Thiran Jayasundera

Management of autoimmune retinopathies with immunosuppression

OBJECTIVE To report the results of treating autoimmune retinopathy (AIR) with immunosuppression therapy. METHODS Retrospective review of 30 consecutive patients with AIR followed for 3 to 89 months (median, 17 months) who were treated with immunosuppression (systemic or local). Subgroups were cancer-associated retinopathy (CAR), nonparaneoplastic AIR (npAIR), and npAIR with cystoid macular edema (npAIR/CME). Outcome measures were improvement of Snellen visual acuity by at least 2 lines, expansion of the visual field area by more than 25%, and resolution of CME. RESULTS Overall, 21 of 30 patients (70%) showed improvement. All 6 CAR patients, 7 of 13 (54%) with npAIR, and 8 of 11 (73%) with npAIR/CME showed improvement. Five of 21 patients (24%) had improvement in visual acuity, 15 of 21 (71%) had expansion of visual field area, and 6 of 11 (55%) had resolution of CME. Twenty-six of 30 patients exhibited diffuse retinal atrophy without pigment deposits. An autoimmune family history was common in all the groups: npAIR, 69% (9 of 13); npAIR/CME, 64% (7 of 11); and CAR, 50% (3 of 6). CONCLUSIONS Long-term treatment with immunosuppression resulted in clinical improvement in all subgroups of AIR. The most responsive subgroup was CAR; the least was npAIR. These results challenge the commonly held belief that AIR is untreatable.

Melanoma-Associated Retinopathy: A Paraneoplastic Autoimmune Complication

OBJECTIVES To study 11 patients with melanoma-associated retinopathy (MAR) to clarify the reliability of various methods of diagnostic testing, to determine the underlying antigenic retinal proteins, and to study the clinical histories and types of associated melanomas. METHODS Clinical data were obtained from patients with melanoma who developed marked visual problems. Testing included electroretinography, kinetic visual fields, comparative studies of Western blots, and indirect immunohistologic examination to detect antiretinal antibodies, as well as proteomic studies to identify underlying antigenic retinal proteins. RESULTS Patients with MAR typically have rapid onset of photopsias, scotomata, and loss of central or paracentral vision. Ophthalmoscopy seldom shows significant changes early, but electroretinograms are abnormal. Results of Western blots and immunohistologic examination can show antiretinal antibodies but not always. Most patients (9 of 11) had a strong family history of autoimmune disorders. Any type of melanoma (cutaneous, choroidal, ciliary body, or choroidal nevi) may be associated with this paraneoplastic autoimmune reactivity. MAR may precede or follow the diagnosis of melanoma. Patients with MAR have the same antigenic retinal proteins that have been associated with cancer-associated retinopathy. In addition, 2 new antigenic retinal proteins, aldolase A and aldolase C, were found. CONCLUSIONS There was a high prevalence of positive family histories of autoimmune disease in patients with MAR. To confirm the disorder, multiple clinical and serum diagnostic techniques (Western blot or indirect immunohistologic examination) are needed. Two newly observed antigenic retinal proteins, aldolase A and aldolase C, are associated with MAR.

RP2 Phenotype and Pathogenetic Correlations in X-Linked Retinitis Pigmentosa

OBJECTIVES To assess the phenotype of patients with X-linked retinitis pigmentosa (XLRP) with RP2 mutations and to correlate the findings with their genotype. METHODS Six hundred eleven patients with RP were screened for RP2 mutations. From this screen, 18 patients with RP2 mutations were evaluated clinically with standardized electroretinography, Goldmann visual fields, and ocular examinations. In addition, 7 well-documented cases from the literature were used to augment genotype-phenotype correlations. RESULTS Of 11 boys younger than 12 years, 10 (91%) had macular involvement and 9 (82%) had best-corrected visual acuity worse than 20/50. Two boys from different families (aged 8 and 12 years) displayed a choroideremia-like fundus, and 9 boys (82%) were myopic (mean error, -7.97 diopters [D]). Of 10 patients with electroretinography data, 9 demonstrated severe rod-cone dysfunction. All 3 female carriers had macular atrophy in 1 or both eyes and were myopic (mean, -6.23 D). All 9 nonsense and frameshift and 5 of 7 missense mutations (71%) resulted in severe clinical presentations. CONCLUSIONS Screening of the RP2 gene should be prioritized in patients younger than 16 years characterized by X-linked inheritance, decreased best-corrected visual acuity (eg, >20/40), high myopia, and early-onset macular atrophy. Patients exhibiting a choroideremia-like fundus without choroideremia gene mutations should also be screened for RP2 mutations. CLINICAL RELEVANCE An identifiable phenotype for RP2-XLRP aids in clinical diagnosis and targeted genetic screening.

Clinical phenotypes and prognostic full-field electroretinographic findings in Stargardt disease.

PURPOSE To investigate the relationships between clinical and full-field electroretinographic (ERG) findings and progressive loss of visual function in Stargardt disease. DESIGN Retrospective cohort study. METHODS We performed a retrospective review of data from 198 patients with Stargardt disease. Measures of visual function over time, including visual acuity, quantified Goldmann visual fields, and full-field ERG data were recorded. Data were analyzed using SAS statistical software. Subgroup analyses were performed on 148 patients with ERG phenotypic data, 46 patients with longitudinal visual field data, and 92 patients with identified ABCA4 mutations (46 with 1 mutation, and 47 with 2 or more mutations). RESULTS Of 46 patients with longitudinal visual field data, 8 patients with faster central scotoma progression rates had significantly worse scotopic B-wave amplitudes at their initial assessment than 20 patients with stable scotomata (P = .014) and were more likely to have atrophy beyond the arcades (P = .047). Overall, 47.3% of patients exhibited abnormal ERG results, with rod-cone dysfunction in 14.2% of patients, cone-rod dysfunction in 17.6% of patients, and isolated cone dysfunction in 15.5% of patients. Abnormal values in certain ERG parameters were associated significantly with (maximum-stimulation A- and B-wave amplitudes) or tended toward (photopic and scotopic B-wave amplitudes) a higher mean rate of central scotoma progression compared with those patients with normal ERG values. Scotoma size and ERG parameters differed significantly between those with a single mutation versus those with multiple mutations. CONCLUSIONS Full-field ERG examination provides clinically relevant information regarding the severity of Stargardt disease, likelihood of central scotoma expansion, and visual acuity deterioration. Patients also may exhibit an isolated cone dystrophy on ERG examination.

Consensus on the Diagnosis and Management of Nonparaneoplastic Autoimmune Retinopathy Using a Modified Delphi Approach

PURPOSE To develop diagnostic criteria for nonparaneoplastic autoimmune retinopathy (AIR) through expert panel consensus and to examine treatment patterns among clinical experts. DESIGN Modified Delphi process. METHODS A survey of uveitis specialists in the American Uveitis Society, a face-to-face meeting (AIR Workshop) held at the National Eye Institute, and 2 iterations of expert panel surveys were used in a modified Delphi process. The expert panel consisted of 17 experts, including uveitis specialists and researchers with expertise in antiretinal antibody detection. Supermajority consensus was used and defined as 75% of experts in agreement. RESULTS There was unanimous agreement among experts regarding the categorization of autoimmune retinopathies as nonparaneoplastic and paraneoplastic, including cancer-associated retinopathy and melanoma-associated retinopathy. Diagnostic criteria and tests essential to the diagnosis of nonparaneoplastic AIR and multiple supportive criteria reached consensus. For treatment, experts agreed that corticosteroids and conventional immunosuppressives should be used (prescribed) as first- or second-line treatments, though a consensus agreed that biologics and intravenous immunoglobulin were considered appropriate in the treatment of nonparaneoplastic AIR patients regardless of the stage of disease. Experts agreed that more evidence is needed to treat nonparaneoplastic AIR patients with long-term immunomodulatory therapy and that there is enough equipoise to justify randomized, placebo-controlled trials to determine if nonparaneoplastic AIR patients should be treated with long-term immunomodulatory therapy. Regarding antiretinal antibody detection, consensus agreed that a standardized assay system is needed to detect serum antiretinal antibodies. Consensus agreed that an ideal assay should have a 2-tier design and that Western blot and immunohistochemistry should be the methods used to identify antiretinal antibodies. CONCLUSIONS Consensus was achieved using a modified Delphi process to develop diagnostic criteria for nonparaneoplastic AIR. There is enough equipoise to justify randomized, placebo-controlled trials to determine whether patients with nonparaneoplastic AIR should be treated with long-term immunomodulatory therapy. Efforts to develop a standardized 2-tier assay system for the detection of antiretinal antibodies have been initiated as a result of this study.

Peripapillary Dark Choroid Ring as a Helpful Diagnostic Sign in Advanced Stargardt Disease

PURPOSE To investigate the prevalence of a peripapillary dark choroid ring on fluorescein angiography (FA) and the associated clinical features in patients with Stargardt disease. DESIGN Retrospective review of 135 patients with Stargardt disease. METHODS The presence or absence of a peripapillary dark choroid ring on FA was noted and was compared with patient demographics and clinical features. RESULTS Thirty-seven percent (50/135) had a peripapillary dark choroid ring on FA. When evaluated in subgroups, this sign was present in 41% (9/22) of patients with 2 causative ABCA4 mutations, in 28% (5/18) of patients with 1 causative ABCA4 mutation and a clinical diagnosis of Stargardt disease, and in 38% (36/95) of patients with a clinical diagnosis of Stargardt disease pending mutational analysis. Ninety-four percent (44/47) of patients for whom mutational testing confirmed the presence of ABCA4 mutations demonstrated a dark choroid sign. The peripapillary dark choroid ring sign was associated with diffuse flecks (P < .001), worse logarithm of the minimal angle of resolution visual acuity (P = .03), larger central scotoma size (P = .0146), and the presence of complete macular atrophy (P = .0017) compared with patients without this sign. CONCLUSIONS The presence of a peripapillary dark choroid ring on FA should prompt further evaluation for Stargardt disease by examination of peripheral retinal FA images for a dark choroid sign, followed by subsequent ABCA4 mutation screening.

Diagnostic Fundus Autofluorescence Patterns in Achromatopsia

PURPOSE To describe the unique diagnostic fundus autofluorescence (FAF) patterns in patients with achromatopsia and the associated findings on optical coherence tomography (OCT). DESIGN Observational case series. METHODS We evaluated 10 patients with achromatopsia by means of best-corrected visual acuity (BCVA), ophthalmoscopy, Goldmann visual field, full-field electroretinography (ffERG), OCT, and FAF photography. FAF patterns were compared with patient age and foveal changes on OCT. RESULTS Patients fell into two dichotomous age groups at the time of evaluation: six patients ranged from 11 to 23 years of age, and 3 patients ranged from 52 to 63 years of age. All patients had severely reduced photopic ffERG responses, including those exhibiting preserved foveal structure on OCT. The younger patients had absent to mild foveal atrophy on OCT, and four of the six demonstrated foveal and parafoveal hyperfluorescence on FAF. In addition, a 7-month-old child with compound heterozygous mutations in CNGA3 demonstrated similar foveal hyperfluorescence. The older patients demonstrated advanced foveal atrophy and punched-out foveal hypofluorescence with discrete borders on FAF imaging corresponding to the area of outer retinal cavitation on OCT. CONCLUSIONS Foveal hyperfluorescence is an early sign of achromatopsia that can aid in clinical diagnosis. In our cohort, patients with achromatopsia demonstrated age-dependent changes in FAF, which are likely to be progressive and to correlate with foveal atrophy and cavitation on OCT. This finding may be useful in charting the natural course of the disease and in defining a therapeutic window for treatment.

Digital Quantification of Goldmann Visual Fields (GVFs) as a Means for Genotype–Phenotype Comparisons and Detection of Progression in Retinal Degenerations

PURPOSE To develop a reliable and efficient digital method to quantify planimetric Goldmann visual field (GVF) data to monitor disease course and treatment responses in retinal degenerative diseases. METHODS A novel method to digitally quantify GVFs using Adobe Photoshop CS3 was developed for comparison to traditional digital planimetry (Placom 45C digital planimeter; Engineer Supply, Lynchburg, Virginia, USA). GVFs from 20 eyes from 10 patients with Stargardt disease were quantified to assess the difference between the two methods (a total of 230 measurements per method). This quantification approach was also applied to 13 patients with X-linked retinitis pigmentosa (XLRP) with mutations in RPGR. RESULTS Overall, measurements using Adobe Photoshop were more rapidly performed than those using conventional planimetry. Photoshop measurements also exhibited less inter- and intraobserver variability. GVF areas for the I4e isopter in patients with the same mutation in RPGR who were nearby in age had similar qualitative and quantitative areas. CONCLUSIONS Quantification of GVFs using Adobe Photoshop is quicker, more reliable, and less user dependent than conventional digital planimetry. It will be a useful tool for both retrospective and prospective studies of disease course as well as for monitoring treatment response in clinical trials for retinal degenerative diseases.

Prevalence of Antiretinal Antibodies in Acute Zonal Occult Outer Retinopathy: A Comprehensive Review of 25 Cases

PURPOSE To perform a comprehensive review and to investigate the presence and role of autoimmune antibodies in 25 cases of acute zonal occult outer retinopathy (AZOOR) identified using the classification originally proposed by J. Donald Gass. DESIGN Observational case series. METHODS Setting: Institutional. STUDY POPULATION Twenty-five patients were identified by characteristic symptoms (abrupt onset of photopsias, followed by large scotomata at or connected to the blind spot), ocular findings (paucity of pigmentary changes with no sign of vitreous inflammation and abnormal electroretinogram in at least 1 eye), and a negative family history for retinitis pigmentosa. OBSERVATION PROCEDURES Patients underwent a full comprehensive ophthalmologic examination, fundus retinography, Goldmann kinetic visual field (GVF), and full-field electroretinogram (ffERG). Blood samples were also obtained to verify for the presence of antiretinal antibodies by Western blot analysis. MainOutcome Measures: Clinical presentation, best-corrected visual acuity (BCVA), fundus abnormalities, visual field defects, ffERG changes, and presence of antiretinal antibodies. RESULTS Sixteen patients (64%) presented with photopsias, 56% (14/25) with night blindness, and 56% (14/25) with loss of peripheral vision. Sixty-four percent (16/25) of cases were bilateral. All patients demonstrated retinal vascular attenuation, optic nerve head pallor, and mottling of retinal pigment epithelium. The most common visual field changes included enlargement and expansion of the blind spot extending into large pericentral or other types of scotomata (64%). Both scotopic and photopic ffERG values were abnormal and affected to a similar degree in our patients. Nine patients (36%) had a greater than 20% asymmetry in ERG values between the 2 eyes. All patients had antiretinal antibodies on Western blot with an average of 6.6 bands. CONCLUSION Evidence suggests that AZOOR is a unique form of autoimmune retinopathy and retinal manifestation suggests possible antiretinal antibody leakage from the disc margin with spread of immune products under the retina, resulting in large scotomata that connect to the optic nerve head.

Structure/Psychophysical Relationships in X-Linked Retinoschisis

Purpose To compare structural properties from spectral-domain optical coherence tomography (SDOCT) and psychophysical measures from a subset of patients enrolled in a larger multicenter natural history study of X-linked retinoschisis (XLRS). Methods A subset of males (n = 24) participating in a larger natural history study of XLRS underwent high-resolution SDOCT. Total retina (TR) thickness and outer segment (OS) thickness were measured manually. Shape discrimination hyperacuity (SDH) and contour integration perimetry (CIP) were performed on an iPad with the myVisionTrack application. Sensitivity was measured with fundus-guided perimetry (4-2 threshold testing strategy; 10-2 grid, spot size 3, 68 points). Correlation was determined with Pearsons r correlation. Values are presented as the mean ± SD. Results Mean macular OS thickness was less in XLRS patients (17.2 ± 8.1 μm) than in controls (37.1 ± 5.7 μm; P < 0.0001) but mean TR thickness was comparable (P = 0.5884). For patients, total sensitivity was lower (13.2 ± 6.6 dB) than for controls (24.2 ± 2.4 dB; P = 0.0008) and had a strong correlation with photoreceptor OS (R2 = 0.55, P = 0.0001) and a weak correlation with TR thickness (R2 = 0.22, P = 0.0158). The XLRS subjects had a logMAR best corrected visual acuity (BCVA) of 0.5 ± 0.3 that was associated with OS (R2 = 0.79, P < 0.0001) but not TR thickness (R2 = 0.01, P = 0.6166). Shape DH and CIP inner ring correlated with OS (R2 = 0.33, P = 0.0085 and R2 = 0.47, P = 0.0001, respectively) but not TR thickness (R2 = 0.0004, P = 0.93; R2 = 0.0043, P = 0.75, respectively). Conclusions When considered from a single visit, OS thickness within the macula is more closely associated with macular function than TR thickness within the macula in patients with XLRS.