QUANTITATIVE ANALYSIS OF STRUCTURAL ALTERATIONS IN THE CHOROID OF PATIENTS WITH ACTIVE BEHÇET UVEITIS.

PURPOSE: To quantitatively analyze in vivo morphology of subfoveal choroid during an acute attack of Behçet uveitis. METHODS: In this prospective study, 28 patients with Behçet uveitis of ≤4-year duration, and 28 control subjects underwent enhanced depth imaging optical coherence tomography. A novel custom software was used to calculate choroidal stroma-to-choroidal vessel lumen ratio. Subfoveal choroidal thickness was measured at fovea and 750 µm nasal, temporal, superior, and inferior to fovea. Patients underwent fluorescein angiography and indocyanine green angiography. Receiver operating characteristic curve and area under the curve were computed for central foveal thickness. The eye with a higher Behçet disease ocular attack score 24 was studied. The main outcome measures were choroidal stroma-to-choroidal vessel lumen ratio and choroidal thickness. RESULTS: The mean total Behçet disease ocular attack score 24, fluorescein angiography, and indocyanine green angiography scores were 7.42 ± 4.10, 17.42 ± 6.03, and 0.66 ± 0.73, respectively. Choroidal stroma-to-choroidal vessel lumen ratio was significantly higher in patients (0.413 ± 0.056 vs. 0.351 ± 0.063, P = 0.003). There were no significant differences in subfoveal choroidal thickness between patients and control subjects. Choroidal stroma-to-choroidal vessel lumen ratio correlated with retinal vascular staining and leakage score of fluorescein angiography (r = 0.300, P = 0.036). Central foveal thickness was significantly increased in patients (352.750 ± 107.134 µm vs. 263.500 ± 20.819 µm, P < 0.001). Central foveal thickness showed significant correlations with logarithm of minimum angle of resolution vision, Behçet disease ocular attack score 24, total fluorescein angiography score, retinal vascular staining and/or leakage and capillary leakage scores of fluorescein angiography, and total indocyanine green angiography score. At 275 µm cutoff, diagnostic sensitivity and specificity of central foveal thickness for acute Behçet uveitis were 89% and 72%, respectively (area under the curve = 0.902; 95% CI = 0.826-0.978, P < 0.001). CONCLUSION: There was choroidal stromal expansion which was not associated with thickening of the choroid. Central foveal thickness may be used as a noninvasive measure to assess inflammatory activity in early Behçet uveitis.

Optical coherence tomography imaging in uveitis.

Optical coherence tomography (OCT) is a non-contact noninvasive technique that allows in vivo imaging of the retina, choroid, optic nerve head, retinal nerve fiber layer, and the anterior structures of the eye. It was introduced into clinical practice two decades ago. Advances in OCT technology have been achieved by searching ultra-high-resolution OCT, adaptive optics OCT, eye-tracking OCT, and changes in signal detection technique from time-domain (TD) to spectral-domain (SD) detection. Today, SD OCT has become a part of routine uveitis practice. Apart from its diagnostic value in uveitis, OCT has enabled objective assessment of treatment response and provided predictive value for visual recovery and prognosis of uveitic entities. It is the standard diagnostic technique in the detection, monitoring of treatment, and determination of prognosis in uveitic macular edema as well as other inflammatory macular pathologies, including epiretinal membrane formation, vitreomacular traction, foveal atrophy, and lamellar/full-thickness macular holes. OCT has also shed light on the pathophysiology of several posterior uveitic entities. SD OCT has enabled visualization of four lines in the sensory retina which represent the external limiting membrane, the photoreceptor inner and outer segment junction, the photoreceptor outer segment and the retina pigment epithelium junction, and the retina pigment epithelium-choriocapillaris complex. Thus, we have gained substantial information about the pathologic and structural changes in uveitic conditions with primary or secondary outer retinal involvement. SD OCT has also provided invaluable information on the inner retinal and the vitreoretinal interface changes in uveitic conditions. With the introduction of enhanced depth imaging, visualization of the choroid and choriocapillaries has become possible. Therefore, OCT has become an indispensible ancillary test in the diagnosis and management of inflammatory diseases involving the retina and/or the choroid. As OCT technology continues to develop further it will provide new insights into the retinal and choroidal structure and the pathogenesis of posterior uveitic entities.

An Algorithm for the Diagnosis of Behçet Disease Uveitis in Adults.

Purpose: To develop an algorithm for the diagnosis of Behçet's disease (BD) uveitis based on ocular findings.Methods: Following an initial survey among uveitis experts, we collected multi-center retrospective data on 211 patients with BD uveitis and 207 patients with other uveitides, and identified ocular findings with a high diagnostic odds ratio (DOR). Subsequently, we collected multi-center prospective data on 127 patients with BD uveitis and 322 controls and developed a diagnostic algorithm using Classification and Regression Tree (CART) analysis and expert opinion.Results: We identified 10 items with DOR >5. The items that provided the highest accuracy in CART analysis included superficial retinal infiltrate, signs of occlusive retinal vasculitis, and diffuse retinal capillary leakage as well as the absence of granulomatous anterior uveitis or choroiditis in patients with vitritis.Conclusion: This study provides a diagnostic tree for BD uveitis that needs to be validated in future studies.

Effect of Interferon alfa-2a Treatment on Adaptive and Innate Immune Systems in Patients With Behçet Disease Uveitis.

Purpose: To investigate the effect of interferon alfa-2a on T regulatory (Treg) cells, T helper 17 (Th17) cells, and expression of Toll-like receptors (TLRs) in Behçet disease (BD) patients with uveitis. Methods: Twenty-seven patients who received interferon alfa-2a for active BD uveitis despite conventional immunomodulatory therapies and healthy controls were enrolled. Peripheral blood Treg and Th17 cell frequencies were determined by flow cytometry as gated cells for CD3+CD4+Foxp3+ and CD3+CD4+IL17A+, respectively. Th17 RAR-related orphan receptor (ROR)γt mRNA expression was verified by real-time PCR (RT-PCR). Treg and Th17 cell cytokines were detected by ELISA in the supernatant of short-term cell cultures. RT-PCR was used to assess expression of TLR-2, TLR-3, TLR-4, TLR-8, and TLR-9 using cDNA prepared from CD4+ T cells and monocytes. Results: Treg and Th17 cell frequencies and Th17 RORγt expression were significantly elevated, and IL-10 concentration in Treg cell supernatants was significantly lower in BD patients than in controls. Th17 IL-17, IL-6, IL-21, IL-22, IL-23, IFN-γ, and TNF-α concentrations were significantly higher and all TLR expressions were significantly elevated in patients. Interferon alfa-2a led to a significant reversal in Treg and Th17 cell frequencies, Th17 RORγt expression, Treg and Th17 cell cytokine production, and TLR expression by CD4+ T cells and monocytes. Conclusions: Despite a relative increase in Treg cells, impaired IL-10 production suggests that Treg dysfunction may play a role in induction of BD uveitis. Favorable effects of interferon alfa-2a may be associated with recovery of Treg cell function, suppression of Th17 cells, and reduced expression of TLRs on CD4+ T cells and monocytes.

Visual field analysis in patients with Parkinson's disease.

BACKGROUND: To evaluate visual field changes in patients with Parkinson's disease. METHODS: Standard automated perimetry of 14 patients (28 eyes) with Parkinson's disease (PD) were compared with controls. PD patients with Unified Parkinson's Disease Rating Scale (UPDRS) score below 25 were included in the study. RESULTS: Visual field indices including mean deviation (-4.69+/-2.72 vs. -1.71+/-1.30, p=0.0008), pattern standard deviation (3.94+/-1.94 vs. 2.30+/-0.41, p=0.001), and corrected pattern standard deviation (3.23+/-2.18 vs. 1.20+/-0.91, p=0.003), were significantly worse in patients with PD when compared with the control group. Bilateral glaucoma-like visual field defects were evident in six patients. CONCLUSION: Parkinson's patients had worse visual field indices suggesting a common insult in the etiopathogenesis of nerve fiber layer damages observed in glaucoma and PD.

Unilateral paraneoplastic optic disc edema and retinal periphlebitis in pineal germinoma.

PURPOSE: To describe a unilateral ocular paraneoplastic syndrome in pineal germinoma. OBSERVATIONS: A 24-year-old male presented with diplopia, excessive thirst, and frequent urination. Cranial MRI showed a mass in pineal gland. Dorsal midbrain syndrome signs were present. Examination showed optic disc edema and segmental retinal periphlebitis in right and normal fundus in left eye. Rheumatologic work-up was negative. Brain biopsy confirmed pineal germinoma. Retinal findings were attributed to paraneoplastic syndrome. Resolution of optic disc edema and retinal periphlebitis occurred following chemotherapy and focal irradiation. CONCLUSIONS: and importance: To date there are two published case reports on bilateral optic disc edema and retinal periphlebitis occurring as a paraneoplastic syndrome in pineal germinoma. This is the first report on a patient with pineal germinoma who had unilateral paraneoplastic involvement characterized by optic disc edema and retinal periphlebitis and who showed complete resolution of ocular disease after treatment of underlying tumor.

Screening for Depression and Anxiety in Patients with Active Uveitis.

PURPOSE: To screen for psychological disorders in patients with active uveitis. METHODS: Patients were screened for depression (BDI-II), state anxiety (STAI-I), VR-QOL (NEI-VFQ-25), and HR-QOL (SF-36). Association of depression and anxiety with sociodemographic and clinical parameters and with VR-QOL and HR-QOL were analyzed. Multivariate linear regression models were constructed for NEI-VFQ-25 and SF-36 subscales. RESULTS: Of 99 patients, 37.3% screened positive for depression and 52.5% for anxiety. Depressed patients had lower visual acuity in the better seeing eye (p = 0.013) and more frequently panuveitis (p = 0.018). Anxious patients were younger (p = 0.009), had earlier onset of uveitis (p = 0.015), and had more frequently panuveitis (p = 0.016). Bivariate comparisons showed significant associations between psychological disorders and VR-QOL and HR-QOL. Significant bivariate associations were mostly lost in multivariate analyses for anxiety, but were preserved for depression. CONCLUSIONS: A positive screening test for depression and anxiety is common in patients with uveitis. Low vision and panuveitis are associated with depression. Depression is associated with impairment of VR-QOL and HR-QOL.

Intravitreal bevacizumab for treatment of uveitic macular edema.

PURPOSE: To evaluate the short-term safety and efficacy of intravitreal bevacizumab for the treatment of cystoid macular edema (CME) secondary to uveitis. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: Thirteen patients undergoing treatment for recalcitrant uveitic macular edema at one referral center. METHODS: Charts of patients who received one 2.5-mg intravitreal injection of bevacizumab in one eye were reviewed for clinical information including best-corrected Snellen visual acuity (VA), examination findings, optical coherence tomography (OCT) results, and fluorescein angiography results. Kaplan-Meier survival analysis was used to calculate probability success rates. The statistical significance of change in mean retinal thickness and VA was assessed using repeated-measures analysis of variance. MAIN OUTCOME MEASURES: Assessments of changes in best-corrected Snellen VA and OCT retinal thickness were made. RESULTS: Six (46.15%) patients had a decrease in foveal thickness at the end of the follow-up, whereas 5 (38.4%) patients had an improvement of VA by > or =2 lines 84 days or more after the injection. Mean retinal thickness showed a significant decrease over the follow-up (P<0.02). The change in mean logarithm of the minimum angle of resolution VA over the follow-up was not significant (P>0.05). Survival analysis showed that the probability of any improvement in VA increased progressively starting at 6 weeks and reached 81% at 14 weeks. No significant ocular or systemic adverse effects were observed. CONCLUSIONS: These results suggest that a single intravitreal injection of bevacizumab is well tolerated and is associated with short-term improvement in VA and decreased OCT retinal thickness in a considerable proportion of patients with uveitic CME resistant to conventional therapy. Further evaluation of intravitreal bevacizumab for uveitic CME in controlled randomized studies is warranted.

Adjustable suture surgery for correction of various types of strabismus.

BACKGROUND AND OBJECTIVE: This study was conducted to analyze the efficacy of the adjustable suture technique for correction of strabismus in patients with different types of strabismus. PATIENTS AND METHODS: This was an observational case series of patients who underwent the adjustable suture technique for correction of strabismus. A total of 33 adult patients (16 males and 17 females) with a minimum postoperative follow-up period of 6 months were included in the study. Patients were analyzed in three groups (patients with exotropia, esotropia, and vertical deviations). Success criteria determined were percentage change in the angle of deviation for far and near fixation, need for reoperation, and relief of diplopia. RESULTS: The median percentage change in the angle of deviation for far and near fixation was 86.60% and 84%, 92.50% and 94.44%, and 100% and 100% in the exotropia, esotropia, and vertical deviation groups, respectively. There was no need for reoperation, and postoperative adjustment performed 24 hours after surgery was needed in 30.3% of patients due to diplopia. CONCLUSIONS: The adjustable suture technique seems to be an effective method in the correction of various types of strabismus.

Review for Diagnostics of the Year: Multimodal Imaging in Behçet Uveitis.

Behçet disease is a chronic relapsing multisystem inflammatory disorder. Ocular involvement is characterized by a bilateral recurrent non-granulomatous panuveitis and retinal vasculitis. Posterior segment findings vary during the course of the disease, in parallel with the relapsing and remitting intraocular inflammation. Structural alterations occur with increased disease duration. Fluorescein angiography is the gold standard in revealing the extent and severity as well as the leaky and/or occlusive nature of retinal vasculitis. Multimodal imaging using color fundus photography, fluorescein angiography, and optical coherence tomography is essential in visualizing diagnostic features, detecting structural changes, and monitoring disease activity and response to treatment in patients with Behçet uveitis.

Interferon Alpha for the Treatment of Cystoid Macular Edema Associated with Presumed Ocular Tuberculosis.

PURPOSE: To report the efficacy and safety of interferon (IFN) α-2a in patients with cystoid macular edema (CME) associated with presumed ocular tuberculosis (TB). METHODS: We reviewed the clinical records of 5 patients with presumed ocular TB who had been treated with IFN α-2a for recurrent CME during or after completion of anti-tubercular therapy. IFN α-2a was administered at an initial dose of 3 million IU per day and then tapered after the initial response. Treatment efficacy was assessed by central macular thickness (CMT) measurement using spectral-domain optical coherence tomography and visual acuity. RESULTS: Three patients were men, and 2 were women. Patients were aged between 38 and 66 years. Mean CMT was 483 ± 178.6 µm at baseline, 302.3 ± 56 µm at 1 week, 312.3 ± 49.5 µm at 1 month, and 286.2 ± 31.9 µm at 3 months. Mean LogMAR visual acuity was 0.6 ± 0.4 at baseline, 0.4 ± 0.3 µm at 1 week, 0.3 ± 0.3 at 1 month, and 0.3 ± 0.3 at 3 months. The treatment was interrupted for 10 days because of neutropenia after 2 weeks in 1 patient and discontinued in another after 10 days because of intolerance. Total treatment duration was 3-24 months in the remaining 4 patients. CONCLUSION: The present small case series suggests that IFN α-2a may be an effective and safe therapeutic option for CME that is associated with presumed ocular TB.

Diverse Clinical Signs of Ocular Involvement in Cat Scratch Disease.

OBJECTIVES: To describe ocular manifestations, diagnosis, and treatment of cat scratch disease. MATERIALS AND METHODS: Clinical records of patients with ocular cat scratch disease were reviewed. RESULTS: Thirteen eyes of 10 patients (7 female, 3 male) with a mean age of 26.9±18.5 years were included. Nine patients had a history of cat contact and had systemic symptoms associated with cat scratch disease 2-90 days prior to the ocular symptoms. Ocular signs were: neuroretinitis in 4 eyes (associated with serous retinal detachment in the inferior quadrant in 1 eye), optic neuropathy in 2 eyes (1 papillitis and optic disc infiltration, 1 optic neuritis), retinal infiltrates in 6 eyes, retinochoroiditis in 1 eye, branch retinal arteriolar occlusion in 3 eyes, and endophthalmitis in 1 eye. Visual acuities at presentation were 1.0 in 7 eyes, 0.3 in 1 eye, ≤0.1 in 4 eyes, and light perception in 1 eye. Bartonella henselae immunoglobulin (Ig) M and/or IgG were positive in all patients. Systemic antibiotic therapy was administered in all patients. Systemic corticosteroid treatment (15-40 mg/day) was added to the therapy in 4 patients, following 5 days of intravenous pulse methylprednisolone in 2 patients. Treatment was ongoing for 1 patient and the mean treatment duration of the other 9 patients was 47±14.5 days. Visual acuities at final visit were 1.0 in 9 eyes, 0.8 in 1 eye, 0.4 in 1 eye, and no light perception in 1 eye. CONCLUSION: Cat scratch disease may present with different ocular signs and should be considered in the differential diagnosis in patients with such presentations.

Failure to Integrate Quantitative Measurement Methods of Ocular Inflammation Hampers Clinical Practice and Trials on New Therapies for Posterior Uveitis.

Uveitis is one of the fields in ophthalmology where a tremendous evolution took place in the past 25 years. Not only did we gain access to more efficient, more targeted, and better tolerated therapies, but also in parallel precise and quantitative measurement methods developed allowing the clinician to evaluate these therapies and adjust therapeutic intervention with a high degree of precision. Objective and quantitative measurement of the global level of intraocular inflammation became possible for most inflammatory diseases with direct or spill-over anterior chamber inflammation, thanks to laser flare photometry. The amount of retinal inflammation could be quantified by using fluorescein angiography to score retinal angiographic signs. Indocyanine green angiography gave imaging insight into the hitherto inaccessible choroidal compartment, rendering possible the quantification of choroiditis by scoring indocyanine green angiographic signs. Optical coherence tomography has enabled measurement and objective monitoring of retinal and choroidal thickness. This multimodal quantitative appraisal of intraocular inflammation represents an exquisite security in monitoring uveitis. What is enigmatic, however, is the slow pace with which these improvements are integrated in some areas. What is even more difficult to understand is the fact that clinical trials to assess new therapeutic agents still mostly rely on subjective parameters such as clinical evaluation of vitreous haze as a main endpoint; whereas a whole array of precise, quantitative, and objective modalities are available for the design of clinical studies. The scope of this work was to review the quantitative investigations that improved the management of uveitis in the past 2-3 decades.

Conservative treatment of isolated medial orbital wall fractures.

The decision to use surgical or nonsurgical treatment for orbital blow-out fractures is still controversial. Previously, it was advocated that all blow-out fractures should be treated surgically based on the conception that extraocular muscles were blown out and trapped in the fracture area. However, a shift to a more conservative approach occurred gradually, most likely due to the evidence of spontaneous improvement. The medical records of two patients who were diagnosed as having an isolated medial wall fracture with medial rectus muscle displacement into the ethmoid sinus, as demonstrated by computed tomography, were reviewed. Both patients showed improvement only with conservative therapy.

Efficacy of intravenous immunoglobulin treatment in refractory uveitis.

PURPOSE: To assess the efficacy of intravenous immunoglobulin (IVIg) therapy in patients with severe uveitis otherwise unresponsive to conventional immunomodulatory agents. METHODS: Data on five consecutive patients treated with IVIg and followed to the present time by one of the authors (CSF) were reviewed. All patients had severe and recalcitrant uveitis of diverse etiologies. Main outcome measures were control of intraocular inflammation, steroid-sparing effect, visual acuity, and side effects. RESULTS: The duration of IVIg therapy was 3 to 36 months (mean, 16.8 months). Treatment was effective in controlling the intraocular inflammation in 3 of 5 patients. One of those patients required maintenance of systemic steroids at a dose of 10 mg per day. Visual acuity has stabilized or improved in these three patients. No immediate or long-term side effect was observed in any of the patients. CONCLUSIONS: Intravenous immunoglobulin therapy was an effective therapeutic modality in the treatment of three of five patients with severe uveitis that was unresponsive to conventional immunomodulatory agent(s). No adverse events were observed.

Prevalence and levels of serum antibodies to gram negative microorganisms in Turkish patients with HLA-B27 positive acute anterior uveitis and controls.

PURPOSE: Acute anterior uveitis (AAU), seronegative spondyloarthropathies such as ankylosing spondylitis and reactive arthritis form the group of "HLA-B27-associated diseases." The aim of this study was to analyze the prevalence and levels of serum antibodies against gram negative bacteria in Turkish patients with AAU. METHODS: Twenty-five patients each with previously diagnosed HLA-B27 positive and negative AAU and 25 age-and sex-matched healthy control subjects were included in the study. Serum IgM, IgG and IgA antibodies to Yersiniae enterocolitica, Campylobacter jejuni and Chlamydia trachomatis were measured using enzyme linked immunosorbent assay (ELISA). Categorical data were analyzed by chi-square test. Serum levels were analyzed using the Kruskal-Wallis test. RESULTS: The prevalence of serum IgM, IgG and IgA antibodies did not differ significantly between the HLA-B27 positive AAU, HLA-B27 negative AAU and control groups with the exception of serum IgA antibodies against Yersiniae enterocolitica. IgA antibody against Yersiniae enterocolitica was found to be more frequently positive in the control group. Comparison of serum IgM, IgG and IgA antibody levels did not significantly differ between three groups. CONCLUSIONS: Serum antibody positivity against Yersiniae enterocolitica, Campylobacter jejuni and Chlamydia trachomatis is not frequent in the HLA-B27 positive and negative AAU patients. Serum levels of IgM, IgG, and IgA antibodies also did not show significant difference between three groups. No association between these microorganisms and the etiology of AAU was evident.

Neovascularization of the optic disc in Behçet's disease.

PURPOSE: To investigate the mechanisms involved in the development of neovascularization of the optic disc (NVD) in Behçet's disease and to evaluate the effects of medical and laser treatments. METHODS: This is a retrospective study of 26 consecutive Behçet's patients (38 eyes) with NVD who presented between 1990 and 2004 at our university hospital. Information on age at presentation, sex, disease duration, laterality of NVD, ocular findings, fluorescein angiographic findings, visual acuity, medical treatment, laser photocoagulation, surgical procedures, and the follow-up period was collected. Eyes with diffuse capillary leakage on fluorescein angiography were defined as having inflammation-induced NVD, and eyes with extensive retinal capillary nonperfusion were defined as having ischemia-induced NVD. RESULTS: Eighteen patients were male, and eight were female. Mean age at presentation was 25.4 +/- 4.9 years. Median disease duration was 5.5 months. Median follow-up was 24 months. Twelve patients had bilateral NVD; 14 had unilateral NVD. Inflammation-induced NVD was seen in 87% of the eyes, and ischemia-induced NVD in 13%. Initial treatment with high-dose corticosteroids combined with conventional immunosuppressive agents was effective in 45% of the eyes with inflammation-induced NVD. Retinal laser photocoagulation was effective in three of five eyes with ischemia-induced NVD. Treatment with interferon alpha-2a resulted in resolution of NVD in all seven patients who received this agent for inflammation- or ischemia-induced persistent NVD. Final visual acuity was less than 0.1 in 24% of the eyes. CONCLUSIONS: Inflammatory mechanisms seem to predominate in the pathogenesis of NVD in Behçet's disease. The results of this study suggest that the response to intensive anti-inflammatory and conventional immunosuppressive treatment is not satisfactory; retinal laser photocoagulation may be ineffective even in eyes with retinal ischemia, but interferon alpha-2a seems to be effective for the treatment of Behçet's patients with NVD.

Electroretinographic improvement after rituximab therapy in a patient with autoimmune retinopathy.

PURPOSE: To describe the effect of rituximab on full-field electroretinography (ERG) in a patient with nonparaneoplastic autoimmune retinopathy (npAIR). OBSERVATIONS: A 58-year-old male patient with visual complaints, positive anti-retinal antibodies and negative work-up for cancer was diagnosed with npAIR. Visual acuity and ancillary tests were normal except abnormal ERG in both eyes. The patient was given one course of rituximab 375 mg/m2/week for 4 weeks and cyclophosphamide 1 gr/m2/month for 6 months. A second course of rituximab was necessary as autoantibody titers showed no change and as new antibodies were noted after treatment with rituximab and cyclophosphamide. Electroretinography was repeated after the first course of rituximab, after cyclophosphamide, and the second course of rituximab therapy. CONCLUSIONS AND IMPORTANCE: Rituximab therapy led to marked improvement in full-field ERG readings and regression of symptoms was reported by the patient after rituximab infusions. The effect of rituximab in npAIR was objectively demonstrated with ERG.