Hideyuki Tsukitome

RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis

Abstract Purpose: To investigate genetic and clinical features of patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations. Methods: Five Japanese families with LCA were recruited. We performed complete ophthalmic examinations, with optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Genetic analysis was performed with whole-exome sequencing analysis and Sanger sequencing. Results: We identified RPE65 mutations in two unrelated LCA patients from two families. Case 1: A 5-month-old girl was diagnosed with LCA because of nystagmus, loss of vision and non-recordable ERG. She was the only one affected in her non-consanguineous family, and exhibited novel compound heterozygous RPE65 mutations (c.177C>G, p.H59Q and c.183_184insT, p.D62X). Case 2: A 30-year-old woman, who had night blindness and poor ocular pursuit during the first year of life, exhibited severe retinal degeneration and non-recordable ERG. She was the only affected in her non-consanguineous family, and showed a homozygous RPE65 mutation (c.1543C>T, p.R515W). Conclusions: By using whole-exome sequencing analysis, three RPE65 mutations were identified in two Japanese patients with LCA. This approach would be useful for identification of disease-causing mutations of LCA.

A Case of Sustained Intraocular Pressure Elevation after Multiple Intravitreal Injection of Ranibizumab and Aflibercept for Neovascular Age-Related Macular Degeneration.

Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are widely used to treat neovascular age-related macular degeneration (nAMD). Although these treatments are effective, multiple injections have recently been recommended to ensure that there is a good long-term prognosis. However, sustained intraocular pressure (IOP) elevations have been reported to develop after multiple injections of anti-VEGF agents. We present our findings of a case of uncontrolled and persistent IOP elevation after switching from intravitreal ranibizumab injections to intravitreal aflibercept injections. A 74-year-old Japanese man without a history of glaucoma underwent 22 ranibizumab injections for nAMD and suddenly developed an elevated IOP after the 22nd injection. Although the subsequent medical treatment led to normalization of his IOP, the subretinal fluid under the central fovea remained even after the 25th injection of ranibizumab. Thus, ranibizumab treatment was switched to bimonthly intravitreal aflibercept injections in conjunction with glaucoma medications. His IOP recovered to within the normal range; however, after the 11th aflibercept injection, there was a sudden elevation of his IOP in spite of the continued glaucoma medications. Due to this sustained IOP elevation, his aflibercept injections were suspended for 16 weeks. Because his IOP could not be normalized by a full glaucoma medication regimen, the patient underwent trabeculotomy, which resulted in a lowering of the IOP to normal levels. We conclude that patients who receive serial intravitreal injections of anti-VEGF agents need to be closely monitored because severe and sustained ocular hypertension can develop.

Changes in angle of optic nerve and angle of ocular orbit with increasing age in Japanese children

Purpose To study changes in the opening angle of the optic nerve and the angle of the ocular orbit with increasing age in normal Japanese children. Methods We studied 147 normal children (aged 6 months to 18 years) who had undergone CT as a diagnostic procedure. Measurements were performed on axial CT images that included the entire optic nerve of both eyes. The opening angle of the optic nerve was defined as the angle formed by the intersection of a line running through the left optic nerve and a vertical line passing through the centre of the nose. The opening angle of the orbit was defined as the angle formed by the intersection of a line running tangentially along the deep lateral wall of the left orbit and a vertical line passing through the centre of the nose. The relationship between age and these opening angles was analysed by regression analysis. Results The correlation between age and opening angle of the optic nerve was not significant. In contrast, the opening angle of the orbit decreased relatively rapidly until about 2–3 years of age, and then it stabilised. The decrease in the opening angle of the orbit with increasing age was significant (p<0.001). The relationship between these two parameters was best fitted by a logarithmic regression curve. Conclusions Because the opening angle of the orbit decreased significantly with increasing age, this factor must be considered when diagnosing and treating strabismus in children.

Annual incidences of visual impairment during 10-year period in Mie prefecture, Japan

PurposeTo determine the annual incidence of visual impairment in a Japanese population during a 10-year period.MethodsWe examined the physical disability certificates issued yearly between 2004 and 2013 in Mie prefecture, Japan. During this period 2468 visually impaired people were registered under the newly defined Act on Welfare of the Physically Disabled Persons’ criteria. The age, sex distribution, and causes of visual impairment were determined from the certificates.ResultsThe major causes of visual impairment during the ten-year period were glaucoma (23.3%), diabetic retinopathy (17.3%), retinitis pigmentosa (12.2%), macular degeneration (9.0%), chorioretinal degeneration or high myopia (7.4%), optic atrophy (5.8%), stroke or brain tumor (5.4%) and cataracts (3.7%). The incidence of glaucoma was significantly higher throughout the period (2004–2013), and that of diabetic retinopathy was lower between 2007 and 2013. The incidence of retinitis pigmentosa did not change significantly during the 10-year period. The incidence of macular degeneration tended to increase between 2004 and 2007, but it decreased significantly between 2007 and 2013.ConclusionsThe results indicate that in Japan, the rates of the major causes of visual impairment altered in the most recent 10-year period reflecting the recent changes in the social background and advances in ocular and systemic treatment.

Peripheral capillary nonperfusion and full-field electroretinographic changes in eyes with frosted branch-like appearance retinal vasculitis.

We report a patient with frosted branch-like appearance retinal vasculitis associated with peripheral capillary nonperfusion and full-field electroretinographic changes. A 62-year-old man presented with sudden bilateral decreased vision accompanied by headaches. His best-corrected visual acuity was 0.01 in both eyes. Fundus examination and fluorescein angiography showed bilateral frosted branch-like appearance retinal vasculitis, and spectral-domain optical coherence tomography showed severe macular edema in both eyes. The cerebrospinal fluid analyses showed an increased lymphocyte count and protein levels. He was treated with systemic corticosteroid therapy, and his best-corrected visual acuity improved to 0.8 OD and 1.0 OS at 6 months after onset. However, fluorescein angiography showed a lack of capillary perfusion in the periphery, and the oscillatory potentials on full-field electroretinography were severely reduced in both eyes. These findings indicated extensive retinal ischemia and inner retinal dysfunction, and that fluorescein angiography and full-field electroretinograms can be useful during follow-up of eyes with frosted branch-like appearance retinal vasculitis.

A case of developmental glaucoma suspected from megalophthalmos represented by obstetric ultrasonography

A male neonate was delivered normally in the 38th week of gestation. The patient weighed 2730 g and was 48.8 cm long at birth. The Apgar score was 10. He was referred to the Department of Ophthalmology, Mie University Hospital by a local ophthalmologist for megalophthalmos and elevated IOP in both eyes (OU) on the 10th day after birth. He had no significant family history. Family history revealed that the mother of the patient was a 20-year-old primipara receiving systemic steroid therapy for chronic nephritis. Obstetric ultrasonography at 30 gestational weeks had revealed the neonate to have megalophthalmos OU. At 35 gestational weeks, the ocular axial length measurements OU were 23–25 mm (Fig. 1) and about 24 mm based on B-scan ultrasonography and magnetic resonance imaging (MRI) images (Fig. 2), respectively. A disproportion in volume between eye and orbit was noticed, but no other abnormal findings were detected on the images. An ophthalmic examination revealed diffuse corneal opacification and corneal edema OU; consequently, the fundus could not be observed. The horizontal corneal diameter was 14 mm in the right eye (OD) and 13 mm in the left eye (OS). The intraocular pressure on a Perkins hand-held applanation tonometer was 34 mmHg OD and 42 mmHg OS. The diagnosis was bilateral early-onset developmental glaucoma. On his 17th day of life, the patient underwent a trabeculotomy of about 120 dextent OU with a scleral flap at

Clinical preferences and trends of anti-vascular endothelial growth factor treatments for diabetic macular edema in Japan

To determine the current clinical preferences of anti‐vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan.

Fallbericht über anhaltende Erhöhung des Augeninnendrucks nach multiplen intravitrealen Injektionen mit Ranibizumab und Aflibercept zur Behandlung der neovaskulären altersbedingten Makuladegeneration

Intravitreale Injektionen mit Wirkstoffen gegen den vaskulären endothelialen Wachstumsfaktor (VEGF) sind eine gängige Behandlungsmaßnahme bei neovaskulärer altersbedingter Makuladegeneration (nAMD). Obwohl diese Behandlungen sehr effektiv sind, sind in jüngster Zeit multiple Injektionen empfohlen worden, um auch langfristig für eine günstige Prognose zu sorgen. Es liegen jedoch Berichte über einen Anstieg des Augeninnendrucks (AID) nach multiplen Injektionen mit Anti-VEGF-Wirkstoffen vor. Wir präsentieren hier einen Fall von unkontrollierter persistierender AID-Erhöhung nach der Umstellung von intravitrealen Ranibizumab- auf Aflibercept-Injektionen. Bei einem 74-jährigen japanischen Mann ohne Glaukom in der Vorgeschichte, der zur Behandlung einer nAMD 22 Ranibizumab-Injektionen erhalten hatte, stieg nach der 22. Injektion der AID unvermittelt an. Die daraufhin eingeleitete medikamentöse Therapie führte zwar zur Normalisierung des AID, doch unterhalb der Fovea centralis lag auch nach der 25. Ranibizumab-Injektion noch subretinale Flüssigkeit vor. Daher erfolgte eine Umstellung der Therapie von Ranibizumab auf 2-monatliche intravitreale Injektionen mit Aflibercept, begleitet von Glaukom-Medikamenten. Der AID kehrte daraufhin in den Normalbereich zurück. Nach der 11. Aflibercept-Injektion kam es trotz der weiterhin angewandten Glaukom-Medikamente wiederum zu einem plötzlichen AID-Anstieg. Aufgrund dieser anhaltenden AID-Erhöhung wurden die Aflibercept-Injektionen für 16 Wochen ausgesetzt. Da es auch mit einem umfassenden Glaukom-Medikationsschema nicht gelang, den AID zu normalisieren, unterzog sich der Patient einer Trabekulotomie, die zur Rückkehr des AID in den Normalbereich führte. Wir gelangen zu der Schlussfolgerung, dass Patienten, die serielle intravitreale Injektionen eines Anti-VEGF-Wirkstoffs erhalten, aufmerksam überwacht werden müssen, da sich eine schwere und anhaltende okuläre Hypertension entwickeln kann.

Möglichkeiten in der Anti-VEGF-A-Therapie

Die Neutralisation vom VEGF-A hat sich in der Behandlung der feuchten altersbedingten Makuladegeneration (AMD) durchgesetzt. Zur Verbesserung der Therapie werden antiVEGF-A-kombinierte Therapieansätze beforscht, die zusätzliche pathologische Mechanismen unterbinden. In klinischen Studien wie Fovista [1] oder ONYX [2] wird versucht, die Stabilität neuer Gefäße zu vermindern. Komplementfaktoren wären weitere mögliche effektive Targets. Die Bedeutung des Komplements zeigt sich am CD46, einem von fast jeder Zelle exprimierten Rezeptor, der verhindert, dass das Komplementsystem die eigenen Zellen angreift. In der Studie von Lyzogubov et al. zeigt eine CD46 Knock-out-Maus alle Symptome der AMD, vor allem geographische Atrophie. Wie ein Komplement das retinale Pigmentepithel (RPE) schädigt, konnten die Autoren Brandstetter et al. zeigen. Das Komplementprodukt C5a «primed» RPE Zellen zur Ausbildung eines Inflammasoms, das die RPE-Zellfunktionen in einem entzündlichen Phänotyp ändert. Änderungen der Zellfunktion durch Inflammasome sind durch einen Regulator des Zellmetabolismus, den mTOR (mammalian Target of Rapamycin) verknüpft. Tatsächlich konnten Ma et al. zeigen, dass mTOR-Hemmung die chorioidale Neovaskularisation im Mausmodell effektiv reduzieren kann. Fazit für Klinik ist, dass die Kombinationstherapie erhebliche Verbesserungen der bisherigen Anti-VEGF-A-Therapie ermöglicht, wie aktuelle klinische Studien zeigen. Untersuchungen zu Mechanismen der lokalen Komplement-Aktivierung zeigen neue Targets auf. Prof. Dr. Olaf Strauß olaf.strauss@charite.de

Bilateral retinal detachment in Werner syndrome.

PURPOSE To report the development of bilateral retinal detachment in a patient with Werner syndrome. METHODS Retrospective chart review. A 44-year-old woman diagnosed with Werner syndrome developed bilateral retinal detachment. The fundus in both eyes showed patchy chorioretinal atrophy similar to that seen in high myopia, with the retinal detachment limited to the posterior pole. Two weeks after performing vitrectomy in the right eye, vitrectomy was performed in the left eye. RESULTS After the surgeries, both retinas were reattached. During the surgeries, we observed an excessively liquefied vitreous and a posterior hyaloid membrane that was tightly attached to the retina. The retinal break was located along the superotemporal arcade and over an area of the patchy chorioretinal atrophy in both eyes. The chorioretinal atrophy and vitreous liquefaction appeared to be excessive for the patients age and axial lengths (right: 26.66 mm, left: 27.04 mm). CONCLUSION Vitreoretinal changes found in this case might have been partially because of the premature aging associated with Werner syndrome.