PURPOSE:We investigated factors associated with delayed diagnosis of childhood onset uveitis. DESIGN:Prospective Cohort: United Kingdom Uveitis in Childhood National Inception Cohort (UNICORN) Study SUBJECTS: Children (aged < 18 years) newly diagnosed with non-infectious uveitis between 1st March 2020 and 28th February 2023. METHODS:Descriptive analysis of disease onset and presentation, with linear and logistic regression modelling to identify factors independently associated with increased time from onset to diagnosis (symptomatic disease) and structural complications at diagnosis (all cases). RESULTS:Among 221 children (median age, 10.9 years; 52% girls), the majority, 69%, were diagnosed following symptomatic onset, most commonly with redness, pain, or photophobia. Median time from symptom onset to diagnosis was 9 days (range, 0-568), with 50% having at least one complication at presentation with symptomatic onset. Independent predictors of increased time to diagnosis, following adjustment for the COVID-19 pandemic 'lockdown' period were bilateral disease (adjusted coefficient 38.1 days, 95% confidence interval 8.7 to 67.6, p = .01) and initial presentation to primary care versus eye services (62.6, 13.7 to 111.5, p = 0.01). Structural complications at diagnosis were independently associated with younger age (odds ratio 1.4, 1.3 to 1.7, p < 0.001) and socioeconomic deprivation (4.5 for lowest quintile, 1.5 to 13.2, p < 0.01). CONCLUSIONS:Delays in diagnosis occur in childhood uveitis of symptomatic onset, with symptoms being prevalent in disease. Improved awareness of this blinding disorder among primary-care practitioners, standardized referral pathways for childhood eye complaints, and equitable access to eye services are needed to prevent childhood onset, life-long visual disability.

Voretigene neparvovec can improve visual function in children with RPE65-associated inherited retinal dystrophy. However, the effect of rapid asymmetric visual improvement on binocular development and amblyopia remains uncertain.A young child underwent sequential treatment 8 months apart. After right-eye treatment, visual acuity improved, fixation switched and a manifest left esotropia developed. Left-eye visual acuity subsequently deteriorated. We describe this as reverse amblyopia in a novel context: reversal of the interocular amblyopic pattern following treatment-induced visual improvement without fellow-eye penalisation. Despite left-eye treatment, refractive correction and attempted occlusion, the marked visual asymmetry persisted. This case highlights a potential binocular effect of rapid unilateral visual improvement and the need for close monitoring between sequential treatments.

BACKGROUND/OBJECTIVES:Adalimumab (ADA) is a well-established treatment for refractory paediatric uveitis; however, some patients remain inadequately controlled on standard biweekly dosing. Weekly ADA injections are increasingly used, though evidence in paediatric cohorts remains limited. This study evaluates outcomes of escalation to weekly ADA in children with refractory uveitis and explores the relevance of serum drug levels and anti-ADA antibodies (AAA). SUBJECTS/METHODS:Patients with idiopathic uveitis at two tertiary centres in the UK treated with weekly adalimumab were retrospectively reviewed. Demographic, clinical and laboratory data were collected, including age at escalation, systemic diagnosis, serum ADA levels, AAA titres pre- and post-escalation, clinical response and complications. Treatment success was defined as ≤0.5+ anterior chamber cells and <2 drops/day of steroid eye drops at 3 months, or most recent follow-up where escalation occurred within 3 months of review. RESULTS:15 patients were included. Mean age at escalation was 11 years (range: 3-17). 11 (73%) had a systemic diagnosis; most commonly juvenile idiopathic arthritis (60%). Median serum level pre-escalation was 10.1 mg/L (IQR: 7.8-11.9) and 18.1 mg/L (IQR: 14.8-22.1) post escalation. AAAs were detectable in 7/15 (47%) pre-escalation, 2/15 (13.3%) post-escalation. Success occurred in 10/15 (67%), with visual acuity stable and improved in 93%. No serious systemic adverse events were reported. CONCLUSIONS:Weekly ADA offers a safe and effective treatment alternative for children with refractory uveitis, including those with AAAs. These findings support its inclusion in future treatment pathways, though the predictive value of serum levels and AAAs remains uncertain and warrants further investigation.

PURPOSE:Childhood-onset sarcoidosis (COS) is a rare granulomatous autoinflammatory condition characterised by arthritis, dermatitis, and uveitis which includes early-onset forms (sporadic or Blau syndrome) and a later-onset form resembling adult sarcoidosis. Ocular involvement often occurs early and may be a prominent, sight-threatening feature. Despite this, COS is sparsely described in the literature. This case series aims to characterise the ocular manifestations, complications, and outcomes in COS. METHODS:A review of patients diagnosed with COS under a tertiary paediatric uveitis service. Data collected included age at onset, clinical findings, diagnostic methods, treatments, ocular complications, and visual acuity (VA) at presentation and last follow-up. RESULTS:Six patients were identified, all of whom presented with granulomatous uveitis. Four had posterior segment involvement including choroiditis and optic disc swelling. The mean age of ocular disease onset was 7 years. Diagnosis was supported by elevated serum angiotensin converting enzyme (ACE) followed by lymph node biopsy (n = 3), skin biopsy (n = 2), and/or NOD2 mutation (n = 3). All received systemic immunosuppression: methotrexate (n = 6), adalimumab (n = 5), mycophenolate (n = 2), oral corticosteroids (n = 3), and infliximab (n = 1). Complications included uveitic glaucoma (n = 2), cataract (n = 3), and chorioretinal scarring (n = 1). VA improved or remained stable in most, with one case of persistent visual impairment. CONCLUSION:COS-related uveitis demonstrates an aggressive, chronic course with early onset, bilateral involvement, and frequent complications with potential to cause visual loss. Careful ophthalmic screening in children with known or suspected sarcoidosis is critical.

Sialidosis, also known as Mucolipidosis Type I, is a rare condition caused by defects in the NEU1 gene which causes the accumulation of sialylated peptides, oligosaccharides, and glycoproteins leading to neurological decline. Haematopoetic stem cell transplantation has been performed in the symptomatic phase twice in the literature but has failed to prevent deterioration. We report on a case where a 4-year-old child was diagnosed with pre-symptomatic sialidosis due to investigation following the incidental detection of a cherry-red spot prior to the onset of neurological symptoms. We performed haematopoetic stem cell transplantation with a matched unrelated cord blood unit with optimal timing prior to clinical decline, achieving full donor engraftment with a largely uneventful post-transplant recovery followed by a period of relative clinical stability. However, subsequent neurological decline detailed by clinical history and radiological findings has occurred suggesting a lack of disease responsiveness to transplantation despite optimal timing. We go on to provide supporting laboratory investigations detailing sialidosis fibroblast culture as part of a novel cross-correction assay and compare results to other transplant responsive lysosomal storage disorders such as mucopolysaccharidosis type 1-H and detail a lack of cross-correction in concordance with our clinical findings. We conclude that conventional allogeneic haematopoetic stem cell transplantation is not a viable disease-modifying treatment option in sialidosis, even when performed optimally in the pre-symptomatic phase, and suggest that alternative treatment options must be explored to improve outcomes in this condition.

PURPOSE:The objective of this study was to assess the clinical outcomes of surgical management of primary congenital glaucoma (PCG) in a cohort of children treated at Manchester Royal Eye Hospital, Manchester, United Kingdom, over a five-year period. METHODS:This retrospective observational study analysed data from 18 children (31 eyes) diagnosed with PCG between 2019 and 2024. Clinical characteristics, surgical details, intraocular pressure (IOP), optic nerve status, and the need for further surgical intervention were recorded and analysed. RESULTS:The cohort consisted of 14 male and 4 female children, with a mean age at diagnosis of 14 months. Thirteen children had bilateral PCG, and five had unilateral involvement. Presenting features included excessive tearing and increased corneal diameter. The average preoperative IOP was 32 mmHg. Surgical treatment led to significant reductions in both IOP and corneal diameter. Optic disc cupping reversed in most cases. Only two eyes required additional glaucoma surgery. No significant intraoperative complications were recorded. CONCLUSION:Surgical intervention in paediatric glaucoma at a tertiary centre produced favourable anatomical and functional outcomes, with a low reoperation rate. Early diagnosis and timely surgical management remain crucial in preventing vision loss in children with PCG.

BACKGROUND:We aimed to provide, through the Uveitis in Childhood National Cohort Study, population-based evidence on incidence, distribution and disease characteristics for childhood onset non-infectious uveitis. METHODS:Eligible children and young people (<18 years) were those newly diagnosed with non-infectious uveitis between 1 March 2020 and 28 February 2023. Cases were identified and recruited through passive surveillance across a multicentre network. Descriptive analysis of demographic, socioeconomic and clinical characteristics at diagnosis is reported alongside incidence rates, relative rates by region and sociodemographic patterning. RESULTS:468 cases were identified, providing a minimal national disease incidence of 1.89/100 000 (95% CI 1.72 to 2.07). Among the 255 children recruited, anterior uveitis was predominant (76.9%) and 65% of cases were bilateral. Peak incidence was at 11-15 years. Children resident in deprived areas and those from non-White ethnic backgrounds were over-represented (28% and 31% of the cohort). One in seven children (15%) had a diagnosis of juvenile idiopathic arthritis (JIA), and 5% had tubulointerstitial nephritis. Although bilaterally poor vision was uncommon (16.8%), 44.3% had lost some vision in at least one eye. CONCLUSIONS:There is a need to reconsider how best to deliver paediatric rheumatological and eye care that meets the needs of young people, as well as young children, with uveitis. The predominance of non-JIA-related uveitis calls for a shift in focus. There appears to be socioeconomic drivers of disease risk, which are worthy of future exploration and which have implications on the delivery of care for this chronic and blinding disease.

To present functional and anatomical outcomes of subretinal therapy with Voretigene Neparvovec (VN) in patients treated in one of the four specialist UK gene therapy centres. Single-centre, retrospective case series of patients affected by an inherited retinal dystrophy (IRD) caused by a pathogenic biallelic RPE65 mutation and treated with VN. Complete ophthalmic examination was planned preoperatively and 2, 4 and 8 weeks and 3, 6, 12, 18 and 24 months after surgery, and included visual acuity (VA) assessment (normal and low luminance), colour vision, contrast sensitivity, dark-adapted full-field stimulus threshold, macular optical coherence tomography (OCT) and fundus autofluorescence. Fourteen eyes of 8 patients were included with a mean follow-up of 26 months. Mean final VA improved by 2 lines, and improvements were noted in most other functional tests. Central retina thickness (CRT) remained fairly stable in the majority of patients, whereas 2 eyes experienced a reduction >30 μm. The status of ellipsoid band and external limiting membrane remained stable in all patients, except one. Peripapillary atrophy (PPA) was present in 5 eyes of 3 patients at the baseline; postoperative progression was noted in both eyes of one patient. No patient developed new PPA or chorioretinal atrophy (CRA) involving the macular area after treatment. Five eyes of 3 patients developed CRA at the retinotomy site, that progressed in 3 of them. Our study confirmed the effectiveness of subretinal VN therapy in terms of improvement of visual function. CRA was confirmed as a common postoperative complication, with limited functional impact.

Abstract Introduction: We describe the perceptions and experiences of health care services during the COVID-19 pandemic of those newly diagnosed with a rare, chronic inflammatory eye disorder. Methods: We undertook a cross-sectional study nested within a longitudinal multi-centre inception cohort study. Participants were families and young people (aged under 18 years) newly diagnosed with childhood uveitis. Using a validated tool, the Health Foundation COVID-19 Survey, we captured qualitative and quantitative data. Quantitative data were analysed using descriptive summary statistics. Qualitative, free text responses were analysed using content and thematic analysis. Results: Responses received from 60 families between 1st September 2020 and 30th March 2022 were analysed. Despite two in five reporting challenges in accessing medication, the majority felt comfortable accessing healthcare services (8%, 95% CI 3 - 18%, of participants expressed discomfort, versus 28%, 95% CI 26 – 28% of general population). Thematic analysis identified five themes: the value of protected spaces to safely access care; the positive role of digital health tools the experience of immature telemedicine; disintegration of care; and dealing with uncertainty. Discussion: Our findings suggest that families of children with a rare chronic condition had greater confidence in accessing healthcare during the pandemic than the general population. Nevertheless, to ensure more robust health services for such populations in future times of disruption, developments in telemedicine should be directly informed by the experiences of those with rare disease. The development of new healthcare processes which ensure the whole healthcare team has adequate information to support families should be prioritised.

Objectives: Pediatric uveitis is a rare but sight -threatening condition. Prompt and adequate treatment is crucial to preserve vision and avoid long-term complications. In cases that are resistant to corticosteroids and disease -modifying anti -rheumatic drugs (DMARDs), anti -tumor necrosis (anti-TNF) biologic agents are usually added. In this study, we report our experience with adalimumab (ADA) anti-TNF use in this group of patients. Methods: This is a retrospective observational study conducted in a tertiary pediatric uveitis clinic, in Manchester Royal Eye Hospital. All patients were pediatric patients (aged 2-18 years old) under follow-up during the period of six months. The patients' data were analyzed according to the diagnosis, age of onset of uveitis, systemic medications used before and concomitantly with ADA, duration of uveitis before starting ADA, its effect, and time to notice the therapeutic effect in controlling inflammation. Finally, cases were reviewed for the development of anti -drug antibodies. Results: Forty-two patients were included in the study. Idiopathic uveitis was diagnosed in 47.6% of patients and 40.5% of patients were associated with juvenile idiopathic arthritis (JIA). Most (97.6%) of patients were using topical steroids before starting ADA and 95.2% continued using steroids after established ADA use, but systemic steroid use was reduced from 33.3% to 14.3%. The most common non -biologic DMARD used before ADA was methotrexate (MTX) (90.5%). One-third of the patients started ADA between 6 and 12 months after the diagnosis of uveitis, while this percentage dropped to 9.5% the year after diagnosis. Seventy-eight percent of patients acquired complete clinical control of inflammation on ADA use. Almost 78.6% of patients showed a full response in less than six months. In eight patients who were not controlled or were transiently controlled on ADA, three patients had positive anti -drug antibodies. In one patient, antidrug antibodies were identified after 12 years of ADA use, and in another, after 4 years. Conclusion: Adalimumab is an effective, well -tolerated drug in children with uveitis refractory to nonbiologic DMARD therapy. DMARDs were usually used alongside ADA in this cohort and few patients had confirmed ADA antibodies.

PURPOSE:To determine the pattern(s) of onset, variation, and progression of retinopathy in patients with mucopolysaccharidoses (MPS). DESIGN:Prospective, longitudinal, observational study. PARTICIPANTS:Between November 2015 and March 2023, individuals with MPS were recruited from ophthalmology clinics at the Manchester Royal Eye Hospital, United Kingdom. METHODS:Participants underwent assessment of visual acuity, corneal clouding, and intraocular pressure, along with fundoscopy, ultrawidefield (UWF) color fundus photography, fundus autofluorescence (FAF) imaging, OCT, and electroretinography (ERG), where feasible. MAIN OUTCOME MEASURES:Evaluation of findings from clinical examination, retinal imaging, and ERG studies to ascertain the presence and patterns of retinopathy. RESULTS:Data were collected for 75 patients, including 45 with MPS I, 9 with MPS II, 13 with MPS IVA, and 8 with MPS VI, aged 3 to 53 years. Fundus photography was conducted in 65 patients, FAF in 61 patients, OCT in 58 patients, and electrodiagnostic studies in 36 patients. Retinopathy was defined as signs of retinal disease evident through retinal examination or fundus photography, such as depigmentation, bone-spicule pigmentation, vascular tortuosity, retinal pigment epithelium (RPE) mottling/other changes, macular atrophy/puckering/epiretinal membranes, FAF findings such as a central hyperautofluorescent dot, hyperautofluorescent parafoveal ring, hypoautofluorescent lesions around fovea (double bull's eye), areas of hyper/hypoautofluorescence, and extrafoveal changes, OCT imaging features such as central external limiting membrane (ELM) thickening, RPE disturbance, photoreceptor layer loss, parafoveal retinal atrophy, and outer retinal/intrachoroidal cavities, or ERG studies revealing rod-mediated retinopathy or rod-cone dystrophy. Retinopathy was confirmed in 32 patients, including 25 with MPS I, 4 with MPS II, 1 with MPS IVA, and 2 with MPS VI. Five participants were first diagnosed with retinopathy with clinical examination, and 31 participants were identified on UWF color fundus photography supported by FAF and OCT. A total of 21 patients exhibited ERG abnormalities consistent with retinopathy. Fifteen of the total 32 participants described symptoms of nyctalopia. The onset of retinopathy varied substantially, with initial detection between 2 and 53 years of age. CONCLUSIONS:Patients with MPS as young as 2 years may develop retinopathy, diagnosed through fundus examination, ophthalmic imaging, or ERG. Emerging treatments, including gene therapy, may prevent or stabilize retinopathy. Phenotypic data and natural history of MPS-related retinopathy are thus of paramount importance. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found after the references.

We aimed to develop and assess age-appropriate child and young person, self and proxy report tools to capture and characterise eye symptoms in childhood ocular inflammatory disease. Children and young people aged under 18 years diagnosed with inflammatory eye disease (uveitis), and their families, were recruited to a multiphase study, involving: text and pictogram items generation through focus groups and interviews (Phase 1), pre-testing face validity analysis including and discussion amongst a multidisciplinary professional panel (Phase 2), and pre-piloting (Phase 3) and piloting (Phase 4) of the instrument amongst a representative sample of the target population. A total of 170 participants, comprising 113 children/young people and 57 parents/carers, were recruited. Phase 1 resulted in the generation of 60 items. Following phases 2 to 3, these items were developed into self-completion, and assisted self-completion tools for children aged 9 years and older, and those aged under 9 years respectively, and a proxy score, for completion by parents and carers. Correlations scores between individual item and whole domain scoring were above 0.58 for the self-completion tools and above 0.39 for the proxy completion tool. Initial Cronbach’s alpha for the tool overall was good at 0.84, with within-domain alphas of 0.81 – 0.87. In conclusion, these instruments demonstrate the feasibility of capturing ocular sensations in children and young people, with a patient centred development approach resulting in tools with high rates of completion, and acceptable internal instrument consistency. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement National Institute for Health and Care Research (NIHR Clinician Scientist award CS-2018-18-ST2-005) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The London - Queen Square Research Ethics Committee (REC reference 19/LO/0729) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Individual level data are not being made available for this study involving human research participant data. Consent for publication of raw data was not obtained (as this approach may have led to differential non-inclusion of certain patient groups). The dataset could in theory pose a threat to confidentiality. Guidance was sought from relevant Ethics Committee.

Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that leads to cell injury. Urinary glycosaminoglycans (GAG) are often used as a biomarker in MPS diseases for diagnosis and to monitor treatment efficacy. This study evaluated leukocyte GAGs (leukoGAG) and skin GAGs as alternate biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and tissue injury. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG levels in leukocytes was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoCS and leukoDS levels were significantly higher in the MPS VI group than the control group (leukoCS: 37.9 ± 10.2 and 2.9 ± 1.5 μg/μg protein, respectively, p = 0.005; leukoDS: 0.26 ± 0.2 and 0.0 ± 0.0 μg/μg protein, respectively, p = 0.028) with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2, leukoCS (32.0 ± 11.8 vs 6.9 ± 3.1 μg/mg protein, p = 0.005) and leukoDS (0.4 ± 0.1 and 0.2 ± 0.1 μg/mg protein, p = 0.020) were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.

Tubulointerstitial nephritis and uveitis (TINU) is a rare autoimmune disorder often triggered by drugs and infections. Since the onset of the COVID-19 pandemic, we have observed an unusual cluster of paediatric cases. Four children (3 females) were diagnosed with TINU (median age 13 years) following a kidney biopsy and ophthalmologic assessment. Presenting symptoms included abdominal pain (3 cases), fatigue, weight loss and vomiting (2 cases). At presentation, median eGFR was 50.3 ml/min/1.73m2 (range 19.2–69.3). Anaemia was common (3 cases) with median haemoglobin of 10.45 g/dL (range 8.4–12.1). Two patients were hypokalaemic and 3 had non-hyperglycaemic glycosuria. Median urine protein:creatinine ratio was 117 mg/mmol (range 68–167). SARS-CoV-2 antibodies were detected in 3 cases at presentation. All were asymptomatic for COVID-19 with a negative PCR. Kidney function improved following high-dose steroids. However, disease relapse was observed during steroid tapering (2 cases) and upon discontinuation (2 cases). All patients responded well to further high dose steroids. Mycophenolate mofetil was introduced as a steroid-sparing agent. At latest follow up (range 11–16 months), median eGFR was 109.8 ml/min/1.73m2. All four patients continue on mycophenolate mofetil, with 2 patients applying topical steroids for uveitis. Our data suggest that SARS-CoV-2 infection might be a trigger for TINU.

Uveitis in children and young people (CYP) is a rare but potentially debilitating condition. Steroid eye drops are the first step in treatment and poor compliance may result in vision-threatening complications. This study aims to measure compliance with prescribed eye drops prospectively in a child-specific manner. Patients aged 0–18 years attending a tertiary paediatric uveitis clinic using steroid drops were recruited. Both the CYP, and person with parental responsibility (PPR) completed questionnaires about compliance. A subgroup had bottles of Prednisolone 1% drops dispensed and weighed at the first appointment and reweighed at follow-up. The weight reduction was compared with expected weight change over the interval. The study was completed by 42 patients of the 50 patients recruited. Thirty-one CYP and their respective PPR completed both questionnaires, 11 completed only one questionnaire (9 CYP, 2 PPR). Drop errors for all eye drops were reported more than “once a week” by 13/39 CYP (33.3%, 95% CI: 19.1%–50.2% of respondents), and 3/31 PPR (9.7%, CI: 19.1%–50.2% of respondents). Many PPR could not recall prescribed drop frequency (n = 13/31, 40.6%, CI: 23.7%–59.4% of respondents). Twelve patients had bottles weighed and returned. Insufficient weight reduction was found in 9 (75%, CI: 42.8%–94.5%). Within the eye drop weighing subgroup three participants (25%, CI: 5.5%–57.2%) used <50% the expected weight of drops. This study demonstrated poor eye drop compliance in CYP with uveitis. Self-reported compliance was unreliable in this population. Worryingly, some patients miss more than 50% of drops and may suffer sub-optimal disease control.