Update on the systemic management of noninfectious uveitis in children and adolescents.

Noninfectious uveitis (NIU) in children and adolescents is a rare but treatable cause of visual impairment in children. Treatments for pediatric NIU and their side effects, along with the risks of vision loss and the need for long-term disease monitoring, pose significant challenges for young patients and their families. Treatment includes local and systemic approaches and this review will focus on systemic therapies that encompass corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (csDMARD), and biological disease-modifying antirheumatic drugs (bDMARD). Treatment is generally planned in a stepwise approach. Methotrexate is well-established as the preferential csDMARD in pediatric NIU. Adalimumab, an antitumor necrosis factor (TNF) agent, is the only bDMARD formally approved for pediatric NIU and has a good safety and efficacy profile. Biosimilars are gaining increasing visibility in the treatment of pediatric NIU. Other bDMARD with some evidence in literature for the treatment of pediatric NIU include infliximab, tocilizumab, abatacept, rituximab and, more recently, Janus kinase inhibitors. Important aspects of managing children on these systemic therapies include vaccination issues, risk of infection, and psychological distress. Also, strategies need to address regarding primary nonresponse/secondary loss of response to anti-TNF treatment, biological switching, and monitoring regimens for these drugs. Optimal management of pediatric uveitis involves a multidisciplinary team, including specialist pediatric uveitis and rheumatology nurses, pediatric rheumatologists, psychological support, orthoptic and optometry support, and play specialists.

Intravitreal Fluocinolone 0.19mg Implant in the Management of Chronic Non-Infectious Uveitis: 12-Month Outcomes from a Single Tertiary Centre.

AIM: To present efficacy and safety of 0.19 mg fluocinolone acetonide insert (FAi) to treat chronic noninfectious uveitis (NIU) in a single referral center. METHODS: A retrospective observational clinical study of 11 eyes with NIU complicated by chronic cystoid macular edema (CMO). RESULTS: The main indication for treatment was chronic CMO in all 11 eyes. The mean central retinal thickness (CRT) at baseline was 435 µm ± 176, improving to 296 µm ± 67 at 12 months. Raised intraocular pressure (IOP) was the commonest adverse event. An IOP >21 mmHg was observed in three eyes, and >30 mmHg in one eye, managed with topical therapy. The mean best corrected visual acuity (BCVA) was stable at 12 months. There were no observed recurrences of uveitis. Two eyes received adjunctive treatment for worsening CRT. CONCLUSIONS: Our results suggest FAi is an effective maintenance treatment for NIU with favorable functional and anatomical outcomes.

Paracentral Acute Middle Maculopathy in A Young Girl Treated with Interferon-Beta for Nasopharyngeal Carcinoma.

PURPOSE: To describe a case of interferon-beta retinopathy associated with paracentral acute middle maculopathy. CASE REPORT: A 15-year-old girl with Epstein-Barr virus-positive advanced nasopharyngeal carcinoma WAS REFERRED with reduced visual acuity. Multimodal imaging findings, including optical coherence tomography angiography, at presentation and evolution following cessation of interferon therapy are presented. CONCLUSION: The presentation of paracentral acute middle maculopathy in this patient supports the presumed ischaemic pathogenesis in interferon retinopathy. The imaging findings provide evidence of deep capillary plexus involvement in interferon retinopathy with evolution to permanent structural damage within the inner nuclear layer.

High dose cefuroxime causing retinal toxicity in a patient undergoing trabeculectomy.

PURPOSE: To present a case of severe retinal toxicity secondary to high dose intracameral cefuroxime administered during trabeculectomy glaucoma surgery. We describe the clinical features and management, and describe serial multimodal imaging and electrophysiological findings. Intracameral cefuroxime (ICC) and subconjunctival cefuroxime (SCC) are routinely administered during ocular surgeries to prevent postoperative endophthalmitis. Cefuroxime toxicity with both standard (1mg/0.1mL) and high doses of ICC (2-100mg) and SCC (31.25mg) have been reported. To the best of our knowledge, this is the first report of cefuroxime retinal toxicity in trabeculectomy surgery, which is of particular significance because of the possible differences in pharmacokinetics within the eye. OBSERVATIONS: A 69-year-old male with primary open-angle glaucoma, underwent right trabeculectomy, augmented with mitomycin C (0.2mg/mL). The patient inadvertently received cefuroxime 12.5mg/0.1mL as an intracameral rather than a subconjunctival injection. Within 4 hours, the error was discovered and the patient underwent immediate anterior chamber (AC) washout. His right best-corrected visual acuity was hand movements, and he rapidly developed uveitis including AC cells and moderate vitritis and haze. Optical coherence tomography (OCT) demonstrated serous macular detachment, characteristic schisis-like changes in the outer nuclear layer and ellipsoid zone disruption. Multi-focal electroretinograms (ERG) identified deficits undetected by full-field ERG. He was successfully managed with intensive local topical corticosteroid, non-steroidal therapy and peri-ocular corticosteroid injection. CONCLUSIONS AND IMPORTANCE: As ICC and SCC are routinely used in intra-ocular surgery to prevent endophthalmitis, ophthalmologists need to be aware of this potential complication and consider this in patients with unexplained reduced vision post-operatively. Theatre teams need to be vigilant about potential dilution and administration errors to ensure that the correct concentration and volume of cefuroxime is given via the correct route. We highlight the risks of high dose intracameral injection, including uveitis and retinal toxicity, and the utility of serial OCT, and full-field and multi-focal ERGs in this condition. We report a favourable outcome with significant and rapid improvement in retinal structure and function observed during follow-up. A literature review of the condition is presented.

Avascular Necrosis of Bone in Patients with Uveitis Treated with Systemic Corticosteroids.

PURPOSE: To identify the prevalence, risk factors and outcomes of avascular necrosis (AVN) in patients with chronic uveitis. METHODS: A retrospective study of patients with corticosteroid-induced AVN treated at Manchester Uveitis Clinic between 1991 and 2019. RESULTS: From a cohort of 4478 patients, 1698 had been treated with systemic corticosteroids. Five patients with AVN were identified (prevalence 0.29%). The mean age at diagnosis of AVN was 49 years. All 5 patients were using systemic immunosuppression. Four patients developed femoral head AVN in 7 joints, one had bilateral knee osteonecrosis. The mean duration of corticosteroid before AVN was 38 months; the mean dose at onset was 17mg/day and the mean cumulative dose was 18,860mg. Three patients required total hip replacements but management was conservative for others. There was no permanent disability. CONCLUSIONS: AVN is a rare but severe complication of corticosteroid therapy. Clinicians should be vigilant for symptoms of bone pain as early detection and cessation of corticosteroids can reverse incipient AVN and avoid surgery.

Ocular Involvement in the Histiocytoses: A Literature Review with an Illustrative Case Series.

PURPOSE: To describe and illustrate recent reclassification and clinical descriptions of the histiocytoses, diagnosis and management, and effects on the eye and adnexae. PATIENTS AND METHODS: Literature review with an illustrative case series of seven patients with histiocytosis and ophthalmic involvement from a single tertiary centre. RESULTS: Skin lesions with signs including eyelid mass, orbital bone destruction, bizarre keratic precipitates, limbal or iris mass, haemorrhagic anterior uveitis, subretinal lesions of uncertain etiology, ischaemic retinopathy, optic neuropathy, and apparent steroid-resistant inflammations should be comprehensively investigated. CONCLUSIONS: Ophthalmic involvement in histiocytosis is rare. Clinical manifestations vary from limited single-organ disease to lethal systemic infiltration or malignancy. Radiology may identify lesions for biopsy. Histology with appropriate markers is essential. Oncology advice may be required.

Evaluating the Safety, Efficacy and Patient Acceptability of Intravitreal Fluocinolone Acetonide (0.2mcg/Day) Implant in the Treatment of Non-Infectious Uveitis Affecting the Posterior Segment.

Long-acting, slow-release injectable fluocinolone intravitreal implants have been approved for the treatment of non-infectious uveitis affecting the posterior segment. We summarise the development of intravitreal fluocinolone implants and discuss the technology including pharmacokinetics. We conducted a systematic review of evidence for the efficacy, safety and patient acceptability of fluocinolone 0.18 mg and 0.19 mg injectable implants. We summarise evidence from the pivotal phase 3 studies that lead to the approval of these implants and evaluate real-world including disease-specific evidence. Safety including injection-related events and long-term adverse events is presented.

Proposing a Neurotropic Etiology for Acute Posterior Multifocal Placoid Pigment Epitheliopathy and Relentless Placoid Chorioretinitis.

Purpose: To reassess the underlying pathophysiology of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and relentless placoid chorioretinitis (RPC) through comparison with the non-inoculated eye of the von Szily animal model of neurotropic viral retinal infection. Methods: Narrative review. Results: Literature reports of isolated neurotropic viral entities and rising serological viral titers in APMPPE after presentation support a potential direct infective etiology. In general, viral transport along axons results in mitochondrial stasis and disruption of axoplasmic flow. Clinical manifestations of axoplasmic flow disruption in APMPPE/RPC may signify the passage of virus along the neuronal pathway. From a case series of 11 patients, we demonstrate a timely, spatial, and proportional association of optic disc swelling with APMPPE lesion occurrence. Signs within the inner retina appear to precede outer retinal lesions; and acute areas of outer nuclear layer (ONL) hyperreflectivity appear to be the result of coalescence of multiple hyperreflective foci resembling axonal spheroids (which occur as a consequence of axoplasmic disruption) and follow the Henle fiber layer neurons. Underlying areas of retinal pigment epithelium (RPE) hyper-autofluorescence follow ONL hyperreflectivity and may signify localized infection. Areas of apparent choriocapillaris hypoperfusion mirror areas of RPE/Bruch's membrane separation and appear secondary to tractional forces above. Increases in choroidal thickness with lesion occurrence and focal areas of choriocapillaris hypoperfusion are observed in both APMPPE/RPC and the von Szily model. Conclusions: The neurotrophic infection model provides significant advantages over the existing primary choriocapillaris ischemia hypothesis to account for the range of imaging signs observed in APMPPE and RPC.

Tubulointerstitial nephritis and uveitis (TINU) syndrome: a review.

Inflammation of renal interstitium and uveal tissue establishes the two components of tubulointerstitial nephritis and uveitis (TINU) syndrome. Although believed to occur more frequently in young females, a broad spectrum of patients can be affected. Both renal and eye disease can be asymptomatic and may not manifest simultaneously, having independent progressions. Renal disease manifests as acute kidney injury and may cause permanent renal impairment. Eye inflammation can manifest in different anatomical forms, most commonly as bilateral anterior uveitis and may progress to a chronic course. TINU syndrome accounts for approximately 1%-2% of uveitis in tertiary referral centres. A literature review covering the clinical features, pathogenesis, diagnosis and treatment is presented.

Intra and inter-rater agreement of inflammatory choroidal neovascular membrane measurements using optical coherence tomography angiography.

PURPOSE: Automated measurement algorithm software is not routinely available in optical coherence tomography angiography (OCTA) devices and manual measurement of choroidal neovascular membrane (CNVM) size is necessary. Our aim was to determine intra- and inter-rater agreement of inflammatory CNVM manual measurements obtained with OCTA. METHODS: OCTA (Triton® Topcon Corporation) images in patients with inflammatory CNVM were imported into ImageJ software v1.50 (NIH image). Two experienced observers performed manual area and perimeter measurements independently, and one of the observers performed the same measurements twice. Agreement was evaluated with intraclass correlation coefficients (ICC) and concordance correlation coefficients (CCC). Bland-Altman plots were plotted to graphically assess concordance. Statistical analysis was performed using STATA v13.0. RESULTS: Sixteen eyes of 16 subjects, with a mean age of 39.0 ± 16.6 years (range 13-71), were included. Mean CNVM area and perimeter was 124.83 ± 117.80 and 4.20 ± 2.00 mm, respectively. Intra-rater ICC for both area and perimeter measured was 0.99 (95% confidence interval (CI) 0.99-0.99). Inter-rater ICC for area and perimeter measured was 0.95 (95%CI 0.87-0.98) and 0.81 (95%CI 0.17-0.94), respectively. Intra-rater CCC for both area and perimeter measured was 0.99 (95%CI 0.99-0.99). Inter-rater CCC for both area and perimeter measured was 0.91 (95%CI 0.81-0.99) and 0.66 (95%CI 0.44-0.88), respectively. CONCLUSIONS: Inflammatory CNVM manual measurement showed high intra-rater agreement and moderate inter-rater agreement. Repeatability and reproducibility studies are essential in manual analysis to establish thresholds that can distinguish measurements variation from true clinical change. An automatic algorithm may be helpful to accurately grade lesions and monitor disease activity and response to treatment.

Multimodal Evaluation of Presumed Tuberculous Serpiginous-Like Choroiditis.

Purpose: To evaluate multimodal imaging findings in longitudinal follow-up of a patient with presumed tuberculous serpiginous-like choroiditis (TB-SLC). Method: We evaluated multimodal imaging in a 62-year-old male with TB-SLC. Correlation between optical coherence tomography angiography (OCTA), swept-source OCT (SS-OCT) and fundus autofluorescence (FAF) at defined disease stages and evolution of observed imaging descriptors during long-term follow-up has not been previously reported. Results: OCTA of the active lesion demonstrated defined areas of choriocapillaris hypoperfusion, suggesting inflammatory vascular occlusive pathology. Over 9-month follow-up, OCTA illustrated sequential improvement in choriocapillaris flow, suggesting vascular remodeling. This correlated with progressive change in FAF signal and transition to diffuse hypoautofluorescence. SS-OCT demonstrated focal choroidal thickening and retinal pigment epithelium elevation in acute phase and resolution in time. Conclusion: Multimodal imaging, particularly novel non-invasive technologies such as OCTA and SS-OCT, improves our understanding of the pathogenesis and evolution of disease in TB-SLC.

Incidence, management and outcome of raised intraocular pressure in childhood-onset uveitis at a tertiary referral centre.

BACKGROUND/AIMS: To investigate the incidence, management and outcome of uveitis and raised intraocular pressure (IOP) in children treated at the Manchester Uveitis Clinic (MUC). METHODS: This was a retrospective, observational study of patients who presented with uveitis under the age of 16 to the MUC from July 2002 to June 2016. RESULTS: A total of 320 children were included in the study. Out of these, 55 (17.2%) patients (75 eyes) were found to have raised IOP requiring treatment. The mean age at diagnosis of uveitis and at first recorded raised IOP was 8.2±4.3 and 10.8±3.6 years, respectively. The pre-treatment IOP was 32.3±6.6 mm Hg and the IOP at the final visit was 15.5±3.7 mm Hg (median follow-up period, 43.7 months) on a median number of 0 medications. Twenty-eight eyes (37.3%) required glaucoma drainage surgery, and eight eyes (12.5%) had cyclodiode laser before this. Kaplan-Meier analysis showed that 11.5% of eyes required glaucoma surgery at 1 year after diagnosis of raised IOP, increasing to 50.0% by 5 years. The best-corrected visual acuity at diagnosis of uveitis was 0.26±0.42 logMAR, which remained stable at 0.28±0.65 logMAR at final follow-up visit. Four eyes (5.3%) from four patients fulfilled the definition of blindness by the WHO criteria. The mean cup:disc ratio at final follow-up was 0.4. CONCLUSION: Our cohort of children with raised IOP appeared to have a good outcome overall through aggressive medical and surgical management. Regular long-term follow-up is recommended, and early surgical intervention in eyes with uncontrolled IOP can prevent loss of vision.

Miliary tuberculosis developing during adalimumab treatment for Behçet's disease with uveitis.

Tumour necrosis factor-alpha (TNF-α) is a key proinflammatory cytokine in non-infective uveitis (NIU). Adalimumab, an anti-TNF-α monoclonal antibody, is approved for the treatment of severe NIU by the European Medicines Agency. There is a recognised risk of serious infections, including tuberculosis (TB), during anti-TNF-α therapy in systemic immune-mediated diseases. We describe miliary pulmonary TB during adalimumab therapy for severe NIU. To our knowledge, this is the first detailed report of this complication in a patient with uveitis. We present the challenges of managing vision-threatening uveitis during life-threatening infection necessitating withdrawal of adalimumab and oral immunosuppression therapy. Uveitis activity was controlled during anti-TB therapy with oral corticosteroid therapy.

Precipitants of 5-Fluorouracil in Trabeculectomy Bleb Management: A Comparative Laboratory Study.

AIM: Concerns regarding 5-Fluorouracil (5-FU) corneal toxicity have resulted in various ways of reducing its corneal exposure during post-operative trabeculectomy bleb manipulation. This study investigates the properties of various topical agents used to induce the precipitation of this compound. MATERIALS AND METHODS: This is a double-blind, descriptive, laboratory study comparing five different potential precipitants of 5-FU (proxymetacaine (proxy), oxybuprocaine (oxy), ametho-caine (ameth), fluorescein (flor), proxymetacaine + fluorescein (proxy-flor) to a control group (normal saline). A 0.01 mL of each anonymized agent was applied next to a clear round comparison marker in a transparent sterile container set on a dark background. 5-FU (0.01 mL of 50 mg/mL) was subsequently applied to each agent. The induced changes in transparency were imaged and compared to the transparency of the central marker. For each application, pH changes were also noted. RESULTS: Proxy, flor and proxy + flor did not result in any discernible 5-FU precipitation. Oxy resulted in a moderate visible change, and ameth produced very significant precipitation. Application of proxy, oxy, ameth, and proxy + flor resulted in the neutralization of the 5-FU's alkaline pH. CONCLUSION: We propose using a cotton-tipped bud dipped in ameth applied at the injection site as the recommended method to avoid 5-FU corneal exposure in these cases. CLINICAL SIGNIFICANCE: Practitioners should be aware of the differences in precipitation of 5-FU by different types of topical anesthetics and modify techniques of anesthesia and 5-FU administration accordingly.How to cite this article: Mercieca KJ, Fenerty CH, Steeples LR, Drury B, Bhargava A. Precipitants of 5-Fluorouracil in Trabeculectomy Bleb Management : A Comparative Laboratory StudyJ Curr Glaucoma Pract 2018;12(2):64-66.

An unusual case report of primary vitreoretinal lymphoma.

BACKGROUND: Primary vitreoretinal lymphoma (PVRL) is a rare ocular condition and its diagnosis remains a challenge. The clinical presentation is variable and it can masquerade as chronic intermediate or posterior uveitis. We report an unusual case of primary central nervous system lymphoma (PCNSL) presenting as migrating retinal lesions with unique shapes. The diagnostic challenges are described and the clinical features of intraocular lymphoma are reviewed. CASE PRESENTATION: A 53 year-old gentleman presented with unilateral visual disturbance and a wide area of retinal whitening with sharp borders temporal to the macula, corresponding to hyper-reflective subretinal changes on optical coherence tomography (OCT). The lesion resolved spontaneously after 6 weeks but was replaced by multiple punctate sub-retinal and sub-retinal pigment epithelial lesions. The second eye was involved 4 months later and there were new areas of hyper-reflective changes in both eyes, which migrated nasally within a week, with no evidence of scarring in the previous sites. The diagnosis of diffuse B-cell lymphoma was made on brain biopsy when the patient subsequently presented with acute confusion and magnetic resonance imaging brain scan showed a frontal lesion. Following systemic chemotherapy, the sub-retinal changes resolved with complete restoration of retinal architecture and improvement in visual acuity. CONCLUSION: We report an unusual case of PVRL presenting as migrating retinal lesions with unique shapes. PVRL is a great imitator and a high index of clinical suspicion is required in unexplained ocular lesions to prevent a delay in diagnosis.

Atypical sarcoidosis-associated uveitis: diagnostic challenges.

Sarcoidosis is a multisystem disease of unknown aetiology with pulmonary involvement in most patients. Uveitis is common and often characteristic. We report a case of ocular sarcoidosis with grossly atypical contiguous optic neuropathy and choroiditis and describe the diagnostic challenges in this highly unusual presentation. High-dose systemic corticosteroid and immunosuppressive treatment was required for sustained control of intraocular inflammation.

Clinical Outcomes of Intravitreal Preservative-Free Triamcinolone Preparation (Triesence®) for Cystoid Macular Oedema and Inflammation in Patients with Uveitis.

PURPOSE: To assess the outcomes of intravitreal benzyl alcohol-free triamcinolone acetonide suspension in uveitis-related macular oedema. METHODS: Single-center retrospective cohort study of 66 injections to 44 eyes of 40 patients. Uveitis diagnosis, systemic and local therapy, intraocular pressure (IOP), central retinal thickness (CRT), number of injections, time to re-injection and side-effects were noted during 6-months minimum follow-up. RESULTS: Sixty eight percent of eyes received a single injection. 18% required 2 injections, and 13% received ≥3 injections with mean time to second and third injections of 25.5 and 52.7 weeks, respectively. 90% of injections were unilateral. Mean CRT reduced, and by 12-weeks visual acuity improvement >0.3logMar was achieved in 46%. Cataract progression (47%) and IOP>21 mmHg (45%) were the commonest adverse events. CONCLUSION: Preservative-free triamcinolone is an additional option for uveitis-related macular oedema, particularly in unilateral cases, with favorable CRT and visual outcomes. Repeat injections may be necessary, and the period of efficacy varies between eyes.