Letters

1. Saihan Z, Webster AR, Luxon L, Bitner-Glindzicz M. Update on Usher syndrome. Curr Opin Neurol. 2009;22(1):19-27. 2. Le Quesne Stabej P, Saihan Z, Rangesh N, et al. Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study. J Med Genet. 2012;49(1):27-36. 3. Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat. 2011;32 (5):557-563. 4. Rivolta C, Sweklo EA, Berson EL, Dryja TP. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000;66(6):1975-1978. 5. Jonkman MF. Revertant mosaicism in human genetic disorders. Am J Med Genet. 1999;85(4):361-364. 6. Daiger SP, Sullivan LS, Bowne SJ. RetNet: Retinal Information Network. http: //www.sph.uth.edu/RetNet/. Accessed October 25, 2014. 7. Van Camp G, Smith R. Hereditary hearing loss homepage. http: //hereditaryhearingloss.org/. Accessed October 25, 2014. 8. Yu N, Kruskall MS, Yunis JJ, et al. Disputed maternity leading to identification of tetragametic chimerism. N Engl J Med. 2002;346(20):1545-1552.

Asymptomatic Retinal Gumma Ocular syphilis, caused by the spirochete Treponema pallidum, presents a diagnostic dilemma because of the myriad ways in which it can appear. Anterior scleritis, uveitis involving any portion of the uveal tract, retinitis, retinal vasculitis, optic neuritis, diffuse retinal edema, exudative retinal detachment, and acute syphilitic posterior placoid chorioretinitis have all been described with varying degrees of regularity.1-3 Gummata, or luetic granulomas, result from tertiary syphilis. They are most commonly found in the liver but can be found in other organs. They are formed by local reactions to spirochetes after the immune system fails to kill them. Herein, we describe a case of an asymptomatic retinal gumma without active intraocular inflammation. Report of a Case | A man in his early 50s with a history of human immunodeficiency virus, type 1 diabetes mellitus, and hyperlipidemia presented for a routine diabetic screening examination without ophthalmic complaints. He had a history of syphilis 10 years prior to presentation, which was treated with oral penicillin. His rapid plasma reagin was nonreactive 1 year prior to presentation. Visual acuity was 20/20 − 3 OD and 20/20 − 1 OS. Anterior segment and vitreous were unremarkable without inflammation in both eyes. Dilated ophthalmoscopy revealed a neurosensory detachment in the inferior macula of the right eye including the fovea. Subretinal yellow lesions smaller than 100 μm in diameter were also present, as

was slightly elevated, poorly demarcated yellow discoloration in the central portion of the neurosensory detachment. The left fundus was within normal limits. Fluorescein and indocyanine green angiography revealed early poorly delineated hyperfluorescence within the neurosensory detachment, with continued leakage and pooling of fluorescein (Figure 1). There was no late leakage from peripheral vasculature or from the optic nerve. Optical coherence tomography demonstrated shallow subretinal fluid with hyperreflective foci predominantly within the outer retina (Figure 2). There was also disruption of the retinal pigment epithelium with a pigment epithelial detachment and associated hyperreflective subretinal material. Laboratory testing revealed newly positive rapid plasma reagin results at a level of 4:1 and positive fluorescent treponemal antibody absorption. Toxoplasma antibody titers and purified protein derivative skin testing results were negative. He received 18 million units of intravenous penicillin per day for 14 days. The subretinal fluid began to resolve immediately, with complete resolution after 6 months. There had been no recurrence of inflammatory signs through 3 additional months of follow-up (Figure 2). Discussion | Retinochoroidal findings in ocular syphilis are not uncommon. While reports of retinitis, neurosensory retinal detachment, retinal edema, macular chorioretinitis, and neuroretinitis are frequent, they invariably involve vitritis, papillitis, and/or vasculitis, or the subretinal fluid disappears within days of presentation as is the case with acute syphilitic posterior placoid chorioretinitis.1-4 Our patient lacked these other inflammatory signs and the subretinal fluid was not transient, making his constellation of findings unique. The optical coherence tomographic finding of a pigment epithelial detachment and associated ill-defined subretinal hyperreflective material that resolved with treatment suggests a deep inflammatory origin. Because our patient was asymptomatic, his unusual findings likely represent a choroidal gumma. To our knowledge, there are no recent reports of choroidal gumma in the literature through Medline. Textbooks prior to the 1930s (going back to the 1800s) discuss gumma within the eye; however, recent references simply state it is possible to develop choroidal gumma and do not provide cases as examples.1-4 The location and optical coherence tomographic characteristics of the lesion shown herein suggest focal inflammation deep to the retina, which could represent early granuloma forma-

Figure 1. Color Fundus Photograph, Fluorescein Angiograms, and Indocyanine Green Angiograms of the Right Eye on Presentation A

B

C

A, Color fundus photograph shows neurosensory retinal detachment involving the fovea with an underlying poorly demarcated yellow/white lesion and small subretinal yellow lesions. B and D, Early-phase (B) and late-phase (D) fluorescein angiograms show patchy hyperfluorescence without vasculitis or

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D

E

leakage from the optic nerve. C and E, Early-phase (C) and late-phase (E) indocyanine green angiograms show deep hyperfluorescence without optic nerve edema.

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Figure 2. Optical Coherence Tomography Through the Center of the Neurosensory Detachment A

B

C

D

A, Optical coherence tomography on presentation demonstrates subretinal fluid, hyperreflective foci, and disrupted retinal pigment epithelium including ill-defined subretinal hyperreflectivity. B, Two weeks after treatment with intravenous penicillin. C, Three months after treatment. D, Six months after treatment.

tion. It is important to consider syphilis in the differential diagnosis of such cases, even in the absence of symptoms or other more typical signs of inflammation.

Funding/Support: This work was supported in part by an unrestricted grant from Research to Prevent Blindness.

Douglas K. Sigford, MD Shlomit Schaal, MD, PhD Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky.

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Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Role of the Funder/Sponsor: Research to Prevent Blindness had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Corresponding Author: Shlomit Schaal, MD, PhD, Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E Muhammad Ali Blvd, Louisville, KY 40202 ([email protected]).

1. McLeish WM, Pulido JS, Holland S, Culbertson WW, Winward K. The ocular manifestations of syphilis in the human immunodeficiency virus type 1-infected host. Ophthalmology. 1990;97(2):196-203.

Published Online: December 26, 2014. doi:10.1001/jamaophthalmol.2014.5232.

2. Yang P, Zhang N, Li F, Chen Y, Kijlstra A. Ocular manifestations of syphilitic uveitis in Chinese patients. Retina. 2012;32(9):1906-1914.

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Letters

3. Eandi CM, Neri P, Adelman RA, Yannuzzi LA, Cunningham ET Jr; International Syphilis Study Group. Acute syphilitic posterior placoid chorioretinitis: report of a case series and comprehensive review of the literature. Retina. 2012;32(9): 1915-1941. 4. Pichi F, Ciardella AP, Cunningham ET Jr, et al. Spectral domain optical coherence tomography findings in patients with acute syphilitic posterior placoid chorioretinopathy. Retina. 2014;34(2):373-384.

COMMENT & RESPONSE

Fourteen Patients With Fifty-Eight Eyes To the Editor I read with interest the article by Birnbaum et al titled “Correlation Between Clinical Signs and Optical Coherence Tomography With Enhanced Depth Imaging Findings in Patients With Birdshot Chorioretinopathy.”1 The authors examined 14 patients; we are told that 21 eye examinations were done in symptomatic patients, but there was no mention of the number of examinations done on asymptomatic patients. Even though there were 14 patients, the authors stated there were 58 eyes. For example, their Table 1 states that 33 eyes did not have photopsias while 25 did. (Photopsias were graded on a 7-step scale ranging from 0-3 by half-step increments using an undisclosed method; 25 eyes had a score >0.) Similarly, 58 eyes’ worth of optical coherence tomographic data were generated for 4 different features as shown in their Table 2. The implication is not only that there was a potential to use both eyes of a patient but also that the same eye was measured more than once for some patients. Since 58 is not evenly divisible by 14 or 21, there must have been a variable number of examinations per patient and a variable number of eyes used per patient. The statistical tests used in the study (the Pearson product moment correlation and the Spearman rank correlation) have as a basic assumption independence of the observations from each other. These statistical tests would be appropriate if 58 eyes of 58 patients were analyzed; instead, both eyes of an untold number of patients were measured more than once an untold number of times. These steps can lead to biased estimates of the strength of the association because the cases with multiple measurements are no longer random samples from some larger population. The estimates of the significance of the correlation are also incorrect because there is an artificial expansion of the number of cases by measuring eyes more than once, making us more likely to believe the observed correlation would not have happened by chance alone. The analysis of data with this structure requires a more sophisticated approach. Methods with generalized estimating equations have been used for this type of data.2 The authors should provide additional analysis that correctly accounts for the inconsistent use of 2 eyes per patient as well as the measurement of the same eye repeatedly in some patients. In addition, it would be helpful to know how the authors retrospectively graded photopsias into 7 levels of severity. Richard F. Spaide, MD Author Affiliation: Vitreous Retina Macula Consultants of New York, New York. Corresponding Author: Richard F. Spaide, MD, Vitreous Retina Macula Consultants of New York, 460 Park Ave, Fifth Floor, New York, NY 10022 ([email protected]). Published Online: November 20, 2014. doi:10.1001/jamaophthalmol.2014.4650. jamaophthalmology.com

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Spaide reported receiving royalty and consulting funds from Topcon Medical Systems and in the last 3 years having served as a consultant to Bausch & Lomb, Teva Pharmaceuticals, and ThromboGenics. No other disclosures were reported. 1. Birnbaum AD, Fawzi AA, Rademaker A, Goldstein DA. Correlation between clinical signs and optical coherence tomography with enhanced depth imaging findings in patients with birdshot chorioretinopathy. JAMA Ophthalmol. 2014; 132(8):929-935. 2. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics. 1988;44(4):1049-1060.

In Reply We thank Spaide for his critical review. He is correct in that data were included for each point at which complete data were available within the study period. Thus, more than 1 set of data points could be included for each patient. His main concern centers on the multiple examinations per patient, that we did not account for these data dependencies in the statistical analysis, and that this would overestimate the significance of the correlations. The purpose of this analysis was to determine whether the presence of suprachoroidal fluid might be a parameter that clinicians can use to follow the activity of patients with birdshot chorioretinopathy. The data set was not large enough for the more rigorous statistical analysis described by Spaide. Furthermore, the conclusions of this article were meant to be hypothesis generating rather than definitive proof. After the original analysis reported in this article, we performed an evaluation of the relationship between the clinical symptom of photopsias and the optical coherence tomographic finding of suprachoroidal fluid in a larger group of patients with longitudinal follow-up. The analysis of these data accounts for the correlations between eyes and over time within a person. The results support the current finding and are being submitted for publication. Another criticism relates to the number of visits or examinations for symptomatic patients, which we agree might have been a source of bias. Spaide’s third criticism is that an undisclosed grading scheme was used for shimmering or photopsias. The grading scale is defined in the Methods section. These data were able to be defined retrospectively as all patients with birdshot chorioretinopathy in our clinic are asked at each visit to grade their subjective symptoms. The data were therefore available to be converted to a numeric value. Half steps were assigned to patients whose symptoms fell between the defined grades as determined by the physician examining the patient. We apologize if this was not clear in the article. While the data presented in our article are based on a small number of patients, they do suggest a possible objective means of following disease activity and are of heuristic value for further research. In absence of more standardized objective tools at this point, we hope our study can be the catalyst for more prospective research in this area.

Andrea D. Birnbaum, MD, PhD Amani A. Fawzi, MD Debra A. Goldstein, MD (Reprinted) JAMA Ophthalmology March 2015 Volume 133, Number 3

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Asymptomatic retinal gumma.

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