Hirokazu Nishiwaki

Efficacy of surgical removal of the internal limiting membrane in diabetic cystoid macular edema.

Purpose: To evaluate the efficacy of surgical removal of the internal limiting membrane (ILM) in diabetic cystoid macular edema (CME). Methods: Prospective, noncomparative, interventional case series including 21 eyes of 18 consecutive patients with diabetic CME. Vitrectomy with separation of the posterior hyaloid and induction of posterior vitreous detachment had been performed previously on nine eyes. Pars plana vitrectomy for removal of the ILM was performed. Results: CME resolved in eyes that underwent initial vitrectomy and in those with long-standing (>1 year) CME after previous vitrectomy. Postoperative best-corrected visual acuity improved by ≥2 lines of a Snellen equivalent in 14 eyes (67%) (P < 0.01). The mean foveal thickness (distance between the inner retinal surface and the retinal pigment epithelium) decreased from 553 &mgr;m to 221 &mgr;m at 4 weeks (P < 0.001). No recurrences or deterioration of CME was observed during the entire follow-up period (mean, 17.8 months; range, 8–34 months). Conclusion: Surgical removal of the ILM might be an effective procedure for reducing CME in patients with diabetes. A prospective, randomized, controlled study is necessary to further evaluate the efficacy of the procedure.

A new fluorescent imaging procedure in vivo for evaluation of the retinal microcirculation in rats

We investigated a new method for in vivo evaluation of the retinal microcirculation in rats using a cell-permeant fluorescent dye, acridine orange (AO), which stains cell nuclei and cytoplasm, and a scanning laser ophthalmoscope (SLO). AO, which binds and interacts with DNA and RNA, and thus stains cell nuclei and cytoplasm, was administered intravenously to rats. Fluorescein angiography was performed after administration of the AO, and fundus images were recorded on S-VHS videotape by means of an SLO. Argon laser was used as an exciter of the dye. The retinal vessels were stained with the dye, rendering the retinal microvasculature clearly visible. Cell nuclei and vessel walls were observed as greater fluorescence and lesser fluorescence, respectively. Leukocytes were also observed as highly fluorescent dots moving through the vessels. The results suggest that SLO visualization of AO uptake by cells may be a useful procedure for the evaluation of retinal microcirculation in vivo in rats.

Role of posterior vitreous detachment induced by intravitreal tissue plasminogen activator in macular edema with central retinal vein occlusion.

Purpose: To evaluate the effects of posterior vitreous detachment (PVD) in macular edema associated with central retinal vein occlusion (CRVO) treated with intravitreal tissue plasminogen activator (tPA). Methods: The authors conducted a retrospective study of 36 eyes of 36 patients with macular edema by CRVO treated with intravitreal tPA. In 16 of 21 eyes without pretreatment PVD, PVD developed after the treatment. Multiple linear regression analysis was used to evaluate the correlation between logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) changes and several variables. Results: The VA and macular thickness significantly improved after treatment. The pretreatment logMAR VA (R = 0.646; P < 0.0001), PVD development after tPA (R = −0.303; P = 0.025), and age (R = 0.255; P = 0.050) correlated with the logMAR VA at final visit. The greater improvement in logMAR VA was correlated only with PVD development (R = 0.467; P = 0.0041). Macular thickness in the eyes with PVD development was significantly less than without PVD development at the 6-month visit and the end of follow-up. Conclusion: The findings suggest that PVD development after intravitreal tPA may partly contribute to the resolution of macular edema and a better VA outcome.

Is removal of internal limiting membrane always necessary during stage 3 idiopathic macular hole surgery

Purpose: To determine the indications for internal limiting membrane (ILM) removal in stage 3 idiopathic macular holes (MHs). Methods: Focal posterior vitreous detachments (PVDs) at MH rims were examined preoperatively by optical coherence tomography and binocular slit-lamp fundus examination in 19 patients retrospectively. All eyes underwent pars plana vitrectomy and creation of a PVD, and some eyes underwent a second surgery to remove the ILM. Indications of ILM removal for MH closure were discussed. Results: Preoperatively, 9 eyes did not (non-PVD group) and 10 eyes did (PVD group) have complete focal PVDs. In all nine eyes in the non-PVD group, MHs were closed after the creation of a PVD without ILM peeling (P < 0.05, &khgr;2 test). In the PVD group, 5 eyes (50%) had MHs closed by making PVD complete without ILM removal, and 5 eyes (50%) required ILM removal in a second surgery. In the end, closure of MHs was achieved in all eyes. Conclusion: Anatomic closure of stage 3 idiopathic MHs without a PVD at the rim of the hole may be achieved only by creating a PVD without ILM removal.

The choroidal circulation assessed by laser-targeted angiography

The choroid plays an important role in supplying nutrients to and removing waste products from the outer region of the retina. Abnormal choroidal blood flow can disrupt normal retinal function and lead to alterations in visual function. Visualization of the choriocapillaris in vivo is a great challenge to understanding its normal physiology and involvement in the disease process. Laser-targeted angiography (LTA) is a relatively new method used to visualize and analyze the choroidal circulation. Carboxyfluorescein (CF), encapsulated in heat-sensitive liposomes, is released locally in the choroid through the application of a heat beam provided by an infrared laser. Video angiograms are generated with excitation illumination provided by an argon laser. Obtained images are highly selective to the choriocapillaris and are sharply contrasted against underlying and overlying structures. The images can be obtained repetitively, during which period the circulating liposome concentration is sufficient to generate adequate angiograms. These high-quality images have revealed three distinct phases (filling, plateau, and draining) of the choriocapillaris. In the plateau phase, a cluster of lobules fed by a common arteriole has been uniformly illuminated. This defined cluster area does not change in size while an infrared laser is continuously applied to the same spot, which demonstrates that each cluster is functionally independent and no physiological communication exists between them. Only in posterior regions do the angiograms demonstrate during the filling and draining phases that each lobule is filled from a central spot and drained along a peripheral ring, showing honeycomb flow patterns. The regional differences in choriocapillaris flow patterns revealed by LTA suggests that the choriocapillaris provides a more highly efficient system of outflow in posterior regions than in peripheral regions. LTA is useful in analyzing choroidal circulation in vivo and has the potential for clinical application in the future. Additionally, LTA has a unique capability to image choroidal neovascularization in animal models and it promises potential application in age-related macular degeneration (AMD).

Laser Targeted Photo-occlusion of Rat Choroidal Neovascularization Without Collateral Damage †¶

Abstract Laser targeted photo-occlusion (LTO) is a novel method being developed to treat choroidal neovascular membranes (CNV) in age-related and other macular degenerations. A photosensitive agent, encapsulated in heat-sensitive liposomes, is administered intravenously. A low power laser warms the targeted tissue and releases a bolus of photosensitizer. The photosensitizer is activated after it clears from the normal choriocapillaris but not from the CNV. Forty-five experimental CNV were induced in seven rats. Five weeks after LTO, complete occlusion was observed by laser targeted angiography (LTA) in 76% of treated CNV, and partial occlusion was found in the remaining 24%. The tissues outside the CNV but within the area treated by LTO showed no flow alteration and no dye leakage. All untreated CNV were patent on LTA at 5 weeks. Light microscopy and electron microscopy confirmed the results in treated and control lesions. Moreover, treated areas next to lesions showed normal photoreceptors, retinal pigment epithelium (RPE), Bruchs membrane and choriocapillaris. These results indicate that LTO may improve current photodynamic therapy by alleviating the need for repeated treatments and by avoiding the long-term risks associated with damage to the RPE and occlusion of normal choriocapillaries.

Quantitative evaluation for blood-retinal barrier breakdown in experimental retinal vein occlusion produced by photodynamic thrombosis using a new photosensitizer

Purpose. To establish a rat model of retinal vein occlusion (RVO), we applied photodynamic thrombosis using a new photosensitizer. By measuring the breakdown of the blood-retinal barrier (BRB), we evaluated the model quantitatively. We also investigated how hypertension and retinal pigment epithelium (RPE) influence the breakdown of BRB after RVO. Methods. We modified a slit lamp biomicroscope for photodynamic thrombosis. The light source was changed from white light to argon laser, which made it possible to perform fluorescein angiography (FAG) simultaneously during photodynamic thrombosis. We irradiated with a continuous diode laser to occlude three retinal veins in a rat after PAD-S31 injection. The breakdown of BRB was quantitated by measuring extravasated Evans blue dye in albino and pigmented rats. We compared hypertensive rats (SHR) to nor-motensive rats (WKY) and sodium iodate-treated rats to normal rats. Results. High photosensitivity of PAD-S31 made it possible to occlude any retinal veins within 120 seconds at a low dose of 10 mg/kg without retinal thermal burn at the occlusion site. Simultaneous FAG enabled us to observe the formation of thrombus during diode laser irradiation. Our measured value of intraretinal Evans blue correlated with the range of serous retinal detachment. Both albino and pigmented rats demonstrated stable and constant values of Evans blue. SHR recovered from the breakdown of BRB after venous occlusion more slowly than WKY. Sodium iodate-treated rats had smaller breakdowns of BRB and recovered earlier than normal rats. Conclusions. In this study, we established the stable and constant rat model of RVO efficiently by using a new photosensitizer. Our simultaneous FAG method was considered to have an advantage of several potential clinical applications. Our rat model of RVO allows us to study factors associated with the recovery from damage by RVO.

Experimental macular edema induced by macular venule occlusion in monkey.

Purpose. Visual prognosis after retinal vein occlusion varies, because it may be affected by macular edema or an avascular area. The mechanism describing how macular edema and avascular areas occur, however, has not been clearly understood. We induced macular edema in cynomolgus monkeys by occluding macular venules to evaluate the retinal microcirculation. Method. We produced venous occlusion by applying dye laser in three cynomolgus monkeys. Macular edema was examined by slit lamp biomicroscopy and optical coherence tomography. Acridine orange leukocyte fluorography (AOLF) and fluorescein angiography were performed to study blood flow and vascular leakage before and after laser application. Results. We observed three types of retinal changes in the macular area: (1) macular edema did not develop; (2) macular edema developed, but improved with avascular area formation; (3) macular edema developed, but disappeared without avascular area formation. Under physiological conditions, observation revealed that leukocytes flowed from arterioles into either superior or inferior venules. When macular edema did not develop, most leukocytes from arterioles escaped into the adjacent non-occluded venules. In contrast, when macular edema occurred, leukocyte flow became stagnated. Macular edema developed when capillary leakage was observed from venules and subsequently arterioles, but disappeared when an avascular area was formed by arteriole occlusion. Conclusions. We demonstrated that experimental macular edema could be induced by macular venule occlusion in monkeys. According to our observation by AOLF, whether macular edema is induced or not depends on the function of collateral routes of the remaining non-occluded venules. We could consider that a gradual increase in intravascular pressure was associated with the avascular area formation.