Quantitative analysis of vitreous inflammation using optical coherence tomography in patients receiving sub-Tenon's triamcinolone acetonide for uveitic cystoid macular oedema

Background/aims: To evaluate the vitreous signals obtained on spectral domain optical coherence tomography (SD-OCT) in patients with uveitic cystoid macular oedema (CMO) and compare these signals before and after sub-Tenon's triamcinolone acetonide injection. Methods: Retrospective study with standardised longitudinal imaging preintervention and postintervention. The study cohort comprises 22 patients (22 eyes) with uveitic CMO receiving a sub-Tenon's triamcinolone acetonide (STTA) injection. Post hoc analysis of SD-OCT images using custom software provided an ‘absolute’ measurement of vitreous signal intensity, which was expressed as a ratio to the retinal pigment epithelium intensity (‘VIT/RPE-relative intensity’) in arbitrary units. Main outcome measure: Difference in VIT/RPE-relative intensity before and after treatment. Results: Treatment with STTA resulted in a significant reduction in VIT/RPE-relative intensity, which was associated with both a reduction in central retinal thickness (CRT) and improvement in visual acuity. Mean (SD) VIT/RPE-relative intensity pretreatment was 0.139 (0.074) versus 0.053 (0.028) post-treatment (p=3×10−5). Mean (SD) CRT was 581 μm (119 μm) pretreatment versus 333 μm (95 μm) post-treatment (p=2×10−8); the mean reduction in CRT was 248 (95% CI 189 to 306). The correlation coefficient between VIT/RPE-relative intensity and CRT was 0.534 (p=0.011) and between VIT/RPE-relative intensity and visual acuity was 0.702 (p=0.0001). Conclusions: This study provides evidence that the OCT-derived VIT/RPE-relative intensity may be useful as a quantitative and objective marker of disease activity and treatment response in uveitis complicated by CMO. This first longitudinal study of this novel OCT parameter is an encouraging step in the development of sensitive objective OCT-based endpoints for trials of efficacy in uveitis

Outer Retinopathies Associated with COVID-19 Infection:Case Reports and Review of Literature

Background. The coronavirus disease (COVID-19) is a highly contagious disease with profound health implications. It can affect any part of the body with variable severity. Various ophthalmic manifestations of coronavirus disease have been documented. Case Presentations. We reported three cases of outer retinopathies associated with COVID-19 infection. All three patients were young females. The first two patients presented within days of COVID-19 infection with complaints of black spots in the eyes. Multimodal retinal imaging showed lesions consistent with acute macular neuroretinopathy. Lesions were bilateral in the first patient and unilateral in the second one. Our third patient presented with blurred vision in one eye, 3 months after a suspected COVID-19 infection. Retinal imaging showed outer retinopathy. Our patients’ vision was good and maintained during the follow-up. All three were monitored on observation only, and symptoms and lesions improved with time. Conclusion. In conclusion, COVID-19-related thromboinflammatory response can result in localized vascular inflammation and hypoperfusion in any of the retinal capillary plexuses or choriocapillaris resulting in ischemia of the corresponding retinal or choroidal layers

Elevation of conjunctival epithelial CD45INTCD11b⁺CD16⁺CD14⁻ neutrophils in ocular Stevens-Johnson syndrome and toxic epidermal necrolysis

PURPOSE. Ocular complications related to Stevens-Johnson Syndrome (SJS)–Toxic Epidermal Necrolysis (TEN) may persist and progress after resolution of systemic disease. This is thought to be related in part to persistent ocular innate-immune signaling. In this study, our aim was to characterize infiltrative conjunctival cellular profiles during acute (<12 months) and chronic (>12 months) disease. METHODS. Consecutive patients presenting with SJS-TEN over a 12-month period were followed for 1 year. Detailed clinical examination and conjunctival impression cell recovery was analyzed by flow cytometry for the presence of intraepithelial leukocytes and compared with healthy controls (n = 21). RESULTS. Ten patients were recruited of whom six had acute disease and five were classified as TEN (SCORTEN = 1, n = 4). Conjunctival inflammation was graded as absent/mild in a total of nine patients; but despite this, evidence of fornix shrinkage was observed in nine subjects. This inversely correlated with disease duration (P < 0.05). A reduction in percentage of CD8αβ(+) T cells compared with controls (80% vs. 57%; P < 0.01) was associated with a corresponding increase in the number/percentage of CD45(INT)CD11b(+)CD16(+)CD14(−) neutrophils (186 vs. 3.4, P < 0.01, 31% vs. 0.8%, P < 0.001). Neutrophils inversely correlated with disease duration (r = −0.71, P = 0.03), yet there was no absolute change in the CD8αβ(+) or neutrophil populations during the study period (P = 1.0). CONCLUSIONS. These data highlight that a neutrophilic infiltrate is present in mildly inflamed or clinically quiescent conjunctival mucosa in patients with ocular SJS-TEN, where neutrophil numbers inversely correlate with disease duration. Neutrophil persistence endorses the hypothesis of an unresolved innate-inflammatory process that might account for disease progression

Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada disease is a rare, multisystem, autoimmune disorder with numerous clinical manifestations, mediated through a T-helper 1 response against melanocytes in the eye, inner ear, central nervous system, hair and skin. We describe a 20-year-old British-Honduran man with recent worsening headache and photophobia, vomiting and visual blurring. On examination, his pupils reacted sluggishly and visual acuities were bilaterally reduced. Optical coherence tomography showed gross retinal swelling and neurosensory detachments. MR scan of the brain was normal, but cerebrospinal fluid showed a reactive picture with 258 ×10 lymphocytes./L (normal ≤5×10/L). Following treatment with immunosuppression (prednisolone, tacrolimus, mycophenolate mofetil, adalimumab), he made a full recovery. Clinicians should consider Vogt-Koyanagi-Harada disease in patients presenting with headache with acute profound visual loss. A prompt diagnosis and immunosuppressive therapy can lead to complete resolution

Ocular surface glucocorticoid bioavailability in health and disease.

<p>Evaluation of tear film glucocorticoid profiles as surrogate readouts of net ocular surface glucocorticoid bioavailability, defines cortisol depletion (reduced cortisol∶cortisone (F∶E ratio, mean±SE) during active untreated pseudomonas keratitis (PSK) but not herpes simplex keratitis (HSK), and amplification during chronic clinically quiescent immune-mediated disease (MMP, mucous membrane pemphigoid; SJS/TEN, Stevens-Johnson Syndrome/Toxic-epidermal Necrolysis). Statistical analysis performed using t-test with two-tailed Mann Whitney post -test. * = P<0.05.</p

Putative interaction of TLR signaling and local regulation of cortisol in the human cornea.

<p>(A) Under physiological conditions, autocrine synthesis of cortisol in corneal epithelial cells contributes to the immunoprotection of the ocular surface mucosa. During induction of ocular surface TLRs cytokines are released in a ligand and cell specific manner. (B) On TLR3 ligation such as chronic immune -mediated disease e.g. SJS-TEN, synthesis of a diverse spectrum of cytokines primarily from the corneal epithelial cells, induces <u>weak</u> monocyte chemotaxis and differentiation to M1 macrophages. These cytokines <u>potently attenuate</u> M1 cortisol biosynthesis leading to a net reduction of ocular surface cortisol levels, promoting recruitment of inflammatory cells necessary for resolving the initial trigger. By contrast, on TLR4 ligation (C) activation of keratocytes to a fibroblast phenotype, form the first line of defense producing chemokines that <u>potently</u> induce monocyte migration to the site of infection for rapid eradication of bacterial invasion. Attenuation of M1 cortisol production is less pronounced and this facilitates resolution of the inflammatory response, limiting tissue damage thereby preserving optical clarity (and sight).</p

Regulation of cytokine production with Cortisol/Dexamethasone on TLR3 or TLR4 stimulated Primary Human Corneal Fibroblasts (PHKF).

<p>Both cortisol (▪, black square) and dexamethasone (▪, gray square) reduced cytokines: VEGF, CCL5, IFN-γ, CXCL-10, IL-8 and GCSF (B) after either or both TLR 3 and 4 stimulation of PHKF. (Values =  Mean+SE, normalising to No Cortisol/Dexamethasone (□, white square) for each treatment n = 3; Statistical analysis 2-way ANOVA with Bonferroni post-test; *p<0.05, **p<0.01, ***p<0.001).</p

Macrophage infiltration in human keratitis.

<p>(A) Immunohistochemistry of the normal human central corneal epithelium showed no evidence of CD68 positive resident macrophages or basal TLR4 expression, although there was some basal TLR3 expression. Corneal stromal infiltration of CD68 positive cells is seen in both herpetic and gram negative keratitis associated with increased TLR3 and TLR4 expression in the corneal epithelium, respectively. (B–E) Migration assay showing culture supernatants of corneal cells having chemotactic potential on monocytes. Cell supernatants from PHCEC/PHKF stimulated with TLR3 (poly I∶C) or TLR4 (LPS) ligands for 16 h were tested for the ability to induce monocyte migration. ‘S’ denotes culture supernatants from PHCEC/PHKF cultures generated from 3 corneal donors, tested on a single allogenic PBMC donor. ‘D’ denotes 3 different PBMC donors subjected to culture supernatant from a single donor derived PHCEC/PHKF treated with TLR3 and TLR4 ligands. Data show that both LPS and Poly I∶C stimulation of corneal cells induce monocyte migration but LPS stimulation of PHKF has the greatest chemotactic potential. (Panels D and E). (F) Culture supernatants from experiments A–D (TLR3 and TLR4 induction of PHCEC/PHKF for 16 h) downregulates M1 macrophage 11β-HSD1 activity. Statistical analysis was carried using one-way ANOVA and comparisons were drawn with untreated control cells vs. TLR3/TLR4 treated cells.</p

Pre-receptor regulation of glucocorticoids and TLR expression in human corneal cells.

<p>(A) RT-PCR of PHCEC, PHKF showing expression of the major genes for the pre-receptor regulation of glucocorticoids: 11β-HSD1, 11β-HSD2, H6PD and GR. Macrophages, M1 and M2, also express 11β-HSD1 but not 11β-HSD2. All cell types demonstrate 11β-HSD1 oxo-reductase activity (B), most marked in M1 macrophages. (C) TLR 1–9 induction did not alter 11β-HSD1 activity in either PHCEC or PHKF after stimulation for 16 h.</p