To report IgG4-related ophthalmic disease (IgG4-ROD) presenting as posterior scleritis in a pediatric patient. A 7-year-old girl presented with proptosis, painful eyelid swelling, and restricted extraocular movements (EOM) of her left eye (OS). Visual acuity (VA) was 20/20 in right eye (OD) and counting fingers (CF) at 1 foot in OS. Slit lamp examination revealed 2 + anterior chamber (AC) cells, optic disc edema (ODE) with elevated appearance of macula in OS. Optical coherence tomography (OCT) showed significant subretinal fluid (SRF) in macula, B-scan ultrasound (US) demonstrated T-sign in OS. Orbital MRI was also consistent with posterior scleritis and periorbital inflammation. Extensive systemic work-up was unremarkable. Thus, the patient was started on intravenous methylprednisolone (IVMP) 30 mg/kg/day for 3 days, along with topical therapy in OS, which led to an improvement of proptosis, EOM restriction, AC cells, as well as ODE and SRF in macula in OS. Fluorescein angiography (FA) showed leakage from optic disc in OS. The patient was then switched to oral prednisone with slow tapering and started on methotrexate (MTX). Given the recurrence of proptosis and painful eyelid swelling on systemic steroid tapering, serum IgG4 levels were ordered and found to be elevated at 149.9 mg/dL (range, 1–99). Therefore, the patient was diagnosed as ‘possible’ IgG4-ROD (based on diagnostic criteria) and started on infliximab (7.5 mg/kg) and IVMP monthly infusions with continuation of MTX 20 mg weekly and slower tapering of oral prednisone, which led to resolution of clinical findings, improvement of VA to 20/20 in OS. Posterior scleritis may be the initial presentation of IgG4-ROD in children. Refractory course is not uncommon. Biologics are effective in the long-term control of inflammation.

PURPOSE:To present a case of presumed limited granulomatosis with polyangiitis (GPA) associated with anterior scleritis and ciliary body inflammatory granuloma which was treated with systemic rituximab (RTX), oral mycophenolate mofetil, and intravitreal (IVT) dexamethasone implant. OBSERVATIONS:We report a patient presenting with sectoral scleritis and ciliary body granuloma in the left eye. The patient also had a nasal sinus granuloma which was biopsied three times with negative results for malignancy and fungal infections. The patient underwent a diagnostic vitrectomy, which was also negative for lymphoma, bacterial and fungal infections. Subsequently, intravenous methylprednisolone and oral methotrexate were started, but significant improvement was achieved only following initiation of intravenous RTX, oral mycophenolate mofetil, and IVT dexamethasone implant. CONCLUSION:Therapeutic management of scleritis associated with limited GPA can be very challenging; early diagnosis can help to eliminate potential complications. Our result showed that RTX, mycophenolate mofetil, and IVT dexamethasone implant can be beneficial in treatment-resistant cases.

PURPOSE:To present a case of recurrent uveitic macular edema (UME) treated with intravitreal faricimab injection. METHODS:Single case report from a tertiary referral center. OBSERVATIONS:A 63-year-old Caucasian female presenting with recurrent UME due to birdshot chorioretinopathy (BSCR) in both eyes. UME had been treated with multiple agents including intravenous methylprednisone, posterior subtenons and intravitreal triamcinolone acetonide injection, dexamethasone implant, mycophenolate mofetil, and adalimumab with limited improvement and development of intolerance. Moreover, optical coherence tomography also revealed recurrence of UME with subretinal fluid in both eyes. After treatment with one dose of intravitreal faricimab injection, complete resolution of UME was achieved and maintained for three months. CONCLUSION:The findings of this case hint towards the potential simultaneous effect of angiopoietin-2 blockade along with vascular endothelia growth factor A inhibition by faricimab in managing treatment-resistant UME. Nonetheless, more studies focusing on the role of intravitreal faricimab in UME are required.

Background Ocular inflammatory diseases, including scleritis and uveitis, have been widely treated with immunomodulatory therapies (IMTs) as a steroid-sparing approach. Such strategy includes conventional therapies (antimetabolites, alkylating agents, and calcineurin inhibitors) as well as biologic agents like adalimumab, infliximab, rituximab, and tocilizumab. Cyclophosphamide (CP) is an alkylating agent and mainly inhibits the functioning of both T and B cells. Though known to have potential adverse events, including bone marrow suppression, hemorrhagic cystitis, and sterility, CP has been shown to be efficacious, especially in recalcitrant cases and when used intravenous (IV) for a limited period. Main findings We conducted a retrospective case-series to assess the safety and efficacy of CP therapy for patients with severe ocular inflammatory diseases who failed other IMTs. Medical records of 1295 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were reviewed. Seven patients (10 eyes) who received CP therapy for ocular inflammatory diseases with at least one year of follow-up were included. The mean age of the patients (4 males, 3 females) was 61.6 ± 14.9 (43.0–89.0) years. Clinical diagnoses included necrotizing scleritis (5 eyes), peripheral ulcerative keratitis (2 eyes), orbital pseudotumor (1 eye), HLA-B27 associated panuveitis and retinal vasculitis (2 eyes). Ocular disease was idiopathic in 3 patients, and was associated with rheumatoid arthritis, IgG-4 sclerosing disease, dermatomyositis, and ankylosing spondylitis in 1 patient each. All the patients had history of previous IMT use including methotrexate (5), mycophenolate mofetil (3), azathioprine (1), tacrolimus (1), adalimumab (2), infliximab (4), and rituximab (1). The mean follow-up time was 34.4 ± 11.0 (13–45) months, and mean duration of CP therapy was 11.9 ± 8.8 (5–28) months. Remission was achieved in 5 patients (71.4%). Four patients (57.1%) experienced transient leukopenia (white blood cell count < 4000/mL). Short conclusion CP therapy can be considered a potentially effective and relatively safe therapeutic option for patients with severe ocular inflammatory diseases who failed other IMTs including biologics (TNFa and CD20 inhibitors).

PURPOSE:The index review aims to provide an update on the role of corticosteroids and steroid-sparing immunomodulatory therapy (IMT) in managing patients with infectious uveitis. METHOD:Narrative literature review. RESULTS:Corticosteroids and immunomodulatory therapy (IMT) focus on the host defense system instead of the pathogen, adjusting exaggerated inflammatory reactions to reduce potential harm to ocular tissues. Systemic or local corticosteroids are primarily selected as adjunctive medication for infectious uveitis. Concomitant corticosteroids have also been used in cases of paradoxical worsening in ocular tuberculosis and immune recovery uveitis in cytomegalovirus (CMV) retinitis. While there is no well-established evidence to support the use of IMT in infectious uveitis, it is occasionally used in clinical settings to treat persistent inflammation following resolution of infection such as cases of ocular tuberculosis and ocular syphilis where an insufficient response is observed with corticosteroids. CONCLUSION:There is no consensus on the position of immunomodulatory therapy in the management of infectious uveitis with different etiologies. The index review provides an overview of available adjunctive corticosteroids and IMT options to assist clinicians in managing such disease entities more efficiently.

Cytomegalovirus (CMV) anterior uveitis and corneal endotheliitis are the most common ocular diseases caused by CMV infections in immunocompetent patients. The incidence of CMV corneal endotheliitis is relatively high in middle-aged men. CMV corneal endotheliitis presents with mild anterior chamber inflammation, corneal edema, keratic precipitates, and elevated intraocular pressure. It resembles Posner-Schlossman syndrome and Fuchs uveitis because of the elevated intraocular pressure. Without proper diagnosis and treatment, it may progress to bullous keratopathy or glaucoma, necessitating keratoplasty or glaucoma surgery. Therefore, early diagnosis and treatment are important for a good prognosis. Aqueous humor analysis can facilitate the diagnosis of CMV corneal endotheliitis, and early antiviral treatment can decrease the risk of corneal compensation or glaucomatous optic atrophy. In this article, we review the epidemiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of CMV corneal endotheliitis along with the evidence for early clinical diagnosis and active antiviral treatment.

Abstract Background Repository corticotropin injection (RCI) has been suggested to exert immunomodulatory and anti-inflammatory effects in ocular inflammation. The index retrospective study aimed to evaluate the efficacy and tolerability of subcutaneous RCI in patients with active scleritis or uveitis. Main body Medical records of patients who were diagnosed with different types of active scleritis or uveitis and received RCI for more than six months at a tertiary eye center were reviewed. Patient characteristics including age, sex, comorbidities, clinical findings, treatment details, and adverse events were recorded. A total of 17 eyes of 17 patients were included. Median age was 43 years old and 53% of patients were male. Mean treatment duration was 25.4 ± 15.5 months. Indications for RCI therapy were scleritis (7 anterior and 1 posterior) (47.8%), panuveitis (17.4%), retinal vasculitis (17.4%), chronic/recurrent anterior uveitis (13%), and posterior uveitis (4.35%). RCI was initiated at a dose of 40 to 80 units 3 times weekly. Given the adequate control of inflammation, RCI was successfully discontinued in four patients (23.5%). Prior to RCI therapy, 14 (82.3%) patients were on oral prednisone at an average of 10 mg daily (range 2.5–40 mg), and two (11.7%) patients discontinued prednisone immediately before initiating RCI due to side effects. After six months of therapy, the prednisone dose was reduced in four (23.5%) patients to an average of 3 mg daily (range 1–5 mg) and was stopped in eight (53%) patients. Concomitant immunomodulatory therapies (IMTs) included mycophenolate mofetil (23.5%) and methotrexate (23.5%), and adalimumab (23.5%). Ten patients were on IMTs prior to using RCI, and during the course of treatment, IMT was stopped in two patients and reduced in one. Side effects included insomnia (23%), hypertension (11.7%), lower extremity edema (11.7%), hyperglycemia (11.7%), weight gain (11.7%), and infection (5.8%). Conclusion RCI may be considered as a potential therapy with acceptable tolerability for patients with non-infectious scleritis or uveitis.

PURPOSE:To ascertain whether the use of ultra-wide-field fluorescein angiography (UWFFA) at baseline visit alters the assessment of disease activity and localization, as well as the management of patients presenting to a tertiary uveitis clinic. DESIGN:Retrospective comparison of diagnostic approaches. METHODS:Baseline visits of 158 patients who presented to the Uveitis Clinic at the Byers Eye Institute at Stanford between 2017 and 2022 were evaluated by 3 uveitis-trained ophthalmologists (I.K., A.B., and H.G.). Each eye had undergone clinical examination along with ultra-wide-field fundus photography (UWFFP) (Optos Plc), spectral-domain optical coherence tomography (SD-OCT, Spectralis Heidelberg, Heidelberg Engineering) and UWFFA (Optos Plc) at the baseline visit. Investigators were asked to successively determine disease activity, localization of disease (anterior, posterior or both), and management decisions based on clinical examination and UWFFP and SD-OCT (Set 1) and Set 1 plus UWFFA (Set 2). The primary outcome was the percentage of eyes whose management changed based on the availability of UWFFA compared with Set 1. RESULTS:The mean age of the patients was 46.9 ± 22.4 years (range, 7-96), and 91 (57.6%) were female. With Set 1 alone, 138 eyes (55.2%) were found to have active disease; localization was anterior in 58 eyes (42.0%), posterior in 53 eyes (38.4%), and anterior + posterior in 27 eyes (19.6%). With Set 2, 169 eyes of 107 patients had active anterior, posterior, or panuveitis. In comparison with Set 1, assessment with Set 2 identified additional 31 eyes (18.3%) with active disease (P = .006) and an additional 31 eyes (18.3%) having disease in both anterior + posterior segments (P < .001). Regarding the primary outcome, management was changed in 68 eyes (27.4%) in Set 2 compared with Set 1. CONCLUSIONS:Baseline UWFFA may alter assessment of disease activity, localization, and management decisions compared with clinical examination with only UWFFP and SD-OCT for eyes with uveitis. Thus, UWFFA may be considered as an essential tool in the evaluation of patients with uveitis at the baseline visit.

Purpose:To present a case of birdshot chorioretinopathy (BCR) in a Chinese patient with HLA-A29 positivity.Observations:A 45-year-old Chinese female presented at a tertiary Ophthalmology Clinic with complaints of frequent headaches as well as blurred vision, photophobia, and pressure in the left eye (OS). The patient had a significant ocular history of left orbital cavernous hemangioma status post lateral orbitotomy and resection. Uncorrected visual acuity was 20/20 in the right eye (OD) and 20/40 in OS (pinhole 20/30). Funduscopic examination demonstrated optic disc edema, left eye worse than right eye, and vascular tortuosity in both eyes (OU). Late phase fluorescein angiography (FA) showed extensive perivascular and optic disc leakage and peripheral capillary leakage in OU. Laboratory evaluations were positive for human leukocyte antigen-A29 (HLA-A29). The patient was started on 40 mg prednisone daily; mycophenolate mofetil 500 mg twice daily was subsequently added.At the 3-month consultation visit to the Uveitis Clinic, dilated funduscopic examination revealed 1+ vitreous cells and improved optic disc edema in OU. FA showed improved vascular and optic disc leakage in OS but worsened leakage in OD. At this point, indocyanine green angiography (ICGA) was ordered which revealed hypocyanescent lesions throughout the choroid that were centered on the optic disc, supporting and confirming the diagnosis of BCR.Conclusions and Importance:The index patient is the first reported case of BCR in an HLA-A29 positive Asian patient.

Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post HCT with sustained long-term virologic and clinical response after CMV-specific T-cell therapy. This case highlights the need to consider VST as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post HCT.

OBJECTIVE:To evaluate the functional implications of angiographic macular leakage without the presence of intraretinal fluid on optical coherence tomography (OCT) in eyes with intermediate, posterior, or panuveitis. METHODS:Retrospective study on patients with a diagnosis of intermediate, posterior, or panuveitis. Patients who had fluorescein angiography, OCT, and multifocal electroretinography (mfERG) within a predetermined time frame were included. Demographic and clinical data including types of ocular inflammation and best-corrected visual acuity (BCVA), in addition to OCT, fluorescein angiography, and mfERG data were collected. The study cohort was divided into 2 groups based on the presence of angiographic macular leakage and macular edema (ME): group 1 (no ME and no macular leakage) and group 2 (presence of macular leakage without ME). RESULTS:A total of 29 patients (43 eyes) were included in the study, with 13 patients (17 eyes) in group 1 and 16 patients (26 eyes) in group 2. No statistically significant differences in age, sex, anterior-chamber cells, lens status, vitreous cells, vitreous haze, BCVA, or mean central subfoveal thickness were found between groups 1 and 2. All mfERG values, including N1 and P1 response densities and timings for rings 1-5, did not show any statistically significant difference between group 1 and 2. No correlation was found between either BCVA or central subfoveal thickness and any of mfERG values for rings 1-3. CONCLUSIONS:In absence of ME, angiographic macular leakage in eyes with uveitis might not be associated with worse macular function when compared with eyes without angiographic macular leakage.

Gene therapy has emerged as a research topic of choice in recent years. The eye in particular is one of few organs of the body for which gene therapy has received Food and Drug Administration approval, and it remains a field of great interest for gene therapy development. However, its associated immune and inflammatory reactions may render the treatment ineffective or harmful, which are of particular concern for the eyes due to their susceptibility to inflammation. The severity of immune and inflammatory reactions depends on the choice of vector and its route of administration. Furthermore, most preclinical and clinical studies have shown that the dose of vectors is correlated with the degree of humoral response and ocular inflammation. The route of administration directly impacts the degree of immune and inflammatory reaction. Subretinal delivery produces a weaker humoral response than the intravitreal route. However, some studies have demonstrated that the subretinal delivery induces a stronger inflammatory reaction. On the other hand, several instances of vision loss due to severe late onset intraocular inflammation were reported in a clinical trial involving intravitreal delivery of viral vectors. When compared with the intravitreal route, suprachoroidal gene delivery has been shown to produce weaker humoral response. However, unlike the subretinal space, the suprachoroidal space is not known to have immune privilege status. Inflammatory reactions following ocular gene therapy are typically mild and most clinical and preclinical studies have shown that they can be controlled with topical, local or systemic steroids. However, severe inflammatory responses may occur and require aggressive management to avoid permanent vision loss. Further investigations are required to elucidate and expand our knowledge of inflammatory reactions, and their optimal management, following ocular gene therapy.

Purpose:To report a patient who developed a cancer associated retinopathy (CAR) like syndrome in the setting of pembrolizumab and lenvatinib combination therapy for metastatic endometrial carcinoma. Symptoms resolved with normalization of objective functional tests following cessation of medications.Observations:A 52-year-old female with history of endometrial carcinoma, managed with pembrolizumab infusions and daily oral lenvatinib treatment for 18 months, presented to a tertiary eye center with complaints of nyctalopia, photosensitivity and photopsia. Further investigations revealed a reduction in b-wave amplitude on full field ERG (ffERG), a mild color vision deficit, and positive antiretinal antibodies against carbonic anhydrase II, enolase and arrestin. A preliminary diagnosis of CAR was made. One month following diagnosis, the patient discontinued both lenvatinib and pembrolizumab and subsequently reported significant improvement in her eye symptoms and vision. Repeat ffERG had normalized with a robust b-wave, with an improvement noted on repeat color vision testing. A presumed diagnosis of immunotherapy-induced retinopathy was made, with clinical findings mimicking CAR.Conclusions and importance:Pembrolizumab and lenvatinib treatment may be associated with a reversible retinopathy, with presentation very similar to CAR.

A 58-year-old male who underwent cataract extraction with combined intraocular lens and Hydrus® Microstent (Ivantis Inc, Irvine, CA, US) implantation 2 years ago in the right eye (OD) due to advanced glaucoma presented with blurry vision in right eye (OD) for 3 months. The visual acuity was 20/60 and slit-lamp examination indicated mild anterior chamber inflammation with unexposed, functioning tube shunt superotemporally in OD. Optical coherence tomography demonstrated cystoid macular edema (CME) with subretinal fluid. Fluorescein angiography demonstrated petaloid pattern leakage of CME. Gonioscopy revealed a kinked appearance of a Hydrus® Microstent protruding into the anterior chamber and causing iris chafing. Topical ketorolac tromethamine and prednisolone acetate were started. At the 2nd month of follow-up, the anterior chamber was quiet, and the CME resolved completely. Protruded kinked Hydrus® Microstent may lead to acute iridocyclitis and CME through iris chafing, which may be responsive to topical anti-inflammatory drops.

Purpose: To evaluate the safety of intravenous high-dose pulse methylprednisolone succinate (IVHDM) in the management of severe or refractory non-infectious pediatric uveitis. Methods: We reviewed all uveitis patients who were <= 16 years of age and who received IVHDM with a dose of >= 500 mg per day (1-3 days a month) for at least 3 months during their management at a tertiary care eye hospital. Results: Twenty pediatric patients with severe or refractory uveitis who received IVHDM were identified. Six patients received IVHDM either once, as a preoperative medication, or at a lower dose than 500 mg, and were excluded. The remaining 14 patients received IVHDM for at least 4 months. Age (mean +/- SD) was 11.9 +/- 2.4 years and 50% were female. Duration of treatment was 14.2 +/- 7.5 months. Thirteen patients received IVHDM in combination with other immunomodulatory therapy (IMT). Except for two outliers, IVHDM was given at a dose of 8-25 mg/kg per infusion. Three major adverse events (AEs) occurred in two patients: a single episode of bradycardia, compression fracture following minor trauma and adrenal insufficiency. The number of AEs (major and minor) strongly correlated with duration of treatment (p=0.004) and moderately correlated with the cumulative dose/weight (p=0.051). Weight gain was associated with the use of concomitant oral steroids and not with duration of treatment or cumulative dose. Conclusion: IVHDM may be a valid therapeutic option for aggressive/refractory pediatric uveitis. The reported AEs in this series can also be attributed to the concurrent IMT or the underlying disease itself.