Fundus diseases represent a leading cause of blindness worldwide (Li et al., 2023; He et al., 2023) The comprehensive evaluation of these conditions—encompassing retinal vascular diseases, chorioretinitis, retinal degenerative diseases, macular diseases, and optic nerve disorders—is crucial for accurate diagnosis, management, and monitoring of disease progression (Noh et al., 2023; Yu et al., 2025; Ji et al., 2023). Fluorescein angiography (FA) has been widely regarded as the gold standard imaging modality for assessing retinal and choroidal circulation (Ahmed et al., 2021; Hans et al., 2022). Conventional FA, which involves intravenous FA (IVFA), provides dynamic visualization of blood flow, vascular leakage, and pathological changes (Bulson and Faridi, 2017; Chen et al., 2022). However, IVFA is associated with potential side effects ranging from transient nausea and vomiting to rare but severe anaphylactic reactions (Ebrahimiadib et al., 2023; Hitosugi et al., 2004; Kornblau and El-Annan, 2019; Su et al., 2012). Furthermore, traditional FA has a limited field of view, typically capturing a limited area of the posterior pole, thereby missing peripheral retinal pathology that is critical in many retinal diseases (Temkar et al., 2019; Manivannan et al., 2005). Recent technological advancements have led to the development of ultra-wide-field (UWF) imaging systems, which have revolutionized retinal assessment. These systems enable comprehensive visualization of up to 200^o field of the retina, including the far periphery, facilitating the detection of peripheral pathologies that were previously difficult to document (Lip et al., 2020; Tsui et al., 2013; Friberg et al., 2008). The integration of UWF imaging with FA has significantly enhanced our ability to evaluate a wide spectrum of retinal diseases.

Orally administered fluorescein angiography (oral FA) combined with ultra-wide-field imaging represents a significant innovation in retinal imaging. This technique involves oral administration of fluorescein dye followed by UWF imaging to provide detailed visualization of retinal vasculature and pathology (Marziali et al., 2022; Manoharan et al., 2017). Compared to conventional IVFA, oral FA offers several potential advantages: reduced risk of adverse reactions associated with intravenous injection, improved patient comfort and acceptance (particularly in pediatric populations and needle-phobic individuals), and the logistical simplicity of avoiding venipuncture. While the application of IVFA with UWF imaging for evaluating various fundus disorders has been well documented, studies focusing on oral FA remain limited. Previous studies have primarily explored this technique in pediatric populations (Elhusseiny et al., 2023; Marmoy et al., 2022), with few reports systematically evaluating its utility across a broad age spectrum or comparing its performance across different retinal disease categories. Furthermore, comprehensive assessments of image quality, circulation timing, and safety profiles of oral FA in diverse patient populations are lacking.

This study aims to systematically evaluate the clinical utility of oral FA by: 1) Assess whether oral FA provides diagnostic image quality comparable to that of IVFA across a broad spectrum of fundus diseases; 2) Evaluate its feasibility and performance across different disease categories and age groups; 3) Document the pharmacokinetic profile of oral FA, including circulation time and phase visualization; 4) Determine the safety of oral FA. By systematically analyzing these objectives, we seek to establish the clinical utility and limitations of oral FA and provide evidence for its potential role as a viable alternative to conventional IVFA in the management of ocular diseases.

Fluorescein angiography (FA) is a key technique for diagnosing retinal diseases (Lv et al., 2023). However, the risk of severe allergic reactions associated with IVFA remains a significant concern in clinical practice (Occhiutto et al., 2012; Ghaleb et al., 2025). Oral FA substantially reduces this risk, yet its widespread application has long been limited by perceived poor image quality (Jiang et al., 2022; Nayak and Ghose, 1987). This study, utilizing ultra-wide-field scanning laser ophthalmoscopy and an appropriate dose of sodium fluorescein, systematically evaluated the image quality, circulation time, and safety of oral FA across different age groups and various retinal diseases. The results demonstrate that oral FA is suitable not only for children but also generates high quality, diagnostically valuable images in adult and elderly patients, serving as a safe, effective, and convenient alternative to IVFA.

Previous research on oral FA has primarily focused on pediatric populations, especially preschoolers and school-aged children (Yamao et al., 2021; Conner et al., 2023; Ling et al., 2022). This is mainly due to lower acceptance and poorer cooperation with venipuncture in children, whereas the oral route is more readily accepted by both young patients and their parents. For instance, Yamao et al. showed that oral FA combined with ultra-wide-field imaging effectively evaluated key findings such as the foveal avascular zone (FAZ) and neovascularization in children (Yamao et al., 2021). Although Hara et al. demonstrated the feasibility of oral FA in 1787 patients, systematic subgroup comparisons were not performed (Hara et al., 1998). However, these studies lacked systematic evaluation in adult and elderly populations. Our study enrolled 382 patients (676 eyes), covering a wide age range from 4 to 83 years, and performed stratified analysis based on age and disease type, addressing the shortcomings of previous studies with a single population and inadequate stratification. It not only confirmed the advantages of oral FA in children but also, for the first time, systematically compared image quality and circulation characteristics in adult and elderly patients, expanding the applicable scope of oral FA.

This study shows that high quality angiograms can be obtained with oral FA in the vast majority of cases. Overall, 374 out of 382 cases (662 out of 676 eyes) were classified as high quality. Clinically useful images were obtained in 381 cases (99.7%), with only one case yielding low-quality images due to vitreous hemorrhage. When stratified by age, no statistically significant differences were found in the average image quality scores among the different age groups (P > 0.05), suggesting that oral FA maintains stable image quality across all age ranges. This finding is important considering that earlier studies focused predominantly on pediatric populations and rarely included adults or the elderly. When grouped by disease type, all groups maintained high image quality scores, yet a statistically significant difference was observed between retinal vascular diseases and retinal degenerative diseases. This discrepancy may be related to different pathological and physiological changes in various diseases. Retinal degenerative diseases, such as retinitis pigmentosa, are primarily characterized by a progressive loss of photoreceptors and retinal pigment epithelium (RPE) (Viktoria et al., 2023; Xiaoqian et al., 2022). This often leads to attenuation of retinal vessels and widespread RPE atrophy. The subsequent reduction in both vascular density and the masking effect of the RPE may result in a clearer, higher-contrast angiographic image, as the fluorescent dye circulates through a less crowded and less obscured vascular bed. Conversely, retinal vascular diseases, including diabetic retinopathy and retinal vein occlusions, are frequently associated with pathological changes that directly impair image clarity. Media opacities such as vitreous hemorrhage, intraretinal edema, and hard exudates can scatter and attenuate the fluorescent signal. Furthermore, the presence of extensive capillary dropout or non-perfusion can reduce the overall fluorescence intensity in large areas of the retina. These factors collectively contribute to the relatively lower, though still diagnostically adequate, image quality scores in this category. Previous oral FA studies (Conner et al., 2023; Ling et al., 2022), limited primarily to children, could not perform such cross-disease comparisons. Therefore, our data provide new insights into the performance of oral FA across different patient populations.

This study also systematically recorded three key time points after oral fluorescein administration: first appearance time, detailed visualization time, and optimal visualization time. The results showed no statistically significant differences in these time points among the different age groups (P > 0.05). This indicates that even in elderly patients, the absorption and circulation of fluorescein have not shown significant delay, further supporting the feasibility of oral FA across the entire age spectrum. Among disease groups, the optic nerve diseases group had the shortest circulation times at all phases, while the retinal vascular diseases group was slightly longer, possibly related to the fact that the latter often accompanies blood circulation disorders. However, no statistical differences were reached between groups, indicating stable pharmacokinetic characteristics of oral FA across different retinal diseases.

Compared to IVFA, oral FA has several advantages. Firstly, the incidence of adverse reactions to oral FA is usually lower than that of IVFA (Garcia et al., 1999; Kelley and Kincaid, 1979; Watson and Rosen, 1990). No serious adverse events have been reported in previous oral FA studies (Barteselli et al., 2013; Kwan et al., 2006). For example, Hara et al. assessed the safety of oral FA in 1787 patients and found only 31 (1.7%) experienced minor symptoms like itching or nausea, with no severe adverse reactions observed (Kelley and Kincaid, 1979). In our study, mild adverse reactions occurred in 8 patients (2.1%), including 2 cases of mild rash and 6 cases of nausea, all of which resolved spontaneously within 1 hour. No severe allergic reactions were observed. Notably, 6 patients in this study had a history of fluorescein allergy, but no adverse reactions were observed after taking oral FA, further demonstrating the safety of oral FA. Compared to IVFA, oral FA significantly reduces the risk of allergies, especially suitable for patients with a history of allergies. Secondly, oral FA does not require needle venipuncture, making it more acceptable to patients, especially minors. In this study, all minor patients completed the oral FA and obtained high quality contrast images. Therefore, oral FA is suitable for patients who cannot tolerate venipuncture or cannot cooperate, especially pre-school and school-age children.

Despite its advantages, oral FA has certain limitations. First, it struggles to capture images of the early ocular circulation phases, such as the arterial phase. In this study, the arterial phase was absent in almost all cases. The slower rise in plasma sodium fluorescein concentration after oral administration compared to intravenous injection nearly prevents the capture of early retinal arterial perfusion. This makes oral FA less suitable for conditions requiring observation of early retinal vascular filling, such as central retinal vein occlusion. However, for most retinal diseases, including diabetic retinopathy, uveitis, and macular diseases, it provides sufficient diagnostic information. Second, the bitter taste of the sodium fluorescein solution may be difficult for some patients to tolerate, potentially preventing successful ingestion. Mixing the dye with sugar or fruit juice can help improve its taste.

This study also has several limitations. First, although the sample size is larger than in previous studies, the number of cases in certain subgroups (such as the optic nerve diseases) remains relatively small. This may limit the statistical power to detect subtle differences in image quality or circulation timing within these specific disease categories. Future studies with larger, more balanced cohorts are needed to confirm these subgroup findings. Second, while we included a broad spectrum of fundus diseases, certain rare or complex conditions may not have been sufficiently represented. Expanding the range of diseases in future investigations would help to further validate the generalizability of oral FA in diverse clinical scenarios. Third, this was a single-center study and the findings may be influenced by local patient demographics, equipment-specific factors, or institutional practices. Further multi-center studies involving diverse geographic and clinical settings would help to corroborate our results and strengthen the external validity of oral FA as a widely applicable diagnostic tool.

Oral FA is a safe, well-tolerated, and clinically effective imaging modality for evaluating retinal diseases across different age groups. Our results confirm its utility not only in children but also in adults and the elderly. The ability to obtain high quality, diagnostically adequate images without the need for intravenous access makes oral FA a promising alternative to conventional IVFA, particularly in settings where patient comfort, safety, and resource efficiency are prioritized. In summary, our study systematically validates the safety and applicability of oral FA across different ages and diseases in a large cohort, demonstrating its promise as a viable alternative to IVFA for specific populations such as pediatric, needle-phobic, or allergy-prone patients.