Kengo Ikesugi

The Effect of the H-1152P, a Potent Rho-Associated Coiled Coil-Formed Protein Kinase Inhibitor, in Rabbit Normal and Ocular Hypertensive Eyes

Purpose: We wanted to determine the intraocular pressure (IOP)-lowering effect of H-1152P by utilizing a rabbit ocular hypertension-glaucoma model and normal eyes. H-1152P is a potent, Rho-associated, coiled, coil-forming protein kinase (ROCK) inhibitor. Methods: IOPs were monitored by a pneumatonometer in New Zealand White rabbits that were given topically administered H-1152P or vehicle alone. Animals were divided into four groups followed by topical administration of 0.1, 1.0, 10, and 28 mM H-1152P. To study the IOP-lowering effects on an elevated IOP model, a rabbit ocular hypertension model was created by water loading. All studies were carried out by monitoring of IOPs on H-1152P-administered right eyes and phosphate-buffered saline (PBS)-administered left eyes. Results: In normotensive IOP rabbits, topical administration of H-1152P significantly decreased IOPs by 46.1 ± 5.0% at 1% (28 mM) solution. This effect was dose dependent, as the maximum reduction of IOPs were observed between 60 and 90 min after topical administration (3.6 ± 0.9 mmHg, 5.4 ± 0.7 mmHg, 6.8 ± 0.7 mmHg, and 7.2 ± 1.9 mmHg at 0.1, 1.0, 10, and 28 mM H-1152P). In addition, in the rabbit ocular hypertension model, the topical administration of H-1152P (28 mM) significantly lowered IOPs starting at 30 minutes and lasting up to 300 minutes after water loading. The maximum IOP reduction, however, was observed at 90 minutes after water loading (10.6 ± 2.3 mmHg). No serious side effects were observedin ocular tissues except for some conjunctival congestion that shortly disappeared within 3 hours.Conclusion: Topical administration of H-1152P potently decreased rabbit normotensive IOPs in a dose-dependent manner, and the duration of the IOP lowering was also elongated in a dose-dependent manner. In addition, H-1152P has a potent IOP-lowering effect on an ocular hypertension model. These result suggested that H-1152P could be a candidate for the next generation of glaucoma therapy.

The Effect of the Rho-Associated Protein Kinase Inhibitor, HA-1077, in the Rabbit Ocular Hypertension Model Induced by Water Loading

Purpose: The aim of this study was to investigate the intraocular pressure (IOP)-lowering effect of a new anti-glaucoma drug, the Rho-associated protein kinase (ROCK) inhibitor, HA-1077, in a rabbit ocular hypertension model. Methods: Experiments were carried out in 18 male New Zealand white rabbits, with ocular hypertension induced by water loading. Animals were divided into three groups followed by topical administration of 1 mM, 2 mM, and 3 mM HA-1077 in the left eye. As a control, phosphate buffered saline was administered in the opposite eye. Results: After administration of HA-1077 eye drops, there was a significant time- and dose-dependent decrease of the IOP. While minor conjunctival injection was seen in a few cases, no abnormalities of the anterior chamber or fundus were observed. Conclusions: This is the first report of the effect of the ROCK inhibitor, HA-1077, on the IOP in an ocular hypertension model. Study results indicated that HA-1077 has a strong IOP-lowering effect.

Screening for diabetic retinopathy using new mydriasis-free, full-field flicker ERG recording device

Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Therefore, it is important to detect DR accurately during mass screening. The purpose of this study was to determine whether a small, hand-held, mydriasis-free, full-field flicker electroretinographic (ERGs) device called RETeval can be used to screen for DR. To accomplish this, we recorded full-field flicker ERGs with this device from 48 normal eyes and 118 eyes with different severities of DR in patients with diabetes mellitus (DM). This system delivered a constant flash retinal luminance by adjusting the flash luminance that compensated for changes in the pupil size. Our results showed that there were significant correlations between the severity of DR and the implicit times (P < 0.001; r = 0.55) and the amplitudes (P = 0.001; r = −0.29). When the implicit time was used for the index, the area under the receiver operating characteristic curve was 0.84 for the detection of DR, and was 0.89 for the detection of DR requiring ophthalmic treatments. These results suggest that the implicit times of the flicker ERGs recorded by the small, mydryasis-free ERG system can be used as an adjunctive tool to screen for DR.

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.

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.

Factors Affecting Mydriasis-Free Flicker ERGs Recorded With Real-Time Correction for Retinal Illuminance: Study of 150 Young Healthy Subjects

Purpose A small, full-field flicker electroretinogram (ERG) recording system was recently developed to record flicker ERGs without mydriasis (RETeval). The device delivers a stimulus with constant retinal illuminance by adjusting the retinal luminance to compensate for changes in the pupillary area. The purpose of this study was to determine what factors affect the fundamental components of the flicker ERGs recorded by RETeval in young healthy subjects. Methods Flicker ERGs were recorded with the RETeval system from 150 eyes of 150 young healthy subjects (age, 20-29 years). Univariate and multivariate linear regression analyses were performed to identify the factors that affected the implicit times and amplitudes of the fundamental component of the flicker ERGs. The independent variables included age, sex, refractive error, axial length, and pupillary area. Results Multivariate regression analyses indicated that a longer axial length (P = 0.03) and larger pupillary area (P = 0.008) were independent factors that were significantly associated with longer implicit times of the fundamental component of the flicker ERGs. Multivariate regression analyses also showed that the female sex (P = 0.03) was an independent factor, which was significantly associated with larger amplitude fundamental component of the flicker ERGs. Conclusions These results indicate that the fundamental components of the RETeval flicker ERGs are significantly affected by the axial length, pupillary area, and sex of young healthy subjects. The results also suggest that it would be better to compensate for the Stiles-Crawford effect when flicker ERGs are recorded with natural pupils.

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

Method of Quantifying Size of Retinal Hemorrhages in Eyes with Branch Retinal Vein Occlusion Using 14-Square Grid: Interrater and Intrarater Reliability

Purpose. To describe a method of quantifying the size of the retinal hemorrhages in branch retinal vein occlusion (BRVO) and to determine the interrater and intrarater reliabilities of these measurements. Methods. Thirty-five fundus photographs from 35 consecutive eyes with BRVO were studied. The fundus images were analyzed with Power-Point® software, and a grid of 14 squares was laid over the fundus image. Raters were asked to judge the percentage of each of the 14 squares that was covered by the hemorrhages, and the average of the 14 squares was taken to be the relative size of the retinal hemorrhage. Results. Interrater reliability between three raters was higher when a grid with 14 squares was used (intraclass correlation coefficient (ICC), 0.96) than that when a box with no grid was used (ICC, 0.78). Intrarater reliability, which was calculated by the retinal hemorrhage area measured on two different days, was also higher (ICC, 0.97) than that with no grid (ICC, 0.86). Interrater reliability for five fundus pictures with poor image quality was also good when a grid with 14 squares was used (ICC, 0.88). Conclusions. Although our method is subjective, excellent interrater and intrarater reliabilities indicate that this method can be adapted for clinical use.

Idiopathic Intracranial Hypertension in a Prepubertal Pediatric Japanese Patient Complicated by Severe Papilledema.

Purpose: To report a rare case of idiopathic intracranial hypertension (IIH) in a prepubertal pediatric patient. Case Report: The patient was an 11-year-old Japanese boy. Initially, an ophthalmologist found severe papilledema, and the patient was diagnosed with IIH. He was unresponsive to conservative therapy, and a ventriculoperitoneal shunt was inserted in the Neurosurgery Department because the visual impairment was severe. Twelve months after the shunt, the improvement in vision was limited due to optic disc atrophy. Conclusion: Ophthalmologists need to be more aware of II, especially in cases with severe papilledema that can lead to permanent reduction of vision.