Exome sequencing and genome-wide association analyses unveils the genetic predisposition in hydroxychloroquine retinopathy.

OBJECTIVES: To unveil the candidate susceptibility genes in chloroquine/hydroxychloroquine (CQ/HCQ) retinopathy using whole exome sequencing (WES) and genome-wide association study (GWAS). METHODS: Patients with a diagnosis of CQ/HCQ retinopathy based on the comprehensive demographic and ocular examination were included. The peripheral blood was extracted for WES and GWAS analyses. The Chinese Han Southern database from 1000 genomes was used as control group to compare the affected percentage. Multivariate logistic regression analysis adjusted for age, HCQ dose, duration and renal disease were used to analyze the correlation between genetic variants and visual outcome. A poor vision outcome was defined as visual acuity <6/12. An abnormal anatomical outcome was defined as disruption of ellipsoid zone in the fovea. RESULTS: Twenty-nine patients with an average age of 60.9 ± 13.4 years, treatment duration of 12.1 ± 6.2 years, daily dose of 8.5 ± 4.1 mg/kg, and the cumulative dose of 1637.5 ± 772.5 g, were genotyped. Several candidate genes associated with CQ/HCQ retinopathy were found, including RP1L1, RPGR and RPE65, with a difference of affected percentage over 50% in mutation between the case and control groups. New foci in CCDC66: rs56616026 (OR = 63.43, p = 1.63 × 10-8) and rs56616023 (OR = 104.7, p = 5.02 × 10-10) were identified significantly associated with HCQ retinopathy. Multivariate analysis revealed increased genetic variants were significantly associated with poor functional (OR = 1.600, p = 0.004) and structural outcome (OR = 1.318, p = 0.043). CONCLUSIONS: Several candidate susceptibility genes including RP1L1, RPGR, RPE65 and CCDC66 were identified to be associated with CQ/HCQ retinopathy. In addition to disease susceptibility, patients with increased genetic variants are more vulnerable to poor visual outcomes.

Progressive macular ischemia in retinal vasculopathy with cerebral leukodystrophy.

PURPOSE: We present a case of retinal vasculopathy with cerebral leukodystrophy and review the usefulness of optical coherence tomography angiography (OCT-A) in the assessment of long-term outcomes. CASE DESCRIPTION: A 31-year-old woman developed sudden-onset scotoma in her right eye. Fundus examination and fluorescein angiography showed a patch of soft exudate and capillary nonperfusion in the posterior pole and outside the vascular arcades. OCT-A revealed that the initial vessel density (VD) of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) of the right eye were 32% and 49.2%, respectively. Interestingly, over time, the VD of the SCP and DCP gradually decreased to 23.1% and 26.2%, respectively. In contrast, the initial VD of the SCP and DCP of the left eye were both stable at 44.3% and 56.2%, respectively, and only decreased slightly to 39.3% and 45.7%, respectively, over time. The average VD loss of the SCP and DCP, assessed over 1 year, was 8% and 13%, respectively, in the right eye, and 3% and 6%, respectively, in the left eye. CONCLUSION: Based on this case report, in which we demonstrated a long-term decline in VD of the macula in a young woman with mild retinal vasculopathy with cerebral leukodystrophy, we suggest that there is a potential and valuable role for OCT-A in this rare disease.

PADAr: physician-oriented artificial intelligence-facilitating diagnosis aid for retinal diseases.

Purpose: Retinopathy screening via digital imaging is promising for early detection and timely treatment, and tracking retinopathic abnormality over time can help to reveal the risk of disease progression. We developed an innovative physician-oriented artificial intelligence-facilitating diagnosis aid system for retinal diseases for screening multiple retinopathies and monitoring the regions of potential abnormality over time. Approach: Our dataset contains 4908 fundus images from 304 eyes with image-level annotations, including diabetic retinopathy, age-related macular degeneration, cellophane maculopathy, pathological myopia, and healthy control (HC). The screening model utilized a VGG-based feature extractor and multiple-binary convolutional neural network-based classifiers. Images in time series were aligned via affine transforms estimated through speeded-up robust features. Heatmaps of retinopathy were generated from the feature extractor using gradient-weighted class activation mapping++, and individual candidate retinopathy sites were identified from the heatmaps using clustering algorithm. Nested cross-validation with a train-to-test split of 80% to 20% was used to evaluate the performance of the screening model. Results: Our screening model achieved 99% accuracy, 93% sensitivity, and 97% specificity in discriminating between patients with retinopathy and HCs. For discriminating between types of retinopathy, our model achieved an averaged performance of 80% accuracy, 78% sensitivity, 94% specificity, 79% F1-score, and Cohen's kappa coefficient of 0.70. Moreover, visualization results were also shown to provide reasonable candidate sites of retinopathy. Conclusions: Our results demonstrated the capability of the proposed model for extracting diagnostic information of the abnormality and lesion locations, which allows clinicians to focus on patient-centered treatment and untangles the pathological plausibility hidden in deep learning models.

The association of aldosterone with papillophlebitis and retinal artery occlusion: A case report.

PURPOSE: To explore the association between elevated blood aldosterone levels and papillophlebitis and retinal artery occlusion in a young, healthy woman. CASE DESCRIPTION: A 19-year-old woman with an unremarkable medical history presented with sudden-onset visual loss in the right eye, which lasted for 10 hours. Fundus examination revealed retinal whitening, splinter hemorrhages, disc swelling, and tortuous vessels in the right eye. Optical coherence tomography revealed inner retinal thickening. Fluorescein angiography demonstrated a delayed arteriovenous transit time and delayed filling of the cilioretinal artery circulation. Further workup showed a high aldosterone level and aldosterone-to-renin ratio. The patient was treated with steroid pulse therapy and combined intravitreal injection of dexamethasone implant and aflibercept. Visual acuity was recovered from count finger at initial presentation to 6/15 on the fifth day. For over 2 months, the fundal manifestations gradually subsided. Three months after the episode, her visual acuity further improved to 6/6.7. CONCLUSION: This report emphasizes the potential role aldosterone plays in the complex disease mechanism of retinal vasculopathy. In addition, steroid pulse therapy is more effective when applied in conjunction with combined intravitreal injection therapy for rescuing impaired vision caused by retinal vascular occlusion.

Increased Risk of Central Serous Chorioretinopathy among Patients with Nonorganic Sleep Disturbance.

PURPOSE: Patients with central serous chorioretinopathy (CSC) typically present with acute visual impairment and metamorphopsia. The disease previously has been associated with psychological stress. Population-based cohort studies on the risk of CSC among patients with nonorganic sleep disturbance (NOSD) are limited. An early sign of psychiatric disorder was probably sleep disturbance. Furthermore, psychological stress may be caused by sleep disturbance. We investigated the relationship between NOSD and the incidence of CSC. DESIGN: Longitudinal cohort study. Participants. We used the Longitudinal Health Insurance Database and collected the data of 53,743 NOSD patients without CSC between 2000 and 2005 as the study group. Four-fold controls were selected randomly from those without neither sleep disturbance nor a CSC history with frequency matching of age, sex, and index-year. METHODS: The difference in sex, age group, comorbidities, and steroid use between the two groups was analyzed by the χ 2 test. Cox-proportional hazard regression was utilized to estimate the hazard ratio (HR) and 95% confidence intervals (95% CI) for comparison of the two groups. Kaplan-Meier analysis was applied to measure the cumulative incidence of CSC. Furthermore, the log-rank test was used to test the incidence difference between the two groups. Main Outcome Measures. The incidence rate of CSC in the following years until 2011 was detected. RESULTS: During a mean follow-up of 7.36 ± 2.88 years, NOSD patients had a higher incidence of CSC than the controls (3.10 vs. 1.86 per 10,000 person-years; adjusted HR, 1.65; 95% CI, 1.34-2.02). Men had a higher risk of CSC than women. Sensitivity analyses stratified by sex, age group, or comorbidity condition showed consistently that NOSD patients had a higher risk of CSC than their controls. Dose-response showed that higher NOSD severity had even higher CSC risk. CONCLUSIONS: NOSD is an independent indicator for the increased risk of subsequent CSC development.

Spatiotemporal integration of visual stimuli and its relevance to the use of a divisional power supply scheme for retinal prosthesis.

A wireless photovoltaic retinal prosthesis is currently being studied with the aim of providing prosthetic vision to patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). The major challenge of a photovoltaic device is its limited power efficiency. Our retinal prosthetic design implements a unique divisional power supply scheme (DPSS) system that provides the electrical power generated by all of the solar cells to only a subset of electrodes at any moment in time. The aim of the present study was to systematically characterize the spatiotemporal integration performance of the system under various DPSS conditions using human subjects and a psychophysical approach. A 16x16 pixels LED array controlled by Arduino was used to simulate the output signal of the DPSS design, and human performance under different visual stimulations at various update frequencies was then used to assess the spatiotemporal capability of retinal prostheses. The results showed that the contrast polarity of the image, image brightness, and division number influenced the lower limit of the update frequency of the DPSS system, while, on the other hand, visual angle, ambient light level, and stimulation order did not affect performance significantly. Pattern recognition by visual persistence with spatiotemporal integration of multiple frames of sparse dots is a feasible approach in retinal prosthesis design. These findings provide an insight into how to optimize a photovoltaic retinal prosthesis using a DPSS design with an appropriate update frequency for reliable pattern recognition. This will help the development of a wireless device able to restore vision to RP and AMD patients in the future.

Defined cell adhesion for silicon-based implant materials by using vapor-deposited functional coatings.

The field of implantable electronics relies on using silicon materials due to the merits of a well-established fabrication process and favorable properties; of particular interest is the surface modification of such materials. In the present study, we introduce a surface modification technique based on coatings of functionalized Parylene on silicon substrates, where the modified layers provide a defined cell adhesion capability for the resultant silicon materials/devices. Functionalization of Parylene was achieved during a one-step chemical vapor deposition (CVD) polymerization process, forming NHS ester-functionalized Parylene, and subsequent RGD attachment was enabled via a conjugation reaction between the NHS ester and amine groups. The modification procedures additionally provided a clean and gentle approach to avoid thermal excursions, intense irradiation, chemicals, or solvents that might damage delicate structures or sensitive molecules on the devices. The modification layers exhibited excellent mechanical strength on the substrate, meeting the high standards of the American Society for Testing and Materials (ASTM), and the resultant cell adherence property was verified by a centrifugation assay and the analysis of attached cell morphologies; the results collectively demonstrated robust and sustainable modification layers of the NHS ester-functionalized Parylene and confirmed that the cell-adherence property imparted by using this facile modification technique was effective. The modification technology is expected to benefit the design of prospective interface properties for silicon-based devices and related industrial products.

Hyperhomocysteinemia Causes Chorioretinal Angiogenesis with Placental Growth Factor Upregulation.

Hyperhomocysteinemia is a risk factor for atherosclerosis, which may also be associated with retinal vascular disease, diabetic retinopathy, retinal vein occlusion, and glaucoma. For this study, we established a hyperhomocysteinemia animal model to explore homocysteine (hcy)-related choroidal angiogenesis and possible related factors. We injected Sprague Dawley (SD) rats with different concentrations of hcy and performed color fundus imaging, fluorescein angiography, image-guided optical coherence tomography, and retinal histology to observe the retinal and choroidal changes. Subsequently, we observed prominent choroidal vasculature with congested and tortuous retinal and choroidal vessels in fundus angiographies of the hyperhomocysteinemia animal model. In the histological study, the choroidal capillaries proliferated in the hcy-treated eyes, mimicking choroidal neovascularization. Disrupted retinal pigment epithelium (RPE), abnormal branching vascular network (BVN), and polyp-like structures were also observed in the hcy-treated eyes. Furthermore, we found that placental growth factor (PlGF), but not vascular epithelial growth factor (VEGF), was the key mediating factor of this phenomenon. Our findings suggest that hyperhomocysteinemia might cause choroidal angiogenesis.

Homocysteine Facilitates Prominent Polygonal Angiogenetic Networks of a Choroidal Capillary Sprouting Model.

Purpose: To investigate the effects of homocysteine on choroidal angiogenesis, we established an ex vivo choroidal sprouting explant model and examined the potential growth factors for angiogenesis. Methods: Choroid fragments with retinal pigment epithelium were isolated from mouse and embedded in Matrigel. Homocysteine at different concentrations were added to the culture mediums. The choroidal explants were observed at different time points, and the total area of choroidal sprouting was measured and analyzed. Results: Homocysteine evoked choroidal capillary sprouting by inducing capillary endothelial cell proliferation with pericyte formation and by facilitating polygonal angiogenetic networks. In some cases, vascular lumens were observed in the newly forming capillaries facilitated by homocysteine. The choroidal sprouting effect of homocysteine can only be observed at a certain range of homocysteine concentration, with 1-mM homocysteine exhibiting the most significantly increased choroidal sprouting areas. Isolectin overexpression was noted in the homocysteine-treated group. Possible growth factors for angiogenesis were detected through immunofluorescent staining, which demonstrated the overexpression of platelet-derived growth factor C and angiopoietin 1 in the homocysteine-treated preparations only. In these preparations, platelet-derived growth factor C was highly expressed in the tip cells of sprouting capillaries. Conclusions: We therefore conclude that platelet-derived growth factor C and angiopoietin 1 may play key roles in the choroid angiogenesis evoked by homocysteine.

Large gene deletion and changes in corneal endothelial cells in a family with choroideremia.

PURPOSE: We provided the first report of an association between changes in corneal endothelial cells, retina, and choriocapillaris in a choroideremia family. METHODS: Four members of an Asian choroideremia family, comprising two affected patients and two carriers, were evaluated. All participants underwent complete eye examinations, including visual acuity (VA), slit-lamp examination, ophthalmoscopy, perimetry, and electrophysiology tests. In addition, images of corneal endothelium were captured with a noncontact specular microscope. Genomic DNA amplification and whole-genome cytogenic array analysis were used to confirm the diagnosis of choroideremia and determine the molecular basis of the phenotype. RESULTS: In the affected patients, funduscopy revealed characteristic features of RPE and chorioretinal atrophy. The slit-lamp biomicroscopy disclosed unexpected pigmented punctate lesions in the corneal endothelium in one of them. Surprisingly, specular microscopy detected decreased endothelial cell density (ECD) with features of pleomorphism and polymegethism. Genomic DNA analysis revealed large deletion (~4.5 mega base pairs) of the entire CHM gene and encompassed region. In carriers, funduscopy revealed stippling pigmentary change despite normal electrophysiological results. Specular microscopy also disclosed reduced ECD with features of pleomorphism and polymegethism. CONCLUSIONS: To our knowledge, this is the first description of corneal changes in choroideremia patients. The loss of corneal ECD is conspicuous and is accompanied by pleomorphism and polymegethism in this family. The observed changes in corneal endothelium may be associated with larger encompassed regions of the CHM gene defect or dysfunction in the blood-aqueous barrier. It warrants further investigation and clarification of the pathophysiology and associations between retinal and corneal changes in choroideremia.

Efficacy of intravitreal injection of anti-vascular endothelial growth factor agents for stage 4 retinopathy of prematurity.

PURPOSE: To investigate the efficacy of intravitreal injection of anti-vascular endothelial growth factor agents for Stage 4 retinopathy of prematurity. METHODS: Retrospective case series study. The medical records of patients receiving intravitreal injection of anti-vascular endothelial growth factor agents for Stage 4 retinopathy of prematurity from January 2007 to May 2012 in Taipei Veterans General Hospital were reviewed. RESULTS: A total of 13 eyes of 7 patients (3 boys and 4 girls) with Stage 4 retinopathy of prematurity were included. The mean gestational age and birth weight were 27.6 ± 2.6 weeks (range, 24.5-30.5 weeks) and 893.1 ± 293.2 g (range, 550-1422 g), respectively. The mean age at the time of injection was 38.2 ± 1.9 weeks (range, 36.0-41.5 weeks) postmenstrual age, and the mean follow-up period was 37.8 ± 19.5 months (range, 11.0-67.5 months). The active neovascularization regressed rapidly, and the anatomical outcomes were favorable in all patients. One eye developed recurrent retinal hemorrhage with localized retinal detachment 21 weeks after initial treatment, which resolved after a second injection. There were no ocular or systemic complications in these patients. CONCLUSION: Intravitreal injection of anti-vascular endothelial growth factor agents may be effective as monotherapy or as supplement to failed laser treatment for patients with Stage 4 retinopathy of prematurity without additional surgical intervention. Further randomized controlled trials are necessary to compare the clinical efficacy and safety with other conventional interventions.

Sub-internal limiting membrane hemorrhage treated with intravitreal tissue plasminogen activator followed by octafluoropropane gas injection.

Sub-internal limiting membrane (sub-ILM) hemorrhage is a relatively rare disease which is associated with different etiologies and often leads to loss of visual acuity. We report two cases of sub-ILM hemorrhage, both confirmed by optical coherence tomography (OCT) and treated with an intravitreal injection of tissue plasminogen activator (tPA) followed by an octafluoropropane (C3F8) pneumopexy and a strict postoperative prone positioning. The hemorrhage was totally resolved and complete visual recovery was achieved in both cases. We found tPA hemolysis with C3F8 pneumopexy to be a safe and effective method for treating sub-ILM hemorrhage.

Hyperhomocysteinemia in patients with polypoidal choroidal vasculopathy: a case control study.

PURPOSE: To determine whether elevated plasma homocysteine and serum high sensitivity C-reactive protein (hsCRP) levels, two established risk factors of vascular diseases, are associated with polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective case-control study. METHODS: One hundred and nineteen consecutive patients with PCV and 119 matched controls were enrolled in a tertiary hospital from September 2008 to June 2013. Plasma homocysteine and serum hsCRP levels were measured. Associations among plasma homocysteine, serum hsCRP levels and PCV were further evaluated using multivariable logistic regression analysis. RESULTS: The median plasma homocysteine level was significantly higher in patients with PCV than in the controls (12.20 µmol/L vs. 9.80 µmol/L, p<0.001). The median serum hsCRP level was slightly higher in the PCV group (0.16 mg/dl vs. 0.11 mg/dl in control group, p = 0.07). After multivariable logistic regression analysis, each 1 µmol/L increase of plasma homocysteine was associated with a 1.5-fold increase in likelihood of having PCV (OR, 1.54; 95% confidence interval (CI), 1.33-1.79, p<0.001). CONCLUSIONS: Hyperhomocysteinemia was associated with PCV and might play a role in the pathogenesis of PCV.

Involvement of SDF1a and STAT3 in granulocyte colony-stimulating factor rescues optic ischemia-induced retinal function loss by mobilizing hematopoietic stem cells.

PURPOSE: Granulocyte colony-stimulating factor (G-CSF) has been applied clinically for several years. In this study, we used G-CSF to induce the mobilization of hematopoietic progenitor cells into peripheral blood in an ischemia-induced retinal degeneration model. METHODS: Male Sprague-Dawley rats received G-CSF treatment for 5 days following optic ligation. Histologic and functional evaluations were performed and results were compared with those from untreated rats. Real-time PCR, Western blotting, and immunohistochemical analyses were used to evaluate the expression of retinal cell markers and other substances. RESULTS: Retinal histology showed that transient optic ligation induced retinal cell loss. Postischemia, animals that received G-CSF treatment had a higher retinal cell survival rate than that of control animals. Analysis of apoptosis showed that retinas from G-CSF-treated animals exhibited fewer apoptotic cells than those from control retinas. Immunoblotting analyses indicated the presence of greater numbers of CD34-, but less chemokine receptor type 4 (CXCR4)-, and stromal cell-derived factor 1 alpha (SDF1α)-positive cells in the G-CSF-treated ischemic retinas than in ischemic retinas without treatment 14 days after ischemia. The ischemic retinas from G-CSF-treated animals displayed upregulated Thy1 and opsin expression compared with the retinas from untreated animals. Electroretinography indicated superior retinal function in animals treated with G-CSF than in untreated animals postischemia, and that STAT3 might play an important role. CONCLUSIONS: Our results suggest that G-CSF reduces optic ischemia-induced retinal cell loss, possibly through STAT3-regulated mobilization of hematopoietic progenitor cells to the retina.

Short-term external buckling with pneumatic retinopexy for retinal detachment with inferior retinal breaks.

PURPOSE: To introduce a new approach for short-term external scleral buckling with pneumatic retinopexy for the management of rhegmatogenous retinal detachment with inferior retinal breaks. DESIGN: Retrospective, noncomparative, interventional case series. METHODS: A review of 33 consecutive eyes of 31 patients who underwent external buckling with pneumatic retinopexy for uncomplicated rhegmatogenous retinal detachment with inferior retinal breaks from December 2006 through December 2010. An external buckle was made of a 505 sponge sutured along the blunt side of a 279 tyre (MIRA Inc). The buckle was inserted deeply into the inferior fornix without suture after pneumatic retinopexy and was kept in place for 3 days. Primary and final anatomic outcomes, visual acuity, and adverse events were recorded. RESULTS: All patients tolerated the procedure. The mean follow-up period was 24.0 months (range, 9 to 61 months). Primary success, defined as successful retinal reattachment within 6 months without further treatment, was achieved in 29 (87.9%) eyes. All patients attained final retinal reattachment (100%). Overall, the mean best-corrected visual acuity improved significantly at the end of follow-up (0.30 logarithm of the minimal angle of resolution units; Snellen equivalent, 6/12), compared with the preoperative best-corrected visual acuity (0.82 logarithm of the minimal angle of resolution units; Snellen equivalent, 6/38; P < .001). CONCLUSIONS: Short-term external buckling with pneumatic retinopexy is a novel and effective treatment for rhegmatogenous retinal detachment with inferior retinal breaks, with a comparable success rate with other treatment methods. This approach also can avoid complications of long-term buckle implantation. Further comparative cohort studies may be necessary to compare the clinical efficacy with other conventional operations.

Responses of rabbit retinal ganglion cells to subretinal electrical stimulation using a silicon-based microphotodiode array.

PURPOSE: With subretinal prostheses, retinal ganglion cells (RGCs) are activated by electrical stimulation of the retinal neural network. The aim of this study was to evaluate the efficacy of silicon-based solar cells in evoking RGC responses by electrically stimulating the photoreceptor side of an isolated retina. METHODS: A light-bleached retina of an adult New Zealand White rabbit was placed with its photoreceptor side down onto a silicon chip that consisted of a 4 × 4 microphotodiode array (MPDA). The stimulating current was elicited by activating the solar cell with a 532-nm laser light source. Responses of the ON and OFF alpha RGCs on electrical stimulation were recorded extracellularly. Recorded RGCs were then injected with 4% N-(2-aminoethyl)-biotinamide hydrochloride to allow cell type identification. RESULTS: Using a design that includes a circumvented ground electrode, the authors successfully evoked spiking responses by the ON and OFF alpha RGCs in an isolated rabbit retina using low light power to activate the MPDA (equivalent to 39 µC/cm(2)). The charge density-dependent response and the frequency-dependent pair-pulse suppression were characterized. The spike latency of the RGC responses triggered by electrical stimulation was equivalent to the latency of its light response, which supports the hypothesis that the activation is mediated by the retinal neural network. CONCLUSIONS: Reliable activation of RGCs by electrical stimulation in vitro using an MPDA demonstrates the feasibility of developing solar cell-based subretinal prostheses that potentially could be developed into a power-free device able to restore vision.

High-altitude retinopathy after climbing Mount Aconcagua in a group of experienced climbers.

BACKGROUND: Visual disturbances after high-altitude exposure were first reported in 1969. Manifestations may include retinal hemorrhage, papilledema, and vitreous hemorrhage. METHODS: We observed a group of 6 experienced climbers who ascended Mt Aconcagua to an altitude of 6,962 m in February 2007. Visual acuity study, intraocular pressure study, visual field study, nerve fiber layer analysis, eye Doppler, laboratory studies, fundus photography, and intravenous fluorescein angiography were performed on the climbers before and after their exposures to high altitude. RESULTS: In all six study subjects, retinal vascular engorgement and tortuosity were present in varying degrees in both eyes. One of the climbers had both retinal hemorrhage and pulmonary edema. Of the two subjects who had visual field defects, one had severe nerve fiber layer defects of both eyes. Furthermore, laboratory studies of this climber showed a high level of antiphospholipid antibody. Significant reduction of the left ocular blood flow was also noted on this subject's eye Doppler examination after the Mt Aconcagua expedition. CONCLUSION: Various high-altitude retinopathies were observed in the experienced climbers of this study. As high-altitude pursuits become more popular, attention should be paid to the increasing prevalence of high-altitude retinopathy.

Enzyme assay and clinical assessment in subjects with a Chinese hotspot late-onset Fabry mutation (IVS4 + 919G→A).

Newborn screening for Fabry disease in Taiwan Chinese has revealed a high incidence of the late-onset GLA mutation IVS4 + 919G→A (∼1 in 1,500-1,600 males). We studied 94 adults with this mutation [22 men, 72 women; mean age: men 57.8 ± 6.0 (range 42-68), women 39.1 ± 14.1 years (range 19-82)]. Plasma α-galactosidase A activity assay was 10.4 ± 11.2% of normal in the men and 48.6 ± 19.5% of normal in the women. Echocardiography in 90 of the adults revealed left ventricular hypertrophy (LVH) in 19 (21%), including 14 of 21 men (67%) and 5 of 69 women (7%). Microalbuminuria, based on the urine albumin-to-creatinine ratio measured on at least two occasions, was present in 17 of 86 subjects (20%) (men: 5/20, 25%; women 12/66, 18%). At least one ocular manifestation consistent with Fabry disease was present in 41 of 52 subjects (79%) who underwent ophthalmologic examination, including 8 (15%) with conjunctival vessel tortuosity, 15 (29%) with cornea verticillata, 10 (19%) with Fabry cataract, and 34 (65%) with retinal vessel tortuosity. Among subjects over 40 years of age, men were more likely than women to have LVH [14/21 (67%) vs 5/25 (20%), p < 0.001]. Cardiovascular, renal and ocular abnormalities are highly prevalent in adult Taiwan Chinese subjects with the Fabry mutation IVS4 + 919G→A. Our findings contribute to the limited understanding of the course of this late-onset disease variant and underscore the need for close follow up in such patients.

Transient hyperopia after intensive treatment of hyperglycemia in newly diagnosed diabetes.

PURPOSE: Our aim was to observe the transient hyperopia during the intense glucose reduction in patients with newly diagnosed diabetes and severe hyperglycemia. STUDY DESIGN: Consecutive cases were observed. RESULTS: Totally 4 men and 1 woman with a mean age of 48 years were enrolled. In the 4 patients who received insulin, the hyperopia developed at 4.2 days after the initiation of treatment on average and reached a peak at 11.7 days; they recovered at 64.0 days. The other subject who received oral hypoglycemia agents revealed a peak change at 17 days and recovered at 70 days. A broader hyperopic change of 6.25 dpt was found in the patient with high myopia (-16 dpt). No significant difference was observed in the corneal curvature, axial length, lens thickness or depth of the anterior chamber during the course. The stable value of the accommodation amplitude and lens thickness may indicate that the cause of refraction change was due to the alteration in the reflection index of the lens. CONCLUSION: Intensive glucose reduction may cause transient hyperopia changes in newly diabetic patients and results in blurred vision.