Marco Nardi

Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO

Summary of consensus a. All patients with GO should (Fig. 1):Be referred to specialist centers;Be encouraged to quit smoking;Receive prompt treatment in order to restore andmaintain euthyroidism.b. Patients with sight-threatening GO should be treatedwith i.v. GCs as the first-line treatment; if the responseis poor after 1–2 weeks, they should be submitted tourgent surgical decompression.c. The treatment of choice for moderate-to-severe GO isi.v. GCs (with or without OR) if the orbitopathy isactive;surgery(orbitaldecompression,squintsurgery,and/or eyelid surgery in this order) should beconsidered if the orbitopathy is inactive.d. In patients with mild GO, local measures and anexpectant strategy are sufficient in most cases, buttreatment may be justified if QoL is affectedsignificantly. In memoriam This document is dedicated to the memory of MarkPrummel (1956–2005), one of the founders ofEUGOGO, who greatly contributed to expanding ourunderstanding of clinical and therapeutic aspects of GO.

Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy.

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

Cigarette Smoking and Treatment Outcomes in Graves Ophthalmopathy

Cigarette smoking is a risk factor for Graves ophthalmopathy [1]. Ophthalmopathy is more frequent and tends to be more severe in smokers than in nonsmokers [2]. Smoking may influence ophthalmopathy through direct irritative effects or by modulating immune reactions that occur in Graves ophthalmopathy [1]. Radioiodine therapy for Graves hyperthyroidism seems to be associated with an increased risk for progression of ophthalmopathy [3-5], but this view is not shared by all investigators [6, 7]. Discrepant results may be related to confounding variables, one of which may be smoking. Severe Graves ophthalmopathy can be treated with medical therapy, usually by glucocorticoids with or without orbital radiation therapy or by orbital decompression [8]. Results of medical treatment are not always satisfactory, and the reasons for nonuniform treatment outcome are not fully understood. We sought to determine whether cigarette smoking influences the untoward effects of radioiodine therapy on ophthalmopathy and the effectiveness of medical therapy for severe ophthalmopathy. Methods Patients Study 1 Study 1 included 300 patients receiving radioiodine treatment for Graves hyperthyroidism with mild or no ophthalmopathy. Mild ophthalmopathy was defined as proptosis less than 22 mm, intermittent or no diplopia, absence of optic neuropathy, and mild conjunctival and periorbital inflammation. Exclusion criteria were severe ophthalmopathy, large goiter requiring thyroidectomy, and contraindications to glucocorticoids. The 300 patients, who previously took part in a study analyzing the effect of radioiodine on ophthalmopathy [5], were assigned by computer-generated random numbers to treatment with radioiodine alone or radioiodine followed by a 3-month course of oral prednisone (initial dosage, 0.4 to 0.5 mg/kg of body weight per day) [3]. Five patients in the radioiodine plus prednisone group were lost to follow-up. Smoking habits did not differ in the two groups. Study 2 This retrospective study included 150 consecutive patients with severe ophthalmopathy (110 women and 40 men; mean age, 41 years [range, 30 to 63 years]) treated from 1989 to 1995 with orbital radiation therapy (20 Gy per eye) and high-dose oral prednisone (initial dose, 80 to 100 mg) [9]. The prednisone dose was gradually tapered, and therapy was discontinued after 6 months. Severe ophthalmopathy was defined as proptosis of 22 mm or more, inconstant or constant diplopia, and marked inflammatory soft-tissue changes with or without optic neuropathy. The study was approved by the institutional review board, and informed consent was obtained from patients. Smoking Habits The number of cigarettes smoked was measured in pack-years, expressed as x = a x b/c, where a = number of cigarettes smoked per day, b = number of years of smoking, and c = 20 cigarettes per pack. Patients who had refrained from smoking for less than 1 year were considered smokers. Smokers were subdivided into light ( 10 pack-years), moderate (11 to 19 pack-years), and heavy smokers ( 20 pack-years). Ocular Evaluation Ocular evaluation, performed by one examiner who was blinded to treatment and smoking groups, included assessment of soft-tissue changes; measurement of proptosis (by Hertel exophthalmometry), ocular tension, and lid width; evaluation of eye muscle function (Hess chart or computerized perimetry); and determination of visual acuity. The activity score was determined according to the method of Mourits and colleagues [10], which includes consideration of seven manifestations (spontaneous retrobulbar pain, pain with eye movements, eyelid erythema, eyelid edema, conjunctival injection, chemosis, and swelling of the caruncle); one point was given to any manifestation, for a score from 0 (no activity) to 7 (very high activity). Each patient provided a self-assessment evaluation sheet. Appearance, progression, and alleviation of ophthalmopathy were defined according to major and minor criteria [5]. Major criteria were variations in exophthalmometer readings and lid width of 2 mm or more, diplopia (intermittent, inconstant, or constant), variations in activity score of 2 points or more, and changes in visual acuity of 1/10 or more. Minor criteria were variations in soft tissues or self-assessment. Appearance, progression, and alleviation of ophthalmopathy were defined by changes in at least two major criteria and one minor criterion [5]. Statistical Analysis Differences in the prevalence of smokers in the two studies were analyzed by using a chi-square test with Yates correction for continuity. Exact binomial 95% CIs were calculated for all proportions. Patients in study 1 were included in an intention-to-treat analysis in which the effects of radioiodine or radioiodine plus prednisone on ophthalmopathy were evaluated according to the predefined criteria outlined above. Role of the Study Sponsor Neither funding source had a role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Study 1 Among patients who received radioiodine alone, 23 (15.3% [95% CI, 10% to 22%]) had progression of ophthalmopathy. Ocular conditions were unchanged in the remaining 127 patients [5]. Among patients who received radioiodine plus prednisone, 0 had progression and 50 of 75 (66.7% [CI, 55% to 77%]) had alleviation of eye disease [5]. In the group that received radioiodine alone, ophthalmopathy progressed in 4 of 68 nonsmokers (5.9% [CI, 3% to 9%]) and 19 of 82 smokers (23.2% [CI, 13% to 33%]) (P = 0.007). In the group that received radioiodine plus prednisone, ophthalmopathy was alleviated in 37 of 58 nonsmokers (63.8% [CI, 51% to 78%]) and 13 of 87 smokers (14.9% [CI, 10% to 22%]) (P < 0.001) (Table 1). Table 1. Smoking Behavior and Outcome of Mild Graves Ophthalmopathy Study 2 Of 150 consecutive patients, 85 (57%) were smokers. Sixty patients (40%) had an excellent or good response to therapy and 59 (39.3%) had a moderate response. Ophthalmopathy remained unchanged in 26 patients (17.3%) and progressed in 5 (4.3%). Duration of ophthalmopathy did not differ among groups. Sixty-one of 65 nonsmokers (93.8% [CI, 90% to 98%]) and 58 of 85 smokers (68.2% [CI, 57% to 78%]) (P < 0.001) responded to therapy (Table 2). Thirty-three of the 58 smokers who responded to therapy (56.9% [CI, 45% to 68%]) and 5 of 27 nonresponders (18.5% [CI, 9% to 29%]) were light smokers (P = 0.01). Table 2. Smoking Behavior and Outcome of Treatment of Severe Graves Ophthalmopathy with Orbital Radiation Therapy and High-Dose Glucocorticoids Discussion The results of our randomized study showed that cigarette smoking was associated with progression of mild ophthalmopathy, seen in 15% of patients after radioiodine therapy. In addition, smoking was associated with reduced efficacy of glucocorticoids given concomitantly with radioiodine. In the retrospective study, smoking and degree of smoking seemed to adversely affect the outcome of orbital radiation therapy and high-dose glucocorticoid treatment in patients with severe ophthalmopathy. Cigarette smoking is a risk factor for Graves ophthalmopathy. The prevalence of smoking is higher in patients with Graves disease who have ophthalmopathy than in those who do not have ophthalmopathy [1], and some [2, 11, 12] but not all [13] studies show a relation between degree and duration of smoking and severity of ophthalmopathy. Tallstedt and associates [4] reported that progression of ophthalmopathy after radioiodine therapy was more frequent in smokers than in nonsmokers, although differences were not statistically significant. Similarly, in a small series of Chinese women, Kung and coworkers [14] found no differences between smokers and nonsmokers in the progression of ophthalmopathy after radioiodine therapy. The differences between our results and those of previous studies may be explained by the larger number of patients and the consequent greater power of our study. Ethnic factors may also be important: Asian patients have a lower risk for ophthalmopathy, and the prevalence of smoking among Asian women is low [11]. Medical management of severe ophthalmopathy mostly relies on orbital radiation therapy or treatment with high-dose steroids, but results are not always favorable [8]. This may be related to several factors, including the long duration or limited activity of ophthalmopathy [8]. Our results suggest that smoking also negatively affects treatment outcome. Of note, several smokers in study 1 had no progression of ophthalmopathy after radioiodine therapy, and the condition improved with concomitant prednisone treatment. Similarly, in study 2, several smokers had excellent or good responses to orbital radiation therapy and high-dose glucocorticoid therapy. This implies that cigarette smoking is only one of many risk factors involved in the progression of ophthalmopathy. Identification of such risk factors should be a goal of future research so that treatment may be improved and disease may be prevented. The mechanisms by which cigarette smoking may affect the course of Graves ophthalmopathy and its response to treatment are largely unknown [1]. Besides having direct irritative effects, smoking may affect immune reactions occurring in the retro-orbital space [15]. Cytokines present in the retro-orbital tissues of patients with Graves ophthalmopathy [16] exert several actions relevant to the pathogenesis of the disease, including induction of expression of MHC class II molecules, heat-shock proteins, and adhesion molecules [16]. Cytokines also stimulate orbital fibroblasts to proliferate and to secrete glycosaminoglycans; the latter are responsible for most manifestations of the disease [15]. Smoking may intervene in cytokine-mediated paracrine and autocrine actions because smoking-induced hypoxia in the retrobulbar space stimulates the release of cytokines [17]. Interleukin-1 may play a pivotal role in this context, and interleuki

Blindness following cosmetic injections of the face.

Background: Complications following facial cosmetic injections have recently heightened awareness of the possibility of iatrogenic blindness. The authors conducted a systematic review of the available literature to provide the best evidence for the prevention and treatment of this serious eye injury. Methods: The authors included in the study only the cases in which blindness was a direct consequence of a cosmetic injection procedure of the face. Results: Twenty-nine articles describing 32 patients were identified. In 15 patients, blindness occurred after injections of adipose tissue; in the other 17, it followed injections of various materials, including corticosteroids, paraffin, silicone oil, bovine collagen, polymethylmethacrylate, hyaluronic acid, and calcium hydroxyapatite. Conclusions: Some precautions may minimize the risk of embolization of filler into the ophthalmic artery following facial cosmetic injections. Intravascular placement of the needle or cannula should be demonstrated by aspiration before injection and should be further prevented by application of local vasoconstrictor. Needles, syringes, and cannulas of small size should be preferred to larger ones and be replaced with blunt flexible needles and microcannulas when possible. Low-pressure injections with the release of the least amount of substance possible should be considered safer than bolus injections. The total volume of filler injected during the entire treatment session should be limited, and injections into pretraumatized tissues should be avoided. Actually, no safe, feasible, and reliable treatment exists for iatrogenic retinal embolism. Nonetheless, therapy should theoretically be directed to lowering intraocular pressure to dislodge the embolus into more peripheral vessels of the retinal circulation, increasing retinal perfusion and oxygen delivery to hypoxic tissues. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.

Clinical Features of Dysthyroid Optic Neuropathy: A European Group on Graves Orbitopathy (EUGOGO) Survey

Background: This study was performed to determine clinical features of dysthyroid optic neuropathy (DON) across Europe. Methods: Forty seven patients with DON presented to seven European centres during one year. Local protocols for thyroid status, ophthalmic examination and further investigation were used. Each eye was classified as having definite, equivocal, or no DON. Results: Graves’ hyperthyroidism occurred in the majority; 20% had received radioiodine. Of 94 eyes, 55 had definite and 17 equivocal DON. Median Clinical Activity Score was 4/7 but 25% scored 3 or less, indicating severe inflammation was not essential. Best corrected visual acuity was 6/9 (Snellen) or worse in 75% of DON eyes. Colour vision was reduced in 33 eyes, of which all but one had DON. Half of the DON eyes had normal optic disc appearance. In DON eyes proptosis was > 21 mm (significant) in 66% and visual fields abnormal in 71%. Orbital imaging showed apical muscle crowding in 88% of DON patients. Optic nerve stretch and fat prolapse were infrequently reported. Conclusion: Patients with DON may not have severe proptosis and orbital inflammation. Optic disc swelling, impaired colour vision and radiological evidence of apical optic nerve compression are the most useful clinical features in this series.

Tear osmolarity measurement using the TearLab Osmolarity System in the assessment of dry eye treatment effectiveness.

PURPOSE To evaluate the efficacy of three commercially available lubricant eye drops for the treatment of mild, dry, irritated eyes. METHODS Randomized, investigator-masked evaluation of 60 patients in which 20 patients used carboxymethylcellulose sodium (CMC), 0.5% (Cellufresh), Allergan Inc., Irvine, CA) (group 1); 20 patients used a drop containing polyethylene glycol 400, 2.5% and sodium hyaluronate (Blink Intensive Tears, Abbott Medical Optics Inc., Santa Ana, CA) (group 2); and 20 patients used HP Guar 0.18% (Systane, Alcon Laboratories Inc., Ft. Worth, TX) (group 3). Study visits were at baseline and 1 month. Tests performed at both visits included Schirmer, tear-film break-up time (TBUT), visual acuity, fluorescein staining, tear osmolarity and wavefront aberrometry. Osmolarity testing was performed prior to instillation of the lubricant eye drops and then a final time 5min after instillation of the drop at both day 1 and day 30. Tear osmolarity was performed only in the right eye and only one time before and after instillation of lubricant eye drops. RESULTS At day 1 the mean reduction in osmolarity 5min after instillation of the lubricant eye drop was, -5.0+/-1.9 in group 1, -9.0+/-4.2 in group 2 and -5.0+/-2.2 in group 3. At day 30 the mean reduction in osmolarity 5min after instillation of the lubricant eye drop was, -5.6+/-2.3mOsm/L in group 1; -9.9+/-2.8mOsm/L in group 2 and -4.5+/-1.8mOsm/L in group 3. The differences were statistically significant between groups 1 and 2, and 2 and 3. There was a reduction of osmolarity from day 1 to day 30 but the differences were not statistically significant. We feel that after a 30-day treatment with the lubricant eye drops, the lower osmolarity values could indicate that the tear film is progressing towards a more normal osmolarity value. A future study could examine the tear osmolarity value after 60 or 90 days of usage. LogMAR best-corrected visual acuity (BCVA) results showed an improvement in group 2 compared with baseline with no change in BCVA in groups 1 and 3. There was no statistically significant change from day 1 to 1 month in TBUT, while the Schirmer test showed an improvement in all groups at 1 month. CONCLUSIONS Assessment of tear osmolarity provides the most objective, measurable test for determining improvement in dry eye patients. The instillation of any artificial tear or lubricant eye drop should decrease the tear-film osmolarity. The results found that polyethylene glycol 400, 0.25% and sodium hyaluronate (Blink Intensive Tears) significantly improved tear osmolarity compared with carboxymethylcellulose sodium (CMC), 0.5% (Cellufresh) and HP Guar 0.18% (Systane after instillation.

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures

Aim: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves’ orbitopathy (GO) receiving surgery for disfiguring proptosis. Method: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. Results: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. Conclusions: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells

AIM Limbal cultures restore the corneal epithelium in patients with ocular burns. We investigated the biological parameters instrumental for their clinical success. METHODS We report a long-term multicenter prospective study on 152 patients carrying corneal destruction due to severe ocular burns, treated with autologous limbal cells cultured on fibrin and clinical-grade 3T3-J2 feeder cells. Clinical results were statistically evaluated both by parametric and nonparametric methods. RESULTS Clinical outcomes were scored as full success, partial success and failure in 66.05, 19.14 and 14.81% of eyes, respectively. The total number of clonogenic cells, colony size, growth rate and presence of conjunctival cells could not predict clinical results. Instead, the clinical data provided conclusive evidence that graft quality and likelihood of a successful outcome rely on an accurate evaluation of the number of stem cells detected before transplantation as holoclones expressing high levels of the p63 transcription factor. No adverse effects related to the feeder layer have been observed and the regenerated epithelium was completely devoid of any 3T3-J2 contamination. CONCLUSION Cultures of limbal stem cells can be safely used to successfully treat massive destruction of the human cornea. We emphasize the importance of a discipline for defining the suitability and the quality of cultured epithelial grafts, which are relevant to the future clinical use of any cultured cell type.

Orbital Decompression in Graves' Ophthalmopathy by Medial and Lateral Wall Removal

Objective The objective of this study is to describe a technique for balanced orbital decompression and to analyze the results. Methods and Materials We conducted a retrospective study of 140 patients (276 orbits). Orbital decompression was carried out by removal of the medial orbital wall by ethmoidectomy and complete removal of the lateral wall by bringing out the entire sphenoid wing together with part of the zygomatic bone down to the inferior orbital fissure. Results One hundred thirty-six patients underwent bilateral decompression, 4 patients underwent monolateral decompression. Proptosis was reduced on average by 5.3 mm; 28 (20%) patients showed onset or worsening of diplopia. Conclusions Medial and lateral approach allows a balanced orbital decompression. As some patients may present different degrees of proptosis and visual impairment, we stress the importance of carefully weighing the preoperative conditions of the individual patient when choosing the surgical approach.

Ophthalmological and neuro-ophthalmological involvement in Churg-Strauss syndrome: a case report.

Abstract• Background: It is well known that different types of eye involvement may develop during the course of systemic vasculitides. • Methods: We report here a case of Churg-Strauss syndrome (allergic granulomatous angiitis) characterized by the presence of multiple ophthalmological and neuro-ophthalmological lesions, i.e., mononeuritis of the fourth cranial nerve, multifocal choroidal ischaemia, and bilateral ischaemic optic neuropathy. • Results: Ischaemic lesions in the posterior ciliary plexus and chorio-retinal circulation, which appeared simultaneously after a phase of disease activity, were documented. • Conclusion: The simultaneous occurrence of multiple ocular features in a patient with Churg-Strauss syndrome suggests that regional vasculitis may be the pathological mechanism underlying the multiple ophthalmological lesions in this disorder.