Abstract
Purpose:
To determine classification criteria for cytomegalovirus (CMV) anterior uveitis
Design:
Machine learning of cases with CMV anterior uveitis and 8 other anterior uveitides.
Methods:
Cases of anterior uveitides were collected in an informatics-designed preliminary database, and a final datafubase was constructed of cases achieving supermajority agreement on the 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 anterior uveitides. The resulting criteria were evaluated on the validation set.
Results:
One thousand eighty-three of cases of anterior uveitides, including 89 cases of CMV anterior uveitis, were evaluated by machine learning. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6). Key criteria for CMV anterior uveitis included unilateral anterior uveitis with a positive aqueous humor polymerase chain reaction assay for CMV. No clinical features reliably diagnosed CMV anterior uveitis. The misclassification rates for CMV anterior uveitis were 1.3 % in the training set and 0% in the validation set, respectively.
Conclusions:
The criteria for CMV anterior uveitis had a low misclassification rate and appeared to perform sufficiently well for use in clinical and translational research.
PRECIS
Using a formalized approach to developing classification criteria, including informatics-based case collection, consensus-technique-based case selection, and machine learning, classification criteria for cytomegalovirus (CMV) anterior uveitis were developed. Key criteria included unilateral anterior uveitis with positive aqueous humor polymerase chain reaction assay for CMV. The resulting criteria had a low misclassification rate.
With the advent of clinically available polymerase chain reaction (PCR) methodology for detecting cytomegalovirus (CMV) DNA, it became evident that CMV could cause an anterior uveitis in immunocompetent individuals.1,2 The pathogenesis appears to be due to replicating CMV in the eye, as evidenced by the detection of CMV DNA and RNA in the anterior chamber using PCR on aqueous specimens obtained by paracentesis.1–3 The disease is distinct from CMV retinitis seen in immunocompromised patients. Although CMV anterior uveitis has been reported from multiple countries, most reports come from Asian countries.3 In the United States, it is estimated to cause ~2% of cases of viral anterior uveitis.3,4 Whether this regional variation represents environmental factors, genetic susceptibility, or a combination of factors is unknown at this time.
Cytomegalovirus anterior uveitis has several clinical appearances, including a recurrent acute hypertensive anterior uveitis consistent with Posner Schlossman syndrome, a Fuchs Uveitis Syndrome (FUS)-like chronic anterior uveitis, and less frequently a recurrent or chronic anterior uveitis with iris atrophy.2,3,5–7 Adding to the difficulty of diagnosis is that none of these phenotypes is consistently due to CMV. In regions with a high prevalence of CMV anterior uveitis, ~50% of Posner Schlossman patients will have CMV anterior uveitis, and ~40% of FUS-like eyes will have CMV anterior uveitis.5 No differences in phenotype can be detected between eyes with Posner Schlossman syndrome with and without CMV, and although there are differences between eyes with FUS and with FUS-like CMV anterior uveitis, they do not appear to be consistent enough for reliable diagnosis.5 Eyes with FUS-like CMV anterior uveitis are more likely to have endotheliitis, nodular or “coin-like” endothelial lesions, and iris atrophy without heterochromia.2,5,6,7 The importance of correct diagnosis is emphasized by the clinical response of CMV anterior uveitis to topical ganciclovir therapy, including better intraocular pressure control, inflammation control, and diminishing endothelial cell loss.8,9
The Standardization of Uveitis Nomenclature (SUN) Working Group is an international collaboration, which has developed classification criteria for 25 of the most common uveitides using a formal approach to development and classification.10–16 Among the anterior uveitides studied was CMV anterior uveitis.
Methods
The SUN Developing Classification Criteria for the Uveitides project proceeded in four phases as previously described: 1) informatics, 2) case collection, 3) case selection, and 4) machine learning.11,14,16
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.11
Case collection and case selection.
De-identified clinical information was entered into the SUN preliminary database by the 76 contributing investigators for each disease as previously described.14,16 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.14,16 Because the goal was to develop classification criteria, only cases with a supermajority agreement (>75%) that the case was the disease were retained in the final database (i.e. were “selected”).
Machine learning.
The final database then was randomly separated into a training set (~85% of cases) and a validation set (~15% of cases) for each disease as described in the accompanying article.16 Machine learning was used on the training set to determine criteria that minimized misclassification. The criteria then were tested on the validation set; for both the training 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 CMV anterior uveitis, the diseases against which it was evaluated were: Herpes simplex virus (HSV) anterior uveitis, varicella zoster virus (VZV) anterior uveitis, juvenile idiopathic arthritis (JIA)-associated anterior uveitis, spondylitis/HLA-B27-associated anterior uveitis, tubulointerstitial nephritis with uveitis (TINU), Fuchs uveitis syndrome, sarcoidosis-associated anterior uveitis and syphilitic anterior uveitis.
Comparison of cases from Asian patients and non-Asian patients.
For categorical variables, comparison of cases of CMV anterior uveitis in Asian and non-Asian patients was performed with the chi-square test or the Fisher’s exact test if a cell was less than 5. For continuous variables, the Wilcoxon rank sum test was used. P-values are nominal and two-sided.
The study adhered to the principles of the Declaration of Helsinki. Institutional Review Boards (IRBs) at each participating center reviewed and approved the study: the study typically was considered either minimal risk or exempt by the individual IRBs.
Results
One hundred twelve cases of CMV anterior uveitis were collected, and 89 cases (79%) achieved supermajority agreement on the diagnosis during the “selection” phase and were used in the machine learning phase. These cases of CMV anterior uveitis were compared to 994 cases of other anterior uveitides, including 123 cases of VZV anterior uveitis, 101 cases of HSV anterior uveitis, 146 cases of Fuchs Uveitis Syndrome, 202 cases of JIA-associated anterior uveitis, 184 cases of spondylitis/HLA-B27-associated anterior uveitis, 94 cases of TINU, 112 cases of sarcoidosis-associated anterior uveitis, and 32 cases of syphilitic anterior uveitis. The characteristics of the cases with CMV anterior uveitis at presentation to a SUN Working Group Investigator are listed in Table 1. The comparison of characteristics of Asian and non-Asian cases is shown in Table 2. Differences between Asian and non-Asian cases included: 1) slightly older age in Asian cases; 2) greater proportion of cases with chronic uveitis in Asian cases; and 3) greater proportion of cases with mutton fat or nummular keratic precipitates (Figure 1) in Asian cases. The criteria developed after machine learning are listed in Table 3. No phenotypic features were selected, and detection of CMV in the aqueous with PCR was selected by machine learning as necessary for diagnosis. The one case selected by the selection committee for inclusion in the final data base without a positive PCR for CMV had an acute hypertensive anterior uveitis with corneal edema and elevated intraocular antibodies to CMV on Goldmann-Witmer analysis of an aqueous humor sample obtained by paracentesis. The overall accuracy for anterior uveitides was 97.5% in the training set and 96.7% in the validation set (95% confidence interval 92.4, 98.6).16 The misclassification rate for CMV anterior uveitis in the training set was 1.3% and in the validation set 0%.
Table 1.
Characteristics of Cases with Cytomegalovirus Anterior Uveitis
| Characteristic | Result |
|---|---|
| Number cases | 89 |
| Demographics | |
| Age, median, years (25th 75th percentile) | 53 (39, 62) |
| Age category, years (%) | |
| ≤16 | 2 |
| 17–50 | 39 |
| 51–59 | 29 |
| ≥60 | 29 |
| Gender (%) | |
| Men | 65 |
| Women | 35 |
| Race/ethnicity (%) | |
| White, non-Hispanic | 25 |
| Black, non-Hispanic | 8 |
| Hispanic | 2 |
| Asian, Pacific Islander | 43 |
| Other | 9 |
| Missing/unknown | 13 |
| Uveitis History | |
| Uveitis course (%) | |
| Acute, monophasic | 7 |
| Acute, recurrent | 37 |
| Chronic | 55 |
| Indeterminate | 1 |
| Laterality (%) | |
| Unilateral | 97 |
| Unilateral, alternating | 0 |
| Bilateral | 3 |
| Ophthalmic examination | |
| Cornea (%) | |
| Normal | 80 |
| Corneal edema | 19 |
| Keratitis | 1 |
| Keratic precipitates (%) | |
| None | 10 |
| Fine | 27 |
| Round | 33 |
| Stellate | 8 |
| Mutton Fat | 17 |
| Numular | 6 |
| Anterior chamber cells (%) | |
| Grade ½+ | 28 |
| 1+ | 34 |
| 2+ | 22 |
| 3+ | 2 |
| 4+ | 0 |
| Missing | 14 |
| Hypopyon (%) | 0 |
| Anterior chamber flare (%) | |
| Grade 0 | 61 |
| 1+ | 29 |
| 2+ | 10 |
| 3+ | 0 |
| 4+ | 0 |
| Iris (%) | |
| Normal | 69 |
| Posterior synechiae | 9 |
| Sectoral iris atrophy | 2 |
| Patchy iris atrophy | 9 |
| Diffuse iris atrophy | 15 |
| Heterochromia | 2 |
| Intraocular pressure (IOP), involved eyes | |
| Median, mm Hg (25th, 75th percentile) | 18 (14, 30) |
| Proportion patients with IOP>24 mm Hg either eye (%) | 54 |
| Vitreous cells (%) | |
| Grade 0 | 93 |
| ½+ | 3 |
| 1+ | 1 |
| 2+ | 2 |
| 3+ | 0 |
| 4+ | 0 |
| Laboratory | |
| Aqueous PCR positive for CMV* (% cases) | 99 |
PCR = polymerase chain reaction. CMV = cytomegalovirus. PCR positive for CMV in 88/89 cases tested.
Table 2.
Characteristics of Cases of Cytomegalovirus Anterior Uveitis in Asian and non-Asian Patients
| Characteristic | Asian Cases | Non-Asian Cases | P-value |
|---|---|---|---|
| Number cases | 38 | 51 | |
| Demographics | |||
| Age, median, years (25th 75th percentile) | 56 (40, 65) | 51 (36, 56) | 0.03 |
| Gender (%) | 0.92 | ||
| Men | 66 | 65 | |
| Women | 34 | 35 | |
| Uveitis History | |||
| Uveitis course (%) | 0.002 | ||
| Acute, monophasic | 4 | 9 | |
| Acute, recurrent | 20 | 50 | |
| Chronic | 76 | 39 | |
| Indeterminate | 0 | 2 | |
| Laterality (%) | 0.79 | ||
| Unilateral | 97 | 98 | |
| Bilateral | 3 | 2 | |
| Ophthalmic examination | |||
| Cornea | 0.80 | ||
| Normal | 82 | 76 | |
| Corneal edema | 18 | 22 | |
| Keratitis | 0 | 2 | |
| Keratic precipitates (%) | <0.001 | ||
| None | 16 | 9 | |
| Fine | 8 | 41 | |
| Round | 24 | 39 | |
| Stellate | 8 | 8 | |
| Mutton Fat | 32 | 0 | |
| Numular | 10 | 2 | |
| Anterior chamber cells (%) | 0.57 | ||
| Grade ½+ | 21 | 33 | |
| 1+ | 32 | 35 | |
| 2+ | 29 | 18 | |
| 3+ | 3 | 2 | |
| Anterior chamber flare (%) | 0.32 | ||
| Grade 0 | 58 | 63 | |
| 1+ | 26 | 31 | |
| 2+ | 16 | 6 | |
| Iris (%) | |||
| Normal | 33 | 42 | 0.27 |
| Posterior synechiae | 13 | 6 | 0.21 |
| Iris atrophy | 16 | 36 | 0.11 |
| Heterochromia | 3 | 2 | 0.67 |
| Intraocular pressure (IOP), involved eyes | |||
| Median, mm Hg (25th, 75th percentile) | 18 (14, 30) | 17 (15, 30) | 0.82 |
| Percent patients with IOP>24 mm Hg either eye | 42 | 37 | 0.64 |
| Vitreous cells (%) | 0.88 | ||
| Grade 0 | 92 | 94 | |
| ½+ | 5 | 2 | |
| ≥1+ | 3 | 4 |
Figure 1.
Nummular corneal endothelial lesion in a case with cytomegalovirus anterior uveitis.
Table 3.
Classification Criteria for Cytomegalovirus Anterior Uveitis
| Criteria |
| 1. Evidence of anterior uveitis |
| a. anterior chamber cells |
| b. if anterior vitreous cells are present, anterior chamber inflammation should be present |
| c. no evidence of retinitis |
| AND |
| 2. Evidence of cytomegalovirus infection in the eye |
| a. Positive PCR* for cytomegalovirus on aqueous specimen |
| Exclusions |
| 1. Positive serology for syphilis using a treponemal test |
| 2. Evidence of sarcoidosis (either bilateral hilar adenopathy on chest imaging or tissue biopsy demonstrating non-caseating granulomata) |
| 3. Aqueous specimen PCR positive for herpes simplex virus or varicella zoster virus |
PCR = polymerase chain reaction
Discussion
The low misclassification rate for the criteria in Table 3 is due in part to the requirement for laboratory confirmation of the diagnosis of CMV anterior uveitis. This requirement occurs in part because no one phenotype can be reliably diagnosed as CMV anterior uveitis and because the CMV anterior uveitis-like phenotypes can occur in the absence of CMV disease.3,5,17 For a Posner Schlossman-like phenotype, no features reliably distinguish between cases due to CMV and those where CMV cannot be detected.5 For Fuchs uveitis syndrome and FUS-like CMV anterior uveitis, endotheliitis, endothelial cell loss, and nodular endothelial lesions, often “coin-shaped” and with a surrounding halo, all suggest CMV disease.3,5,17 Furthermore, Fuchs uveitis syndrome’s iris atrophy is diffuse, may transilluminate, and typically results in heterochromia, whereas the iris atrophy with CMV anterior uveitis is typically is “patchy”, does not transilluminate, and rarely produces heterochromia.3,17 Fuchs uveitis syndrome has been thought to have a post-infectious pathogenesis with Rubella most often implicated in Caucasian patients,18,19 and as such should be distinguished from the “FUS-like” anterior uveitis due to CMV, seen most often in Asian patients Using a Goldmann-Witmer analysis of aqueous from eyes with Fuchs uveitis syndrome, elevated levels of antibodies to Rubella have been detected, suggesting an immunologic response to Rubella. Conversely, real time PCR for Rubella nearly always is negative (and positive only in younger patients) in the aqueous from eyes of patients with Fuchs, suggesting that Fuchs may not be due to active viral infection,18,19 but rather may be due to an immunologic response to prior infection. However, an uncontrolled case series using metagenomic deep sequencing, a more sensitive method for detecting viral RNA, detected Rubella RNA in the eyes of three patients with Fuchs uveitis syndrome, suggesting that low level viral replication may have a role in the pathogenesis of Fuchs.20 Nevertheless, it currently remains uncertain as to whether Fuchs is due to viral replication, an immunologic response to the virus, or a more complex combination of the two. Cytomegalovirus anterior uveitis tends to have milder inflammation and lower endothelial cell counts than HSV and VZV anterior uveitis, providing clinical clues, but these features are suggestive and do not reliably distinguish between CMV anterior uveitis and either HSV or VZV anterior uveitis.21 Because CMV anterior uveitis is uncommon in the West, and other viral infectious anterior uveitides often can be diagnosed reliably on morphologic grounds, paracentesis for aqueous PCR for viruses may not be performed routinely.4,16 Nevertheless, the diagnosis of CMV anterior uveitis requires aqueous paracentesis for PCR for CMV, and CMV should be sought in those cases with a compatible syndrome and especially those cases with suggestive features.
A case series from France of patients with CMV anterior uveitis suggested that Caucasian patients may have a different presentation than Asian patients, as no cases of “FUS-like” anterior uveitis were seen among their cases.22 Sixty-nine percent of the cases in this series presented as a Posner Schlossman syndrome, and 31% as a chronic anterior uveitis.22 In the cases in SUN data base, the comparison of cases of CMV anterior uveitis in Asian and non-Asian patients demonstrated a greater proportion of chronic uveitis in Asian cases and a greater proportion of recurrent uveitis in non-Asian cases. These results might be compatible with the differing morphologic variants reported previously, but the SUN data set did not have sufficient syndromic data to confirm this reported difference.
The presence of any of the exclusions in Table 3 suggests an alternate diagnosis, and the diagnosis of CMV anterior uveitis should not be made in their presence. In prospective studies many of these tests will be performed routinely, and the alternative diagnoses excluded. However, in retrospective studies based on clinical care, not all of these tests may have been performed. Hence the presence of an exclusionary criterion excludes CMV anterior uveitis, but the absence of such testing does not exclude the diagnosis of CMV anterior uveitis if the criteria for the diagnosis are met.
Classification criteria are employed to diagnose individual diseases for research purposes.15 Classification criteria differ from clinical diagnostic criteria, in that although both seek to minimize misclassification, when a trade-off is needed, diagnostic criteria typically emphasize sensitivity, whereas classification criteria emphasize specificity,15 in order to define a homogeneous group of patients for inclusion in research studies and limit the inclusion of patients without the disease in question that might confound the data. The machine learning process employed did not explicitly use sensitivity and specificity; instead it minimized the misclassification rate. Because we were developing classification criteria and because the typical agreement between two uveitis experts on diagnosis is moderate at best,14 the selection of cases for the final database (“case selection”) included only cases which achieved supermajority agreement on the diagnosis. As such there may be cases which the clinician believes are CMV anterior uveitis, but which do not satisfy classification criteria.
In conclusion, the criteria outlined in Table 3 appear to perform well enough for use as classification criteria for CMV anterior uveitis.
Grant support:
Supported by grant R01 EY026593 from the National Eye Institute, the National Institutes of Health, Bethesda, MD, USA; the David Brown Fund, New York, NY, USA; the Jillian M. And Lawrence A. Neubauer Foundation, New York, NY, USA; and the New York Eye and Ear Foundation, New York, NY, USA.
Footnotes
Writing committee: Douglas A. Jabs, MD, MBA2,3,; Laure Caspers, MD4; Soon-Phaik Chee, FRCOphth, FRCS (G), FRCS (Ed), MMed (Singapore)5; Anat Galor, MD, MSPH6; Debra Goldstein, MD7; Peter McCluskey, MD8; Philip I. Murray, PhD, FRCP, FRCS, FRCOphth9; Neal Oden, PhD10; Alan G. Palestine, MD11; James T. Rosenbaum, MD12,13; Jennifer E. Thorne, MD, PhD2,3; Brett E. Trusko, PhD, MBA.14
Affiliations: 1Members of the SUN Working Group are listed online at ajo.com. From 2the Department of Epidemiology, the Johns Hopkins University Bloomberg School of Public Health; 3the Wilmer Eye Institute, the Department of Ophthalmology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4the Department of Ophthalmology, CHU St. Pierre, Universite Libre de Bruxelles, Brussels, Belgium; 5Singapore National Eye Centre, Singapore Eye Research Institute, Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Duke-NUS Medical School, Singapore; 6the Department of Ophthalmology, the University of Miami Miller School of Medicine, Miami, FL, USA; 7the Department of Ophthalmology, the Northwestern Feinberg School of Medicine, Chicago, IL, USA; 8the Save Sight Institute, Department of Ophthalmology, University of Sydney School of Medicine, Sydney, NSW, Australia; 9the Academic Unit of Ophthalmology, University of Birmingham, Birmingham, UK; 10the Emmes Company, LLC, Rockville, MD, USA; 11the Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Co, USA; 12the Departments of Medicine and Ophthalmology, Oregon Health and Science University, Portland, OR, USA; 13the Legacy Devers Eye Institute, Portland, OR, USA; 14the Department of Medicine, Texas A&M University, College Station, TX, USA.
Conflict of Interest: Douglas A. Jabs: none; Laure Caspers: none; Soon-Phaik Chee: consultant and grant support: AbbVie Pte, Ltd, Alcon Laboratories, Inc., Bausch & Lomb Surgical, Carl Zeiss, Inc., HOYA Medical Singapore Pte, Ltd, Johnson & Johnson Vision, Leica Microsystems, Inc., Ziemer Ophthalmics AG; grant support only: Allergan, Gilead Sciences, Inc., Santen Pharmaceutical Asia Pte, Ltd, Ziemer Ophthalmics AG; Anat Galor, MD: none; Debra Goldstein: none; Peter McCluskey: none; Philip I. Murray: none; Neal Oden: none; Alan G. Palestine: none; James T. Rosenbaum: consultant: AbbVie, Eyevensys, Gilead, Horizon, Janssen, Novartis, Roche, Santen, UCB; grant support: Pfizer; royalties: UpToDate; Jennifer E. Thorne: Dr. Thorne engaged in part of this research as a consultant and was compensated for the consulting service; Brett E. Trusko: none.
Publisher's Disclaimer: This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
REFERENCES
- 1.van Boxtel LA, van der Lelij A, van der Meer J, Los LI. Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients. Ophthalmology 2007;114:1358–62. [DOI] [PubMed] [Google Scholar]
- 2.Chee SP, Bascal K, Jap A, et al. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol 2008;145:834–40. [DOI] [PubMed] [Google Scholar]
- 3.Chan NS, Chee SP, Caspers LB, Bodaghi B. Clinical features of CMV-associated anterior uveitis. Ocular Immunol Inflamm 2018;26:107–15. [DOI] [PubMed] [Google Scholar]
- 4.Anwar Z, Galor A, Albini TA, Miller D, Perez V, Davis JL. The diagnostic utility of anterior chamber paracentesis with polymerase chain reaction in anterior uveitis. Am J Ophthalmol 2013;155:781–6. [DOI] [PubMed] [Google Scholar]
- 5.Chee SP, Jap A. Presumed Fuchs heterochromic iridocyclitis and Posner-Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol 2008;146:883–9. [DOI] [PubMed] [Google Scholar]
- 6.Miyanga M, Sugita S, Shimizu N, et al. A significant association of viral loads with corneal endothelial cell damage in cytomegalovirus anterior uveitis. Br J Ophthalmol 2010;94:336–40. [DOI] [PubMed] [Google Scholar]
- 7.Chee SP, Jap A. Immune ring formation associated with cytomegalovirus endotheliitis. Am J Ophthalmol 2011;152:449–53. [DOI] [PubMed] [Google Scholar]
- 8.Chee SP, Jap A. Cytomegalovirus anterior uveitis: outcome of treatment. Br J Ophthalmol 2010;94:1648–52. [DOI] [PubMed] [Google Scholar]
- 9.Su CC, Hu FR, Wang TH, et al. Clinical outcomes of cytomegalovirus-positive Posner Schlossman syndrome patients treated with topical ganciclovir therapy. Am J Ophthalmol 2014;158:1024–31. [DOI] [PubMed] [Google Scholar]
- 10.Jabs DA, Rosenbaum JT, Nussenblatt RB, the Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Report of the first international workshop. Am J Ophthalmol 2005;140:509–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Trusko B, Thorne J, Jabs D, et al. Standardization of Uveitis Nomenclature Working Group. The SUN Project. Development of a clinical evidence base utilizing informatics tools and techniques. Methods Inf Med 2013;52:259–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jabs DA, Busingye J. Approach to the diagnosis of the uveitides. Am J Ophthalmol 2013;156:228–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Okada AA, Jabs DA. The SUN Project. The future is here. Arch Ophthalmol 2013;131:787–9. [DOI] [PubMed] [Google Scholar]
- 14.Jabs DA, Dick A, Doucette JT, Gupta A, Lightman S, McCluskey P, Okada AA, Palestine AG, Rosenbaum JT, Saleem SM, Thorne J, Trusko B for the Standardization of Uveitis Nomenclature Working Group. Interobserver agreement among uveitis experts on uveitic diagnoses: the Standard of Uveitis Nomenclature experience. Am J Ophthalmol 2018; 186:19–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria. Arthritis Care Res 2015;67:891–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.The Standardization of Uveitis Nomenclature (SUN) Working Group. Development of classification criteria for the uveitides. Am J Ophthalmol 2020;volume:pp. [DOI] [PubMed] [Google Scholar]
- 17.Relvas LJ, Caspers L, Chee SP, Zierhut M, Willermain F. Differential diagnosis of viral-induced anterior uveitis. Ocular Immunol Inflamm 2018;26:726–31. [DOI] [PubMed] [Google Scholar]
- 18.Quentin CD, Reiber H. Fuchs heterochromic iridocyclitis: rubella virus antibodies and genome in aqueous humor. Am J Ophthalmol 2004;138:46–54. [DOI] [PubMed] [Google Scholar]
- 19.Ruokonen PC, Metzner S, Ucer A, Torun N, Hofman J, Pleyer U. Intraocular antibody synthesis against rubella virus and other microorganisms if Fuchs’ heterochromic cyclitis. Graefes Arch c Clin Exp Ophthalmol 2010;248:565–71. [DOI] [PubMed] [Google Scholar]
- 20.Gonzales JA, Hinterwirth A, Shantha J, et al. Association of ocular inflammation with rubella virus persistence. JAMA Ophthalmol 2019;137:435–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Takase H, Kubono R, Terada Y, et al. Comparison of the ocular characteristics of anterior uveitis caused by herpes simplex virus, Varicella-zoster virus, and cytomegalovirus. Jpn J Ophthalmol 2014;58:473. [DOI] [PubMed] [Google Scholar]
- 22.Touhami S, Qu L, Angi M, et al. Cytomegalovirus anterior uveitis: clinical characteristics and long-term outcomes in a French series. Am J Ophthalmol 2018;194:134–42. [DOI] [PubMed] [Google Scholar]