U veitis associated with demyelinating diseases, particularly multiple sclerosis (MS), most frequently presents as an intermediate uveitis or pars planitis. ^,,, This subset of ocular inflammation follows a chronic, indolent course that often results in cumulative structural complications such as chronic cystoid macular edema, epiretinal membrane (ERM), and secondary neovascularization. Recent epidemiological updates from 2025 indicate that the burden of MS-associated uveitis is significant and increasing, necessitating more precise monitoring strategies.

Clinicians traditionally monitor disease activity via slit-lamp biomicroscopy and binocular indirect ophthalmoscopy, utilizing the Standardization of Uveitis Nomenclature (SUN) working group criteria for anterior chamber (AC) and vitreous inflammation. Recently, the SUN Working Group has also proposed specific classification criteria for MS-associated intermediate uveitis to distinguish this entity from idiopathic pars planitis based on the underlying demyelinating etiology. Yet, clinical examination alone is limited by subjective grading and may fail to detect peripheral retinal vascular inflammation that can be identified on fluorescein angiography (FA).

In noninfectious posterior uveitis and retinal vasculitis cohorts, ultrawidefield FA (UWF-FA) has shown that subclinical peripheral retinal vascular leakage frequently persists despite the apparent absence of AC and vitreous cells. ^, Leder et al found that UWF-FA detected disease activity not visible on clinical exam, prompting management changes in 51% of patients with noninfectious retinal vasculitis. This evidence supports a role for angiographic findings in monitoring and treatment strategies, though both studies acknowledge the uncertain clinical significance of this subclinical angiographic activity.

Longitudinal data on the prevalence, persistence, and clinical significance of subclinical peripheral vascular leakage specifically in demyelinating disease-associated uveitis remain limited. This population has chronic intermediate uveitis and is relatively homogeneous, unlike the heterogeneous uveitis and retinal vasculitis cohorts studied in prior UWF-FA research. It is therefore unclear whether the high rates of subclinical leakage seen in mixed populations are similarly prevalent or carry the same implications in demyelinating uveitis. This study primarily examines cross-sectional associations between clinical examination, optical coherence tomography (OCT), and UWF-FA findings, while also describing longitudinal trends in a subset of eyes with serial imaging.

The protocol of this retrospective study was approved by the Institutional Review Board (IRB) at the University of Virginia. The requirement for informed consent was waived due to the retrospective nature of the study, and all data were handled in accordance with the Declaration of Helsinki and the Health Insurance Portability and Accountability Act (HIPAA).

This retrospective study with cross-sectional and longitudinal components included patients with a confirmed diagnosis of a demyelinating disease (eg, MS, clinically isolated syndrome) and concurrent uveitis evaluated at a tertiary referral center. Data were collected from eyes at three distinct clinical timepoints: initial presentation (timepoint 1), the first acute uveitis flare (timepoint 2), and the most recent clinical encounter (timepoint 3). For patients who presented with active uveitis at their initial evaluation (9 patients, 30.0% of the cohort), the initial presentation and first acute flare were the same encounter. For these patients, data were recorded only at two timepoints: the initial flare and the most recent encounter. Among the remaining 21 patients (70.0%) who presented with inactive disease or had baseline quiescence documented prior to their first flare, three distinct timepoints were available for longitudinal analysis. The median total follow-up time from initial presentation to the most recent clinical encounter was 47.0 months (IQR [IQR]: 20.5-124.0 months). The median time elapsed between initial presentation and the acute flare was 53.0 months (IQR: 24.0-76.0 months), and between the acute flare and the most recent encounter was 26.0 months (IQR: 1.0-57.5 months).

AC and vitreous cells were graded using SUN Working Group criteria (0 to 4+). An acute uveitis flare was defined as a ≥2-step increase in AC or vitreous cell grade from baseline or new-onset inflammatory activity in a previously quiescent eye. Clinical remission and clinically inactive disease were defined as grade 0 AC cells, grade 0 vitreous cells, and no active retinal or choroidal lesions on clinical examination. In cases classified as panuveitis, any identified active posterior segment lesion precluded designation as clinically inactive disease at that encounter. Macular OCT was used to measure central subfield thickness (CST) and binary measures of intraretinal fluid (IRF), subretinal fluid (SRF), ERM, and macular atrophy (graded qualitatively as significant thinning of the inner or outer retinal layers or retinal pigment epithelium rarefaction). UWF-FA (Optos) was ordered either at the clinician’s discretion for suspicion of disease activity or as part of a routine 6-month angiographic screening protocol. Angiograms were graded by a single masked expert reader for the presence of vascular leakage in three distinct zones: Zone 1 defined the posterior pole (within 2 disc diameters of the fovea and 1 of the optic disc); Zone 2 extended to the anterior borders of the ampullae of the vortex veins; and Zone 3 extended to the ora serrata ( Figure 1 ). Leakage was scored in a binary fashion (present/absent) for each zone. The total anatomic burden of angiographic leakage was quantified using a 0 to 3 ordinal scale based on the number of zones involved. Angiographic quiescence was defined as the complete absence of detectable vascular leakage in Zones 1 to 3 on UWF-FA.

Ultrawidefield fluorescein angiography zones. Zone 1 defines the posterior pole (within 2 disc diameters of the fovea and 1 of the optic disc), Zone 2 extends to the anterior borders of the ampullae of the vortex veins, and Zone 3 extends to the ora serrata.

Primary and exploratory outcomes were defined prior to analysis. Primary outcomes included clinical measures (logMAR visual acuity, AC cells, and vitreous cells), OCT findings (CST, IRF, and SRF), and UWF-FA leakage. The primary objective was to evaluate the longitudinal relationship between these clinical and angiographic markers. To assess clinical-angiographic discordance, concurrent FA and clinical data obtained within the same encounter were directly compared. Exploratory analyses evaluated the progression of cumulative structural damage (ERM and macular atrophy). To account for the correlation between two eyes of the same patient and repeated measures over time, generalized estimating equations (GEE) with an exchangeable correlation matrix were used for binary and ordinal variables. GEE with an exchangeable correlation structure accounted for repeated measures and intereye correlation, permitting inclusion of eyes with either two or three timepoints. Linear mixed models with Bonferroni correction for pairwise comparisons were used for continuous variables (CST, logMAR visual acuity). To address potential ascertainment bias related to the retrospective nature of the imaging intervals, a comparative analysis of baseline characteristics between eyes that underwent FA during at least one monitored timepoint and nonimaged eyes was performed using Mann–Whitney U and Fisher’s exact tests. A sensitivity analysis utilizing GEE modeling was conducted on the restricted subset of eyes that underwent UWF-FA imaging across all three study timepoints. A P value <.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics, version 31.0 (IBM Corp.).