STEROID HYPOPYON FOLLOWING INTRAVITREAL TRIAMCINOLONE ACETONIDE INJECTION IN A PSEUDOPHAKIC PATIENT
Josh E. Amato, Dave H. Lee, Byron A. Santos, Levent Akduman
We report a 64 year-old woman who presented with the complaint of "white-stuffo/oo in the left eye one day after intravitreal triamcinolone acetonide injection. Her past ocular history was positive for a successful limited macular translocation surgery for subfoveal choroidal neovascular membrane secondary to age-related macular degeneration one year previously, cataract surgery with anterior chamber intraocular lens placement 9 months previously, and chronic pseudophakic cystoid macular edema for 6 months. The patient was followed-up with the differential diagnosis of post-injection endophthalmitis versus "steroid hypopyon.o/oo Slit lamp examination four days after the injection revealed white and quiet conjunctiva, clear cornea, and resolving hypopyon with no cells in the anterior chamber. Three weeks after the injection, visual acuity improved from 20/200 to 20/70 with complete resolution of macular edema.
Endophthalmitis after intravitreal triamcinolone has been reported to occur in 1.4% of patients. Patients in the study by Moshfeghi et al. presented with pain, redness, and hypopyon a median of four days after injection. Patients having no capsular barrier presenting with hypopyon one day after intravitreal triamcinolone injection may be observed closely for a few days for resolution of hypopyon prior to being treated as endophthalmitis.
Jennifer E. Thorne, MD, Esen K. Akpek, MD, Faqir A. Qazi, MBBS, FRCS, Diana V. Do, MD, Douglas A. Jabs, MD, MBA
Purpose: To determine the association of underlying medical illnesses with scleritis and the timing of the diagnosis of these medical illnesses with the scleritis. Methods: A retrospective study of 243 consecutive patients with scleritis who presented to a single clinical center over an 18-year period was performed. Each patient's chart was reviewed for the presence of an associated medical illness and for the timing of the diagnosis of the illness relative to the presentation of the scleritis. Results: Of the 243 patients with scleritis, 44% had an underlying medical illness with 37% having a rheumatic disease and 7% having an infection. Of the 107 patients with an associated underlying disease, 77.6% had the disease diagnosed previously, 14% were diagnosed as a result of the initial evaluation, and 8.4% developed the underlying disease during the course of follow-up. Of the patients without evidence of an underlying medical illness at the time of presentation, the rate of developing a rheumatic disease was 4.23% per person-year. Systemic vasculitis was less likely to have been previously diagnosed than other rheumatic diseases (59.1% vs. 83.8%, P=0.015) and more likely to be diagnosed during the initial diagnostic testing (27.3% vs. 8.8%, P= 0.027) Ten patients (4.1%) had either a positive c-ANCA or p-ANCA without clinical evidence of a systemic vasculitis. Four out of the five patients with a positive c-ANCA but without systemic vasculitis required immunosuppressive drugs to control their scleritis. Conclusions: Although associated medical illnesses are frequent among patients with scleritis, the majority are diagnosed prior to the presentation of the scleritis. Systemic vasculitis is less likely than other rheumatic diseases to have been previously diagnosed. Because vasculitis is a potentially life threatening disorder, it should be a focus of the diagnostic evaluation.
CORNEAL ANTIGEN-PRESENTING CELLS (APC): FUNCTION AND IDENTIFY IN INFLAMMATION
P. Hamrah , Y. Liu , S.O. Huq, Q. Zhang , M.R. Dana
Purpose: The normal corneal stroma and epithelium are endowed with large numbers of resident dendritic cells (DCs). The purpose of this study was to examine the phenotype and distribution of these cells in inflammation and to investigate their ability to migrate to draining lymph nodes (LN) and to function as antigen-presenting cells (APCs). Methods: Normal, inflamed and transplanted murine corneas were excised at different timepoints and immunofluorescense staining with multiple antibodies was performed by confocal microscopy on whole-mounted corneas to characterize and evaluate the distribution and phenotype of DCs in inflammation. The migration of corneal DCs to draining LN was tracked in a transplantation model and the allostimulatory capacity of these cells was measured by extracting them in culture and mixing them with responding lymphocytes. Results: DCs and Langerhans cells were present throughout the anterior stroma and the epithelium of normal corneas. While nearly half of these cells were MHC class II+ and costimulatory molecule+ in the periphery, they were uniquely negative for these molecules in the center of the normal cornea, indicating an immature state. During inflammation, in addition to a significant increase of these cells, a majority of the resident DCs underwent maturation. The maturation of corneal DCs was confirmed with transplantation experiments, where immature DCs underwent maturation as early as 24 hours post transplantation. In addition, a population of macrophages was found in the posterior stroma that increased in number and was present throughout the stroma during inflammation. Corneal DCs migrated to ipsilateral cervical draining LN and were able to stimulate alloreactive lymphocytes. Conclusion: Recently identified immature corneal DCs are capable of undergoing maturation in inflammation and migrating to draining LN where they are able to function as APCs. Our results suggest that the cornea is capable of participating in immune and inflammatory responses by virtue of its own heterogeneous population of DCs.
ANALYSIS OF NOD2 (CARD 15) MUTATIONS IN CROHN'S DISEASE PATIENTS WITH UVEITIS
T.M. Martin, J.F. Collins, T.M. Doyle, B.M. Rajska, and J.T. Rosenbaum
Purpose: Mutations in the NOD2 (CARD 15) gene cause an autosomal-dominant form of uveitis called familial juvenile systemic granulomatosis (also called Blau syndrome and Jabs disease). Distinct mutations in NOD2 are also associated with Crohn's disease, an inflammatory condition that may include uveitis. NOD2 mutations influence the clinical presentation of Crohn's disease, but it is not known if mutations in NOD2 contribute specifically to uveitis. Here, we sought to examine the NOD2 gene in Crohn's disease patients with uveitis. Methods: Genomic DNA from a cohort of Crohn's disease patients seen at the Uveitis Clinic at the Casey Eye Institute was examined for mutations in NOD2 using direct sequencing and dHPLC methods. A control group of Crohn's disease patients without ocular involvement was included in the analysis. Statistical analysis was by the Fisher's Exact Test. Results: Eleven Crohn's disease patients with uveitis were genotyped for the 3 most common Crohn's disease muations (R702W, G908R and 1007fs). None of these patients exhibited any of the 3 mutations. In contrast, 9 out of 24 Crohn's disease patients who did not have uveitis had at least one of the 3 disease-associated mutations. The difference between these 2 groups, i.e. 0/11 patients with uveitis versus 9/24 patients without uveitis was significant (P=0.03). the allele frequencies of these mutations among the 9 patients without uveitis were as follows: R702W, 15%; G908R, 6%; and 1007fs, 4%. As expected, none of the Crohn's disease patients (i.e. either with or without uveitis) had any NOD2 mutations known to cause familial juvenile systemic granulomatosis, an autosomal-dominant disease. Conclusions: Although this is a small cohort, absence of the 3 most common NOD2 mutations in the Crohn's disease population with uveitis is striking. The common NOD2 mutations found in Crohn's disease patients do not account for association between Crohn's disease and uveitis.
INTERFERON ALFA-2a TREATMENT IN BEHÇET'S DISEASE: VISUAL ACUITY AFTER 5 YEARS
M. Zierhut, I. Koetter, I. Guenaydin, N. Stuebiger, C.M.E. Deuter
Purpose: Behçet´s disease (BD) is a systemic vasculitis of unknown origin. Up to now ocular involvement, which is present in 60-80 % of patients with BD, had a poor visual prognosis irrespective of immunosuppressive treatment. Now recent open studies have shown that interferon alfa-2a (IFN alfa-2a) is very effective in the treatment of ocular BD and seems to be superior to conventional immunosuppressants like azathioprine or cyclosporin A. The purpose of this study was to evaluate the development of visual acuity (VA) after a follow-up time of at least 5 years in patients with severe ocular BD who were treated with IFN alfa-2a. Methods: We included 15 eyes of 9 patients (male:female = 6:3) with an active panuveitis and / or retinal vasculitis due to BD which had to be refractory to at least one conventional immunosuppressive treatment and / or systemic steroids. Initially patients received IFN alfa-2a in a dosage of 6 million IU/day for at least two weeks. Then the dosage of IFN alfa-2a was tapered to 3 million IU twice a week over several months and finally discontinued if possible. We compared VA at initiation of IFN-therapy to VA at the end of the follow-up time of at least 5 years. Results: Mean follow-up time was 68.8 ± 10.6 months. Mean duration of IFN-treatment was 40.6 ± 17.0 months. With the exception of one patient IFN alfa-2a could be discontinued in complete remission of ocular symptoms. During the follow-up time of at least 5 years 10 eyes showed an increase of VA of two lines or more; in 5 eyes VA remained stable. There was no decrease of VA in any eye. At initiation of IFN-therapy a VA of 0.1 or less was present in 6 eyes, but still in 2 eyes at the end of follow-up. No procedures for improvement of VA (e.g. cataract surgery or vitrectomy) were performed during follow-up time. If a macular oedema was present (11 eyes), a quick response to IFN alfa-2a was seen without the need for additional treatment. No eye developed a pale optic disk during follow-up. Conclusions: Compared to conventional immunosuppressants, interferon alfa-2a seems to be much more effective to prevent a loss or decrease of VA over a long period of time in patients with severe ocular BD.
OUTCOME OF TRABECULECTOMY WITH INTRA-OPERATIVE MITOMYCIN C FOR UVEITIC GLAUCOMA
Larissa Derzko-Dzulynsky, Jason Noble, Catherine Birt, Theodore Rabinovitch
Introduction: In the present study, the outcome of uveitis-related glaucoma treated with MMC augmented trabeculectomy is compared to glaucoma controls without ocular inflammation. Methods: Fifty-one eyes of 51 patients (21 uveitic glaucoma patients and 30 non-uveitic glaucoma patients) were included in the study. Success after treatment with MMC augmented trabeculectomy was compared between the two groups using four outcome classifications: (1) absolute success (intra-ocular pressure (IOP) 21mmHg without glaucoma medications or 5-FU injections); (2) qualified success (IOP 21mmHg with glaucoma medications or 5-FU injections); (3) IOP 18mmHg; (4) IOP 30% of the baseline IOP measurement. Five predictors of success were also compared using Cox analysis. Kaplan-Meier survival curves were constructed. Results: Patients were followed for a mean of 37 months. In all models, uveitis alone emerged as a strong negative predictor of success. Uveitis patients were found to be 3.0 times as likely as the controls to require post-operative glaucoma medications or 5-FU injections (p = 0.056), 3.2 times as likely to have an IOP > 18mmHg (p = 0.037) and 3.5 times as likely not to be able to maintain an IOP 30% below their pre-operative level (p = 0.024). The Kaplan-Meier survival analysis revealed a 47% absolute success rate at 1 year in the uveitis group compared to 83% for the control group (log rank test, p = 0.018). The qualified success rate at 1 year was 95% for the uveitis group and 100% for the controls (log rank test, p = 0.015). Conclusions: Uveitis patients with glaucoma are at increased risk of surgical failure after MMC trabeculectomy and are more likely to require post-operative therapeutic interventions to maintain control of IOP.
INVOLVEMENT OF INFLAMMATION IN PATHOGENESIS OF PIGMENTARY GLAUCOMA
Jun-Song Mo, Michael G Anderson, Simon W. M. John, J. Wayne Streilein
Purpose: DBA/2J (D2) mice are genetically determined to develop pigment dispersion (PD). Dispersal of iris pigment is found in the anterior chamber beginning at age 6 mos, followed by anterior synechiae and obstruction of AqH out-flow drainage pathway. Intraocular pressure begins to increase at age of 6 mos, reaches a peak at 9 mos, and is followed by optic neuropathy. One of the two mutant genes responsible for the disease, Gpnmb, is expressed in bone marrow-derived dendritic cells, implicating immunity/inflammation in the pathogenesis of the disease. In the present study, we tried to determine whether inflammation was involved in development of PD in D2 mice. Methods: AqH was collected from unmanipulated D2 mice, from x-irradiated D2 mice receiving D2 bone marrow cells (these mice had PD similar to that in un-manipulated D2 mice), and from D2 radiation chimeras receiving (D2xC57BL/6)F1 bone marrow cells (these D2 chimeras did not develop PD). To assess integrity of the blood:ocular barrier, protein and leukocyte content in the AqH were analyzed. Results: Elevated protein levels in AqH were first observed in D2 mice at age of 4 mos; proteins level continued to rise thereafter. Leukocytes (90% neutrophils, 10% macrophages) began to appear in AqH at age 6 mos, reached peak at 7 mos (10% neutrophils, 90% macrophages) and then decreased through age 10 mos. Many macrophages contained melanin pigment. AqH from irradiated D2 mice receiving D2 bone marrow cells showed similar results. However, no increased protein levels or leukocytes were observed in AqH from D2 chimeras receiving (D2xB6)F1 bone marrow cells. Summary: Inflammatory reactions were found in the anterior chamber of eyes of D2 mice that develop PD. The time course of intraocular inflammation paralleled the time course of PD development. Bone marrow cells from resistant mice prevented PD in D2 radiation chimeras. Conclusion: Inflammation participates in the pathogenesis of pigment dispersion glaucoma. Together our results suggest that a mutation in Gpnmb expressed in bone marrow cells is responsible for the inflammation.
THROMBOSPONDIN AND ACTIVE TGF-ß PROTECT THE UVEAL TRACT FROM INTENSE, UNRELENTING AUTOIMMUNE UVEORETINITIS
Zamiri P, kitaichi N, Streilein J W
Purpose. Thrombospondin-1 (TSP-1) converts latent TGF-ß into its active form, and active TGF-ß has been implicated in ocular immune privilege. We wished to determine the induction of anterior chamber associated immune deviation (ACAID) and the expression of experimental autoimmune uveoretinitis (EAU) in TSP-1 knockout (TSPKO) mice. Method. Posterior eyecups were produced from eyes of both TSPKO and C57BL/6 mice and the supernatants of these eyecups were examined for their ability to suppress T cell proliferation and IFN-g production in vitro. Ovalbumin (OVA) was injected into the anterior chamber (AC) and the subretinal space (SRS) of TSPKO mice, after which they were immunized with OVA and complete Freund's adjuvant (CFA). Delayed-type hypersensitivity (DTH) was assessed by ear challenge. The eyes of TSPKO and C57BL/6 mice, that received immunization with interphotoreceptor binding protein (IRBP) and CFA supplemented with petrussis toxin (PTX) to induce experimental autoimmune uveoretinitis (EAU) were evaluated clinically for evidence of uveitis. Result. Supernatant of the eyecups from TSPKO mice failed to inhibit IFN-g production as compared to the wild type control. OVA-specific DTH failed to develop in TSPKO mice pretreated with OVA in AC or SRS. EAU was significantly more intense in eyes of TSPKO mice, and the spontaneous resolution of EAU observed within 120 days in eyes of C57BL/6 controls failed to take place in TSPKO mice over 150 days. Conclusions. Mouse eyes deficient in TSP are (a) unable to create an intraocular immunosuppressive microenvironment or to promote ACAID induction, and (b) vulnerable to intense, chronic autoimmune uveoretinitis. Intraocular TSP, and by inference active TGF-ß, are essential for maintaining ocular immune privilege and preventing blinding inflammation.
PANUVEITIS ASSOCIATED WITH PSEUDOTUMOR CEREBRI
Quan Dong Nguyen, Diana V. Do, Eyal Margalit, Jennifer U. Sung
Purpose: To describe a case of panuveitis associated with pseudotumor cerebri in a young girl. Methods: Interventional case report. The patient underwent complete reviews of system, and ophthalmic, neurologic, and medical evaluations. Results: A 12-year-old Korean American girl was referred to our service after experiencing visual disturbances and occasional headache for several months. Past medical history, family history, and social history were unremarkable. Review of systems was significant for a 25-lb weight gain over the past three months. Examination revealed visual acuity of 20/40 in both eyes. Bilateral granulomatous iridocyclitis was present. Funduscopic examination revealed bilateral vitritis and disc edema, left eye greater than right eye. No other retinal pathology was seen. Extensive evaluations were unremarkable. Pediatric neurologic consultation was obtained. Lumbar puncture yielded an opening pressure of 27 cm of water. Analyses of cerebral spinal fluid were normal. Cerebral magnetic resonance imaging was unremarkable. Ocular physical findings and visual symptoms improved after therapy with oral acetazolamide, weight reduction, and low-dose topical prednisolone acetate. Conclusion: The index case may represent the first report of panuveitis associated with a clinical diagnosis of pseudotumor cerebri, and is presented for discussion of (alternative) diagnosis and management.
A CASE OF INFECTED SCLERAL BUCKLE WITH MYCOBACTERIUM CHELONAE ASSOCIATED WITH CHRONIC INTRAOCULAR INFLAMMATION
Scott M. Smetana, Ozay Oz, Dave H. Lee, Levent Akduman
Purpose: To describe a unique case of chronic intraocular inflammation secondary to scleral buckle infection with Mycobacterium chelonae that was successfully treated with buckle explantation. Design: Interventional case report. Methods: Case report. Results: A 59-yar old male with a history of retinal detachment repair at the age of 41 presented with chronic, recurrent intraocular inflammation responsive to topical corticosteroids. Conjunctival erosion with exposure of the scleral buckle occurred five months after initial presentation. The scleral buckle was removed and cultured. After 3 weeks of postoperative topical Tobramycin and Dexamethasone treatment, he has been maintained symptom free without medications. The explanted material grew acid-fast bacilli later identified as M. Chelonae. Conclusion: This case describes a new finding of chronic intraocular inflammation associated with a scleral buckle infected with M. Chelonae and successful resolution of extraocular infection and intraocular inflammation after buckle removal.
David C. Gritz and Ira G. Wong,
Purpose: To examine role of ethnicity in the epidemiology of uveitis through a population-based cross-sectional study. Methods: Epidemiologic and demographic data were collected through a retrospective chart review of all people with uveitis in two target communities over a consecutive twelve-month period. Data on ethnicity was gathered from medical records review and telephone interviews. Population data was available on a quarterly basis. Incidence rates were determined with a dynamic population model. Prevalence ratios were determined using the mid-period population as a denominator. Rates of disease were compared using Fisher's exact test, comparing each ethnic group to all others outside that ethnic group. Results: The mid-period population was 190,734 and was composed of 45% Caucasian, 18.2% Hispanic, 14.5% African, 16.8% Asian, and 5.4% "Other" people. Rates for the "other" groups were not compared with the more defined categories. The overall incidence rate was 50.6 cases per 100,000 person-years and there were no statistically significant difference between ethnic groups. There was a tendency for a higher incidence rate in African-Americans (p=0.14). The prevalence rates were different with African-Americans having the highest (199.3/100,000 people) and Hispanics having the lowest (75.2/100,000 people) ratio of disease. Compared with those outside their ethnic group, African-Americans had higher risk of prevalent uveitis (Odds Ratio; O.R.=1.9, p=0.0001) and Hispanics had lower risk (O.R.=0.60, p=0.01). Conclusions: These data suggest that African-Americans have a higher risk of developing ongoing inflammatory disease after an initial bout of uveitis and Hispanics have a lower risk when compared to those outside their ethnic group.
Jennifer E. Thorne, Esen K. Akpek, Faqir A. Qazi, Diana V. Do, Douglas A. Jabs
Purpose: To determine the association of underlying medical illnesses with scleritis and the timing of the diagnosis of these medical illnesses with the scleritis. Methods: A retrospective study of 243 consecutive patients with scleritis who presented to a single clinical center over an 18-year period was performed. Each patient's chart was reviewed for the presence of an associated medical illness and for the timing of the diagnosis of the illness relative to the presentation of the scleritis. Results: Of the 243 patients with scleritis, 44% had an underlying medical illness with 37% having a rheumatic disease and 7% having an infection. Of the 107 patients with an associated underlying disease, 77.6% had the disease diagnosed previously, 14% were diagnosed as a result of the initial evaluation, and 8.4% developed the underlying disease during the course of follow-up. Of the patients without evidence of an underlying medical illness at the time of presentation, the rate of developing a rheumatic disease was 4.23% per person-year. Systemic vasculitis was less likely to have been previously diagnosed than other rheumatic diseases (59.1% vs. 83.8%, P=0.015) and more likely to be diagnosed during the initial diagnostic testing (27.3% vs. 8.8%, P= 0.027) Ten patients (4.1%) had either a positive c-ANCA or p-ANCA without clinical evidence of a systemic vasculitis. Four out of the five patients with a positive c-ANCA but without systemic vasculitis required immunosuppressive drugs to control their scleritis. Conclusions: Although associated medical illnesses are frequent among patients with scleritis, the majority are diagnosed prior to the presentation of the scleritis. Systemic vasculitis is less likely than other rheumatic diseases to have been previously diagnosed. Because vasculitis is a potentially life threatening disorder, it should be a focus of the diagnostic evaluation.
Charles E. Thirkill
Purpose: An illustration of a collection of unusual immunologic reactions that occur in retinal degenerations. Immune mediated retinal damage results in the inflammatory uveitides such as Birdshot chorioretinopathy, the Vogt-Koyanagi-Harada and Behcet's syndromes. The examples given here represent those with a more subtle; chronic immunologic involvement that develop in diseases not immediately related to the eye. Methods: The indirect fluorescent antibody assay (IFA) and Western blot reactions combine to provide insight into the location of abnormal antibody activity within the retina, and the approximate size of the antigen(s) involved. Together, these techniques supply information on the nature of the patient's hypersensitivity, and permit comparisons with clinical findings to evaluate any possible connection and significance. Results: Immunologic abnormalities of potential pathologic significance typically include a focus of antibody activity upon a single retinal cell layer. If this finding correlates with clinically demonstrable loss or inhibition of the same layer, the significance of the immunologic reaction is enhanced. If the suspect autoantigen is proteinaceous, Western blot reactions can assist in learning its identity because recognized autoantigens of recorded size are located in different cell layers. Accordingly, a correlation between IFA and blots serves to narrow the field of suspected autoantigens that may be involved in the patient's abnormality. Discussion: The neurosensory retina consists of a collection of layers of highly specialized cells and since every layer differs in function, each naturally expresses different antigens. The center of the retina varies in cellular composition from that of the periphery resulting in a concentric antigenic mosaic that could be responsible for the distinct patterns of loss described in several `idiopathic' forms of retinal degenerations. The structural diversity of the retina provides an array of targets for autoimmune reactions, throughout the width and depth of its composition. The complexity of the central nervous system necessitates that the search for immunologic abnormalities of clinical significance recognizes the need to focus upon antibody activity with known autoantigens, or those consistently associated with a particular disease. Other antigens are commonly encountered but if they are not connected with a recognized disease or syndrome, the abnormal antibody activity is recorded and described as `immuno-reactivity with an unknown antigen'. If in time, a collection of patients exhibits the same immunologic abnormality the antigen involved then becomes the subject of further research. Novel immunologic reactions of possible clinical significance are thus identified, and the pool of recognized autoantigens increases. Some of the more understood `immune-mediated retinal degenerations' are those developing in cancer patients in response to anatomically distant malignancies expressing the retinal protein(s) involved in the patient's immunologic abnormality. This process of ectopic sensitization provides the rare opportunity to study an autoimmune disease with a recognized cause, but most retinal degenerations suspected of having an immunologic component have no known derivation. Transient cancers or microbial infections are possibilities in which ocular sensitization could result from the remote expression of cross-reactive antigens, or the process of molecular mimicry in which autoantigenic epitopes are expressed that coincide with small corresponding sequences within the eye. However, a simple cross-reaction is insufficient to incite a pathologic response, other more complex events must transpire within the host before a loss of tolerance progresses to an autoimmune disease. The eight antibody reactions illustrated here, " responsible or not", are those most readily associated with different forms of retinal degenerations, and may give cause to consider autoimmunity as a contributing factor. Supported by Research to Prevent Blindness (RPB), and NEI core grant 1 P30 EY12576-01.