Voretigene Neparvovec for the Treatment of RPE65-associated Retinal Dystrophy: Consensus and Recommendations from the Korea RPE65-IRD Consensus Paper Committee

Mutations in the RPE65 gene, associated with Leber congenital amaurosis, early-onset severe retinal dystrophy, and retinitis pigmentosa, gained growing attention since gene therapy for patients with RPE65-associated retinal dystrophy is available in clinical practice. RPE65 gene accounts for a very small proportion of patients with inherited retinal degeneration, especially Asian patients. Because RPE65-associated retinal dystrophy shares common clinical characteristics, such as early-onset severe nyctalopia, nystagmus, low vision, and progressive visual field constriction, with retinitis pigmentosa by other genetic mutations, appropriate genetic testing is essential to make a correct diagnosis. Also, fundus abnormalities can be minimal in early childhood, and the phenotype is highly variable depending on the type of mutations in RPE65-associated retinal dystrophy, which makes a diagnostic difficulty. The aim of this paper is to review the epidemiology of RPE65-associated retinal dystrophy, mutation spectrum, genetic diagnosis, clinical characteristics, and voretigene neparvovec, a gene therapy product for the treatment of RPE65-related retinal dystrophy.

Clinical and Genetic Findings in Korean Patients with Choroideremia

Purpose@#We share and analyze the clinical presentations and genotypes of Korean male patients and female carriers who visited our clinic. @*Methods@#Six male patients and three female carriers with comprehensive ophthalmic examinations and next-generation sequencing were included. Detailed clinical features were identified using visual field (VF) test and multimodal imaging including color fundus photography, fundus autofluorescence (FAF), and optical coherence tomography (OCT). @*Results@#Six male patients were diagnosed with choroideremia at the median age of 25 years. Before genetic testing, three patients (50.0%) were clinically diagnosed with choroideremia, while the other three patients (50.0%) with retinitis pigmentosa. Patients showed different types of hemizygous CHM variants, including two nonsense variants, c.715C>T:p.(Arg239*) and c.799C>T:p.(Arg267*); two frameshift variants, c.1584_1587del:p.(Val529Hisfs*7) and c.403_404del:p.(Asp135Phefs*9); one splicing variant c.1511-28_1511-2del; and one exon 2-8 duplication. The latter three variants were novel. Two female carriers had heterozygous exon 2-8 duplication and the other one female carrier had heterozygous nonsense variant c.715C>T:p. (Arg239*). Fundus showed diffuse yellow-whitish scleral reflex and granular pigmented lesions. FAF showed multiple patchy hypofluorescence lesions, sparing macula. OCT showed thinning of outer nuclear layer, ellipsoid zone, retinal pigment epithelium layer, choroid thickness, interlaminar bridges, outer retinal tubulations, and microcysts in the inner nuclear layer. VF showed ring scotoma pattern with small amount of remaining central field. Asymptomatic female carriers showed variable fundus findings and mild changes in OCT. @*Conclusions@#A detailed description of the genotypes with three novel mutations and phenotypes of six choroideremia patients and three CHM mutation female carriers are presented.

A Prototype of a Stereoacuity Test Using a Head-Mounted Display

Purpose@#To evaluate the test-retest reliability of a contour-based stereoacuity test using a head-mounted display (HMD) and compare it with other stereotests. @*Methods@#Thirty-two healthy adults aged 23-47 years were recruited from a tertiary hospital between August 2017 and July 2018. Two separate contour-based circles (crossed disparity: 135-1,350 arcsecs) were generated on a high-resolution phone display (Galaxy S7; Samsung, Seoul, Korea) using an HMD (Galaxy Gear VR). Two images were independently projected to each eye as graded circles with a random dot background. The results of the new HMD stereotest were compared to those of the standard Randot and TNO stereotests. The test-retest reliability was assessed using the Bland-Altman plot and Cohen’s kappa statistics. @*Results@#Among the 32 study participants, 17 (53%) were males and the mean age was 30.1 ± 4.8 years (range: 23-47). The mean stereoacuity was 160.3 ± 53.5 arcsecs in the first HMD stereotest (HMD1), 28.4 ± 12.5 arcsecs in the Randot stereotest, 96.1 ± 83.5 arcsecs in the TNO stereotest, and 143.3 ± 47.7 arcsecs in the second HMD stereotest (HMD2). The Bland-Altman plot showed a mean difference of 0.042 (-0.189 to +0.272, 95% limits of agreement) between HMD1 and HMD2. The reliability analysis showed an intraclass correlation coefficient of 0.499 (p = 0.022) and agreement of 81.25% in Cohen’s kappa statistics (Cohen’s kappa index = 0.119, p = 0.017). @*Conclusions@#The HMD stereotest without monocular cues showed fair test-retest reliability and reproducibility. Further studies using a high resolution display are needed to confirm the validity of the HMD stereotest.

Effectiveness of Inferior Oblique Myectomy in Unilateral Superior Oblique Palsy Depending on Magnitude of Hyperdeviation

Purpose@#To evaluate surgical outcome and effectiveness of inferior oblique (IO) myectomy on unilateral superior oblique palsy (SOP) as a primary treatment. @*Methods@#This study is a retrospective review of the medical records of 99 patients who had undergone IO myectomy due to SOP as a first-line treatment. Sixty-five patients with hyperdeviation of 15 prism diopters (PD) or less were categorized into group 1, 22 patients with hyperdeviation between 16 PD to 20 PD into group 2, and 12 patients with hyperdeviation higher than 20 PD into group 3. Preoperative hyperdeviation, postoperative hyperdeviation, and improvement of head tilting were then compared between the 3 groups. Surgery was determined to be successful when the post-op residual hyperdeviation is less than 5 PD, or when the improvement of hyperdeviation and head tilting was noted, for the patients who had preoperative deviation less than 5 PD, and without hypercorrection. @*Results@#All groups showed significant improvement of hyperdeviation, and the amount of correction was larger in group with larger preoperative hyperdeviation. 80.3%, 95.0%, and 90.9% of patients showed improvement of head tiling and success rate was 87.7%, 77.3%, and 50.0% in group 1, 2, and 3 respectively. Group 1 and 2, group 2 and 3 had no significant difference in success rate but only group 1 and 3 had significant difference. @*Conclusions@#Considering success rate with improvement of head position, self-titrating and possibility of overcorrection, IO myectomy could be an effective option as a first-line surgical treatment for unilateral SOP with hyperdeviation of 20 PD or less. However, due to a 50% success rate in patients with hyperdeviation larger than 20 PD, a secondary operation must be considered following IO myectomy, or a two-muscle procedure must be considered as a primary treatment.

Accuracy of the Hand-held Wavefront Aberrometer in Measurement of Refractive Error

Purpose@#To compare refractive error measured by hand-held wavefront aberrometers with postcycloplegic autorefraction (AR) and cycloplegic refraction (CR). @*Methods@#The medical records of patients who received refractive measurements using the wavefront aberrometer, postcycloplegic AR, and CR between January 2014 and January 2016 were retrospectively analyzed. The mean differences, 95% confidence intervals, and limits of agreement (LOA) were calculated for the refractive vector components (M, J0, and J45). @*Results@#Fifty-one patients (9.0 ± 5.5 years, male 41.2%) were enrolled in this study, and only the right eye of each was included. Refractive errors ranged from -9.25 to +7.25 diopters (D) for spherical equivalent (median, 0.75 D). The M component was not significantly different among the three methods (p = 0.080). However, the J0 vector component was significantly different (p < 0.001). After post hoc analysis, the wavefront aberrometer obtained more positive values for J0 compared to the other methods. The J45 component was not significantly different among the three methods (p = 0.143). The mean difference between the wavefront aberrometer and postcycloplegic AR was -0.115 D (LOA, -1.578 to 1.348 D) for M, 0.239 D (LOA, -0.371 to 0.850 D) for J0, and -0.015 D (LOA, -0.768 to 0.738 D) for J45. The mean difference between the wavefront aberrometer and CR was -0.220 D (LOA, -1.790 to 1.350 D) for M, 0.300 D (LOA, -0.526 to 1.127 D) for J0, and -0.079 D (-0.662 to 0.504 D) for J45. @*Conclusions@#The wavefront aberrometer showed good agreement with postcycloplegic AR and CR in spherical equivalents, but tended to produce slightly myopic results. The wavefront aberrometer also overestimated with-the-rule astigmatism. Therefore, we recommend that the device be used for estimations of refractive error, which may be useful for patients who have postural difficulties, live in undeveloped countries, or are bedridden.

Superior Oblique Atrophy on Magnetic Resonance Imaging with Clinical Features in Unilateral Superior Oblique Palsy

Purpose@#To investigate the correlation of superior oblique (SO) atrophy of magnetic resonance imaging (MRI) with clinical features including surgical success in unilateral SO palsy. @*Methods@#This study was a retrospective review of the records of 38 patients who had undergone inferior oblique (IO) myectomy due to SO palsy between January 2017 and March 2019 at our hospital. The patients with more than a 40% decrease of cross-section areas using preoperative orbital MRI were categorized into the atrophic group (16 patients). We compared surgical outcomes between the atrophic and non-atrophic groups. @*Results@#Preoperative IO over-action and vertical deviation showed no significant difference, but the excyclotorsion in paralytic eyes were more frequent in the atrophic group and the surgical success (62.5% vs. 95.5%), and the degree in improvement of vertical deviation (7.17 ± 5.19 prism diopters [PD] vs. 11.05 ± 5.59 PD) was significantly lower in the atrophic group. The degree of SO atrophy showed a weak correlation with the degree of improvement of hypertropia or diopter differences of bilateral head tilting. @*Conclusions@#SO atrophy, detected using preoperative MRI of unilateral SO palsy patients did not show a definite correlation with clinical features except for excyclotorsion in paralytic eyes but did show a clinically significant correlation with surgical outcomes. Preoperative MRI can therefore be used for predicting surgical outcomes of IO myectomy in unilateral SO palsy patients.

Refractive Outcomes of 4-Year-old Children after Intravitreal Anti-vascular Endothelial Growth Factor versus Laser Photocoagulation for Retinopathy of Prematurity

PURPOSE: To compare long-term refractive outcomes associated with intravitreal anti-vascular endothelial growth factor (VEGF) versus laser photocoagulation treatment for retinopathy of prematurity (ROP). METHODS: A total of 52 eyes from 27 ROP patients treated at two tertiary referral-based hospitals from August 2006 to December 2013 were reviewed. The primary outcome was refractive error measured at the age of 4 years, accounting for within-patient inter-eye correlation. Secondary outcomes included the recurrence rate and treatment complications. RESULTS: The mean age at refraction was 4.7 ± 0.3 years in the laser group (n = 30) and 4.4 ± 0.3 years in the anti-VEGF group (n = 22). No significant differences were noted in gestational age, birthweight, post-menstrual age at treatment, or ROP stage/zone distribution between groups. Mean spherical equivalent was also not significantly different (−1.0 diopters in the laser group and −0.3 diopters in the injection group, p = 0.603). Clustered regression analysis revealed that only gestational age was significantly correlated with mean spherical equivalent (p < 0.001; 95% confidence interval, −0.007 to −0.002). Recurrence was noted in four eyes (13.3%) in the laser group, but this difference was not significant (p = 0.128). There were no major systemic complications reported in either group. CONCLUSIONS: Treatment type, whether laser or anti-VEGF injection, does not appear to influence long-term refractive outcomes in ROP. Concern regarding refractive outcomes should not be the most important factor when selecting ROP treatment modality.

Surgical Management of Concurrent Strabismus and Face Turn in Patients with Infantile Nystagmus

PURPOSE: To investigate the effect of adjusted Kestenbaum surgery in patients with idiopathic infantile nystagmus who were affected by both strabismus and face turn. METHODS: This retrospective consecutive case series included 12 patients with infantile nystagmus who had face turn and strabismus. All patients underwent adjusted Kestenbaum surgery between 1996 and 2014, and primary outcome measures were the postoperative degree of face turn and strabismus. RESULTS: All patients had jerky nystagmus with compensatory face turn and strabismus. Of the 12 patients, eight patients were exotropes and four patients were esotropes. The mean age at surgery was 12.5 ± 10.7 years (range, 2–36 years). The mean postoperative follow-up was 17.8 ± 12.0 months (range, 7–43 months). Surgery was successful in eight (66.7%) out of 12 patients. Improvement of anomalous head posture was satisfactory in all patients, but an angle of deviation within 10 prism diopters was not achieved in four patients. CONCLUSIONS: Adjusted Kestenbaum surgery simultaneously improved both ocular misalignment and face turn with one-stage surgery. Two or three rectus muscles surgery can be considered in these patients because it is not only simpler than four muscles surgery but also can preserve one or two rectus muscles.

Strabismus Surgical Outcomes in Patients with Tonic and Accommodative Convergence Excess Esotropia

PURPOSE: To investigate the surgical outcomes of augmented bilateral medial rectus (BMR) recession in patients with low accommodative convergence/accommodation (AC/A) ratio tonic convergence excess esotropia (ET) compared to high AC/A ratio convergence excess ET. METHODS: This study included patients with esodeviation ≥10 prism diopter at near than at distance fixation who underwent BMR recession. The medical records of all esotropic patients with convergence excess who underwent strabismus surgery were reviewed. Six patients with tonic convergence excess and 10 patients with a high AC/A ratio met the study inclusion criteria. A successful outcome was defined as a near or distance angle of deviation ≤8 prism diopter and a ≤10 prism diopter difference between the two at the final recorded visit. RESULTS: The mean age at surgery was 5.9 ± 1.6 years in the tonic convergence excess ET group and 7.3 ± 2.9 years in the high AC/A ET group (p = 0.301). The average length of the postoperative follow-up was 2.7 years (range, 0.6–8.4 years) in the tonic convergence excess ET group and 4.0 years (range, 0.6–8.4 years) in the high AC/A ET group (p = 0.426). Near-distance disparities were reduced in all patients with tonic convergence excess ET within 10 prism diopter postoperatively, but in only 6 of 10 patients in the high AC/A ET group. Five of 6 patients (83.3%) had successful outcomes in tonic convergence excess ET group; 5 of 10 patients (50%) had successful outcomes in the high AC/A ET group. CONCLUSIONS: In our series, five patients (83%) obtained successful results in the tonic convergence excess ET group compared with 50% in the high AC/A ET group. Augmented BMR recession can be safely performed in esotropic patients with tonic convergence excess.

Ophthalmoplegia in Mitochondrial Disease

PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease. MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO). RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p < 0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group. CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.

Obstructive Sleep Apnea in Patients with Branch Retinal Vein Occlusion: A Preliminary Study

PURPOSE: Our study aimed to determine whether obstructive sleep apnea (OSA) is common among branch retinal vein occlusion (BRVO) patients without systemic risk factors using a Watch PAT-100 portable monitoring device. METHODS: The study participants included consecutive patients with BRVO of less than 3 months duration without any risk factors known to be associated with OSA (diabetes, coronary artery disease, stroke, hematologic diseases, autoimmune disease, etc.) except for hypertension. All patients underwent full-night unattended polysomnography by means of a portable monitor Watch PAT-100 device. The apnea-hypopnea index (AHI) was calculated as the average number of apnea and hypopnea events per hour of sleep, and an AHI score of five or more events was diagnosed as OSA. RESULTS: Among 19 patients (6 males and 13 females), 42.1% (8 of 19) had an AHI reflective of OSA. In the 13 patients who had no concurrent illness, including hypertension, 30.8% (4 of 13) had positive test results for OSA; three of these patients were ranked as mild OSA, while one had moderate OSA. The OSA group had an average AHI of 12.3 ± 7.8, and the average AHI was 2.0 ± 0.9 in the non-OSA group. Although it was not statistically proven, we found that OSA patients experienced a more severe form of BRVO. CONCLUSIONS: We found a higher than expected rate of OSA in BRVO patients lacking concomitant diseases typically associated with OSA. Our findings suggest that OSA could be an additional risk factor in the pathogenesis of BRVO or at least a frequently associated condition that could function as a triggering factor.

Surgical Management of Superior Oblique Muscle Palsy in Hypertropia 16 Prism Diopters or More

PURPOSE: Isolated inferior oblique weakening procedure is an effective treatment for patients with superior oblique muscle palsy who had up to 15 prism diopters (PD) of vertical deviation in the primary position, but 2-muscle surgery is needed for patients with larger deviations. Herein, we report the surgical results of simultaneous 2-extraocular muscle surgery for large primary position hypertropia 16 PD or more caused by superior oblique palsy. METHODS: This study was a retrospective review of the records of patients who presented with central gaze hypertropia 16 PD or more and underwent simultaneous 2-extraocular muscle surgery between January 2003 and June 2014 in Severance Hospital. The patients were divided into 3 groups: 43 patients who underwent inferior oblique (IO) myectomy and contralateral inferior rectus (IR) recession (Group 1), 10 patients who underwent IO myectomy and superior rectus (SR) recession (Group 2), and 8 patients who underwent SR recession and contralateral IR recession (Group 3). Criteria for success included correction of head posture and a primary position alignment within 5 PD of vertical deviation. RESULTS: Mean preoperative alignment at primary gaze was 25.5 ± 7.1 PD (range, 16-60 PD) compared to the postoperative value of -1.3 ± 6.8 PD (range, -20~25 PD) (p < 0.001). Surgery was successful in 49 (80%) patients. Nine (15%) patients were overcorrected and the other 3 (5%) patients were undercorrected. Success rate was the highest in subjects who underwent IO myectomy and contralateral IR recession. Among the 24 patients who did not receive combined horizontal muscle surgery, horizontal deviations decreased from 10.4 ± 2.7 PD to 1.5 ± 5.5 PD (p < 0.001) CONCLUSIONS: Two-muscle surgery can be effective in patients with large hypertropia 16 PD or more. Additionally, horizontal deviations are more likely to be resolved with vertical muscle surgery alone. However, IO myectomy combined with ipsilateral SR recession can cause overcorrection postoperatively, so surgical dose should be reduced when performing weakening procedure of two elevators in one eye.

Real Stereopsis Test Using a Three-Dimensional Display with Tridef Software

PURPOSE: To investigate horizontal image disparity in three-dimensional (3-D) perception using 3-D animations in normal control patients and patients with intermittent exotropia, anisometropic amblyopia, and partially accommodative esotropia. MATERIALS AND METHODS: A total of 133 subjects were included. Stereopsis was measured using the Titmus Stereo test (Stereo Optical Inc., Chicago, IL, USA) and a 3-D stereopsis test with a 15 inch 3-D display laptop, adjusting 3-D parameters of 0 mm horizontal disparity to 15 mm horizontal disparity. RESULTS: When compared with normal controls, the average threshold of the 3-D stereopsis test was significantly reduced for esotropia patients (p<0.001) and for anisometric amblyopia patients (p<0.001), compared to normal controls. No significant difference was observed between normal controls and intermittent exotropia patients (p=0.082). The 3-D stereopsis test was correlated with the Titmus Stereo test (Spearman's rho=0.690, p<0.001). Mean difference in stereoacuity was 1.323 log seconds of arc (95% limits of agreement: 0.486 to 2.112), and 125 (92.5%) patients were within the limits of agreement. CONCLUSION: This study demonstrated that a 3-D stereopsis test with animation is highly correlated with the Titmus Stereo test; nevertheless, 3-D stereopsis with animations generates more image disparities than the conventional Titmus Stereo test. The 3-D stereopsis test is highly predictive for estimating real stereopsis in a 3-D movie theater.

Changes in the Accommodation-convergence Relationship after the Artisan Phakic Intraocular Lens Implantation for Myopic Patients

PURPOSE: To evaluate the change of accommodation-convergence parameters after implantation of Artisan phakic intraocular lens (PIOL). METHODS: Prospective study for the patients with the Artisan PIOL implantation was performed. A total of 37 patients (3 males and 34 females) enrolled the study. Preoperatively, convergence amplitude, the stimulus accommodative convergence per unit of accommodation (AC/A) ratio and the near point of convergence (NPC) were evaluated. After the Artisan PIOL implantation, the identical evaluations were repeated at 1 week, 1, 3, and 6 months after the surgery. RESULTS: Mean age was 24.3 +/- 4.8 years old, and preoperative refractive error was -8.92 +/- 4.13 diopters (D). After the implantation, mean refractive errors significantly decreased to within +/-1.00 D, and noticeable complications were not found. The convergence amplitude and the stimulus AC/A ratio increased 1 month after the surgery, but progressively stabilized afterward to near preoperative values. NPC didn't show any significant change over follow-up period up to 6 months. CONCLUSIONS: These results regarding implantation of the Artisan PIOL revealed the increase of accommodation-convergence relationship within first 1 month after the surgery, but progressive stabilization was noted during follow-up periods.

Influence of Pupil Size on Visual Acuity after Implantation of the TECNIS 1-Piece Intraocular Lens

PURPOSE: To evaluate the influence of pupil size on uncorrected visual acuity and spherical aberration of the TECNIS 1-piece intraocular lens (IOL). METHODS: In this study 61 eyes were implanted with a TECNIS 1-piece IOL. Pupil size was checked by standard pupil card with cobalt blue light postoperatively. Best corrected visual acuity (BCVA) and uncorrected visual acuity (UCVA) were assessed postoperatively. Total spherical aberration and high-order aberration for mesopic pupil size zone were measured. RESULTS: There were no significant differences of spherical equivalent, age, preoperative astigmatism, BCVA between two groups, but small pupil group revealed better UCVA (p = 0.02) and lower ocular aberration than large pupil group. CONCLUSIONS: After cataract surgery, pupil size greater than 5.0 mm increases total aberration. Thus, visual acuity with small pupil after aspheric TECNIS 1-piece IOL implantation show better clinical result on uncorrected visual acuity.

Recurrent Bilateral Retinal Vasculitis as a Manifestation of Post-streptococcal Uveitis Syndrome

We report a case of post-streptococcal uveitis mainly presenting with bilateral recurrent retinal vasculitis in Korea. A 14-year-old Asian female presented with decreased visual acuity of 20 / 30 in the right eye and 20 / 25 in the left eye. The patient had a history of glomerulonephritis nine months before onset of uveitis. The manifestation of uveitis was predominantly retinal vasculitis. We presumed post-streptococcal uveitis because probable streptococcal infection was confirmed by anti-streptolysin O titer elevation. With topical and oral steroid treatments, the patient experienced complete vision recovery. Post-streptococcal uveitis occurs rarely and mostly involves young patients in the form of non-granulomatous anterior uveitis. However, as this case shows, it may primarily involve the posterior uvea without anterior inflammation and may recur.