Reappraisal of the management of Vogt-Koyanagi-Harada disease: sunset glow fundus is no more a fatality.

PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is a primary autoimmune stromal choroiditis. Aim of the study was to gather a body of evidence from the literature and from experts that systemic corticosteroid combined with non-steroidal immunosuppressive therapy should become the standard of care in initial-onset VKH disease. METHODS: Literature was reviewed and leading experts in VKH were consulted in different parts of the world in order to put forward a consensus attitude in the management of initial-onset VKH disease. RESULTS: There was a substantial body of evidence in the literature that early aggressive and sustained corticosteroid and non-steroidal immunosuppressive therapy in initial-onset VKH disease allows to achieve full control of choroidal inflammation, eliminating any subclinical choroidal inflammation, and substantially reduces recurrences with improvement of anatomical and functional outcomes. This was in agreement with experts' opinion and practice. ICGA was the method of choice to monitor disease evolution. CONCLUSION: Since the choroidal space is easily accessible to systemic therapy and because inflammation in VKH disease is exclusively originating from the choroidal stroma, early and sustained treatment right at the onset of the disease process with dual corticosteroid and non-steroidal immunosuppressive therapy can result in full "healing" in many cases preventing sunset glow fundus which results from depigmentation from chronic uncontrolled inflammation.

New concepts in the appraisal and management of birdshot retinochoroiditis, a global perspective.

Birdshot retinochoroiditis (BRC) is a relatively recently described entity. BRC uveitis is predominant in the posterior segment with dual, independent retinal, and choroidal inflammation. The disease has no known extra-ocular inflammation sites and yet features the strongest known HLA association: HLA-A29 is present in close to 100 % of cases. Aim in this mini-review was to readjust the appraisal of BRC in the light of a global approach including the full array of investigational procedures. Historical background and the genesis of the disease name were searched. Global disease description including both the retina and the choroid was given. Retinal involvement was clearly characterized, pointing toward the profuse leakage of retinal vessels of all sizes in early disease and widespread atrophy in under treated patients. The importance of exploration of choroidal disease, unavailable until the early 1990s before the advent of indocyanine green angiography (ICGA) was stressed, allowing early diagnosis of disease. Despite its proven importance to explore the choroid, ICGA is still sparsely used. Existing diagnostic criteria were found to be clearly inappropriate not allowing early diagnosis and are in need to be revised, taking into account both retinal and choroidal aspects of the disease, in order to make early diagnosis possible and hence allow proper management .

Early and sustained treatment modifies the phenotype of birdshot retinochoroiditis.

In this single-centre retrospective case review, we investigate the long-term follow-up of birdshot retinochoroiditis (BRC) patients, analysing the impact of early, vigorous, and prolonged treatment on the evolution of indocyanine green angiography (ICGA) signs and fundus appearance. Treatment delay was calculated for each BRC patient, and patients were classified into two groups--treatment delay of <10 months (early-treatment group) and treatment delay of >10 months (delayed-treatment group). Fundus photographs and ICGA frames from the initial visit and from the last follow-up visit were assessed. Fundus photographs were evaluated for the presence of at least three circumpapillary, typical, rice-shaped birdshot lesions in one eye, inferior or nasal to the optic disc. ICGA pictures were evaluated for the presence of lesions (hypofluorescent dark dots, fuzziness). Differences were compared between the two groups and between the first visit and the last follow-up visit. In the early-treatment group, 5/6 patients had no characteristic BRC fundus lesions, but 7/7 patients in the delayed-treatment group displayed typical lesions. At last follow-up, 5/6 early-treatment patients showed no fundus lesions, and 6/7 delayed-treatment patients retained their fundus lesions. At presentation, all 13 patients exhibited lesions on ICGA. At last follow-up, ICGA lesions had completely disappeared in 4/6 early-treatment patients and 3/7 delayed-treatment patients. Thus, early and sufficiently dosed inflammation-suppressive treatment can prevent the appearance of typical BRC fundus lesions. It is therefore crucial to perform ICGA to detect otherwise occult stromal choroiditis in suspected BRC cases and to initiate adequate therapy immediately.

The influence of anti-VEGF therapy on present day management of macular edema due to BRVO and CRVO: a longitudinal analysis on visual function, injection time interval and complications.

The purpose of this study was to evaluate the impact of intravitreal bevacizumab injections on the management and outcome of patients affected by retinal vein occlusions, their effectiveness on morphological and functional parameters, the modalities of long-term management and the need for additional laser treatment due to ischemic retinal evolution. Patients diagnosed with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) had a comprehensive work-up including complete ophthalmic examination, fluorangiography (FA), optical coherence tomography (OCT), visual field testing (VFT), microperimetry (MP), and laser flare photometry (LFP). In case of BRVO, intraocular bevacizumab injection was performed if significant macular edema/visual deficit was still present 3 months after onset of occlusion and injections were started at presentation in case of CRVO. Post-injection follow-up examination including best corrected visual acuity (BCVA), intraocular pressure (IOP), LFP, OCT, MP, and VFT were performed monthly and recorded at the end of follow-up. Follow-up FA was performed between 12 and 18 months after diagnosis. Injections were repeated in case of recurrence of a significant central macular edema. Patients were subdivided into 2 groups according to number of injections: 1-4 injections or more than 4 injections. The proportion of resolved cases (no recurrence after a minimum follow-up of 12 months) was calculated and correlated with number of injections. In patients needing sustained injections, management modalities were recorded. The proportion of patients having needed laser photocoagulation treatment because of significant ischemic signs was recorded. Fifty-one patients were diagnosed with retinal vein occlusion between 2006 and 2012 at the Centre for Specialized Ophthalmic Care (COS) in Lausanne, Switzerland. Forty-four had enough data and were included in the study. Nine eyes were affected by CRVO and 35 were affected by BRVO. Mean BCVA at presentation was 0.24 ± 0.2 and improved to 0.81 ± 0.38 (p < 0.01) at 48 months. MP improved from 184.9 ± 92 to 362.5 ± 56.2 (p < 0.01) at 42 months follow-up. The number of injections varied from 1 to 25 (mean 5.5 ± 5.43). 31/44 eyes received 1-4 injections (group 1) of which all were recurrence free, with a follow-up of at least 1 years in all. 13/44 eyes received more than 5 injections (group 2) with functional and morphological parameters maintained in 9/13 but only 1/13 patients showed resolution. Rhythm of injection varied from one patient to another but 8/13 patients needing continuous injections had a constant time interval between injections. In 8/44 patients, laser photocoagulation had to be performed due to ischemic complications. The visual outcome using bevacizumab intravitreal injection was exceptionally good and functional parameters such as BCVA, MP, and VFT improved significantly. In about two-thirds of patients, resolution was obtained after 1-4 injections. In one-third of patients, continuous injections were necessary but a constant rhythm for re-injection for each patient could be established allowing to reduce to a minimum follow-up visits. The absence of significant side effects allowed to re-treat apparently without limitation achieving maintained visual function. FA monitoring for the detection of ischemic complications should not be neglected especially in cases where bevacizumab could be discontinued.

Arthropathy, osteolysis, keloids, relapsing conjunctival pannus and gingival overgrowth: a variant of polyfibromatosis?

Polyfibromatosis is a rare fibrosing condition characterized by fibromatosis in different body areas and by keloid formation, and which can be associated with arthropathy and osteolysis. Familial occurrence has been described, but the cause remains unknown. Here, we describe a patient with characteristics of polyfibromatosis with arthropathy who had in addition severe conjunctival fibrosis, distinctive face, gingival overgrowth, and pigmented keloids. We discuss the resemblances and differences with polyfibromatosis and descriptions of other, similar patients. We conclude that at present it remains uncertain whether the patient has a variant of polyfibromatosis or a separate entity.

Reappraisal of birdshot retinochoroiditis (BRC): a global approach.

BACKGROUND: This study aimed to readjust the appraisal of birdshot retinochoroiditis (BRC) in light of a global approach, including the full array of investigational procedures. PATIENTS AND METHODS: This retrospective study reviewed charts of BRC cases treated in the uveitis clinic of our center between 1995 and 2011. We identified 25 patients with BRC; of these, 19 had sufficient data for inclusion in the study. Patients were examined with a standard clinical approach for inflammatory disorders, including dual fluorescence angiography with fluorescein and indocyanine green, perimetry, and laser flare photometry, both at presentation and during follow-up. Spectral optical coherence tomography (OCT) was performed when available. Disease characteristics and evolutionary patterns were reported. RESULTS: Human leucocyte antigen was positive for the A29 allele in all patients. The mean age at presentation was 49.6 ± 10.0 years, the mean diagnostic delay was 21.5 ± 18 months, and the mean follow-up was 85 ± 60 months. Out of 19 patients, three presented with mutton-fat keratic precipitates (KPs), three had no depigmented lesions at presentation, and eight did not fulfill the recommended criterion of three depigmented peripapillar lesions. Cystoid macular edema (CMO) at entry was present in 8/19 cases. Perimetric anomalies were noted in all patients at presentation. In 92 % of cases, fluorescein findings included disc hyperfluorescence, retinal vasculitis of large vessels, and leakage from medium-sized and small vessels. In all patients, a (pseudo)-delay was noted in the arterio-venous circulation time (mean venous dye appearance = 42.1 ± 13.1 s), which reflected massive capillary leakage. At presentation, all patients exhibited indocyanine green angiographic signs, including hypofluorescent dark dots, vessel fuzziness, and areas of diffuse late hyperfluorescence. This allowed early diagnosis in 3/19 patients (16 %) without birdshot fundus lesions at presentation. CONCLUSIONS: BRC is a granulomatous uveitis, and mutton-fat KPs do not exclude the disease. When BRC is suspected, indocyanine green angiography is crucial to allow early diagnosis and to monitor the evolution of choroiditis. Perimetry is an obligate investigation for diagnosis and follow-up. CMO is less frequent than stated earlier. Scores of fluorescein and indocyanine green angiographic signs indicated that choroiditis responded readily to therapy, but retinitis was relatively resistant to therapy.

Granulomatous keratic precipitates in birdshot retinochoroiditis.

With the purpose of facilitating clinical studies of this infrequent disease, an expert panel published research criteria for birdshot retinochoroiditis (RCBRC). The aim of our study was to investigate the sensitivity of the exclusion criteria of the RCBRC as applied to all patients seen in our center with a diagnosis of BRC. This was a single center retrospective study involving all patients with an ocular inflammatory disease seen at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland, between 1995 and 2012. The percentage of patients with a diagnosis of BRC was identified. The exclusion criteria of the RCBRC were applied to all patients and the percentage of patients with absence of keratic precipitates (KPs) and absence of posterior synechiae were calculated. Out of 1,504 new patients, 25 patients (1.66 %; 19 female, 6 male) were diagnosed with BRC and 19 patients had sufficient data to be included in the study (1.26 %, 13 female). All patients were positive for HLA-A29 testing. The sensitivity of the RCBRC with respect to the exclusion criteria applied to our patient cohort was 84.2 % due to the exclusion of three patients showing KPs. Our study supports the motion to re-evaluate the RCBRC, since granulomatous KPs can be present and are more frequent than previously estimated and stringent application of the criteria would lead to a substantial loss of study patients.

Tuberculosis-related choriocapillaritis (multifocal-serpiginous choroiditis): follow-up and precise monitoring of therapy by indocyanine green angiography.

To report the case of a patient initially diagnosed with acute posterior multifocal placoid pigment epitheliopathy (APMPPE), characterized by relentless evolution despite high-dose steroid therapy. An interferon-gamma release assay (IGRA) indicated a diagnosis of suspected tuberculous choriocapillaritis and the disease responded only to massive inflammation suppressive therapy and antibiotic therapy. Case report. Review of clinical features and investigational procedures. Smoldering relentless evolution and subsequent arrest of progression could be precisely monitored by indocyanine green angiography (ICGA). The patient did not recover after standard anti-tubercolosis (TB) therapy combined with corticosteroid. A fourth antibiotic had to be added in order to stop the progression of the retinal disease. In each case of choriocapillaritis such as APMPPE an infectious cause including TB has to be excluded making IGRA tests unavoidable. As the main structure involved is the choriocapillaris the most precise follow-up or monitoring is obtained with ICGA.

Current and emerging medical therapies in the treatment of glaucoma.

INTRODUCTION: Glaucoma is a disease of the eye in which the optic nerve and retinal ganglion cells (RGCs) are injured, leading to the loss of the peripheral visual field and eventually to profound vision loss and blindness. Glaucoma is usually characterized by an increase in intraocular pressure (IOP), which is treated with ocular hypotensive drugs. However, both RGC apoptosis and optic nerve atrophy, due to glaucoma, can occur independently of IOP. AREAS COVERED: This review discusses several current and emerging treatments for glaucoma. Current research is updating the known properties of a number of drugs now used to treat glaucoma. Some drugs may offer neuroprotection, not only reducing vision loss, but restoring injured or compromised RGCs and optic nerve cells. Several molecules now under development aim to lower IOP primarily by enhancing aqueous drainage through conventional pathways of the trabecular meshwork and Schlemm's canal. Gene transfer models are being investigated, and a murine-derived neurotrophic growth factor (NGF) seems to offer the promise of actually restoring visual function in some patients. Drugs that are already widely used are being re-branded in preservative-free formulations. EXPERT OPINION: The ultimate goal in glaucoma research is to find new compounds that will not only normalize IOP, but also arrest or even reverse apoptotic damage to the optic nerve and RGCs to slow the rate of progression of the disease so that it will not interfere with the patient's ability to see and his/her quality of life. This should be obtained with affordable costs, minimal side effects and a reasonable schedule.

The role of serology in active ocular toxoplasmosis.

Our purpose was to examine toxoplasmic serology in relation to episodes of suspected acute toxoplasmic retinochoroiditis and evaluate its use in the appraisal of patients. The mean values of enzymatic immunoassay (EIA) titers for toxoplasmic antibodies were retrospectively compared in patients with active and inactive toxoplasmosis and in a third group of uveitis cases not caused by toxoplasmosis. The proportion of cases under and above a predefined serology value above cut-off was compared in all groups. Between 1995 and 2010, 97 out of 1,276 new uveitis cases seen at the Centre for Ophthalmic Specialized Care (COS), Lausanne, Switzerland were diagnosed as toxoplasmic retinochoroiditis, of which 51 had documented serology available. The mean EIA values for immunoglobulin (Ig) G were 147.75 ± 259.4 IU/ml for patients with active disease, 18.93 ± 23.09 (p < 0.05) for patients with inactive toxoplasmosis and 18.35 ± 20.82 for controls (p < 0.017). The proportion of cases under the designated limit value were 2/51 (4%) in the active retinitinochoroiditis group, 14/27 (52%) (p < 0.05) in the control group, and 7/7 (100%) in the inactive toxoplasmic group (p < 0.001). Three out of 51 cases showed high IgM values in addition to IgG elevation and were primary infections. Toxoplasmosis serology, contrary to popular belief, is useful to confirm active toxoplasmic retinochoroiditis; it is easy to perform, cheap and supports clinical diagnosis in up to 96% of cases, not only by showing positivity but by also showing a significant elevation of titers. In atypical cases serology is not only useful but essential.

HLA-A29 Birdshot Retinochoroiditis in Its 5th Decade: Selected Glimpses into the Intellectual Meanderings and Progresses in the Knowledge of a Long-Time Misunderstood Disease.

The appraisal of HLA-A29 birdshot retinochoroiditis (BRC) was fraught with pitfalls and misunderstandings. Progress in investigational methods has led to better knowledge and management of the disease. Our aim was to assess some of the steps that have led to better characterisation of the clinical entity of BRC. We performed a literature search analysing the relevant progress in disease origin, investigational and imaging methods, clinicopathology and classification, diagnostic criteria and management. Following developments were judged essential in the better appraisal and understanding of the disease: (1) new immunopathological hypotheses regarding the role of endoplasmic reticulum peptidases, (2) the essential importance of HLA testing, (3) relevant imaging modalities among which indocyanine green angiography is crucial, (4) diagnostic criteria that allow early diagnosis and (5) need of an early prolonged, as well as aggressive treatment combining more than one immunosuppressive agent. Based on these findings it is now possible to better define BRC, an indolent however severe disease, unlike thought before, involving the choroidal stroma and the retina independently and concomitantly that can be diagnosed early thanks to indocyanine green angiography and should be treated early and relentlessly.

Sensitivity of laser flare photometry compared to slit-lamp cell evaluation in monitoring anterior chamber inflammation in uveitis.

To study the sensitivity of laser flare photometry (LFP) in monitoring anterior chamber inflammation by correlating LFP measurements with slit-lamp evaluation of aqueous cells in HLA-B27-related uveitis in a prospective trial. Slit-lamp cell evaluation was correlated with LFP-measured flare in a masked fashion in HLA-B27-related uveitis patients receiving standard topical therapy. At the time of 50 and 90% LFP flare reduction, the corresponding reduction of cells was recorded and statistically compared using the sign test. Forty-three episodes (in 43 patients) of acute anterior HLA-B27-related uveitis were included. LFP flare reduction and slit-lamp cell reduction were strongly correlated. LFP was significantly more sensitive for both 50% (P = 0.001) and 90% (P = 0.02) LFP flare reduction in assessing the decrease of anterior chamber inflammation. LFP was superior to slit-lamp cell evaluation in monitoring anterior chamber inflammation in uveitis. Flare, becoming a quantitative parameter when measured by LFP, rather than cells, should be considered the gold standard to measure anterior chamber inflammation in uveitis.

CFSE: A New Method for Identifying Human Limbal Stem Cells and Following Their Migration in Human Cornea.

AIM: To develop a method capable of identifying human corneal limbal stem cells (LSCs) and follow their proliferation and migration in the epithelium. MATERIALS AND METHODS: Ten fresh matched pairs of cadaveric normal human corneas were obtained from donors. Carboxyfluorescein diacetate succinimidyl ester (CFSE) was used to target LSCs. The distribution of CFSE-positive cell clusters was analyzed by fluorescence microscopy by counterstaining with 4',6-diamidino-2-phenylindole (DAPI). Fluorescence was digitally recorded for seven days, and the rate of cell movement was determined. RESULTS: CFSE-labeled cells were tracked in corneas. Analysis of time sequences revealed that they moved centripetally. Daily average CFSE-labeled LSC movement was 0.073±0.01 cm (±SD). CONCLUSION: CFSE allowed us to identify LSCs and to track their centripetal migration from the limbal basal layer to the anterior ocular surface. This experimental system appears to be a valuable tool for further studies on corneal epithelial cell migration and proliferation.

In vivo confocal microscopy in a case of pterygium.

Pterygium is a frequent ocular surface disorder of unknown origin characterized by chronic conjunctival inflammation with a clear central cornea in most patients. A 35-year-old man affected by pterygium in the right eye presented with unremarkable slit-lamp examination of the central cornea, in which in vivo confocal microscopy showed a significant alteration of the superficial epithelial cells, numerous dendritic-like cells in the basal epithelial layer, and loss of keratocytes in the stroma. In vivo confocal microscopy may be helpful in evaluating the immunological and structural changes of the cornea in patients with pterygium and in understanding its pathophysiology.

Comparison of Central Corneal Thickness Measurements Using Ultrasonic Pachymetry, Anterior Segment OCT and Noncontact Specular Microscopy.

PURPOSE: To evaluate and compare central corneal thickness (CCT) values measured with anterior segment optical coherence tomography (AS-OCT), noncontact specular microscopy (NCSM), and ultrasound pachymetry (USP). MATERIALS AND METHODS: CCT was measured in 182 healthy eyes without ocular abnormalities other than refractive errors. Three consecutive measurements of CCT by the same examiner were obtained during the same session. The testing sequence of AS-OCT and NCSM was randomly selected. The USP always was performed after the noncontact examinations. RESULTS: The average CCT measured by AS-OCT, NCSM, and USP were 535.8±35.5, 547.7±38.2, and 537.4±37.5 µm, respectively. The mean differences between modalities were 11.8±14.7 µm (P<0.01) between NCSM and AS-OCT, 10.3±17.7 µm (P<0.01) between NCSM and USP and 1.6±8.6 µm (P=0.02) between USP and AS-OCT. CONCLUSIONS: AS-OCT, NCSM, and USP showed an overall strong agreement in measuring CCT. However, CCT measurements with AS-OCT showed a good correlation to those obtained by USP, NCSM tended to give statistically significant higher CCT readings than either alternative and showed the worse repeatability indices. On the basis of our results, CCT measurement obtained with different instruments cannot be considered directly interchangeable.

Central Serous Chorioretinopathy Misdiagnosed as Posterior Uveitis and the Vicious Circle of Corticosteroid Therapy.

PURPOSE: To determine the proportion of patients with central serous chorioretinopathy (CSCR) mistaken for posterior uveitis and to identify the deleterious consequences. METHODS: Charts of 1,657 patients admitted in the section of inflammatory eye diseases at the Center for Ophthalmic Specialized Care (COS) in Lausanne, Switzerland from 1995 to 2013 were reviewed. CSCR cases misdiagnosed as posterior uveitis or those with superimposed disease due to steroid therapy for uveitis were studied. Delay in diagnosis, specific erroneous uveitis diagnosis and evolution of the disease were also evaluated. Retrospectively, the most useful means for a correct diagnosis of CSCR were the original fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT) when available. RESULTS: Out of a total of 1,657 patients, 15 (0.9%) cases with CSCR were identified. These included 12 subjects misdiagnosed as posterior uveitis and 3 uveitis subjects with superimposed CSCR following corticosteroid therapy for uveitis. The presentation of the disease was largely influenced by improper and continued use of corticosteroids. CONCLUSION: CSCR is a rare but not negligible misdiagnosis in posterior uveitis representing approximately 1% of subjects from a collective series of uveitis cases at a referral center. Investigative measures such as FA, ICGA and OCT are crucial for reaching a correct diagnosis and avoiding disease aggravation due to corticosteroid therapy.