A clinical study on posterior uveitis

AIM OF THE STUDY: To analyse the posterior uveitis with reference to age and sex incidence, laterality, etiology, chronicity, severity, clinical presentation, sequelae, complication and treatment modalities. Primary Objective: 1. To evaluate the various etiological factors and predisposing factors leading on to posterior uveitis. 2. To assess the clinical presentation in different types of posterior uveitis. 3. To diagnose and start treatment after systematic evaluation. Secondary Objective: 1. To assess visual outcome after treatment of Posterior Uveitis since Posterior uveitis treatment is a challenge to all Ophthalmologists. MATERIALS AND METHODS: The study design was a prospective study of 30 patients with age range of 20-45 years with posterior uveitis, conducted in Regional Institute of Ophthalmology and Ophthalmic Eye Hospital during August 2013 to August 2014 for a period of 12 months. Main criteria for diagnosis: 1. Patients having whitish retinal opacities with indistinct borders (focal/multifocal/diffuse) and vitritis suggestive of retinitis. 2. Patients having round yellowish nodule in the fundus (focal/multifocal/diffuse) suggestive of choroiditis. 3. Patients having yellow or grey white, patchy perivascular cuffing suggestive of active vasculitis. 4. Patients having papillitis with multiple serous detachment suggestive of VKH syndrome. 5. Patients having peripheral tubercles. Exclusion criteria: 1. Post surgical cases, 2. Post trauma cases, 3. Intermediate uveitis (predominant vitritis without active chorioretinal lesion), 4. Predominant anterior segment involvement without active chorioretinal lesion), 5. Patients who lost follow up. CONCLUSION: Posterior uveitis is a serious disease associated with vision threatening complications. Posterior uveitis is more common in the age group of 26-35 years. All cases of posterior uveitis is of chronic duration. All cases of posterior uveitis are severe in nature. Retinochoroiditis is the most common anatomical type comprising more than half of the cases. Posterior uveitis due to infectious causes are common than non infectious causes. Toxoplasma is the most common aetiology detected in posterior uveitis. Toxoplasma is the major infectious aetiology found in posterior uveitis. In non infectious causes Vogt Koyanagi Harada syndrome, vasculitis due to collagen vascular diseases are the common causes. With prompt treatment the disease is controlled in all cases of posterior uveitis. Corticosteroids are the most common drugs used for treatment of posterior uveitis. Immuno modulators are used as a steroid sparing agents in non infectious posterior uveitis and retinal vasculitis. Despite adequate control of the disease the visual outcome is comparatively poor in posterior uveitis. The main reason for poor visual prognosis is the structural damage (chorioretinal atrophy in the macula) caused by the disease followed by complications. In posterior uveitis visual prognosis depends upon the aetiology, area of involvement and complications

Novel therapeutic targets in uveitis

Autoimmune posterior uveitis is a potentially blinding ocular disorder characterized by inflammation of the choroid and retina. Etiology is unknown and is assumed to be autoimmune and proposed to involve activation of autoreactive retinal-peptide specific T-cells, blood-retinal barrier breakdown, further leukocyte recruitment and ensuing ocular inflammation. The P2X7 receptor is a transmembrane purinergic receptor activated by high concentrations of ATP. Expression is ubiquitous with highest expression in immune cells. Stimulation results in the production and release of pro-inflammatory cytokines and potentiates leukocyte recruitment. Differences in mechanisms of P2X7 regulation in macrophages, dendritic cells and T cells were explored in vitro. Dendritic cells and macrophages have been proposed to release IL-1β through the NLRP3 inflammasome, requiring TLR4 stimulation followed by P2X7 stimulation. Dendritic cells were found to release IL-1β with TLR4 stimulation only, unlike macrophages which required additional P2X7 stimulus. Potential mechanisms of P2X7 regulation were explored, and it was found that T cells and not macrophages or dendritic cells exhibited significantly potentiated P2X7 mediated dye uptake upon lipid raft disruption. These results suggested a role for lipid rafts in P2X7 regulation in T cells. In vivo experiments utilized animal models of anterior, posterior and pan-uveitis. Mice deficient in P2X7 were protected against developing severe posterior uveitis, and treatment of mice with established EAU with P2X7 specific antagonist A438079 prevented the development of severe panuveitis. Finally, the role of the spleen tyrosine kinase (SYK) was investigated in murine posterior uveitis. Recent research implicates potential crossover of the P2X7 and SYK signalling pathways. SYK inhibition with the specific inhibitor fostamatinib did not prevent the development of uveitis in mice.Open Acces

Intraocular Biopsy and ImmunoMolecular Pathology for "Unmasking" Intraocular Inflammatory Diseases

Intraocular inflammation can hide a variety of eye pathologies. In 33% of cases, to obtain a correct diagnosis, investigation of the intraocular sample is necessary. The combined analyses of the intraocular biopsy, using immuno-pathology and molecular biology, point to resolve the diagnostic dilemmas in those cases where history, clinical tests, and ophthalmic and systemic examinations are inconclusive. In such situations, the teamwork between the ophthalmologist and the molecular pathologist is critically important to discriminate between autoimmune diseases, infections, and intraocular tumors, including lymphoma and metastases, especially in those clinical settings known as masquerade syndromes. This comprehensive review focuses on the diagnostic use of intraocular biopsy and highlights its potential to enhance research in the field. It describes the different surgical techniques of obtaining the biopsy, risks, and complication rates. The review is organized according to the anatomical site of the sample: I. anterior chamber containing aqueous humor, II. iris and ciliary body, III. vitreous, and IV. choroid and retina. We have excluded the literature concerning biopsy for choroidal melanoma and retinoblastoma, as this is a specialized area more relevant to ocular oncology

Retinal vascular involvement in uveitis and new treatment options

The retinal blood vessels can become occluded due to both inflammation and thromboembolic diseases, and the main aim of this thesis is to examine the features of retinal vein occlusion (RVO) in patients with co-existing ocular inflammation to determine risk factors for the development of RVO, risk factors predictive of a poor visual outcome in uveitis, the prevalence of anti phospholipid antibody-based disease and the role of antiphospholipid antibody (aPL) testing. In this thesis, I also explore the efficacy of new treatments for retinal vein occlusion, particularly the Ozurdex intravitreal dexamethasone implant, which can also be used to treat uveitis and uveitis macular oedema. Demographic and clinical variables were extracted from the medical notes of three separate sample groups of patients attending Moorfields Eye hospital including: 1) patients attending a Uveitis clinic between 2009-2011 with a new or past history of RVO; 2) any patient who had aPL testing performed during 2010; 3) patients recruited onto the initial Ozurdex for uveitis phase III clinical trial. 34 RVO events were recorded during a two year period with an overall clinic prevalence of 1.83%. Presenting ocular features and risk factors for RVO in uveitis patients were explored. aPL testing was commonly performed on patients with RVO in an Ophthalmology setting, and the usefulness of this and its relation to RVO events were examined. Finally, follow up data for uveitis patients treated with a single Ozurdex implant were explored to determine the longer-term outcome of this treatment, and the strategies employed as and when patients relapsed, comparing these outcomes with those of the Ozurdex implant

Causes of visual loss in patients with uveitis

The last major study of causes of vision loss in 600 eyes with uveitis was published over 10 years ago and there have been many advances in treatment over this time. In this thesis I undertook a study of 1594 patients (2593 eyes) with uveitis currently attending the clinic, 75% of whom were aged between 24 and 63 years. The type of uveitis, sight threatening complications that developed and treatment were followed from presentation to final follow up. At presentation, 16% of eyes had BCVA ≤ 6/18 (e.g. 6/18-6/36) and 14% of affected eyes had BCVA 6/60 or worse. At one year follow-up, we found 11% of eyes with vision loss to 6/18-6/36 and 8% of eyes with severe visual loss or blindness. In the group of eyes followed up for 10 years or more, 19% developed severe visual loss or blindness and 16% developed vision loss to 6/18-6/36. Chronic macular damage was the main cause of visual loss, accounting for both for visual impairment and for severe visual loss, accounting for 41% and 36% respectively. Cystoid macular oedema accounted for 29% in visual impairment and 19% in severe visual loss or blindness. When classified by uveitis types, CMO was the main cause of vision loss in intermediate uveitis (38%), glaucoma was the leading cause in anterior uveitis (32%), and chronic macular damage accounted for 46% in posterior/panuveitis. Additionally, I looked at the outcome and subsequent impact on vision of ocular surgery for cataract, glaucoma and vitreo-retinal procedures. Visual prognosis after cataract surgery was favourable in anterior and intermediate uveitis. Eyes which underwent glaucoma surgery had vision stabilised or slightly improved over time. The mean log MAR BCVA prior to glaucoma surgery was 0.53+/- 60, and 0.31+/- 49 at final follow-up visit. (P= 0.012). There was no statistically significant improvement in visual acuity in eyes which had undergone vitreo-retinal procedures. The mean logMAR BCVA were 1.1+/-0.82 and 0.87+/-0.80 respectively pre-operative and at last post- op visit. (P=0.28) The 3rd main results chapter looks at patients presenting with retinal vasculitis who had ischemia and the long term outcome for these eyes. Of the 106 eyes which developed ischemia, 24% had vision loss to 6/18-6/36 at presentation, 23% of these had BCVA 6/60 or worse. Chronic macular damage was the main cause of visual impairment and accounted for 36%, macular ischemia accounted for 67% of severe visual loss or blindness. I found that in most eyes with ischemia, visual loss developed early in the first 5 years and do not worsen with time

Autoimmunity in uveitis and other chorioretinal diseases

Uveitis is an inflammation of the vascular layer of the eye, which includes the iris, ciliary body and choroid. However, in practice the term uveitis is usually used as a collective term for any form of intraocular inflammation. Uveitis is a major cause of visual impairment or even blindness. The pathogenesis of uveitis is not fully clarified, but a crucial role of autoimmune reactions has been suggested. Although humoral autoimmune reactions directed against retinal tissue are thought to play an important role in either initiation or modification of diverse chorioretinal disorders including uveitis, they were not as yet systematically measured and their possible clinical impact in retinal diseases was not examined. Understanding of autoimmune processes in ocular diseases might help to further elucidate their pathogeneses and may have consequences for the design of new diagnostic and treatment modalities. In order to improve the understanding of autoimmune processes in ocular diseases this thesis aims to assess the presence of humoral autoimmunity in uveitis and other chorioretinal diseases, including autoimmune retinopathy, and to gain insight in its role

The Retina in Health and Disease

Vision is the most important sense in higher mammals. The retina is the first step in visual processing and the window to the brain. It is not surprising that problems arising in the retina lead to moderate to severe visual impairments. We offer here a collection of reviews as well as original papers dealing with various aspects of retinal function as well as dysfunction. New approaches in retinal research are described, such as the expression and localization of the endocannabinoid system in the normal retina and the role of cannabinoid receptors that could offer new avenues of research in the development of potential treatments for retinal diseases. Moreover, new insights are offered in advancing knowledge towards the prevention and cure of visual pathologies, mainly AMD, RP, and diabetic retinopathy

Determination of the soluble form of the P2X7 receptor in aqueous humour, vitreous humour and serum under normal and pathological conditions: sP2X7R as an indicator of ocular inflammatory status.

Background:P2X7R is a nucleotide receptor, located on the cytoplasmic membrane of all inflammatory and immune cells, that binds extracellular ATP. P2X7R plays a key role in inflammation, mediating activation of the NLRP3 inflammasome and release of cytokines (IL1β), and in regulating several cell death mechanisms. Espression of P2X7R was found in both eye bulb and ocular adnexa. On the ocular surface P2X7R is activated by chemical or mechanical sources of exogenous stress, leading to inflammation, apoptosis and cell proliferation. In the retinal, abnormalities in P2X7R functions have been linked to neuronal loss in glaucoma and neuroinflammatory processes in age-related macular degeneration and diabetic retinopathy. Based on a careful analysis of the recent literature on P2X7R involvement in the pathogenesis of various ocular diseases, this observational interventional study was conducted, aiming to: asses the presence of the soluble form of the purinergic P2X7 receptor (sP2X7R) in aqueous humour and vitreous humour; compare sP2X7R levels in healthy conditions and in the presence of various ocular or systemic pathological conditions with ocular involvement, underlying an inflammatory pathogenesis, such as: glaucoma, Fuchs endothelial dystrophy, pseudoexfoliatio, age-related macular degeneration, diabetes and retinal detachment; compare sP2X7R levels in aqueous humour and vitreous humour with those in serum. Methods:The patients enrolled are represented by subjects undergoing eye surgery at the Ophthalmic Clinic Unit of the Sant'Anna Hospital of Ferrara. In the group of pathological subjects there are aqueous humour and serum samples taken from patients with different ocular pathologies who underwent planned cataract extraction surgery and vitreous humour and serum samples from patients with retinal detachment who underwent vitrectomy surgery. The control group included aqueous humour and serum samples from patients undergoing cataract extraction surgery in the absence of other eye disease and vitreous and serum samples taken from patients undergoing vitrectomy for macular hole or macular pucker. Results:The presence of sP2X7R was assessed, which was found to be detectable in aqueous humour and vitreous humour using a specific ELISA kit. The range concentrations of sP2X7R in aqueous humour control group is 3.89 to 93.87 pg/ml; in pathologic group is 3.55-277.4 pg/ml. In vitreous humour range is 4.21-76.92 pg/ml in the control group, whilst in pathological condition is 28.52 to 284.57 pg/ml. The Kruskal-Wallis Test on the equality of the medians of both control and pathology groups of the acqueous samples, estimates a p-value slightly above the test reliability limit (p-value: 0.05082), confirming that the median value of the sP2X7R concentration measured in the pathology groups is significantly different, if all the data are considered together. Despite this finding, analysing each pathology group compared to the control group, using Dunn's Test to perform the pairwise comparison with the Bonferroni's correction factor, failed to confirm a statistically significant difference. The Kruskal-Wallis Test on the equality of the median of both control and pathology groups of the vitreous samples, does not allow the initial hypothesis to be rejected with probability (p value:0.1999). The test result therefore does not allow the assertion that there is a significant difference between the sP2X7R content in the vitreous of healthy patients and patients with the studied eye diseases. Conclusion:In this study the presence of sP2X7R in aqueous humour and vitreous humour was tested for the first time, and the ELISA kit used proved to be a reliable tool. By examining comprehensively the pathologic groups it can be stated that sP2X7R is a marker of ocular inflammatory status, but the stratification analysis failed to prove a significant correlation with the single pathology. Those data could lay the groundwork for further investigationBackground: P2X7R è un recettore nucleotidico, situato sulla membrana citoplasmatica delle cellule infiammatorie e immunitarie, che lega l'ATP extracellulare. P2X7R svolge un ruolo chiave nell'infiammazione, attivando l'inflammasoma NLRP3 e il rilascio di citochine (IL1β), e nella regolazione di diversi meccanismi di morte cellulare. L'espressione di P2X7R è stata riscontrata sia nel bulbo oculare che negli annessi. Sulla superficie oculare, P2X7R è attivato da stress chimici o meccanici, determinando infiammazione, apoptosi e proliferazione cellulare. A livello retinico, anomalie nelle sue funzioni sono state collegate alla perdita neuronale nel glaucoma e ai processi neuroinfiammatori nella degenerazione maculare legata all'età (DMLE) e nella retinopatia diabetica (RD). Dopo attenta analisi della recente letteratura, è stato condotto questo studio osservazionale interventistico con l'obiettivo di: valutare la presenza della forma solubile del recettore purinergico P2X7 (sP2X7R) nell'umor acqueo e nell'umor vitreo; confrontarne i livelli in condizioni normali e in presenza di differenti patologie oculari o sistemiche con coinvolgimento oculare, con patogenesi infiammatoria: glaucoma, distrofia endoteliale di Fuchs, pseudoesfoliazione, DMLE, diabete e distacco di retina; confrontare i livelli di sP2X7R nell'umor acqueo e vitreo con quelli del siero. Metodi:I pazienti arruolati sono soggetti sottoposti a intervento chirurgico programmato presso la Clinica Oculistica dell'Ospedale Sant'Anna di Ferrara. Il gruppo patoligico comprende campioni di umore acqueo e siero prelevati da pazienti con diverse patologie oculari sottoposti a intervento di estrazione della cataratta e campioni di umore vitreo e siero prelevati da pazienti con distacco di retina sottoposti a intervento di vitrectomia. Il gruppo di controllo comprende campioni di umore acqueo e siero di pazienti sottoposti a intervento di estrazione della cataratta in assenza di altre patologie oculari e campioni di vitreo e siero prelevati da pazienti sottoposti a vitrectomia per foro o pucker maculare. Risultati:La presenza di sP2X7R è stata confermata e rilevata nell'umor acqueo e nell'umor vitreo utilizzando uno specifico kit ELISA. L'intervallo di concentrazioni di sP2X7R nel gruppo di controllo dell'umor acqueo è 3,89-93,87 pg/ml; nel gruppo patologico è 3,55-27,4 pg/ml. Nell'umor vitreo il range è 4,21-76,92 pg/ml nel gruppo di controllo, mentre nel gruppo patologico è 28,52-284,57 pg/ml. Il test di Kruskal-Wallis sull'uguaglianza delle mediane dei gruppi di controllo e patologici dell’umor acqueo stima un valore p leggermente superiore al limite di affidabilità del test (p: 0,05082), confermando che il valore mediano della concentrazione di sP2X7R misurato nei gruppi patologici è significativamente diverso, se si considerano tutti i dati insieme. Nonostante questo risultato, l'analisi di ciascun gruppo patologico rispetto al gruppo di controllo, utilizzando il test di Dunn per il confronto a coppie, applicando il fattore di correzione di Bonferroni, non ha confermato una differenza statisticamente significativa. Il test di Kruskal-Wallis sull'uguaglianza della mediana dei campioni di vitreo tra gruppi di controllo e patologici stima un valore p: 0,1999. Il risultato del test non permette quindi di affermare che esista una differenza significativa tra il contenuto di sP2X7R nel vitreo di pazienti sani e di pazienti con le patologie oculari studiate. Conclusioni: In questo studio è stata testata per la prima volta la presenza di sP2X7R nell'umor acqueo e nell'umor vitreo e il kit ELISA utilizzato si è dimostrato uno strumento affidabile. Esaminando complessivamente i gruppi patologici si può affermare che sP2X7R è un marcatore dello stato infiammatorio oculare, ma l'analisi stratificata non è riuscita a dimostrare una correlazione significativa con la singola patologia. Questi dati potrebbero gettare le basi per ulteriori indagini