Seven-Year Outcomes of Uveitic Macular Edema: The Multicenter Uveitis Steroid Treatment Trial and Follow-up Study Results.

PURPOSE: To evaluate the long-term outcomes of uveitic macular edema (ME). DESIGN: Longitudinal follow-up of a cohort of participants in a randomized clinical trial. PARTICIPANTS: A total of 248 eyes of 177 participants with uveitic ME enrolled in the Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study. METHODS: OCT measurements, taken at baseline and annually, were graded by reading center graders masked to clinical data. Macular edema was defined as a center macular thickness (CMT) ≥240 µm on time-domain OCT or time-domain OCT equivalent. Resolution of ME was defined as normalization of macular thickness on OCT. Relapse of ME was defined as increase in macular thickness to ≥240 µm in an eye that previously had resolution. Visual acuity was measured at each visit with logarithmic visual acuity charts. MAIN OUTCOME MEASURES: Resolution and relapse of ME. Visual acuity. RESULTS: Among 227 eyes with ME followed ≥1 year, the cumulative percent of eyes with ME resolving at any point during 7 years was 94% (95% confidence interval [CI], 89-97). Epiretinal membranes on OCT were associated with a lower likelihood of ME resolution (hazard ratio [HR], 0.74; 95% CI, 0.55-1.01; P = 0.05). Among 177 eyes with resolved ME, the cumulative percent with relapse within 7 years was 43% (95% CI, 32-51). Eyes in which ME resolved gained a mean of 6.24 letters (95% CI, 4.40-8.09; P < 0.001) compared with eyes that remained free from ME during the 1-year follow-up intervals, whereas eyes in which ME did not resolve experienced no gain in vision (mean change -1.30 letters; 95% CI, -2.70 to 0.09; P = 0.065), and eyes that developed ME during the year (incident or relapsed) experienced a mean loss of -8.65 letters (95% CI, -11.5 to -5.84, P < 0.001). CONCLUSIONS: Given sufficient time and treatment, nearly all uveitic ME resolves, but episodes of relapse were common. Visual acuity results were better among eyes with resolved ME, suggesting that control of inflammation and resolution of ME might be visually relevant treatment targets.

Polypoidal Choroidal Vasculopathy Complicating Retinal Laser in Quiescent Uveitis.

A 58-year-old Afro-Caribbean gentleman with a diagnosis of quiescent systemic lupus erythematosus- (SLE-) related occlusive retinal vasculitis was previously treated with sector pan-retinal photocoagulation in his right eye to control temporal retinal neovascularization. At routine review he was found to have a focal area of subretinal fluid in the temporal macula sparing an ischaemic fovea. Fundus fluorescein angiography and indocyanine green angiography confirmed a branching vascular network (BVN) and terminal polys (i.e., polypoidal choroidal vasculopathy (PCV)). Interestingly, the BVN arose within an old laser scar. To our knowledge this is the first report of PCV in uveitis in an Afro-Caribbean patient and of the lesions arising within a laser scar.

Eye care in the intensive care unit.

Ocular surface disease is common in the intensive care population with 20-42% of patients developing corneal epithelial defects. The ocular surface is normally protected by the ability to produce tears, to blink and to close the eyes with rest or sleep. All of these mechanisms can be disrupted in the intensive care population, increasing the risk of developing ocular surface disease. Despite the scale of the problem, eye-care protocols are commonly not instigated and documentation of eye care is often poor. This review details the risk factors for developing ocular surface disease. It also provides evidence-based guidance on protecting the eyes in vulnerable patients, identifying diseases affecting the eye in intensive care patients and delivering the best treatment to the eye. There is growing evidence that adherence to a correctly performed eye-care guideline prevents the majority of corneal problems encountered in the intensive care unit.

Factors Predicting Visual Acuity Outcome in Intermediate, Posterior, and Panuveitis: The Multicenter Uveitis Steroid Treatment (MUST) Trial.

PURPOSE: To identify factors associated with best-corrected visual acuity (BCVA) presentation and 2-year outcome in 479 intermediate, posterior, and panuveitic eyes. DESIGN: Cohort study using randomized controlled trial data. METHODS: Multicenter Uveitis Steroid Treatment (MUST) Trial masked BCVA measurements at baseline and at 2 years follow-up used gold-standard methods. Twenty-three clinical centers documented characteristics per protocol, which were evaluated as potential predictive factors for baseline BCVA and 2-year change in BCVA. RESULTS: Baseline factors significantly associated with reduced BCVA included age ≥50 vs <50 years; posterior vs intermediate uveitis; uveitis duration >10 vs <6 years; anterior chamber (AC) flare >grade 0; cataract; macular thickening; and exudative retinal detachment. Over 2 years, eyes better than 20/50 and 20/50 or worse at baseline improved, on average, by 1 letter (P = .52) and 10 letters (P < .001), respectively. Both treatment groups and all sites of uveitis improved similarly. Factors associated with improved BCVA included resolution of active AC cells, resolution of macular thickening, and cataract surgery in an initially cataractous eye. Factors associated with worsening BCVA included longer duration of uveitis (6-10 or >10 vs <6 years), incident AC flare, cataract at both baseline and follow-up, pseudophakia at baseline, persistence or incidence of vitreous haze, and incidence of macular thickening. CONCLUSIONS: Intermediate, posterior, and panuveitis have a similarly favorable prognosis with both systemic and fluocinolone acetonide implant treatment. Eyes with more prolonged/severe inflammatory damage and/or inflammatory findings initially or during follow-up have a worse visual acuity prognosis. The results indicate the value of implementing best practices in managing inflammation.

Statin Modulation of Human T-Cell Proliferation, IL-1ß and IL-17 Production, and IFN-γ T Cell Expression: Synergy with Conventional Immunosuppressive Agents.

HMG-CoA reductase inhibitors (statins) have been demonstrated to be immunomodulatory for human immune-mediated disease and in experimental models. The aim of this study was to compare statin-mediated immunosuppressive effects on human T-cell responses in vitro with those of conventional immunosuppressives (dexamethasone, cyclosporin A (CsA), mycophenolate, and rapamycin). Statins (atorvastatin, lovastatin, and simvastatin) were investigated for their modulatory effects on human PBMC viability, cytokine profiles, and T-cell proliferation. At concentrations that inhibited anti-CD3/28-stimulated T-cell proliferation (P < 0.01), simvastatin significantly decreased intracellular CD4(+) T-cell expression of IFN-γ (P < 0.01) to levels similar to those induced by conventional immunosuppressives. Atorvastatin and lovastatin also decreased IFN-γ expression, although to a lesser degree (P < 0.05). All three statins reduced levels of IL-17 production (P < 0.01). However, in response to anti-CD3/28 stimulation, simvastatin significantly upregulated IL-1ß production (P < 0.05). The profile of cytokines produced in response to anti-CD3/28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone, suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines. This data supports the hypothesis of selective statin-mediated immunomodulatory effects on human immune cells.

Fluorescein angiography versus optical coherence tomography for diagnosis of uveitic macular edema.

OBJECTIVE: To evaluate agreement between fluorescein angiography (FA) and optical coherence tomography (OCT) results for diagnosis of macular edema in patients with uveitis. DESIGN: Multicenter cross-sectional study. PARTICIPANTS: Four hundred seventy-nine eyes with uveitis from 255 patients. METHODS: The macular status of dilated eyes with intermediate uveitis, posterior uveitis, or panuveitis was assessed via Stratus-3 OCT and FA. To evaluate agreement between the diagnostic approaches, κ statistics were used. MAIN OUTCOME MEASURES: Macular thickening (MT; center point thickness, ≥ 240 µm per reading center grading of OCT images) and macular leakage (ML; central subfield fluorescein leakage, ≥ 0.44 disc areas per reading center grading of FA images), and agreement between these outcomes in diagnosing macular edema. RESULTS: Optical coherence tomography (90.4%) more frequently returned usable information regarding macular edema than FA (77%) or biomicroscopy (76%). Agreement in diagnosis of MT and ML (κ = 0.44) was moderate. Macular leakage was present in 40% of cases free of MT, whereas MT was present in 34% of cases without ML. Biomicroscopic evaluation for macular edema failed to detect 40% and 45% of cases of MT and ML, respectively, and diagnosed 17% and 17% of cases with macular edema that did not have MT or ML, respectively; these results may underestimate biomicroscopic errors (ophthalmologists were not explicitly masked to OCT and FA results). Among eyes free of ML, phakic eyes without cataract rarely (4%) had MT. No factors were found that effectively ruled out ML when MT was absent. CONCLUSIONS: Optical coherence tomography and FA offered only moderate agreement regarding macular edema status in uveitis cases, probably because what they measure (MT and ML) are related but nonidentical macular pathologic characteristics. Given its lower cost, greater safety, and greater likelihood of obtaining usable information, OCT may be the best initial test for evaluation of suspected macular edema. However, given that ML cannot be ruled out if MT is absent and vice versa, obtaining the second test after negative results on the first seems justified when detection of ML or MT would alter management. Given that biomicroscopic evaluation for macular edema erred frequently, ancillary testing for macular edema seems indicated when knowledge of ML or MT status would affect management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Risk of elevated intraocular pressure and glaucoma in patients with uveitis: results of the multicenter uveitis steroid treatment trial.

OBJECTIVE: To report the 2-year incidence of raised intraocular pressure (IOP) and glaucomatous optic nerve damage in patients with uveitis randomized to either fluocinolone acetonide (FA) implants or systemic therapy. Secondarily, we sought to explore patient and eye characteristics associated with IOP elevation or nerve damage. DESIGN: A randomized, partially masked trial in which patients were randomized to either FA implants or systemic therapy. PARTICIPANTS: Patients aged ≥ 13 years with noninfectious intermediate, posterior, or panuveitis active within the prior 60 days for which systemic corticosteroids were indicated were eligible. METHODS: Visual fields were obtained at baseline and every 12 months using the Humphrey 24-2 Swedish interactive threshold algorithm (SITA) fast protocol. Stereoscopic optic nerve photos were taken at baseline and at 3-, 6-, 12-, and 24-month follow-up visits. Masked examiners measured IOP at every study visit. MAIN OUTCOME MEASURES: Glaucoma was diagnosed based on an increase in optic nerve cup-to-disc ratio with visual field worsening or increased cup-to-disc ratio alone, for cases where visual field change was not evaluable, because of missing data or severe visual field loss at baseline. RESULTS: Most patients were treated as assigned; among those evaluated for glaucoma, 97% and 10% of patients assigned to implant and systemic treatment, respectively, received implants. More patients (65%) assigned to implants experienced an IOP elevation of ≥ 10 mmHg versus 24% assigned to systemic treatment (P<0.001). Similarly, 69% of patients assigned to the implant required IOP-lowering therapy versus 26% in the systemic group (P<0.001). Glaucomatous optic nerve damage developed in 23% versus 6% (P<0.001) of implant and systemic patients, respectively. In addition to treatment assignment, black race, use of IOP-lowering medications, and uveitis activity at baseline were associated with incident glaucoma (P<0.05). CONCLUSIONS: Implant-assigned eyes had about a 4-fold risk of developing IOP elevation of ≥ 10 mmHg and incident glaucomatous optic neuropathy over the first 2 years compared with those assigned to systemic therapy. Central visual acuity was unaffected. Aggressive IOP monitoring with early treatment (often including early filtration surgery) is needed to avoid glaucoma when vision-threatening inflammation requires implant therapy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The impact of macular edema on visual function in intermediate, posterior, and panuveitis.

PURPOSE: To evaluate the impact of macular edema on visual acuity and visual field sensitivity in uveitis. DESIGN: This study utilized baseline data from the Multicenter Uveitis Steroid Treatment (MUST) Trial, a randomized, parallel treatment clinical trial comparing alternative treatments for intermediate, posterior and panuveitis. PATIENTS & METHODS: 255 patients (481 eyes with uveitis) recruited at 23 subspecialty centers. Visual acuity, optical coherence tomography and Humphrey 24-2 visual field testing. RESULTS: Macular edema was associated with impaired visual acuity (p < 0.01). Different phenotypes of macular edema were associated with different degrees of visual impairment: cystoid changes without retinal thickening were associated with moderately impaired visual acuity (-5 ETDRS letters), but visual acuity was worse in eyes with retinal thickening (-13 letters) and with both cysts and thickening (-19 letters). Uveitis sufficient to satisfy the study's inclusion criteria was associated with impaired visual field sensitivity, but eyes with macular edema had even worse visual field sensitivity (p < 0.01). CONCLUSIONS: The observation that macular edema substantially reduces visual function suggests macular edema itself is an important endpoint to study in the treatment of uveitis. As uveitis and macular edema both impair visual field sensitivity as measured by Humphrey 24-2 perimetry, both should be considered when evaluating patients with uveitis and raised intraocular pressure for glaucoma.

Rituximab is effective in the treatment of refractory ophthalmic Wegener's granulomatosis.

OBJECTIVE: To investigate the efficacy of rituximab in patients with refractory ophthalmic Wegener's granulomatosis (WG). METHODS: Data from 10 consecutive patients with refractory ophthalmic WG treated with rituximab were retrospectively reviewed. In all patients, the ophthalmic disease was driving treatment decisions, and disease activity had persisted despite standard immunosuppressive treatment. Patients had refractory scleritis (n=3), orbital granulomas causing optic nerve compromise (n=4), or a combination of both conditions (n=3). All patients had been treated with at least 3 different immunosuppressive agents, and 5 patients had previously been treated with tumor necrosis factor alpha blockade. Rituximab was administered intravenously in 2 doses, 2 weeks apart, in combination with standard treatment. Disease activity was monitored clinically by an interdisciplinary approach, including disease activity scoring, immunodiagnostics, and magnetic resonance imaging, as well as by corresponding reductions in the required dose of conventional medication. RESULTS: A beneficial response to treatment with rituximab was seen in all 10 patients, including induction of clinical remission. In all patients, the peripheral blood B cell count fell to zero during treatment with rituximab. Titers of classic antineutrophil cytoplasmic antibodies fell in association with B cell counts, and this reduction was correlated with improved clinical findings. CONCLUSION: In contrast to previous observations, this study showed that treatment with rituximab was associated with clinical improvement in patients with refractory ophthalmic WG.

Metastatic endophthalmitis.

Endophthalmitis carries a poor visual prognosis for patients and can be a potentially blinding condition that may result in loss of the eye. Early diagnosis and prompt treatment are imperative to save the eye. Delay in diagnosis affects visual prognosis and therefore doctors should be aware of the presenting features of endophthalmitis. Urgent ophthalmic referral is advised as soon as a diagnosis is suspected.

Acute retinal necrosis features, management, and outcomes.

OBJECTIVE: To determine the viral diagnosis and factors affecting the visual outcome of eyes with acute retinal necrosis. DESIGN: Nonrandomized, retrospective, interventional, noncomparative series. PARTICIPANTS: A cohort of 22 human immunodeficiency virus-negative patients with acute retinal necrosis (ARN). There were 17 unilateral and 5 bilateral cases. INTERVENTION: Diagnostic vitreous biopsy for polymerase chain reaction (PCR) viral DNA analysis, prophylactic barrier laser posterior to necrotic retina to try to prevent rhegmatogenous retinal detachment (RD), intravenous acyclovir in combination with oral, and vitrectomy for RD repair. MAIN OUTCOME MEASURES: Results of PCR viral DNA analysis, relationship between prophylactic barrier argon laser photocoagulation and occurrence of RD, and visual acuities at presentation and follow-up. RESULTS: Varicella-zoster virus (VZV) was detected in 66.7% (12/18) of eyes (66.7% of patients [10/15]) with vitreous biopsy and herpes simplex virus (HSV) in 22.2% (4/18) of eyes (20% of patients [3/15]). Epstein-Barr virus (EBV) was detected in 16.7% (3/18) of eyes (20% of patients [3/15]), and all the EBV-positive eyes were also positive for VZV. Polymerase chain reaction results were identical in both eyes of bilateral cases (5 patients) and were negative in 11.1% (2/18) of eyes (13.3% of patients [2/15]) biopsied. Systemic corticosteroid treatment given before ARN diagnosis did not appear to increase the risk of developing RD (P = 0.69). Rhegmatogenous RD occurred in 35.3% (6/17) of eyes given prophylactic argon laser treatment and in 80% (8/10) of eyes that could not be lasered prohylactically. Of RDs, 96.3% (13/14) occurred after the third week and up to 5 months from onset of symptoms. The VA after surgical repair of RD improved relative to the presentation acuity in 33.3% (4/12) of eyes. CONCLUSION: Varicella-zoster virus is the leading cause of ARN. We recommend the management of ARN to include prompt diagnosis; prophylactic argon laser retinopexy, preferably within the first 2 weeks to reduce risk of RD; systemic acyclovir; and corticosteroids to control the severe inflammation associated with ARN. Despite the guarded visual prognosis, RD repair may result in improved visual outcomes.

Variable phenotypes in patients diagnosed with idiopathic multifocal choroiditis.

PURPOSE: To report investigations in a case series of patients diagnosed with idiopathic multifocal choroiditis (MFC) in order to determine whether or not a new clinical phenotype could be identified and to determine the long-term visual prognosis. METHODS: Twenty-eight patients were identified from the clinic database of approximately 1200 and subsequently reviewed. After ocular examination, which included fluorescein angiography, 20 of these patients were determined to have idiopathic MFC. Visual outcome, patient demographics, presenting symptoms, the distribution of inflammatory cells, the pattern of chorioretinal lesions and the development of peripapillary atrophy, choroidal new vessels or cystoid macular oedema were compared. RESULTS: The range of follow up was 1-27 years (mean 10 years). A Kaplan-Meier plot showed that approximately 60% of patients maintained their best-corrected visual acuity for 10 years after diagnosis. Poor vision at final review was associated with eyes having choroidal new vessels or cystoid macular oedema. Oral steroids were used to treat 11 patients, of which 10 responded with a visual improvement. The one non-responsive patient had foveal ischaemia angiographically. Generally the idiopathic phenotype was variable and only four patients showed some overlap with known subgroups of MFC. Unusual vascular features were observed in two patients. CONCLUSIONS: No specific phenotype was seen to emerge from this cohort of patients diagnosed with idiopathic MFC, although most were significantly different from the retinal white dot syndromes currently described. The visual prognosis was relatively good and most cases responded to oral steroids.

Cytokines and chemokines in uveitis: is there a correlation with clinical phenotype?

Uveitis is a general term for intraocular inflammation and includes a large number of clinical phenotypes. As a group of disorders, it is responsible for 10% of all registered blind patients under the age of 65 years. Immune-mediated uveitis may be associated with a systemic disease or may be localized to the eye. The pro-inflammatory cytokines interleukin (IL)-1beta, IL-2, IL-6, interferon-gamma and tumor necrosis factor-alpha have all been detected within the ocular fluids or tissues in the inflamed eye together with others, such as IL-4, IL-5, IL-10 and transforming growth factor-beta. The chemokines IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and fractalkine are also thought to be involved in the associated inflammatory response. There have been a number of studies in recent years investigating cytokine profiles in different forms of uveitis with a view to determining what cytokines are important in the inflamed eye. This review attempts to present the current state of knowledge from in vitro and in vivo research on the inflammatory cytokines in intraocular inflammatory diseases.

Multiplex cytokine detection versus ELISA for aqueous humor: IL-5, IL-10, and IFNgamma profiles in uveitis.

PURPOSE: The purpose of this study was to determine levels of IL-2, -4, -5, -10, TNF-alpha, and IFN-gamma in aqueous humor (AH) from patients with active panuveitis, anterior uveitis (AU), and noninflammatory controls by using a flow cytometric mutiplex array (CBA) and to compare with results from ELISA. METHODS: Pooled normal AH was spiked with six cytokines at decreasing concentrations for evaluating the CBA. AH was also obtained from 10 controls (cataract patients) and 36 patients with active uveitis. Cell-free supernatants were added to a cocktail of capture beads and detector antibodies or to antibody-coated wells for CBA and ELISA determination, respectively. RESULTS: CBA demonstrated greater sensitivity for detecting IL-4, IL-10, and TNF-alpha than with ELISA. Increased IFN-gamma was detected in both AU and panuveitis groups compared with controls (P < 0.01). IL-10 was higher in the panuveitis group on steroids (P < 0.01). IL-5 was detected in the control (P < 0.01) and AU groups (P < 0.05) but was undetectable in the panuveitis group (n = 10). Correlations between IFN-gamma and IL-10 were found in all uveitis groups (P < 0.01) but not in controls, whereas TNF-alpha correlations with IL-4/IFN-gamma were obtained in controls but not in the uveitis groups (P < 0.01). CONCLUSIONS: It was possible to measure cytokines titrated into normal AH specimens by CBA, and a greater number of cytokines were detected with increased sensitivity than with ELISA. Elevated IFN-gamma in active uveitis and decreased IL-5 in posterior uveitis suggest Th1 polarity is more marked, with greater uveal tract involvement. The increased IL-10 in the steroid treated group suggests glucocorticoid-induced IL-10 upregulation.

Risk factors for elevated intraocular pressure in uveitis.

PURPOSE: To determine the prevalence of raised intraocular pressure (IOP) in patients with uveitis and to identify risk factors for raised IOP in patients with uveitis. PATIENTS AND METHODS: Consecutive case notes of 257 patients (402 eyes) attending a specialist uveitis clinic during a three-month period were reviewed. Patients with raised IOP were identified and further evaluated. Risk factors for raised IOP were determined. RESULTS: The prevalence of raised IOP in the study eyes was 41.8%. The prevalence of raised IOP requiring treatment was 29.8%. Raised IOP was found in 26.0% of eyes with acute uveitis and 46.1% of eyes with chronic uveitis. This difference was significant (P = 0.002). Similarly the prevalence of raised IOP requiring treatment in acute and chronic uveitis was 15.1% and 33.8%, respectively. This difference was also significant (P = 0.002). Active inflammation was significantly associated with raised IOP (P = 0.031). Steroid usage, increasing age, and number of years since diagnosis were significantly correlated with raised IOP (P = 0.008, P = 0.022, and P = 0.006, respectively); 9.6% of the study eyes developed glaucoma. The majority of these eyes (69.7%) were treated medically. The remainder (30.3%) required both medical and surgical management. CONCLUSION: Raised IOP is significantly more common in patients with chronic intraocular inflammation than those with acute uveitis. Risk factors for elevated IOP that should enable closer monitoring of 'at-risk' eyes have been identified.