Purpose
To determine classification criteria for birdshot chorioretinitis.
Design
Machine learning of cases with birdshot chorioretinitis and 8 other posterior uveitides.
Methods
Cases of posterior uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the infectious posterior uveitides / panuveitides. The resulting criteria were evaluated on the validation set.
Results
One thousand sixty-eight cases of posterior uveitides, including 207 cases of birdshot chorioretinitis, were evaluated by machine learning. Key criteria for birdshot chorioretinitis included a multifocal choroiditis with (1) the characteristic appearance of a bilateral multifocal choroiditis with cream-colored or yellow-orange, oval or round choroidal spots (“birdshot” spots); (2) absent to mild anterior chamber inflammation; and (3) absent to moderate vitreous inflammation; or multifocal choroiditis with positive HLA-A29 testing and either classic “birdshot spots” or characteristic imaging on indocyanine green angiography. Overall accuracy for posterior uveitides was 93.9% in the training set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rates for birdshot chorioretinitis were 10% in the training set and 0% in the validation set.
Conclusions
The criteria for birdshot chorioretinitis had a low misclassification rate and seemed to perform sufficiently well for use in clinical and translational research.
I n 1980 Ryan and Maumenee described a new uveitic disease, birdshot chorioretinitis (BSCR), characterized by vitritis, multifocal choroiditis, and retinal vascular leakage with no to minimal anterior segment inflammation. The following year Gass described additional cases, which he called “vitiliginous chorioretinitis” owing to the appearance of the choroidal lesions. Clinically the choroidal lesions of BSCR are described as multifocal, cream-colored or yellow-orange, and ovoid. Histologically, BSCR is characterized by multifocal choroidal inflammation with mononuclear inflammatory cells and retinal vascular “cuffing.” Patients present with complaints of floaters, blurred vision, flashing lights, vibrating vision, loss of peripheral vision, and/or acquired nyctalopia. Vision is lost owing to either macular edema or diffuse retinal damage with photoreceptor loss. Given sufficient time, macular edema will occur in the majority of BSCR patients. The diffuse retinal damage manifests as visual field loss or an abnormal electroretinogram (ERG). Assessment of the peripheral visual field is important, as the earliest field loss is peripheral, manifested as a relative constriction on Goldmann perimetry or loss of peripheral field on relevant automated field testing (eg, the Humphrey P-60 program), which can be missed by automated perimetry sampling only the central 24 or 30 degrees of field. One study suggested that at presentation automated perimetry of the central field was abnormal in approximately one-third of patients, whereas an abnormal peripheral field was present in ∼75% of patients; and loss of peripheral field correlated with an abnormal ERG. This diffuse retinal damage can be monitored with either visual fields including the peripheral retina or ERG. , The choroidal lesions of BSCR may be hyperfluorescent on fluorescein angiography but often are not well delineated by this modality. Conversely, indocyanine green (ICG) angiography demonstrates the lesions as multifocal hypofluorescent spots and may detect the lesions better than clinical examination, especially early in the disease when the lesions seen on ophthalmoscopy may be difficult to discern. Fluorescein angiography often demonstrates vascular leakage. , Optical coherence tomography demonstrates the choroidal lesions, macular edema (when present), and disruption of the ellipsoid zone of the retina. Enhanced depth OCT imaging of the choroid demonstrates hyporeflective zones in ∼64% of patients. Fundus autofluorescence is abnormal (hypoautofluorescence) in 79% of eyes, and the most frequent finding is peripapillary confluent hypoautofluorescence in ∼73%. Even patients with good visual acuity may have decreased contrast sensitivity and decreased quality of vision. Among the various symptoms, nyctalopia is most associated with an impaired quality of life. ,
There is a strong genetic risk to BSCR, which is associated with the HLA type HLA-A29, with most studies reporting that ∼90%-95% of patients with BSCR are HLA-A29-positive. Early studies suggested that the association was with the subtype HLA-A29.2, but subsequent studies have reported cases that are HLA-A29.1-positive as well. Although HLA-A29 is a risk factor, BSCR is a complex disorder and not a Mendelian one. HLA-A29 is present in 7%-8% of the white population, , , and BSCR is a rare disease, accounting for only ∼7% of posterior uveitides, which themselves account for only ∼5%-20% of all uveitides. If one generously estimates that BSCR accounts for ∼1% of all uveitides in the United States, then the estimated prevalence is ∼1 in 100,000 population. The proportion of people who possess HLA-A29 that develop BSCR would then be estimated as ∼2-3 in 10,000. Hence other, unknown, environmental factors must contribute to the pathogenesis. Nevertheless, the reported occurrence of chorioretinal lesions in HLA-A29 transgenic mice suggests that HLA-A29 may be involved in pathogenesis in an as yet undetermined fashion, perhaps via aberrant antigen presentation.
Although the macular edema of BSCR responds to corticosteroid therapy, it typically relapses at doses of prednisone <15 mg/day, a dose too high for long-term use. , Conversely, immunosuppression is associated with an estimated ∼85% reduction in macular edema, suggesting that if treatment is needed, immunosuppression should be used from the outset. Short-term therapies do not prevent loss of visual field and ERG, , whereas immunosuppression can reverse visual field loss (although not always normalize it). , Intermediate-term studies suggest that immunosuppression of patients with BSCR has a high success rate including preserved acuity, improving (or normal) visual fields, and successful corticosteroid sparing (≤7.5 mg/day). ,
The Standardization of Uveitis Nomenclature (SUN) Working Group is an international collaboration that has developed classification criteria for 25 of the most common uveitides using a formal approach to development and classification. Among the diseases studied was birdshot chorioretinitis.
Methods
The SUN Developing Classification Criteria for the Uveitides project proceeded in 4 phases, as previously described: (1) informatics, (2) case collection, (3) case selection, and (4) machine learning.
Informatics
As previously described, the consensus-based informatics phase permitted the development of a standardized vocabulary and the development of a standardized, menu-driven hierarchical case collection instrument.
Case Collection and Case Selection
De-identified information was entered into the SUN preliminary database by the 76 contributing investigators for each disease, as previously described. , Cases in the preliminary database were reviewed by committees of 9 investigators for selection into the final database, using formal consensus techniques described in the accompanying article. , Because the goal was to develop classification criteria, only cases with a supermajority agreement (>75%) that the case was the disease in question were retained in the final database (ie, were “selected”). ,
Machine Learning
The final database then was randomly separated into a learning set (∼85% of the cases) and a validation set (∼15% of the cases) for each disease, as described in the accompanying article. Machine learning was used on the learning set to determine criteria that minimized misclassification. The criteria then were tested on the validation set; for both the learning set and the validation set, the misclassification rate was calculated for each disease. The misclassification rate was the proportion of cases classified incorrectly by the machine learning algorithm when compared to the consensus diagnosis. For BSCR, the diseases against which it was evaluated included acute posterior multifocal placoid pigment epitheliopathy, multifocal choroiditis with panuveitis (MFCPU), multiple evanescent white dot syndrome, punctate inner choroiditis, serpiginous choroiditis, sarcoidosis-associated posterior uveitis, syphilitic posterior uveitis, and tubercular uveitis.
The study adhered to the principles of the Declaration of Helsinki. Institutional review boards at each participating center reviewed and approved the study; the study typically was considered either minimal risk or exempt by the individual institutional review boards.
Results
Two hundred fifty-seven cases of birdshot chorioretinitis were collected, and 207 (81%) achieved supermajority agreement on the diagnosis during the “selection” phase and were used in the machine learning phase These cases of BSCR were compared to cases of posterior uveitides, including 82 cases of acute posterior multifocal placoid pigment epitheliopathy, 122 cases of serpiginous choroiditis, 51 cases of multiple evanescent white dot syndrome, 138 cases of MFCPU, 144 cases of punctate inner choroiditis, 12 cases of sarcoid posterior uveitis, 35 cases of syphilitic posterior uveitis, and 277 cases of tubercular posterior uveitis (including 96 cases of serpiginous-like tubercular choroiditis). The details of the machine learning results for these diseases are outlined in the accompanying article. The characteristics of cases with birdshot chorioretinitis are listed in Table 1 . The classification criteria developed after machine learning are listed in Table 2 . Key features of the criteria include (1) a bilateral multifocal choroiditis with the characteristic appearance, namely multifocal cream-colored or yellow-orange, round or ovoid choroidal spots (“birdshot spots”; Figure 1 ); (2) absent to minimal anterior chamber inflammation; (3) absent to mild vitritis; and (3) the exclusion of sarcoidosis; or a positive test for HLA-A29 and either the characteristic “birdshot spots” or the characteristic choroidal lesions on indocyanine green angiography. The overall accuracies for posterior uveitides were 93.9% in the learning set and 98.0% (95% confidence interval 94.3, 99.3) in the validation set. The misclassification rate for BSCR in the learning set was 10%, and in the validation set 0%. The disease with which it most often was confused in the learning set was MFCPU.
| Characteristic | Result |
|---|---|
| Number of cases | 207 |
| Demographics | |
| Age, median, years (25th, 75th percentile) | 51 (45, 58) |
| Sex (%) | |
| Male | 39 |
| Female | 61 |
| Race/ethnicity (%) | |
| White, non-Hispanic | 92 |
| Black, non-Hispanic | 0 |
| Hispanic | 1 |
| Asian, Pacific Islander | 0 |
| Other | 0 |
| Missing | 7 |
| Uveitis history | |
| Uveitis course (%) | |
| Acute, monophasic | 1 |
| Acute, recurrent | 1 |
| Chronic | 95 |
| Indeterminate | 3 |
| Laterality (%) | |
| Unilateral | 0 |
| Unilateral, alternating | 0 |
| Bilateral | 100 |
| Ophthalmic examination | |
| Keratic precipitates (%) | |
| None | 100 |
| Anterior chamber cells, grade (%) | |
| 0 | 83 |
| ½+ | 11 |
| 1+ | 5 |
| ≥2+ | 0 |
| Anterior chamber flare, grade (%) | |
| 0 | 93 |
| 1+ | 6 |
| 2+ | 1 |
| ≥3+ | 0 |
| Iris (%) | |
| Normal | 100 |
| IOP, involved eyes | |
| Median, mm Hg (25th, 75th percentile) | 15 (14, 18) |
| Proportion patients with IOP > 24 mm Hg either eye (%) | 2 |
| Vitreous cells, grade (%) | |
| 0 | 13 |
| ½+ | 16 |
| 1+ | 36 |
| 2+ | 32 |
| 3+ | 3 |
| 4+ | 0 |
| Vitreous haze, grade (%) | |
| 0 | 49 |
| ½+ | 19 |
| 1+ | 21 |
| 2+ | 11 |
| ≥3+ | 0 |
| Chorioretinal lesion characteristics | |
| Lesion number (%) | |
| Unifocal (1 lesion) | 0 |
| Paucifocal (2-4) | 0 |
| Multifocal (≥5) | 96 |
| Missing | 4 |
| Lesion shape and character (%) | |
| Ameboid or serpentine | 0 |
| Oval or round | 96 |
| Placoid | 0 |
| Atrophic | 2 |
| Punctate | 0 |
| Wedge-shaped | 0 |
| Missing | 2 |
| Lesion location (%) | |
| Posterior pole involved | 68 |
| Midperiphery and periphery only | 32 |
| Typical lesion size (%) | |
| <250 μm | 31 |
| 250-500 μm | 40 |
| >500 μm | 24 |
| Missing | 5 |
| Other features (%) | |
| Retinal vascular sheathing | 17 |
| Retinal vascular leakage | 33 |
| Choroidal neovascularization | 0 |
| Laboratory data (%) | |
| HLA-A29 positive a | 89 |
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