Report Peripheral Vascular Leakage in Uveitis: Clinical and Angiographic Findings Ultra-widefield fluorescein angiography (UWF FA) has improved our ability to detect peripheral vascular abnormalities such as peripheral vascular leakage (PVL) in patients with uveitis.1,2 Although Campbell et al2 reported in a single center, nonconsecutive, prospective case series that the use of UWF FA changed management of patients with posterior uveitis, the prevalence of PVL on UWF FA using scanning laser ophthalmoscope technology in uveitis, and its association with other clinical and angiographic features, has not been published previously. To lay the foundation for future prospective evaluations, the purpose of this project was to report the prevalence of PVL in patients with uveitis, by anatomic disease classification, and association of PVL with disease stability and with other angiographic and clinical features. We performed a retrospective chart review of all uveitis patients imaged with the Optos P200 UWF FA system between November 8, 2012, and January 15, 2014, at the Casey Eye Institute, which represented nearly every intermediate, posterior, retinal vasculitis, and panuveitis patient who underwent FA during that time period (as well as the few with anterior uveitis who received an FA). Chart review was performed to identify the S.U.N. uveitis classification, presence of cystoid macular edema (CME), and assessment of disease stability.3 For the purposes of this analysis of UWF FA, we separated patients with isolated retinal vasculitis into their own category (defined as inflammatory vascular leakage and/or sheathing in the absence of choroidal or retinal lesions). Overall clinical assessment was recorded in a binary fashion as either stable (the patient required no additional therapeutic intervention), or “clinically active” (the patient required new or additional therapy). Early and late FA images were evaluated in a standardized, masked fashion by 2 graders (N.V.P., J.T.B) for PVL, diffuse vascular leakage, CME, and optic disc leakage (ODL), grading each as present (1) or absent (0). Discordant grades were adjudicated by a third masked grader (J.P.C.). Figure 1 (available at www.aaojournal.org) displays 2 representative sets of early and late UWF FA images from the dataset. Statistical comparisons were performed using the “prtest” function (for 2-group proportion test), and the logistic function (for univariate and multivariate logistic regression) in Stata v 11.0 (StataCorp, College Station, TX). Multivariate logistic regression was performed including all variables with unilateral association (P < 0.05). The Oregon Health & Science University Institutional Review Board approved this study and the research complied with all Health Insurance Portability and Accountability Act laws and the Declaration of Helsinki. We identified 103 uveitis patients who were imaged with the Optos P200 UWF FA during the study period (12 others were excluded owing to poor image quality). Six patients had anterior uveitis, 27 had intermediate (
anterior) uveitis, 60 had posterior or

panuveitis, and 10 had isolated retinal vasculitis. Table 1 displays the prevalence of PVL and other angiographic features by disease classification and disease stability, which was highest in intermediate uveitis and isolated retinal vasculitis. We observed a higher prevalence of PVL in patients who were felt to be “clinically active” (57%) versus those with well-controlled disease (24%; P ¼ 0.001). However, this demonstrated a significant minority of patients in whom clinicians tolerated a degree of vascular leakage. These trends persisted in nearly every subgroup. Table 2 (available at www.aaojournal.org) displays multivariable logistic regression of angiographic features associated with determination of clinical stability, as well as factors associated with the presence of PVL. Every angiographic feature (PVL, diffuse vascular leakage, CME, ODL) and OCT CME was associated with the decision to escalate therapy, and they were highly correlated, with only OCT CME remaining significant in multivariable logistic regression. Peripheral vascular leakage was associated with ODL, CME, and OCT CME, with ODL and angiographic CME remaining significant in multivariable regression. In summary, we observed that PVL varies by uveitis classification and correlates strongly with other angiographic and clinical features of disease activity. The strength of this study is the rigorous and systematic evaluation of the presence of PVL and the associated clinical features with independent masked examiners, but it is limited by its retrospective design. Although it is interesting to speculate that UWF FA and the presence of PVL may change clinical practice, it is more important to determine how and when it ought to do so, and this remains to be proven.1,2,4 It is clear that PVL alone may not be clinically significant; Orlin et al5 reported finding PVL in patients with white without pressure without any other known retinal disease. However, we show that PVL is associated with vision-threatening complications, including CME, and prospective trials in uveitis may demonstrate that PVL is a modifiable risk factor for incident CME (and vision loss) and merits aggressive treatment. We advocate for the design, funding, and multicenter participation in larger prospective studies to determine the true prevalence of angiographic findings in each uveitis classification, time-dependent associations of PVL with other signs of disease activity, and ultimately whether these findings uniquely merit clinical attention by improving patient outcomes.

JOHN P. CAMPBELL, MD, MPH1,2 ROBERT M. BEARDSLEY, MD3 NEAL V. PALEJWALA, MD1 JUSTIN T. BAYNHAM, MD1 WONCHON LIN, MD4 ERIC B. SUHLER, MD, MPH1,5 JAMES T. ROSENBAUM, MD1,6 CHRISTINA J. FLAXEL, MD1 PHOEBE LIN, MD, PHD1

1

Ophthalmology Volume -, Number -, Month 2015 Table 1. Prevalence of Ultra-widefield Fluorescein Angiographic Features as Determined by Masked Examiners, by Disease Classification and Clinical Assessment of Disease Stability Population

PVL, n (%)

DVL, n (%)

CME, n (%)

ODL, n (%)

All uveitis (n ¼ 103) Clinically active (n ¼ 62) Stable (n ¼ 41) P Anterior uveitis (n ¼ 6) Clinically active (n ¼ 1) Stable (n ¼ 5) Intermediate uveitis (n ¼ 27) Clinically active (n ¼ 21) Stable (n ¼ 6) Posterior or panuveitis (n ¼ 60) Clinically active (n ¼ 35) Stable (n ¼ 25) Retinal vasculitis (n ¼ 10) Clinically active (n ¼ 5) Stable (n ¼ 5)

45 (44) 35 (57) 10 (24) 0.002 0 (0) 0 (0) 0 (0) 17 (63) 14 (67) 3 (50) 22 (37) 17 (49) 5 (20) 6 (60) 4 (80) 2 (40)

26 (25) 17 (27) 6 (15) 0.05 1 (17) 1 (100) 0 (0) 8 (30) 6 (29) 2 (33) 16 (27) 13 (37) 3 (12) 2 (20) 1 (20) 1 (20)

40 (39) 30 (49) 8 (20) 0.002 1 (17) 0 (0) 1 (20) 16 (59) 14 (67) 2 (33) 20 (33) 16 (46) 4 (16) 3 (30) 2 (40) 1 (20)

46 (45) 30 (49) 8 (20)