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Abstract
Aims This study aims to analyse peripapillary atrophy (PPA), its frequency, extent and relation with measures of visual function in patients with birdshot chorioretinitis (BSCR).
Methods Patients of the single-centre prospective COhort of patients with BIRDshot chorioretinitis (ClinicalTrials.gov Identifier: NCT05153057) were included. The areas of the optic nerve head (ONH) and PPA were measured on red–green and autofluorescence fundus images acquired by ultrawidefield retinal photography. The main outcome measure was the frequency of PPA. Correlations between the PPA/ONH ratio and disease duration, age, best corrected visual acuity (BCVA) and visual field results (mean deviation (MD) and the pattern SD (PSD)—Humphrey perimeter 30–2) were evaluated using the Spearman coefficient.
Results A total of 752 eyes from 384 patients (mean age 62.4±12.1 years) were included. The median disease duration was 13.0 (7.0–19.0) years. PPA was observed in 717 (95.4%) eyes. The mean PPA/ONH ratio was 2.9±2.2 on red–green images, 3.1±2.2 on autofluorescence, and these measures were highly correlated (R=0.95, p<0.0001). The ratio of PPA/ONH increased with the duration of the disease (R=0.57, p<0.0001) from 1.6±0.6 in the 0–5 years group to 5.2±2.9 after 25 years and with age (R=0.51, p<0.0001). PPA was also associated with a worse BCVA (R=−0.42, p<0.0001) and worse visual field results: MD (R=−0.41, p<0.0001), PSD (R=0.42, p<0.0001). A strong intereye symmetry of the PPA/ONH ratio was observed (R=0.91, p<0.0001), which was greater than that of BCVA (R=0.58, p<0.0001), MD (R=0.76, p<0.0001) or PSD (R=0.70, p<0.0001).
Conclusions Almost all patients with BSCR exhibit PPA and its extent increases over time. PPA is associated with poorer vision.
- Uveitis
- Optic Nerve
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Birdshot chorioretinitis (BSCR) is a rare posterior uveitis with well-defined criteria which include multifocal choroidal lesions.
WHAT THIS STUDY ADDS
Peripapillary atrophy is almost constantly observed in patients with BSCR, especially in the later stages of the disease.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Peripapillary atrophy can be used as a marker of disease progression in BSCR and could be a supportive finding for its diagnosis.
Introduction
Birdshot chorioretinitis (BSCR) is a rare form of posterior uveitis that affects only the eye. Four decades after its initial description,1 BSCR is now well defined with precise diagnostic and classification criteria.2 This disease is almost exclusively observed in patients of European descent and accounts for about 7% of posterior uveitis in series from Europe or North America.3 BSCR is a model disease by its association with a human leukocyte antigen (HLA) class I antigen: almost all patients—if not all according to many investigators—are HLA-A29 carriers.4 5 The diagnosis of BSCR is usually based on the observation of multifocal, cream-coloured or yellow-orange, bilateral, choroidal, oval or round, ‘birdshot spots’.6 Diffuse hypofluorescent spots may also be seen on indocyanine green angiograms.7 Two pathological case studies suggest that the birdshot spots correspond to non-granulomatous lymphocytic infiltrates in the choroid and the ciliary body, with foci of lymphocytes in the deep choroid, the optic nerve head (ONH) and along the retinal vasculature.8 9 Clinically, beyond the spots, the features of the disease include in a variable manner retinal periphlebitis, macular oedema and papillitis. The manifestations of BSCR vary from one patient to another and over the course of the disease.10 Although peripapillary atrophy (PPA) does not belong to the list of characteristics usually described with BSCR, in one series of 21 cases it has been previously observed in 90% of patients.11 Yet, to our knowledge, PPA has not been the object of a specific assessment in a large cohort of patients with BSCR, nor has its correlation with clinical parameters been analysed. Hence, our goal has been to assess the frequency and the extent of PPA in patients with BSCR using the data from our prospective cohort study. Our secondary objectives were to analyse how PPA varied over the course of the disease and whether it was correlated with the results of visual acuity and visual field (VF) testing.
Methods
This study was based on data from the COhort of patients with BIRDshot chorioretinopathy (CO-BIRD, Identifier: NCT05153057), which was conducted at a single institution (Hôpital Cochin, Paris, France). This prospective study, launched in 2002 and still ongoing, involves patients who are offered a yearly standardised evaluation. Our data collection methods have been previously reported.12–14 The disease diagnosis was based on the criteria defined by an International Consensus Conference and further confirmed by the Standardization of Uveitis Nomenclature group.3 HLA-A29 positivity was an additional inclusion requirement for all the study patients. For every patient, we analysed the data from the last visit. The disease duration was approximated by the time elapsed since the first symptoms. The main outcome measure was the area of the PPA in patients with BSCR. The areas of the ONH and PPA were measured using either red–green or autofluorescence images acquired by ultrawidefield retinal photography (Optos Silverstone, Optos PLC, Dunfermline, UK). Two observers (TFdM and AE) performed the measurements. The ONH and PPA areas were measured using the Optos viewer tools, expressed in square millimetres and used to calculate the PPA/ONH ratio (figure 1). Other causes of PPA unrelated to BSCR (tilted disc syndrome or myopia greater than −6 D) were recorded. Low-quality images resulting from advanced cataracts or other causes of media opacity and retinographies acquired from a system other than the Optos imager were excluded, as well as high-grade papillitis that impeded the precise delineation of the ONH area.
Peripapillary atrophy in patient with birdshot chorioretinitis. (A) Optomap ultrawidefield red–green image. (B–E) Focus on peripapillary atrophy (PPA). (B) Optomap ultrawidefield red–green image. (C) Optomap sensory red-free image. (D) Optomap autofluorescence image. (E) Measurements of PPA (encircled in green) and optic nerve head areas (encircled in red) on optomap red–green image.
In case of extreme PPA, a ratio value of 9 was attributed and a sensitivity analysis was performed to assess the potential introduction of a bias. In this study, the assessment of the visual function was based on visual acuity and VF results. The best corrected visual acuity (BCVA) was measured with a decimal scale, converted for the purpose of data analysis to the logarithm of the minimum angle of resolution and was treated as a continuous variable. The VF testing was performed using automated perimetry (Humphrey VF analyser—Zeiss-Humphrey, San Leandro, California, USA; with the Fastpac full-threshold 30–2 programme) and the mean deviation (MD) and the pattern SD (PSD) were recorded. In patients with advanced VF defects for whom automated perimetry could not be performed, Goldmann perimetry was used and for the study purposes the MD was entered as −30 dB as previously reported.10 Subsequently, another sensitivity analysis was performed to assess the potential introduction of a bias. To this end, every analysis was repeated after excluding the eyes for which MD was recorded as −30 dB.10 The descriptive data are presented as the mean±SD and median with the IQR for continuous variables, and as counts with percentages for categorical variables. Furthermore, correlation analyses were conducted to assess the relationship between PPA/ONH ratio and the following variables: time elapsed since the first symptoms, age, BCVA, MD and PSD. The normality of distributions was assessed graphically and using the Shapiro-Wilk test. Due to a non-normal distribution, a Spearman’s rank correlation coefficient was calculated for the relationship between two variables. The Kruskal-Wallis test was used to compare the mean and median PPA/ONH areas ratio between groups separated by disease duration. Mann-Whitney test was used to compare PPA/ONH areas ratio between two groups. A multivariate analysis of PPA/ONH areas ratio controlling for age and disease duration was performed using multiple linear regression. The statistical analyses, tables and figures were performed using GraphPad Prism V.7 (Prism, San Diego, California, USA). Multiple linear regression modelling was generated using Seaborn Python data visualisation library.15 Statistical significance was determined at a p value of 0.05.
Results
Of 488 patients (976 eyes) included in the CO-BIRD study, the images from 384 patients (752 eyes) were available for the study purposes and 120 patients (224 eyes) were excluded: 101 patients (202 eyes) due to retinography being performed with an imaging system other than Optos and 19 patients (22 eyes) due to low-quality images caused by cataract or keratopathy. Additionally, two patients (three eyes) had a high-grade papillitis which prevented the surface of the ONH from being precisely delineated. Table 1 summarises the demographic features and the measurements of visual function of all patients at the time of their last visit. The study included 156 (40.7%) men and 228 (59.3%) women. The mean age of the patients at the time of imaging for the study was 62.4±12.1 years. The median time elapsed since the first symptoms was 13.0 (12.0) years. The mean BCVA was 0.8±0.3. The median MD was −3.5 dB (−7.0) and the median PSD was 3.3 (4.0). Six eyes (0.8%) presented PPA due to other causes, such as tilted disc syndrome or high myopia. The patients’ age was strongly correlated to the disease duration (R=0.61, p<0.001) (online supplemental figure 1).
Supplemental material
Participant demographics and visual function parameters
The results of the analyses of the PPA are shown in figure 2. The mean ONH area was 2.3±0.5 mm2 and the median 2.2 mm2 (1.0). The mean PPA/ONH areas ratio measured on red–green images was 2.9±2.2 and the median 2.1 (1.8). The mean PPA/ONH ratio measured on autofluorescence image was 3.1±2.2 and the median 2.3 (1.8). In our BSCR cohort, 717 eyes from 360 patients had PPA defined by a PPA/ONH ratio greater than 1. This resulted in a prevalence of 95.4% of eyes and 93.8% of patients (figure 2A). The Spearman coefficient was used to investigate the correlation between the PPA/ONH ratios measured on red–green imaging and autofluorescence imaging. A very strong correlation was found (R=0.95, p<0.0001), allowing us to use only the data from red–green images for the other correlation tests (figure 2B).
Assessment of peripapillary atrophy in our cohort of patients with birdshot chorioretinitis (BSCR). (A) Quantification of peripapillary atrophy (PPA) using two imaging modalities (Optomap red–green (RG) and autofluorescence (AF)). (B) Correlation analysis of PPA assessment measured using two imaging modalities (AF and RG). ONH, optic nerve head.
To explore the clinical relevance of PPA measurements in patients with BSCR, we performed correlation tests between the PPA/ONH ratio and different clinical and demographic parameters (figure 3). First, the PPA/ONH ratio was significantly correlated with the time since the first symptoms (R=0.57, p<0.0001), which was used to approximate the disease duration. This ratio was also significantly correlated with age (R=0.51, p<0.0001). Of the 384 study patients, 360 (93.8%) had PPA in both eyes and 13 (3.4 %) patients had PPA in only one eye. The mean disease duration in patients with unilateral PPA was 6.9±6.6 years, which was shorter than the 14.1±8.2 years recorded in patients with bilateral PPA (p=0.001). The PPA/ONH ratio was also correlated with the BCVA (R=0.42, p<0.0001), the MD (R=0.41, p<0.0001) and the PSD (R=0.42, p<0.0001). A multiple linear regression analysis showed that the disease duration had a greater impact on the PPA/ONH ratio than age (p<0.0001) (online supplemental figure 2). To determine whether PPA evolves with the duration of the disease, we grouped patients according to the time elapsed since the first symptoms. The PPA/ONH ratio increased significantly between the different disease duration groups (p<0.0001) (table 2). In patients with a disease duration of 0–5 years, the mean PPA/ONH ratio was 1.6±0.6, while it increased to 4.4±2.8 in patients with 21–25 years of disease duration. No additional significant progression of PPA was observed in the 31 patients with a disease duration of more than 25 years (online supplemental figure 3).
Correlation of peripapillary atrophy (PPA) with demographic and clinical parameters. Time since the first symptoms (A), age (B), best corrected visual acuity (BCVA) (C), mean deviation (MD) (D) and pattern SD (PSD) (E). ONH, optic nerve head.
PPA/ONH ratio according to disease duration
To assess whether a patient’s age at disease onset influenced PPA, we carried out a targeted analysis on patients whose disease duration was between 16 and 20 years (online supplemental table 1). Within this group, there were no significant differences between patients whose disease onset was before the age of 50 (median PPA/ONH was 2.6 (1.7)) and those whose disease onset was after this age (median PPA/ONH 3.0 (2.6)) (p=0.23). Figure 4 illustrates the intereye symmetry of PPA, BCVA, MD and PSD in our cohort of patients with BSCR. The PPA/ONH ratio showed more symmetrical results (Spearman R=0.91, p<0.0001) compared with BCVA, MD or PSD which had lower Spearman’s R coefficients: 0.58 for BCVA, 0.76 for MD and 0.70 for PSD (p<0.0001).
Intereye symmetry of peripapillary atrophy (PPA)/optic nerve head (ONH) ratio and visual function parameters in patients with birdshot chorioretinitis (BSCR). Scatterplots illustrating the correlation between PPA/ONH ratio (A), best corrected visual acuity (BCVA) (B), mean deviation (MD) (C) and pattern SD (PSD) (D) values of the right (OD) and left eye (OS).
Discussion
We observed PPA in 94% of the patients with BSCR, an almost constant finding in the later stages of the disease. The frequency and the extent of PPA increased with age and disease duration, with a significantly greater impact of the later. Larger areas of PPA were associated both with worse visual acuity and VF results. Furthermore, the area of PPA was more symmetrical than BCVA, MD or PSD. The mechanism leading to PPA in BSCR remains to be understood. It could be linked to chronic leakage around the disk from papillitis, but also from a privileged localisation of lymphocytic infiltrates in the choroidal area adjacent to the disk.16–18 In a previously published multimodal imaging study of 21 patients with BSCR, PPA had already reported to be observed in 90% of cases.11 PPA is found in different diseases such as high myopia, glaucoma or in normal ageing. In myopia and glaucoma, PPA takes more often the form of a temporal crescent of atrophy and consists mainly of β-zone type atrophy.19 20 Khodeiry et al characterised the microstructure of the PPA in patients with BSCR using OCT and observed that it resulted from thinning and interruption of the RPE and Bruch’s membrane corresponding mainly to an α-zone component, unlike in glaucoma or myopia.16
Although our results are based on the analysis of a large number of patients with BSCR, our study has some limitations. We did not evaluate the rate of progression of PPA in each patient, nor the prevalence of PPA at the time of diagnosis. Because of the lack of a clear onset of the disease in many patients and because the diagnosis is often delayed, we used the patients’ reported onset of their symptoms to approximate disease duration. We used a manual delineation method to quantify the PPA area. Two observers contributed to this delineation and the concordance of the measures was verified on test series before the analysis of the full cohort. In the future, automated delineation methods will probably become available and will allow us to measure PPA at each visit and analyse individual rates of progression.21 Studies of PPA in glaucoma or myopia have either used fundus colour images or autofluorescence22 23; we used both methods and obtained similar results with either. We observed a strong intereye symmetry of PPA both in patients with a recent diagnosis of BSCR and in those with a longstanding disease. The strong correlation between PPA and the duration of the disease suggests that it could be used as marker for the evolution of the disease, as illustrated in online supplemental figure 4. When comparing the effects of age and disease duration on the extent of PPA, disease duration was more closely associated with the area of PPA. While some patients are diagnosed shortly after the onset of their first symptoms such as floaters, others seek medical attention much later due to a preserved visual acuity until late in the disease.24 In those patients, PPA can indicate a longstanding condition that may have been neglected before the diagnosis of BSCR. Although the recall of the date of a patient’s first symptoms might be imprecise, we used these data to estimate the duration of the disease. Assessing whether some treatment methods influenced PPA was beyond the scope of this study. Our study lacked an aged-matched control group, which would have allowed us to estimate the prevalence and extent of PPA in the general population. In addition, we included patients who had other factors for PPA, such as high myopia or tilted discs, but they accounted for less than 1% of all patients. Whereas the BSCR spots are often more clearly visible in the nasal inferior quadrant, our study did not explore which quadrant of the peripapillary area was more likely to be affected by atrophy and how this might affect the pattern of VF loss.
Because PPA was observed in almost all patients, it could be useful in distinguishing BSCR from sarcoidosis, particularly in cases where choroidal granulomas mimic birdshot spots online supplemental figure 5. Moreover, spots can become difficult to observe over time as they become confluent or disappear in some cases of remission.25 In these cases, where the spots are only faintly seen or no longer visible, persistent PPA can serve as an indirect marker—although not specific—pointing to BSCR. Furthermore, while the birdshot spots may sometimes only be detected by indocyanine green angiograms, PPA can be directly assessed through a fundus examination. Overall, the results from our study suggest that PPA is a strong marker of disease progression in BSCR and could be a supportive finding for the diagnosis of BSCR.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
Our observational study was approved by the 'Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale’ (ethics approval ID 00011558) and maintained adherence to the Declaration of Helsinki for research involving human subjects. Participants gave informed consent to participate in the study before taking part.
References
Footnotes
Contributors Research conception and study design: TFdM, DM and AB. Data acquisition and research execution: TFdM, AE, SK, LI and AB. Data analysis and interpretation: TFdM, JT and AB. Manuscript preparation: TFdM, AE, JL, JT and AB. Guarantor: AB.
Funding The 'Association d’Ophtalmologie Cochin' contributed to the funding of this study (Grant number: 0005-2024). Dr. Thorne received funding (Grant number: 0001-2024) from the Birdshot Research Fund, Wilmer Eye Institute, Johns Hopkins
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.