rare and usually unsuspected neoplasm. Over a five-year period three female patients aged 22, 71, and 77 years presented with primary myxoid liposarcoma of the orbit. The management of one patient was complicated by a history of orbital decompression for suspected thyroid eye disease. The tumour infiltrates locally beyond a deceptive pseudocapsule, and surgery has to be radical to be effective.

Panretinal photocoagulation was carried out in mini pigs in an attempt to elucidate the mechanisms involved in laser therapy. The effect of the vitreous from these eyes on the proliferation of retinal microvascular endothelial cells was then studied. Vitreous removed 4 days after panretinal photocoagulation had no effect on the proliferation of bovine retinal microvascular endothelial cells in basal medium but inhibited proliferation in growth medium. Control vitreous was mitogenic for the microvascular cells in basal medium but this effect was not observed in growth medium.

We have treated 26 retinal angiomas of less than 4.5 mm in size in 15 eyes using repeated applications of contiguous argon blue green laser burns. All except one of the angiomas regressed without a massive exudative response of treatment. Haemorrhage occurred in two cases but only affected the visual outcome in one eye. Traction retinal detachment persisted in 50% of the large angiomas, despite regression of the tumour.