Publications by authors named "Christine N Kay"

30 Publications

  • Page 1 of 1

Unusual Presentation of Presumed Arteritic Ischemic Optic Neuropathy in Waxy Pale Disc of Retinitis Pigmentosa.

Ophthalmic Surg Lasers Imaging Retina 2021 Jun 1;52(6):350-352. Epub 2021 Jun 1.

This case report describes an unusual presentation of arteritic anterior ischemic optic neuropathy (AAION) in a 68-year-old patient with retinitis pigmentosa (RP) secondary to Usher syndrome. The authors report a patient with RP who presented with rapid unilateral vision loss. A diagnosis of AAION was made by fluorescein angiography and temporal artery biopsy despite the lack of typical optic nerve features of anterior ischemic neuropathy, which were likely masked due to the waxy pale disc associated with RP. .
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http://dx.doi.org/10.3928/23258160-20210528-08DOI Listing
June 2021

Examining Whether AOSLO-Based Foveal Cone Metrics in Achromatopsia and Albinism Are Representative of Foveal Cone Structure.

Transl Vis Sci Technol 2021 05;10(6):22

Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: Adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in patients with achromatopsia (ACHM) and albinism is not always successful. Here, we tested whether optical coherence tomography (OCT) measures of foveal structure differed between patients for whom AOSLO images were either quantifiable or unquantifiable.

Methods: The study included 166 subjects (84 with ACHM; 82 with albinism) with previously acquired OCT scans, AOSLO images, and best-corrected visual acuity (BCVA, if available). Foveal OCT scans were assessed for outer retinal structure, outer nuclear layer thickness, and hypoplasia. AOSLO images were graded as quantifiable if a peak cone density could be measured and/or usable if the location of peak density could be identified and the parafoveal mosaic was quantifiable.

Results: Forty-nine percent of subjects with ACHM and 57% of subjects with albinism had quantifiable AOSLO images. Older age and better BCVA were found in subjects with quantifiable AOSLO images for both ACHM (P = 0.0214 and P = 0.0276, respectively) and albinism (P = 0.0073 and P < 0.0004, respectively). There was a significant trend between ellipsoid zone appearance and ability to quantify AOSLO (P = 0.0028). In albinism, OCT metrics of cone structure did not differ between groups.

Conclusions: Previously reported AOSLO-based cone density measures in ACHM may not necessarily reflect the degree of remnant cone structure in these patients.

Translational Relevance: Until AOSLO is successful in all patients with ACHM and albinism, the possibility of the reported data from a particular cohort not being representative of the entire population remains an important issue to consider when interpreting results from AOSLO studies.
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http://dx.doi.org/10.1167/tvst.10.6.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132001PMC
May 2021

Optical Coherence Tomography Artifacts Are Associated With Adaptive Optics Scanning Light Ophthalmoscopy Success in Achromatopsia.

Transl Vis Sci Technol 2021 01 7;10(1):11. Epub 2021 Jan 7.

Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: To determine whether artifacts in optical coherence tomography (OCT) images are associated with the success or failure of adaptive optics scanning light ophthalmoscopy (AOSLO) imaging in subjects with achromatopsia (ACHM).

Methods: Previously acquired OCT and non-confocal, split-detector AOSLO images from one eye of 66 subjects with genetically confirmed achromatopsia (15 and 51 ) were reviewed along with best-corrected visual acuity (BCVA) and axial length. OCT artifacts in interpolated vertical volumes from CIRRUS macular cubes were divided into four categories: (1) none or minimal, (2) clear and low frequency, (3) low amplitude and high frequency, and (4) high amplitude and high frequency. Each vertical volume was assessed once by two observers. AOSLO success was defined as sufficient image quality in split-detector images at the fovea to assess cone quantity.

Results: There was excellent agreement between the two observers for assessing OCT artifact severity category (weighted kappa = 0.88). Overall, AOSLO success was 47%. For subjects with OCT artifact severity category 1, AOSLO success was 65%; for category 2, 47%; for category 3, 11%; and for category 4, 0%. There was a significant association between OCT artifact severity category and AOSLO success ( = 0.0002). Neither BCVA nor axial length was associated with AOSLO success ( = 0.07 and = 0.75, respectively).

Conclusions: Artifacts in OCT volumes are associated with AOSLO success in ACHM. Subjects with less severe OCT artifacts are more likely to be good candidates for AOSLO imaging, whereas AOSLO was successful in only 7% of subjects with category 3 or 4 OCT artifacts. These results may be useful in guiding patient selection for AOSLO imaging.

Translational Relevance: Using OCT to prescreen patients could be a valuable tool for clinical trials that utilize AOSLO to reduce costs and decrease patient testing burden.
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http://dx.doi.org/10.1167/tvst.10.1.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804582PMC
January 2021

Current Clinical Applications of In Vivo Gene Therapy with AAVs.

Mol Ther 2021 02 10;29(2):464-488. Epub 2020 Dec 10.

Centre de Recherche du CHUQ-Université Laval, Québec, QC, Canada. Electronic address:

Hereditary diseases are caused by mutations in genes, and more than 7,000 rare diseases affect over 30 million Americans. For more than 30 years, hundreds of researchers have maintained that genetic modifications would provide effective treatments for many inherited human diseases, offering durable and possibly curative clinical benefit with a single treatment. This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity. There are now five treatments approved for commercialization and currently available, i.e., Luxturna, Zolgensma, the two chimeric antigen receptor T cell (CAR-T) therapies (Yescarta and Kymriah), and Strimvelis (the gammaretrovirus approved for adenosine deaminase-severe combined immunodeficiency [ADA-SCID] in Europe). Dozens of other treatments are under clinical trials. The review article presents a broad overview of the field of therapy by in vivo gene transfer. We review gene therapy for neuromuscular disorders (spinal muscular atrophy [SMA]; Duchenne muscular dystrophy [DMD]; X-linked myotubular myopathy [XLMTM]; and diseases of the central nervous system, including Alzheimer's disease, Parkinson's disease, Canavan disease, aromatic l-amino acid decarboxylase [AADC] deficiency, and giant axonal neuropathy), ocular disorders (Leber congenital amaurosis, age-related macular degeneration [AMD], choroideremia, achromatopsia, retinitis pigmentosa, and X-linked retinoschisis), the bleeding disorder hemophilia, and lysosomal storage disorders.
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http://dx.doi.org/10.1016/j.ymthe.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854298PMC
February 2021

Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation With Other Measures of Disease Severity.

Am J Ophthalmol 2020 11 22;219:87-100. Epub 2020 May 22.

Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DGOS CIC1423, Paris, France; Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Purpose: To report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study.

Design: Cross-sectional study within a natural history study.

Methods: Setting: multicenter, international.

Study Population: Usher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A.

Observation Procedures: Repeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (V) was assessed with general linear models. Associations between V and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests.

Main Outcome Measures: V (SP) and III4e isopter area (KP).

Results: USH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean V measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher V (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94).

Conclusions: USH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. V was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration.
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http://dx.doi.org/10.1016/j.ajo.2020.05.024DOI Listing
November 2020

Interocular Symmetry of Foveal Cone Topography in Congenital Achromatopsia.

Curr Eye Res 2020 10 13;45(10):1257-1264. Epub 2020 Mar 13.

Ophthalmology & Visual Sciences, Medical College of Wisconsin , Milwaukee, Wisconsin, USA.

: To determine the interocular symmetry of foveal cone topography in achromatopsia (ACHM) using non-confocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). : Split-detector AOSLO images of the foveal cone mosaic were acquired from both eyes of 26 subjects (mean age 24.3 years; range 8-44 years, 14 females) with genetically confirmed - or -associated ACHM. Cones were identified within a manually delineated rod-free zone. Peak cone density (PCD) was determined using an 80 × 80 μm sampling window within the rod-free zone. The mean and standard deviation (SD) of inter-cell distance (ICD) were calculated to derive the coefficient of variation (CV). Cone density difference maps were generated to compare cone topography between eyes. : PCD (mean ± SD) was 17,530 ± 9,614 cones/mm and 17,638 ± 9,753 cones/mm for right and left eyes, respectively ( = .677, Wilcoxon test). The mean (± SD) for ICD was 9.05 ± 2.55 µm and 9.24 ± 2.55 µm for right and left eyes, respectively ( = .410, paired -test). The mean (± SD) for CV of ICD was 0.16 ± 0.03 µm and 0.16 ± 0.04 µm for right and left eyes, respectively ( = .562, paired -test). Cone density maps demonstrated that cone topography of the ACHM fovea is non-uniform with local variations in cone density between eyes. : These results demonstrate the interocular symmetry of the foveal cone mosaic (both density and packing) in ACHM. As cone topography can differ between eyes of a subject, PCD does not completely describe the foveal cone mosaic in ACHM. Nonetheless, these findings are of value in longitudinal monitoring of patients during treatment trials and further suggest that both eyes of a given subject may have similar therapeutic potential and non-study eye can be used as a control.
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http://dx.doi.org/10.1080/02713683.2020.1737138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487033PMC
October 2020

Intraobserver Repeatability and Interobserver Reproducibility of Ellipsoid Zone Measurements in Retinitis Pigmentosa.

Transl Vis Sci Technol 2018 May 4;7(3):13. Epub 2018 Jun 4.

Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.

Purpose: To examine repeatability and reproducibility of ellipsoid zone (EZ) width measurements in patients with retinitis pigmentosa (RP) using a longitudinal reflectivity profile (LRP) analysis.

Methods: We examined Bioptigen optical coherence tomography (OCT) scans from 48 subjects with RP or Usher syndrome. Nominal scan lengths were 6, 7, or 10 mm, and the lateral scale of each scan was calculated using axial length measurements. LRPs were generated from OCT line scans, and the peak corresponding to EZ was manually identified using ImageJ. The locations at which the EZ peak disappeared were used to calculate EZ width. Each scan was analyzed twice by each of two observers, who were masked to their previous measurements and those of the other observer.

Results: On average, horizontal width (HW) was significantly greater than vertical width (VW), and there was high interocular symmetry for both HW and VW. We observed excellent intraobserver repeatability with intraclass correlation coefficients (ICCs) ranging from 0.996 to 0.998 for HW and VW measurements. Interobserver reproducibility was also excellent for both HW (ICC = 0.989; 95% confidence interval [CI] = 0.983-0.995) and VW (ICC = 0.991; 95% CI = 0.985-0.996), with no significant bias observed between observers.

Conclusions: EZ width can be measured using LRPs with excellent repeatability and reproducibility. Our observation of greater HW than VW is consistent with previous observations in RP, though the reason for this anisotropy remains unclear.

Translational Relevance: We describe repeatability and reproducibility of a method for measuring EZ width in patients with RP or Usher syndrome. This approach could facilitate measurement of retinal band thickness and/or intensity.
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http://dx.doi.org/10.1167/tvst.7.3.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989764PMC
May 2018

REPEATABILITY AND LONGITUDINAL ASSESSMENT OF FOVEAL CONE STRUCTURE IN CNGB3-ASSOCIATED ACHROMATOPSIA.

Retina 2017 Oct;37(10):1956-1966

*Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin; †Casey Eye Institute, Oregon Health & Science University, Portland, Oregon; ‡Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin; §Alexandria Faculty of Medicine, University of Alexandria, Alexandria, Egypt; ¶Pangere Center for Inherited Retinal Diseases, The Chicago Lighthouse, Chicago, Illinois; **Vitreo Retinal Associates, Gainesville, Florida; ††Bascom Palmer Eye Institute, University of Miami, Miami, Florida; ‡‡Applied Genetics Technologies Corporation (AGTC), Alachua, Florida; §§Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin; and ¶¶Department of Ophthalmology, University of Florida, Gainesville, Florida.

Purpose: Congenital achromatopsia is an autosomal recessive disease causing substantial reduction or complete absence of cone function. Although believed to be a relatively stationary disorder, questions remain regarding the stability of cone structure over time. In this study, the authors sought to assess the repeatability of and examine longitudinal changes in measurements of central cone structure in patients with achromatopsia.

Methods: Forty-one subjects with CNGB3-associated achromatopsia were imaged over a period of between 6 and 26 months using optical coherence tomography and adaptive optics scanning light ophthalmoscopy. Outer nuclear layer (ONL) thickness, ellipsoid zone (EZ) disruption, and peak foveal cone density were assessed.

Results: ONL thickness increased slightly compared with baseline (0.184 μm/month, P = 0.02). The EZ grade remained unchanged for 34/41 subjects. Peak foveal cone density did not significantly change over time (mean change 1% per 6 months, P = 0.126).

Conclusion: Foveal cone structure showed little or no change in this group of subjects with CNGB3-associated achromatopsia. Over the time scales investigated (6-26 months), achromatopsia seems to be a structurally stable condition, although longer-term follow-up is needed. These data will be useful in assessing foveal cone structure after therapeutic intervention.
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http://dx.doi.org/10.1097/IAE.0000000000001434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537050PMC
October 2017

CILIOCHOROIDAL EFFUSION AND ACUTE MACULAR NEURORETINOPATHY ASSOCIATED WITH CERVICAL TRACTION THERAPY.

Retin Cases Brief Rep 2018 Winter;12(1):24-28

Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, MI.

Purpose: To report an unusual case of ciliochoroidal effusion and presumed acute macular neuroretinopathy associated with cervical traction therapy for the treatment of cervical spinal stenosis.

Methods: Case report.

Results: A 75-year-old man reported sudden onset of a wedge-shaped paracentral scotoma in the right eye. Fundus examination showed a ciliochoroidal effusion in the right eye. Optical coherence tomography revealed intraretinal fluid in both eyes without leakage on fluorescein angiography. B-scan ultrasonography and anterior segment ultrasound biomicroscopy of the right eye showed peripheral ciliochoroidal effusion. He had recently started intensive cervical traction therapy for the treatment of cervical spinal stenosis. There was spontaneous resolution of the choroidal effusion and intraretinal fluid after stopping cervical traction treatments. Optical coherence tomography imaging after resolution of the intraretinal fluid revealed thinning of the outer nuclear layer and attenuation of the ellipsoid and interdigitation zones corresponding to a persistent paracentral scotoma, consistent with acute macular neuroretinopathy.

Conclusion: This is the first report of adverse ocular effects of cervical traction. We postulate that venous and arterial compromise during cervical traction therapy resulted in both ciliochoroidal effusion and a watershed infarct in the outer retina.
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http://dx.doi.org/10.1097/ICB.0000000000000434DOI Listing
February 2018

Residual Foveal Cone Structure in CNGB3-Associated Achromatopsia.

Invest Ophthalmol Vis Sci 2016 08;57(10):3984-95

Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States 2Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States 9Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin, Un.

Purpose: Congenital achromatopsia (ACHM) is an autosomal recessive disorder in which cone function is absent or severely reduced. Gene therapy in animal models of ACHM have shown restoration of cone function, though translation of these results to humans relies, in part, on the presence of viable cone photoreceptors at the time of treatment. Here, we characterized residual cone structure in subjects with CNGB3-associated ACHM.

Methods: High-resolution imaging (optical coherence tomography [OCT] and adaptive optics scanning light ophthalmoscopy [AOSLO]) was performed in 51 subjects with CNGB3-associated ACHM. Peak cone density and inter-cone spacing at the fovea was measured using split-detection AOSLO. Foveal outer nuclear layer thickness was measured in OCT images, and the integrity of the photoreceptor layer was assessed using a previously published OCT grading scheme.

Results: Analyzable images of the foveal cones were obtained in 26 of 51 subjects, with nystagmus representing the major obstacle to obtaining high-quality images. Peak foveal cone density ranged from 7,273 to 53,554 cones/mm2, significantly lower than normal (range, 84,733-234,391 cones/mm2), with the remnant cones being either contiguously or sparsely arranged. Peak cone density was correlated with OCT integrity grade; however, there was overlap of the density ranges between OCT grades.

Conclusions: The degree of residual foveal cone structure varies greatly among subjects with CNGB3-associated ACHM. Such measurements may be useful in estimating the therapeutic potential of a given retina, providing affected individuals and physicians with valuable information to more accurately assess the risk-benefit ratio as they consider enrolling in experimental gene therapy trials. (www.clinicaltrials.gov, NCT01846052.).
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http://dx.doi.org/10.1167/iovs.16-19313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4978151PMC
August 2016

Assessing Photoreceptor Structure in Retinitis Pigmentosa and Usher Syndrome.

Invest Ophthalmol Vis Sci 2016 05;57(6):2428-42

Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States 2Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States 3Department of Biomedical Engineering, Ma.

Purpose: The purpose of this study was to examine cone photoreceptor structure in retinitis pigmentosa (RP) and Usher syndrome using confocal and nonconfocal split-detector adaptive optics scanning light ophthalmoscopy (AOSLO).

Methods: Nineteen subjects (11 RP, 8 Usher syndrome) underwent ophthalmic and genetic testing, spectral-domain optical coherence tomography (SD-OCT), and AOSLO imaging. Split-detector images obtained in 11 subjects (7 RP, 4 Usher syndrome) were used to assess remnant cone structure in areas of altered cone reflectivity on confocal AOSLO.

Results: Despite normal interdigitation zone and ellipsoid zone appearance on OCT, foveal and parafoveal cone densities derived from confocal AOSLO images were significantly lower in Usher syndrome compared with RP. This was due in large part to an increased prevalence of non-waveguiding cones in the Usher syndrome retina. Although significantly correlated to best-corrected visual acuity and foveal sensitivity, cone density can decrease by nearly 38% before visual acuity becomes abnormal. Aberrantly waveguiding cones were noted within the transition zone of all eyes and corresponded to intact inner segment structures. These remnant cones decreased in density and increased in diameter across the transition zone and disappeared with external limiting membrane collapse.

Conclusions: Foveal cone density can be decreased in RP and Usher syndrome before visible changes on OCT or a decline in visual function. Thus, AOSLO imaging may allow more sensitive monitoring of disease than current methods. However, confocal AOSLO is limited by dependence on cone waveguiding, whereas split-detector AOSLO offers unambiguous and quantifiable visualization of remnant cone inner segment structure. Confocal and split-detector thus offer complementary insights into retinal pathology.
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http://dx.doi.org/10.1167/iovs.15-18246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089122PMC
May 2016

Evaluating Efficacy of Aflibercept in Refractory Exudative Age-Related Macular Degeneration With OCT Segmentation Volumetric Analysis.

Ophthalmic Surg Lasers Imaging Retina 2016 Mar;47(3):245-51

Background And Objective: To use automated segmentation software to analyze spectral-domain optical coherence tomography (SD-OCT) scans and evaluate the effectiveness of aflibercept (Eylea; Regeneron, Tarrytown, NY) in the treatment of patients with exudative age-related macular degeneration (AMD) refractory to other treatments.

Patients And Methods: Retrospective chart review of 16 patients refractory to bevacizumab (Avastin; Genentech, South San Francisco, CA)/ranibizumab (Lucentis; Genentech, San Francisco, CA) treatment was conducted. Visual acuity, central foveal thickness (CFT), maximum fluid height, pigment epithelial detachment (PED) volume, sub-retinal fluid (SRF) volume, fluid-free time interval, and adverse effects were evaluated. Automated segmentation analysis was used to quantify improvement.

Results: With aflibercept treatment, there was a statistically significant improvement in visual acuity by 1 line (P = .020), in CFT by 74.02 µm (P = .001), and in maximum fluid height by 31.9 µm (P= .011). Total PED and SRF volume also decreased significantly by 1.50 µm(3) × 10(8) µm(3) (P = .013). Anatomic improvement was confirmed by automated segmentation analysis.

Conclusion: This study demonstrates utility of automated segmentation software in quantifying anatomic improvement with aflibercept treatment in exudative AMD refractory to other anti-vascular endothelial growth factor treatments.
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http://dx.doi.org/10.3928/23258160-20160229-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750045PMC
March 2016

Role for rapid surgical intervention in uveal effusion syndrome with associated optic neuropathy.

Ophthalmic Surg Lasers Imaging Retina 2014 Apr 4;45 Online:e11-3. Epub 2014 Apr 4.

Uveal effusion syndrome (UES) can be associated with nanophthalmos and rarely can present with concomitant optic neuropathy. This case report describes nanophthalmic UES and optic neuropathy treated with early sclerectomies. One month postoperatively, the patient experienced significant improvement in choroidal effusions and optic neuropathy, with increases in visual acuity and visual fields. Early scleral windows surgery for UES with associated optic neuropathy can provide prompt improvement of choroidal swelling, optic nerve edema, and vision, although the relapsing course of this disease presents a challenge to long-term visual prognosis.
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http://dx.doi.org/10.3928/23258160-20140331-04DOI Listing
April 2014

Spectral domain optical coherence tomography findings in CNGB3-associated achromatopsia and therapeutic implications.

Adv Exp Med Biol 2014 ;801:551-7

Department of Ophthalmology, University of Florida College of Medicine, 32610-0284, Gainesville, FL, USA,

We describe the spectral domain OCT findings in two siblings with CNGB3-associated achromatopsia. A 33-year-old female and her 31-year-old sibling were evaluated for mild nystagmus and decreased visual acuity which had been present since childhood. They were each evaluated with full field Ganzfeld electroretinography which demonstrated flat photopic responses and preserved rod function. Genetic testing performed at Carver lab at the University of Iowa confirmed a diagnosis of achromatopsia with identical mutations in the CNGB3 gene. Spectral domain optical coherence tomography was performed which revealed foveal changes in both siblings, with slight phenotypic variations in these genotypically identical siblings. OCT findings in achromatopsia emphasize the importance of early identification and treatment in this disorder.
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http://dx.doi.org/10.1007/978-1-4614-3209-8_70DOI Listing
July 2014

Decreased macular thickness in nonproliferative macular telangiectasia type 2 with oral carbonic anhydrase inhibitors.

Retina 2014 Jul;34(7):1400-6

Department of Ophthalmology and Visual Science, University of Iowa, Iowa City, Iowa.

Purpose: To evaluate whether carbonic anhydrase inhibitors reduce the macular thickness and/or cystic spaces in patients with macular telangiectasia (MacTel) Type 2.

Methods: Retrospective review of patients with nonproliferative cystoid changes associated with MacTel seen at the University of Iowa between 2009 and 2012. Carbonic anhydrase inhibitors were used in 8 patients with MacTel Type 2. Five patients with MacTel Type 2 were observed during this period. Initial and final visual acuities were documented. The presence of cystic spaces and the retinal thickness were measured with spectral-domain optical coherence tomography.

Results: Patients treated with oral carbonic anhydrase inhibitors showed significant reduction in both the cystoid cavities and central macular thickness when compared with the patients who were observed (-12.2 μm; P = 0.020). The reduction in retinal thickness was more pronounced in patients receiving acetazolamide (-20.13 μm; P = 0.007) compared with methazolamide (-6.25 μm; P = 0.177). There was no significant change in visual acuity in patients receiving carbonic anhydrase inhibitors. Five patients with MacTel Type 2 did not receive treatment and demonstrated no change in visual acuity, cystoid cavities, or central macular thickness.

Conclusion: Oral carbonic anhydrase inhibitors, particularly acetazolamide, may decrease macular cystic cavities and reduce central macular thickness but does not appear to improve visual acuity. These findings have yet to be confirmed with a prospective treatment trial.
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http://dx.doi.org/10.1097/IAE.0000000000000093DOI Listing
July 2014

Retinal pigment epithelial detachment in ABCA4-associated Stargardt's disease.

Ophthalmic Surg Lasers Imaging Retina 2013 Jul-Aug;44(4):401-4

University of Florida College of Medicine, Gainesville, Florida 32610-0284, USA.

The authors describe bilateral and sequential pigment epithelial detachment (PED) formation in a 16-year-old girl with ABCA4-associated Stargardt's disease (STGD1). On routine examination, a new large PED was observed in the left eye with late leakage evident on fluorescein angiography suggestive of possible occult choroidal neovascularization. The lesion was therefore treated with bevacizumab, but with no involutional lesion response. Months later, a similar lesion appeared in the right eye. The authors believe this to be the first reported case of acute bilateral and sequential PED development in a patient with ABCA4-associated STGD1. Optical coherence tomography-guided morphological analysis of lesion development in ABCA4 disease with documentation of PED formation may suggest a plausible role for disruption at the level of Bruch's membrane in the pathophysiology of STGD1.
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http://dx.doi.org/10.3928/23258160-20130715-11DOI Listing
February 2014

Fulminant chorioretinitis and papillitis secondary to coxsackievirus B presenting as acute posterior multifocal placoid pigment epitheliopathy with positive response to intravenous immunoglobulin.

Retin Cases Brief Rep 2013 ;7(3):225-31

*Department of Ophthalmology, University of Florida, Gainesville, Florida; and †Retina Associates of Florida, Tampa, Florida.

Purpose: To describe a case of fulminant bilateral papillitis and chorioretinitis in the setting of positive coxsackievirus B titers, which convalesced months after the patient's presentation. The patient presented with an acute posterior multifocal placoid pigment epitheliopathy-like clinical picture and her visual acuity and visual field improved moderately after initiation of treatment with intravenous immunoglobulin.

Methods: Case report of a white female with bilateral blurred vision is presented in this study.

Results: A previously healthy 59-year-old white woman presented with a 3-day history of bilateral blurred vision. Initial visual acuity was hand motion in the right eye and count fingers in the left eye. Extensive workup and imaging was done and she was empirically started on intravenous antibiotics followed 24 hours later by intravenous steroids. The patient was found to have high titers of coxsackievirus B and sustained modest visual acuity and perimetry improvement in one eye after intravenous immunoglobulin infusion.

Conclusion: A case of fulminant bilateral chorioretinitis and papillitis that resulted in bilateral vision loss despite high-dose steroids within 24 hours of initial loss in vision is presented in this study. The patient was found to have high titers of coxsackievirus B3, B4,B5 after presentation and her condition improved after treatment with intravenous immunoglobulin, suggesting a plausible immune component.
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http://dx.doi.org/10.1097/ICB.0b013e31828993c6DOI Listing
January 2015

Targeting photoreceptors via intravitreal delivery using novel, capsid-mutated AAV vectors.

PLoS One 2013 26;8(4):e62097. Epub 2013 Apr 26.

Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States of America.

Development of viral vectors capable of transducing photoreceptors by less invasive methods than subretinal injection would provide a major advancement in retinal gene therapy. We sought to develop novel AAV vectors optimized for photoreceptor transduction following intravitreal delivery and to develop methodology for quantifying this transduction in vivo. Surface exposed tyrosine (Y) and threonine (T) residues on the capsids of AAV2, AAV5 and AAV8 were changed to phenylalanine (F) and valine (V), respectively. Transduction efficiencies of self-complimentary, capsid-mutant and unmodified AAV vectors containing the smCBA promoter and mCherry cDNA were initially scored in vitro using a cone photoreceptor cell line. Capsid mutants exhibiting the highest transduction efficiencies relative to unmodified vectors were then injected intravitreally into transgenic mice constitutively expressing a Rhodopsin-GFP fusion protein in rod photoreceptors (Rho-GFP mice). Photoreceptor transduction was quantified by fluorescent activated cell sorting (FACS) by counting cells positive for both GFP and mCherry. To explore the utility of the capsid mutants, standard, (non-self-complementary) AAV vectors containing the human rhodopsin kinase promoter (hGRK1) were made. Vectors were intravitreally injected in wildtype mice to assess whether efficient expression exclusive to photoreceptors was achievable. To restrict off-target expression in cells of the inner and middle retina, subsequent vectors incorporated multiple target sequences for miR181, an miRNA endogenously expressed in the inner and middle retina. Results showed that AAV2 containing four Y to F mutations combined with a single T to V mutation (quadY-F+T-V) transduced photoreceptors most efficiently. Robust photoreceptor expression was mediated by AAV2(quadY-F+T-V) -hGRK1-GFP. Observed off-target expression was reduced by incorporating target sequence for a miRNA highly expressed in inner/middle retina, miR181c. Thus we have identified a novel AAV vector capable of transducing photoreceptors following intravitreal delivery to mouse. Furthermore, we describe a robust methodology for quantifying photoreceptor transduction from intravitreally delivered AAV vectors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062097PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637363PMC
November 2013

Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid.

Br J Ophthalmol 2013 Jul 20;97(7):895-9. Epub 2013 Apr 20.

University of Florida, College of Medicine, Gainesville, Florida 32610-0284, USA.

Aims: The purpose of this study was to determine the long-term efficacy and safety of valproic acid (VPA) treatment in patients with pigmentary retinal dystrophies.

Methods: A retrospective chart review was conducted on 31 patients with a diagnosis of pigmentary retinal dystrophy prescribed VPA at a single centre. Visual field (VF), visual acuity (VA), length of treatment, liver enzymes and side effects were analysed. VF areas were defined using Goldmann VF (GVF) tracings recorded before, during and after VPA treatment using the V4e isopter for each eye. Using custom software, planimetric areas of VF were calculated.

Results: Five of the patients (10 eyes) had two Goldmann VF tracings, allowing comparison between baseline and follow-up VF. After 9.8 months of VPA, VF decreased by 0.145 cm(2) (26.478%) (p=0.432). For 22 of the patients (41 eyes), VA data was available, and logarithm of the minimum angle of resolution (logMAR) score changed by 0.056 log units (representing a decline in VA) after 14.9 months on VPA (p=0.002). Twelve patients (38.7%) reported negative side effects related to VPA use.

Conclusions: VPA plays a complex role in patients with pigmentary retinal dystrophies and may be associated with VA and field decline as well as adverse side effects. Physicians should use caution with using VPA for pigmentary retinal dystrophies.
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http://dx.doi.org/10.1136/bjophthalmol-2013-303084DOI Listing
July 2013

Elimination of infusion bubbles and uncontrolled reflux in the alcon constellation vitrectomy vision system.

Retina 2013 Apr;33(4):803-6

Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242, USA.

Purpose: To identify the sources and management of 2 problems associated with the Alcon Constellation Vitrectomy (Alcon Laboratories, Inc) System: 1) infusion bubbles and 2) uncontrolled reflux.

Methods: Surgical and analytical videos were evaluated to identify the source of intraoperative bubbles, which localized to the duckbill valve (DV). Intraoperatively, the authors modified the infusion tubing and its control by removing the DV. The DV was repurposed as a one-way valve to block reflux originating from the vitrectomy console.

Results: Twenty consecutive 23-gauge vitrectomies in 20 eyes of 20 subjects from 2 surgeons (S.R.R. and E.H.S.) were reviewed. Infusion bubbles at the DV developed with each transitory tubing pressure drop upon opening of the infusion clamp. Removal of the DV from the infusion line eliminated infusion bubbles in 20 consecutive 23-gauge cases. Adding a one-way valve, which was fashioned from the DV, to the aspiration tubing, resulted in elimination of infusion bubbles and console-originated reflux in 20 eyes. Placement of the DV to block reflux eliminated both uncontrolled and purposeful console-originated reflux.

Conclusion: Intraoperative modification of Constellation tubing may eliminate two potentially harmful problems until manufacturer correction is instituted. Because the authors' modified connections represent off-label connectivity, the manufacturer cannot contact potentially affected surgeons or suggest temporary alternative connectivity improvements.
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http://dx.doi.org/10.1097/IAE.0b013e31826c20c6DOI Listing
April 2013

AAV-mediated gene therapy in the guanylate cyclase (RetGC1/RetGC2) double knockout mouse model of Leber congenital amaurosis.

Hum Gene Ther 2013 Feb;24(2):189-202

Department of Ophthalmology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.

Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1). GUCY2D encodes photoreceptor-specific, retinal guanylate cyclase-1 (RetGC1). Reports of retinal degeneration in LCA1 are conflicting; some describe no obvious degeneration and others report loss of both rods and cones. Proof of concept studies in models representing the spectrum of phenotypes is warranted. We have previously demonstrated adeno-associated virus (AAV)-mediated RetGC1 is therapeutic in GC1ko mice, a model exhibiting loss of cones only. The purpose of this study was to characterize AAV-mediated gene therapy in the RetGC1/RetGC2 double knockout (GCdko) mouse, a model lacking rod and cone function and exhibiting progressive loss of both photoreceptor subclasses. Use of this model also allowed for the evaluation of the functional efficiency of transgenic RetGC1 isozyme. Subretinal delivery of AAV8(Y733F) vector containing the human rhodopsin kinase (hGRK1) promoter driving murine Gucy2e was performed in GCdko mice at various postnatal time points. Treatment resulted in restoration of rod and cone function at all treatment ages and preservation of retinal structure in GCdko mice treated as late as 7 weeks of age. Functional gains and structural preservation were stable for at least 1 year. Treatment also conferred cortical- and subcortical-based visually-guided behavior. Functional efficiency of transgenic RetGC1 was indistinguishable from that of endogenous isozyme in congenic wild-type (WT) mice. This study clearly demonstrates AAV-mediated RetGC1 expression restores function to and preserves structure of rod and cone photoreceptors in a degenerative model of retinal guanylate cyclase deficiency, further supporting development of an AAV-based vector for treatment of LCA1.
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http://dx.doi.org/10.1089/hum.2012.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581260PMC
February 2013

23-gauge pediatric vitrectomy using limbus-based trocar-cannulas.

Retina 2012 May;32(5):1023-7

Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242, USA.

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http://dx.doi.org/10.1097/IAE.0b013e3182533d85DOI Listing
May 2012

Resolution of refractory macular edema because of branch retinal vein occlusion after ozurdex implantation.

Retin Cases Brief Rep 2012 ;6(1):72-5

From the *Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, and †Carver Center for Macular Degeneration, Carver School of Medicine, The University of Iowa, Iowa City, Iowa.

Purpose: To report a case of a woman with a branch vein occlusion and macular edema refractory to grid laser, intravitreal bevacizumab, pars plana vitrectomy with sheathotomy of the arteriovenous branch site, and intravitreal triamcinolone, who had complete resolution of fluid after injection of a dexamethasone intravitreal implant (DEX implant, Ozurdex; Allergan, Inc, Irvine, CA).

Methods: A 75-year-old woman with a branch vein occlusion and macular edema was treated with grid laser, intravitreal bevacizumab, pars plana vitrectomy with sheathotomy, and intravitreal triamcinolone. Neither edema nor vision improved. She was treated with an Ozurdex intravitreal implant.

Results: One month after Ozurdex intravitreal implantation, the patient's visual acuity and edema had improved dramatically. The macula remained flat until 5 months after injection when the edema returned and a second Ozurdex was injected. One month later, the macular edema was significantly less and visual acuity had improved to 20/50 with pinhole.

Conclusion: Ozurdex may be effective in reducing macular edema because of a branch retinal vein occlusion in eyes refractory to multiple other treatments.
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http://dx.doi.org/10.1097/ICB.0b013e3182051febDOI Listing
November 2014

Three-dimensional distribution of the vitelliform lesion, photoreceptors, and retinal pigment epithelium in the macula of patients with best vitelliform macular dystrophy.

Arch Ophthalmol 2012 Mar 14;130(3):357-64. Epub 2011 Nov 14.

Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, University of Iowa, Iowa City, IA 52242, USA.

Objective: To describe the anatomical phenotypes of Best vitelliform macular dystrophy (BVMD) with spectral-domain optical coherence tomography (SD-OCT) in a large series of patients with confirmed mutations in the BEST1 gene.

Methods: In our retrospective observational case series, we assessed 15 patients (30 eyes) with a clinical diagnosis of vitelliform macular dystrophy who were found to have mutations in the BEST1 gene. Color fundus photographs and SD-OCT images were evaluated and compared with those of 15 age-matched controls (30 eyes). Using a validated 3-dimensional SD-OCT segmentation algorithm, we calculated the equivalent thickness of photoreceptors and the equivalent thickness of the retinal pigment epithelium for each patient. The photoreceptor equivalent thickness and the retinal pigment epithelium (RPE) equivalent thickness were compared in all patients, in a region of the macula outside the central lesion for patients with BVMD and outside the fovea in control patients. Paired t tests were used for statistical analysis.

Results: The SD-OCT findings revealed that the vitelliform lesion consists of material above the RPE and below the outer segment tips. Additionally, drusen-like deposition of sub-RPE material was notable, and several patients exhibited a sub-RPE fibrotic nodule. Patients with BVMD had a mean photoreceptor equivalent thickness of 28.3 μm, and control patients had a mean photoreceptor equivalent thickness of 21.8 μm, a mean difference of 6.5 μm (P < .01), whereas the mean RPE equivalent thickness was not statistically different between patients with BVMD and control patients (P = .53).

Conclusions: The SD-OCT findings suggest that vitelliform material is located in the subretinal space and that BVMD is associated with diffuse photoreceptor outer segment abnormalities overlying a structurally normal RPE.

Clinical Relevance: These findings provide new insight into the pathophysiology of BVMD and thus have implications for the development of therapeutic interventions.
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http://dx.doi.org/10.1001/archophthalmol.2011.363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702508PMC
March 2012

Uveitis following intravitreal bevacizumab: a non-infectious cluster.

Ophthalmic Surg Lasers Imaging 2011 Jul-Aug;42(4):292-6

Vitreoretinal Service, Department of Ophthalmology & Visual Sciences, Carver School of Medicine, The University of Iowa, Iowa City, Iowa, USA.

Background And Objective: In this retrospective case series, the authors report seven cases of bevacizumab-related uveitis that occurred within a 4-month period.

Patients And Methods: Seven eyes of six patients developed non-infectious uveitis following bevacizumab intravitreal injections in a cohort of 978 consecutive bevacizumab injections.

Results: The mean age of patients was 74.6 years (range: 26 to 92). All patients developed symptom onset within 1 day of injection. Shared signs and symptoms included corneal edema, anterior chamber and vitreous cell, conjunctival injection, ocular pain, and lack of hypopyon. In all patients, visual acuity returned to within one line of baseline acuity. All seven eyes had been previously injected with bevacizumab, with a mean number of antecedent injections of 6.1 (range: 3 to 12).

Conclusion: A cluster of sterile bevacizumab-related uveitic reactions was described in this case series. Acute onset of symptoms, absence of hypopyon, a predominant anterior segment reaction, and prompt improvement on topical steroid therapy are useful clinical features distinguishing this uveitic syndrome from infectious endophthalmitis.
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http://dx.doi.org/10.3928/15428877-20110603-04DOI Listing
November 2011

Autosomal recessive vitelliform macular dystrophy in a large cohort of vitelliform macular dystrophy patients.

Retina 2011 Mar;31(3):581-95

Department of Ophthalmology and Visual Sciences, Carver Family Center for Macular Degeneration, University of Iowa, Iowa City, Iowa 52242, USA.

Purpose: To report 11 cases of autosomal recessive vitelliform macular dystrophy and to compare their molecular findings and phenotypic characteristics with those of patients with the more common and well-described dominant form of the disease.

Methods: Blood samples were obtained from 435 unrelated individuals with a clinical diagnosis of vitelliform macular dystrophy and screened for mutations in the coding sequences of BEST1. Medical records and retinal photographs of selected patients were reviewed.

Results: Nine of the 435 probands were found to have 2 plausible disease-causing variations in BEST1, while 198 individuals were found to have heterozygous variations compatible with autosomal dominant inheritance. Inheritance phase was determined in three of the recessive families. Six novel disease-causing mutations were identified among these recessive patients: Arg47Cys, IVS7-2A>G, IVS7+4G>A, Ile205del12ATCCTGCTCCAGAG, Pro274Arg, and Ile366delCAGGTGTGGC. Forty-four novel disease-causing mutations were identified among the patients with presumed autosomal dominant disease. The phenotype of patients with recessive alleles for BEST1 ranged from typical vitelliform lesions to extensive extramacular deposits.

Conclusion: The authors provide evidence that two abnormal BEST1 alleles, neither of which causes macular disease alone, can act in concert to cause early-onset vitelliform macular dystrophy.
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http://dx.doi.org/10.1097/IAE.0b013e318203ee60DOI Listing
March 2011

Neurosensory retinal detachment of the macula in retinal phototoxicity documented by optical coherence tomography.

Retin Cases Brief Rep 2010 ;4(2):143-5

From the Department of Ophthalmology, University of South Florida College of Medicine, Tampa, Florida.

Purpose: To report a neurosensory detachment documented by optical coherence tomography in operating light microscope-induced retinal phototoxicity.

Methods: A 53-year-old man had a pars plana lensectomy, core vitrectomy, and posterior chamber sutured intraocular lens implantation in his right eye. The surgery lasted >3 hours.

Results: On postoperative Day 13, best-corrected visual acuity was 20/100. There was retinal pigment epithelial atrophy in the superior macula with subtle pigmentary clumping on its borders. Fluorescein angiography revealed staining in the area of retinal pigment epithelium atrophy with blockage of underlying choroidal fluorescence by the border hyperpigmentation in a pattern typical of phototoxicity. Optical coherence tomography documented a large, central neurosensory detachment. The central macular thickness was 731 μm. Best-corrected visual acuity in the right eye on postoperative Day 31 had improved to 20/60, and the optical coherence tomography had minimal subretinal fluid with a central macular thickness of 226 μm. On postoperative Day 78, there was no subretinal fluid, best-corrected visual acuity was 20/50, and the central macular thickness was 191 μm. Four months postoperatively, best-corrected visual acuity was 20/30.

Conclusion: Microscope light-induced retinal phototoxicity may be associated with a neurosensory detachment.
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http://dx.doi.org/10.1097/ICB.0b013e3181997ce7DOI Listing
November 2014

Composite spectral domain optical coherence tomography images of diabetic tractional retinal detachment.

Ophthalmic Surg Lasers Imaging 2008 Jul-Aug;39(4 Suppl):S99-103

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.

This article describes the spectral domain optical coherence tomography (SD-OCT) findings in three patients with diabetic tractional retinal detachment. Three patients underwent fundus photography and SD-OCT imaging before and after pars plana vitrectomy, endola-ser, and membrane peel. On SD-OCT, all three patients exhibited significant improvement or resolution of subretinal fluid after the surgical release of traction. In this case series, a clinically useful method of visualizing SD-OCT images is demonstrated. Composite images were manually constructed with commercially available software by merging high-density B-scans from the macula and optic nerve. The composite image allowed simultaneous visualization of the effects of proliferative diabetic retinopathy on the macula and optic nerve and is particularly helpful in evaluating tractional macular detachment.
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http://dx.doi.org/10.3928/15428877-20080715-06DOI Listing
September 2008
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