Intraocular lymphomas, including vitreoretinal and choroidal lymphoma, can simulate the clinical presentation of other benign and malignant ocular diseases resulting in diagnostic delays. Multimodal imaging features can raise early clinical suspicion to support appropriate subspecialty referrals and treatment for patients affected by these conditions. This review synthesises current evidence on the diagnostic and prognostic value of characteristic imaging features of these rare malignancies. Findings are reviewed based on imaging modality, including fundus photography, optical coherence tomography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography angiography, and ultrasound. We emphasise discriminative biomarkers that heighten suspicion for either vitreoretinal or choroidal lymphoma, as well as key findings to discriminate between lymphoma and alternative diagnoses. We further describe longitudinal changes in multimodal imaging features that can facilitate tracking disease progression or treatment response. By consolidating modality-specific findings, this review aims to facilitate early referral and accurate diagnosis of these rare malignancies.

PURPOSE:To describe a case of locally invasive conjunctival squamous cell carcinoma (SCC) refractory to plaque radiotherapy. CASE DESCRIPTION:A 69-year-old man presented with a recurrent conjunctival tumor after 6 previous cycles of topical 5-fluorouracil chemotherapy and excisional biopsy showing invasive SCC with positive margins. There was a mild anterior chamber reaction. By the time of repeat excisional biopsy, the conjunctiva had ulcerated with underlying scleralysis associated with histopathologic evidence of scleral involvement by SCC. After subsequent tectonic scleral patch grafting, plaque radiotherapy was applied after which the disease appeared to be controlled for 9 months. The eye then developed progressive conjunctival ulceration and scleralysis with progressive ectropion. Exenteration was performed, revealing locally invasive SCC into palpebral conjunctiva, ciliary body, and choroid. CONCLUSIONS:Conjunctival SCC can be locally invasive with destruction of the globe, despite plaque radiotherapy. Clinicians should be suspicious of invasive diseases in cases of ocular surface squamous neoplasia that are poorly responsive to topical chemotherapy. Associated anterior chamber cell and progressive scleralysis should also raise concern for invasive malignancy.

Intraocular lymphomas, including vitreoretinal and choroidal lymphoma, can simulate the clinical presentation of other benign and malignant ocular diseases resulting in diagnostic delays. Multimodal imaging features can raise early clinical suspicion to support appropriate subspecialty referrals and treatment for patients affected by these conditions. This review synthesises current evidence on the diagnostic and prognostic value of characteristic imaging features of these rare malignancies. Findings are reviewed based on imaging modality, including fundus photography, optical coherence tomography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography angiography, and ultrasound. We emphasise discriminative biomarkers that heighten suspicion for either vitreoretinal or choroidal lymphoma, as well as key findings to discriminate between lymphoma and alternative diagnoses. We further describe longitudinal changes in multimodal imaging features that can facilitate tracking disease progression or treatment response. By consolidating modality-specific findings, this review aims to facilitate early referral and accurate diagnosis of these rare malignancies.

BACKGROUND:Blau syndrome is a rare, autosomal dominant granulomatous disease caused by mutations in the NOD2/CARD15 gene. While the classic triad of arthritis, dermatitis, and uveitis is well known, the full range of cutaneous manifestations remains underexplored. OBJECTIVE:To expand the understanding of cutaneous findings in Blau syndrome, correlate these findings with NOD2 variants, and evaluate treatment outcomes across organ systems. METHODS:A retrospective review of medical records from January 1999 to January 2024 identified 14 patients with Blau syndrome supported by the presence of NOD2 variants. Clinical data on dermatological features, genetics, and treatment responses were analyzed and categorized into specific and non-specific cutaneous findings. RESULTS:Of the 14 patients with Blau syndrome, 85% (12/14) demonstrated skin involvement. Specific findings included lichenoid or granulomatous papules and nodules (50%, 6/12), while non-specific findings (83%, 10/12) were more diverse, including dermatitis (6/10), chronic urticaria (5/10), ichthyosiform eruptions (4/10), vasospastic disorders (5/10), and oral/genital ulcers (2/10). Skin biopsies in three patients with specific findings revealed non-caseating granulomas. Genetic analysis identified multiple NOD2 variants, though no clear genotype-phenotype correlation was observed. TNF-alpha inhibitors demonstrated efficacy in controlling ocular and joint disease. CONCLUSION:Blau syndrome presents with a broader spectrum of cutaneous findings than previously recognized. These findings highlight the importance of dermatological evaluation and a multidisciplinary approach to optimize diagnosis and management.

PURPOSE:To investigate the association between scleritis and thyroid eye disease in a U.S. Midwestern county population. METHODS:Retrospective, case-control study of all patients diagnosed with ocular inflammatory disease in Olmsted County, Minnesota from January 1, 2006, to December 31, 2015. Patients were identified using the Rochester Epidemiology Project database, which contains virtually all medical care in the county. Medical records were reviewed to confirm diagnosis of scleritis. A 3:1 age- and sex-matched control group was also identified using the database. Patient records for the cases and control group were also reviewed to confirm diagnosis of thyroid disease. RESULTS:There were 87 patients with scleritis during the 10-year study period, of which 12 (14%) were diagnosed with thyroid disease. In comparison, there were 261 control patients, of which 30 (11%) had thyroid disease. After adjusting for age, sex, race, smoking status, and history of autoimmune disease, the odds ratio of patients with thyroid disease having scleritis compared to patients without thyroid disease was 1.23 (p = 0.57). However, autoimmune disorders were present in 17 (20%) of scleritis cases versus 16 (6%) patients in the control group (p < 0.001). CONCLUSION:There was no statistically significant association between scleritis and thyroid disease in this study. However, there was a significant association between scleritis and other autoimmune diseases. Further research is needed to explore the pathophysiologic mechanisms and systemic associations in thyroid disease and ocular inflammatory diseases.

Background Vitreoretinal lymphoma (VRL) is a rare intraocular malignancy that poses a diagnostic challenge due to the non-specific clinical presentation that resembles uveitis. The use of spectral domain optical coherence tomography (SD-OCT) has emerged as a valuable imaging tool to characterize VRL. Therefore, we sought to determine the specific OCT features in VRL compared to the uveitides. Methods Retrospective chart review of patients who were seen at Mayo Clinic from January 1, 2010 through December 31, 2022. The medical records and SD-OCT images at time of initial presentation were reviewed in patients with biopsy-proven VRL, intermediate uveitis, or biopsy-confirmed sarcoid posterior uveitis. Patients with VRL or similar uveitides including intermediate uveitis or sarcoid posterior uveitis were included. Results There were 95 eyes of 56 patients in the VRL group and 86 eyes of 45 patients in the uveitis group, of whom 15 (33.3%) were diagnosed with intermediate uveitis and 30 (66.7%) with sarcoid chorioretinitis. The SD-OCT features more commonly seen at initial presentation in VRL patients (vs. uveitis) included preretinal deposits (31.6% vs. 9.3%, p = 0.002), intraretinal infiltrates (34% vs. 3.5%, p < 0.001), inner retinal hyperreflective spots (15.8% vs. 0%, p < 0.001), outer retinal atrophy (22.1% vs. 2.3%, p < 0.001), subretinal focal deposits (21.1% vs. 4.7%, p = 0.001), retinal pigmented epithelium (RPE) changes (49.5% vs. 3.5%, p < 0.001), and sub-RPE deposits (34.7% vs. 0%, p < 0.001). Features more frequently seen in uveitis included epiretinal membrane (ERM) (82.6% vs. 44.2%, p < 0.001), central macular thickening (95.3% vs. 51.6%, p < 0.001), cystoid macular edema (36% vs. 11.7%, p < 0.001), subretinal fluid (16.3% vs 6.4%, p = 0.04), and subfoveal fluid (16.3% vs. 3.2%, p = 0.003). Multivariate regression analysis controlling for age and sex showed absence of ERM (OR 0.14 [0.04,0.41], p < 0.001) and absence of central macular thickening (OR 0.03 [0,0.15], p = 0.02) were associated with VRL as opposed to uveitis. Conclusion OCT features most predictive of VRL (vs. uveitis) included absence of ERM and central macular thickening.

PURPOSE:To describe ocular involvement in subjects with Whipple's disease (WD). METHODS:Retrospective review of documented WD cases seen at Mayo Clinic between 1980 and 2021 with ocular involvement. RESULTS:Of 217 patients with WD, 30 had eye exams and four (two female, median age 58.5 years) had ocular involvement. Findings included anterior/intermediate uveitis (n = 2), intermediate uveitis and phlebitis (n = 1), and chorioretinitis with vitritis (n = 1). The diagnosis was confirmed by vitreous biopsy in three of four cases. In two cases, WD diagnosis was unconfirmed prior to the ocular diagnosis. Systemic manifestations included gastrointestinal symptoms in all patients, synovitis (n = 3), weight loss (n = 2), and pericarditis (n = 1). Mean time from onset of ocular symptoms to ocular diagnosis was 11 months (range 2-28 months). Prior systemic symptoms were present as long as 3 years. CONCLUSIONS:WD is uncommon and ocular involvement is even more rare. However, WD should be considered in the differential for all patients with chronic recalcitrant uveitis, especially in the setting of polyarthralgias and/or gastrointestinal symptoms. Vitreous biopsy is a reliable method to diagnose ocular WD.Abbreviations and Acronyms: Whipple's disease (WD), intestinal lipodystrophy (IL), polymerase-chain reaction (PCR), periodic acid-Schiff (PAS), trimethoprim/sulfamethoxazole (TMP/SMX).

Background: Optic disc edema is a feature of many ophthalmic and neurologic conditions. It remains an underappreciated feature of birdshot chorioretinitis (BSCR), leading to delay in diagnosis and treatment. The purpose of our study was to identify clinical features that are concomitant with optic disc edema and suggest a diagnosis of BSCR. Methods: Retrospective multicenter case series of 29 patients who were referred to a neuro-ophthalmologist or uveitis specialist for evaluation of disc edema and were ultimately diagnosed with BSCR. Results: Fifty-four eyes of 30 patients, from the practices of 15 uveitis specialists, met the eligibility criteria. In addition to disc edema, concomitant features in all patients included vitritis, chorioretinal lesions, and retinal vasculitis. Visual recovery to 20/40 or better occurred in 26 of 29 patients. Visual acuity remained 20/100 or worse in 2 patients previously diagnosed with idiopathic intracranial hypertension, 1 patient previously diagnosed with optic neuritis, and 1 patient for whom treatment was delayed for years, leading to optic disc atrophy. Conclusions: Optic disc edema is a presenting feature in some cases of BSCR. A diagnosis of BSCR should be considered when disc edema occurs with vitritis, chorioretinal inflammation, and retinal vasculitis. Patients should be referred to a uveitis specialist for treatment.

Purpose: To describe the incidence, mechanisms, and clinical characteristics of patients diagnosed with traumatic iritis in a U.S. Midwestern county population. Methods: Retrospective population-based cohort of all residents of Olmsted County, Minnesota diagnosed with traumatic iritis from January 1, 2006, to December 31, 2015. The medical records of patients with traumatic iritis were identified using the Rochester Epidemiology Project database, which contains virtually all medical care in the county. Medical records were reviewed for demographics, presentation, and follow-up data. Incidence rates were calculated per 100,000 per year. Results: There were 156 incident diagnoses of traumatic iritis during the 10-year study period, yielding an age- and sex-adjusted incidence rate of 10.7 per 100,000 per year. Traumatic iritis disproportionately occurred in male (p < 0.001) and Black (p < 0.001) patients. The mean age of diagnosis was 33 years (range: 4-96 years), mean number of traumatic iritis-specific follow-up visits was 2.1 (range: 0-26), and median duration of traumatic iritis-specific follow-up was 11 days (range: 1 day-1.6 years). There were 155 (99.4%) patients with unilateral disease. The most frequent mechanisms of traumatic iritis were sports-related (N = 29, 18.6%), assault-related (N = 23, 14.7%), scratch (N = 22, 14.1%), and work-related (N = 21, 13.5%) injuries. The mean initial and final best-corrected visual acuity (BCVA) of the affected eye was 20/40 and 20/30, respectively. Loss of follow-up was more frequently observed in Black patients (p < 0.001) and patients with smoking history (p = 0.004). Conclusion: Traumatic iritis was most frequently observed in younger males and Black patients. Common mechanisms included sports, assault, scratch, and work-related injuries.

IntroductionNecrotizing scleritis is more likely to be associated with severe pain, poor visual outcomes, increased mortality, and autoimmune disease such as rheumatoid arthritis. The advent of targeted biologic therapy has revolutionized the treatment of rheumatic diseases, and these medications are currently being explored for ocular inflammatory disease - including necrotizing scleritis, which is often refractory to conventional immunomodulatory therapies.Areas coveredThe authors review available therapies for scleritis, including topical treatments and systemic immunosuppressive agents. Particular attention is given to CD20 inhibitors, TNF alpha inhibitors, IL6 inhibitors, and IL1 inhibitors as they are increasingly used to treat ocular inflammatory disease. Finally, the authors touch on surgical techniques for reinforcing necrotic areas of sclera.Expert opinionThe authors advocate for a standardized clinical grading system of scleritis to facilitate large scale, multicenter, and randomized clinical trials evaluating the efficacy of treatment regimens for noninfectious scleritis - particularly for TNF alpha inhibitors, anti-IL6 agents, and combinations of conventional medications. For noninfectious and recalcitrant necrotizing scleritis, the authors recommend initial therapy with mycophenolate mofetil, followed by a TNF alpha inhibitor or rituximab. As a last resort for severely recalcitrant and/or globe threatening cases, alkylating agents may be necessary.

Purpose To update the incidence of uveitis in a Midwestern U.S. county population. Methods Retrospective population-based cohort study. All Olmsted County, Minnesota residents diagnosed with uveitis from January 1, 2006 to December 31, 2015 were identified via the Rochester Epidemiology Project. Diagnoses were confirmed by a uveitis specialist. Results There were 371 incident uveitis cases, yielding an overall age- and sex-adjusted incidence rate of 26.9 per 100,000 per year (95% CI: 24.1-29.7). Females accounted for 202 (54.4%) cases, 306 (82.5%) were White, and 299 (80.6%) were anterior uveitis. Highest incidence was observed in patients >= 65 years old. No difference in incidence existed between sexes (p = .17). Incidence rates increased with age for uveitis overall (all anatomic subtypes) (p < .001), anterior uveitis (p < .001), and posterior uveitis (p < .001). Idiopathic uveitis accounted for 168 (45.3%) cases, more frequently diagnosed in females (50.0%) than males (39.6%) (p = .05). Conclusion Uveitis incidence increased 1.6-fold over a 50-year span in this predominately White U.S. Midwestern county population.

The patient had a wide range of symptoms and comorbidities, resulting in a complicated differential diagnosis. Careful evaluation eventually led to a focus on sexually transmitted infection.

A patient with cytomegalovirus viremia who underwent kidney transplant developed floaters in both eyes that did not improve after painful intravitreal injections of foscarnet and ganciclovir. What would you do next?

PURPOSE:The purpose of this study was to describe an exceedingly rare presentation of secondary vitreoretinal involvement by the uncommon entity "indolent T-cell lymphoproliferative disorder of the gastrointestinal tract" and illustrate the utility of fluorescence in situ hybridization for diagnosis. METHODS:This is a case report. RESULTS:A 57-year-old woman with presumed iritis on chronic topical prednisolone acetate presented with increased vitreous opacities in the right eye. She had a history of biopsy-confirmed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract involving the stomach and duodenum, JAK2 -rearrangement positive, controlled on maintenance oral methotrexate. Vitreous biopsy was unremarkable with small CD3-positive and CD4-positive and CD20-negative lymphocytes, along with histiocytes and fibroblasts. Immunostains showed CD4 positivity, and fluorescence in situ hybridization revealed a JAK2 gene rearrangement, consistent with the patient's previously diagnosed indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. Intravitreal methotrexate injections were started in the right eye. MRI of the brain and lumbar puncture with cytology, MYD88 , IL10, and flow cytometry performed at the time of right eye vitreoretinal lymphoma diagnosis revealed no evidence of central nervous system lymphoma, but subsequent bone marrow biopsy demonstrated 5% involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, JAK2 -rearrangement positive, with a lung nodule on PET computed tomography. She returned 4 months later with fatigue, night sweats, and blurry vision in the left eye with vitreous and anterior chamber cellular infiltration and retinal vasculitis. CONCLUSION:T-cell vitreoretinal lymphoma is rare, and diagnosis can be challenging. Despite inconclusive cytology in this case, interphase fluorescence in situ hybridization detected a JAK2 gene rearrangement, which confirmed the involvement by indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and prompted appropriate treatment and workup for recurrent systemic or central nervous system lymphoma.

Objective To investigate the frequency and clinical features of intraocular paraneoplastic sarcoid-like reaction (SLR) in patients with chronic lymphocytic leukemia (CLL). Methods Retrospective review of patients with CLL from January 1, 1980, to December 31, 2020. Eye examinations were searched for 22 keywords suggestive of SLR, and charts were manually reviewed. Results Of 4209 unique patients with CLL, 1021 (24%) had at least 1 eye examination on record, and 324 (8%) had 1 or more keyword eye examination findings. After manual review, 12 patients (<1%) were identified as having probable SLR with characteristic features (n = 7), possible but not classic (n = 1), or suspect but less likely (n = 4). All patients (n = 8) with probable or possible SLR were White, and half (n = 4) were male. Intraocular SLR was diagnosed a mean of 49.7 months after the CLL diagnosis (n = 7) or preceded the CLL diagnosis by 1 month (n = 1). Involvement was bilateral in 5 patients, with 13 total affected eyes and mean presenting Snellen visual acuity of 20/50. Common characteristic features on initial examination included vitreous cell (n = 13), anterior-chamber cell (n = 10), keratic precipitates (n = 9), posterior synechiae (n = 6), chorioretinal lesions (n = 5), and vitreous haze (n = 5). Treatment included topical corticosteroids alone (n = 5), with sub-Tenon corticosteroids (n = 1), or with steroid-sparing immunosuppressive agents (n = 1) or oral corticosteroids alone (n = 1). After a mean follow-up of 19.8 months, final mean visual acuity was 20/30. Conclusion Intraocular SLRs affect fewer than 1% of patients with CLL. SLR should be on the differential diagnosis list for any CLL patient with ocular complaints, and most patients can be managed successfully with corticosteroids.

EDITORIAL article Front. Med., 24 November 2022Sec. Ophthalmology https://doi.org/10.3389/fmed.2022.1033817

To determine the frequency, characteristics, and clinical course of ophthalmic side effects associated with systemic BRAF inhibitor therapy. Medical records of patients taking BRAF inhibitors for the treatment of systemic malignances at Mayo Clinic, Rochester from 01/01/2010 to 08/30/2021, were retrospectively reviewed. Of 901 patients, 14 (1.6%) patients experienced an ophthalmic side effect. Mean age at presentation of the side effect was 60 years (median 59, range 50–80) and 11 (79%) were male. The most common side effect was uveitis in 7 (50%) patients, followed by dry eye in 4 (29%) patients, and central serous chorioretinopathy in 2 (14%) patients, with singular cases of cranial nerve VI palsy and conjunctival edema. A comparison between individual BRAF inhibitors (vemurafenib vs. dabrafenib vs. encorafenib) revealed that patients taking encorafenib had a shorter interval to any ophthalmic adverse event (mean 55.6 vs. 9.8 vs. 4.0 months, p = 0.03) and were the only patients to experience documented dry eye syndrome (DES) in this series. Outcomes were known in 13 (93%) patients, and ophthalmic adverse effects resolved or were controlled without discontinuing therapy in 10 (77%). Uveitis was successfully treated with topical corticosteroids in 4 patients, while 3 patients with refractory uveitis (2 with panuveitis and 1 with unspecified uveitis) required discontinuation of BRAF inhibitor therapy. Ophthalmic adverse events related to systemic BRAF inhibitor use are rare, with estimated frequency of 1.6%. Most events can be treated with local ophthalmic therapy. BRAF inhibitors provide life-saving therapy, and their discontinuation should be avoided.

OBJECTIVES:We aimed to estimate the risk of HCQ retinopathy and its risk factors among incident users in the community. METHODS:Using the Rochester Epidemiology Project, a record-linkage system, a cohort of incident users of HCQ was identified from 27 counties in the American upper Midwest. HCQ retinopathy was defined based on characteristic paracentral automated 10-2 visual field (10-2 AVF) defects and parafoveal retinal photoreceptor layer changes on spectral domain optical coherence tomography. Cumulative incidence rates were estimated adjusting for competing risk of death. Risk factors for HCQ retinopathy were examined using Cox models. RESULTS:The study included 634 incident HCQ users (mean age at initial HCQ use was 53.7 years, 79% females, 91% white). Most common indications for HCQ were RA (57%) and SLE (19%). The average follow-up length was 7.6 years. Eleven patients developed HCQ retinopathy (91% females, 91% white). The majority used HCQ for RA (91%). The cumulative incidence rate at year 5 was 0%, which increased to 3.9% (95% CI 2.0, 7.4) by 10 years. Taking an HCQ dose ≥5 mg/kg was associated with a hazard ratio (HR) of 3.59 (95% CI 1.09, 11.84) compared with lower doses. There was a 48% increase [HR 1.48 (95% CI 1.03, 2.14)] in the risk of HCQ retinopathy for each 100 g of HCQ cumulative dose. CONCLUSION:The risk of HCQ retinopathy at 10 years of use is lower compared with previous prevalence-based estimations. A dose ≥5 mg/kg was associated with higher HCQ retinopathy risk.