Paul J. Tomlins

Triple-TEN in the treatment of acute ocular complications from toxic epidermal necrolysis

Purpose Toxic epidermal necrolysis (TEN) is a devastating form of Stevens-Johnson syndrome (SJS) with acute and chronic ocular complications. We present a novel aggressive combination strategy, termed “Triple-TEN”, for the management of acute ocular TEN designed to minimize the risk of chronic, blinding sequelae. Methods Two patients with life-threatening TEN accompanied by severe ocular surface defects and fulminant symblephara formation underwent “Triple-TEN” management of their acute ocular disease under aseptic techniques in the critical care setting, after failed treatment with intensive topical therapy and surgical division of symblephara. The Triple-TEN protocol comprises (1) subconjunctival triamcinolone (Kenalog 20 mg) administered into each of the fornices to curb the local inflammatory response without compromising systemic immunity, (2) placement of amniotic membrane tissue mounted on a polycarbonate skirt (ProKera) over the corneal and limbal regions to facilitate reepithelialization of the ocular surface, and (3) insertion of a steeply curved acrylic scleral shell spacer (Technovent, SC21) to vault the lids away from the globe providing a barrier to symblephara formation. Results In both cases, ocular surface inflammation resolved within 4 weeks with no progression of conjunctival cicatrization or evidence of limbal epithelial stem cell failure at 1 year follow-up. There were no long-term complications of the Triple-TEN regimen. Conclusions Aggressive treatment with the Triple-TEN protocol for acute ocular TEN resistant to first-line therapy, may help prevent long-term blinding sequelae.

The Role of 11ß-Hydroxysteroid Dehydrogenase 1 in Adipogenesis in Thyroid-Associated Ophthalmopathy

CONTEXT Thyroid-associated ophthalmopathy (TAO) is a sight-threatening autoimmune disease in which de novo adipogenesis has been identified as a fundamental pathogenic mechanism. 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) increases cortisol bioavailability and is pivotal in mediating glucocorticoid responses in adipose tissue and inflammation. OBJECTIVE In this study we characterize 11beta-HSD1 as a determinant of the adipogenic and inflammatory pathways in TAO orbital fat (OF) compared with normal OF. PATIENTS AND METHODS OF was harvested from 46 TAO and 44 control patients undergoing orbital surgery. Samples were examined by a combination of immunohistochemistry, real-time RT-PCR, primary cell culture, specific enzyme assays, colorimetric proliferation assays, and bead-based ELISA. RESULTS Glucocorticoid (glucocorticoid receptor-alpha,11beta-HSD1, hexose-6-phosphate dehydrogenase) and inflammatory cytokines (IL-1beta, IL-1 receptor, IL-6, TNF-alpha, TNF-alpha inductible protein, TGF-beta2) target genes together with markers of late adipocyte differentiation (fatty-acid-binding-protein-4, glycerol-6-phosphate-dehydrogenase) were highly expressed in TAO whole OF (P < 0.05) compared with controls. Primary cultures of TAO OF stromal cells demonstrated greater 11beta-HSD1 oxoreductase activity (P < 0.05), which was regulated by cytokines, most notably TNF-alpha (P < 0.01), compared with controls. Activity increased across differentiation, and this was most marked in TAO cells (P < 0.01). Similarly, stromal cell proliferation was limited by incubation with cortisol in TAO cells only. Furthermore, cortisone decreased IL-6 (P < 0.005), IL-8 (P < 0.05), and macrophage chemoattractant protein-1 (P < 0.05) production by cultured TAO cells only, an effect that was abrogated by inhibition of 11beta-HSD1. CONCLUSIONS Induction of 11beta-HSD1 activity and expression by inflammatory cytokines (TNF-alpha, IL-6) may enhance orbital adipocyte differentiation (adipogenesis) and limit proliferation in TAO. 11beta-HSD1 may also have a role in regulating the local orbital inflammatory response.

Soluble gp130, an antagonist of IL-6 transsignaling, is elevated in uveitis aqueous humor.

PURPOSE To determine the concentrations of soluble gp130, a natural antagonist of IL-6 transsignaling, in the serum and aqueous humor (AqH) of patients with uveitis. METHODS Serum was obtained from the peripheral blood of patients with active uveitis and healthy control subjects. AqH samples were collected from patients with active uveitis and those without uveitis who were undergoing routine cataract surgery. Samples were centrifuged and the cell-free supernatant frozen at -80 degrees C. Concentrations of sgp130, sIL-6R, and IL-6 were determined by a sandwich ELISA or multiplex bead immunoassay, using standard curves of known concentrations of recombinant cytokines. RESULTS Serum concentrations of sgp130 were not significantly different between control individuals and patients with active anterior uveitis, regardless of the degree of intraocular inflammation cells. By contrast, the concentration of sgp130 in AqH was very low in patients with no or little inflammation, but increased significantly with disease severity. The greatest elevations of AqH sgp130 were found in patients with the highest cellular activity. Simultaneous measurement of IL-6, sIL-6R, and sgp130 revealed a high degree of correlation between the levels of these molecules, especially for sIL-6R and sgp130. CONCLUSIONS Soluble gp130 is increased in the AqH of patients with active uveitis. It is likely that sgp130 partially inhibits the process of IL-6 transsignaling during inflammation. However, the concentration found is still far below that in serum, suggesting that increasing the level of sgp130 further may assist in reducing the inflammatory changes induced by IL-6 transsignaling.

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.

Aqueous Humor Suppression of Dendritic Cell Function Helps Maintain Immune Regulation in the Eye during Human Uveitis

PURPOSE Noninfectious uveitis is characterized by a dysregulated inflammatory or immune response in the eye. It is unclear whether this represents a failure of immune privilege or an overwhelming inflammatory drive that has exceeded the capacity of regulatory mechanisms that are still functioning. The authors investigated immune regulation in the human eye during intraocular inflammation (uveitis) and its impact on dendritic cell (DC) function and subsequent T-cell responses. METHODS Myeloid DCs were isolated from the aqueous humor (AqH) and peripheral blood of patients with active uveitis and characterized by flow cytometry. The effect of uveitis AqH was interrogated in an in vitro model of peripheral blood monocyte-derived DCs from healthy controls. RESULTS Myeloid DCs isolated from uveitic AqH were characterized by elevated major histocompatibility complex classes I and II (MHC I/II), but reduced CD86 compared with matched peripheral blood DCs. Exposure of peripheral blood monocyte-derived DCs from healthy controls to the inflammatory AqH supernatant recapitulated this phenotype. Despite interferon gamma (IFNγ)-dependent upregulation of MHC I, inflammatory AqH was overall suppressive to DC function, with reduced CD86 expression and diminished T-cell responses. This suppressive effect was equal to or greater than that induced by noninflammatory AqH, but was glucocorticoid independent (in contrast to noninflammatory AqH). CONCLUSIONS These data indicate that the ocular microenvironment continues to regulate DC function during uveitis, despite IFNγ-driven upregulation of MHC expression, supporting the hypothesis that immune regulation within the eye is maintained during inflammation.

Long-term biocompatibility and visual outcomes of a hydrophilic acrylic intraocular lens in patients with uveitis

Purpose To report the long‐term visual outcomes and biocompatibility of a single‐piece hydrophilic acrylic intraocular lens (IOL) in patients with uveitis having cataract surgery. Setting Tertiary referral center, Birmingham, United Kingdom. Design Retrospective case review. Methods The review included consecutive uveitis patients in whom phacoemulsification and acrylic IOL implantation was performed by the same surgeon. Outcomes measures are reported as rate/eye‐year and included visual acuity and signs of bioincompatibility. Results The review identified 171 eyes (140 patients; mean age 51 years [range 16 to 85 years]) with uveitis. The mean follow‐up was 3.8 years (range 0.9 to 10.3 years). Signs of uveal bioincompatibility were found in 31 eyes, with visually insignificant deposits on the IOL in 17 eyes. The rate of uveal bioincompatibility was 0.06/eye‐year. Signs of capsule bioincompatibility were found in 107 (63%) of 171 eyes (0.31/eye‐year). Posterior capsule opacification was documented in 102 eyes (0.29/eye‐year); neodymium:YAG laser capsulotomy was required in 31 eyes (0.05/eye‐year). The rate of failure to maintain a 3 logMAR line improvement in corrected distance visual acuity (CDVA) was 0.08/eye‐year; to maintain better than 0.3 logMAR, 0.15/eye‐year; and to maintain either, 0.04/eye‐year. At 1 year, 85% of eyes had a CDVA of better than 0.3 logMAR or maintained a 3 logMAR–line improvement. Eyes with preexisting macular or optic nerve disease had significantly worse visual outcomes. Conclusions The long‐term safety profile of the hydrophilic acrylic IOL was good in uveitis cases, leading to good visual outcomes and a low rate of vision‐impairing uveal and capsule complications. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Conjunctival Neutrophils Predict Progressive Scarring in Ocular Mucous Membrane Pemphigoid

Purpose Ocular mucous membrane pemphigoid (OcMMP) is a rare autoimmune disorder resulting in progressive conjunctival fibrosis and ocular surface failure leading to sight loss in up to 50%. This study was designed to optimize an ocular surface sampling technique for identification of novel biomarkers associated with disease activity and/or progressive fibrosis. Methods Fifty-seven patients with OcMMP underwent detailed examination of conjunctival inflammation and fibrosis using fornix depth measurement. Ocular surface impression cytology (OSIC) to sample superior bulbar conjunctiva combined with flow cytometry (OSIC-flow) profiled infiltrating leukocytes. Profiles were compared with healthy controls (HC) and disease controls (primary Sjögrens syndrome, pSS). Thirty-five OcMMP patients were followed every 3 months for 12 months. Results Overall neutrophils were elevated in OcMMP eyes when compared to pSS or HC (109 [18%] neutrophils/impression [NPI]; 2 [0.2%]; 6 [0.8%], respectively [P < 0.0001]) and in OcMMP patients with no visible inflammation when compared with HC (44.3 [7.9%]; 5.8 [0.8%]; P < 0.05). At 12 months follow-up, 53% of OcMMP eyes progressed, and this was associated with baseline conjunctival neutrophilia (P = 0.004). As a potential biomarker, a value of 44 NPI had sensitivity, specificity, and positive predictive values of 75%, 70%, and 73%, respectively. Notably, eyes with no visible inflammation and raised conjunctival neutrophils were more likely to progress and have a greater degree of conjunctival shrinkage compared to those without raised neutrophils. Conclusions These data suggest that OSIC-flow cytometric analyses may facilitate repeated patient sampling. Neutrophils may act as a biomarker for monitoring disease activity, progressive fibrosis, and response to therapy in OcMMP even when the eye appears clinically uninflamed.

Evaluation of visual function and needs in adult patients with bardet-biedl syndrome.

Purpose: To assess the visual needs of the adult population with Bardet–Biedl syndrome (BBS) and to ensure that this is addressed by a national Bardet–Biedl Service. Methods: A cross-sectional analysis of all adults under a national BBS Clinic (Birmingham, United Kingdom) was performed using the BBS Ophthalmic Assessment Tool, a novel tool designed to capture the key elements of visual function, impact on lifestyle, and clinical findings relevant to BBS. Results: Sixty-two adult patients were confirmed to have BBS. Bardet–Biedl syndrome mutations were identified in 51, most commonly BBS1 (n = 35), BBS2 (n = 6), and BBS10 (n = 5). In 11 patients (18%), BBS had not been diagnosed until adulthood. Median visual acuity was hand motion (range, 0.0 logMAR–no perception of light). More advanced retinopathy was associated with increasing age, worsening visual acuity, and the presence of nystagmus. Forty patients (65%) had undertaken mainstream education with 29 (47%) achieving higher education; 7 patients (11%) had moderate or severe learning difficulties. Most (90%) were registered sight-impaired or severely sight-impaired patients. Conclusion: The BBS Ophthalmic Assessment Tool provides a wide-ranging assessment of ophthalmic status and vision-related needs of the BBS population. This evaluation demonstrates the spectrum of visual disability in this population and its correlation with worsening retinopathy over time.

Alleviating Pain in Oculoplastic Procedures by Reducing the Rate of Injection of Local Anaesthetic

Purpose : To investigate whether the rate of infiltration of local anaesthetic influences the pain or efficacy of local anaesthesia in oculoplastic surgery. Methods : A prospective observational study on consecutive patients undergoing a variety of oculoplastic procedures under local anaesthesia. An observer recorded the rate of injection of local anaesthetic during each procedure. The same mixture of local anaesthetic and the same needle gauge was used in all cases. Patients were asked to rate the pain of both the injection and the surgery using a visual analog scale (VAS). Results : 77 consecutive patients were observed, 39/77 (50.6%) patients were female and the average age was 63.5 years (range 31-94). A statistically significant correlation was found between the rate of injection and the VAS score from the injection (p<0.0001, r=0.42). There was no significant correlation between the injection rate and the VAS score from the procedure itself (p=0.25, r=0.13). Additionally, a significant correlation was found between the injection VAS score and the procedure VAS score (p=0.0002, r=0.42). Conclusion : The slower the rate of injection of local anaesthetic, the less pain was reported by the patient from the injection itself. Indeed the perception of pain from the surgery overall was significantly related to the pain felt during the injection, highlighting the importance of minimising pain during the injection of the local anaesthetic. We conclude that slowing the rate of injection is an effective way of alleviating pain from administration of the anaesthetic.