Clinical course of two siblings with potassium voltage-gated channel modifier subfamily V member 2 (KCNV2)-associated retinopathy.

BACKGROUND: KCNV2-associated retinopathy causes a phenotype reported as "cone dystrophy with nyctalopia and supernormal rod responses (CDSRR; OMIM# 610356)," featuring pathognomonic findings on electroretinography (ERG). Here, we report the clinical courses of two siblings with CDSRR. CASE REPORTS: Patient 1: A 3-year-old boy with intermittent exophoria was referred to our hospital. The patient's decimal best-corrected visual acuity (BCVA) at age 6 was 0.7 and 0.7 in the right and left eyes, respectively. Photophobia and night blindness were also observed. Because the ERG showed a delayed and supernormal b-wave with a "squaring (trough-flattened)" a-wave in the DA-30 ERG, and CDSRR was diagnosed. The patient's vision gradually worsened, and faint bilateral bull's eye maculopathy was observed at the age of 27 years, although the fundi were initially unremarkable. Genetic examination revealed a homozygous missense variant, c.529T > C (p.Cys177Arg), in the KCNV2 gene. Patient 2: The second patient was Patient 1's younger sister, who was brought to our hospital at 3 years of age. The patient presented with exotropia, mild nystagmus, photophobia, night blindness, and color vision abnormalities. The patients' decimal BCVA at age 13 was 0.6 and 0.4 in the right and left eyes, respectively, and BCVA gradually decreased until the age of 24 years. The fundi were unremarkable. The siblings had similar ERG findings and the same homozygous missense variant in the KCNV2 gene. CONCLUSIONS: The siblings had clinical findings typical of CDSRR. High-intense flash ERG is recommended for identifying pathognomonic "squaring" a-waves in patients with CDSRR.

Rescue of exotropia subsequent to pulled-in-two syndrome of the medial rectus muscle occurring during surgery for high myopic strabismus fixus: A case report.

RATIONALE: Pulled-in-two syndrome is one of the significant complications of strabismus surgery. This study aimed to report a case of pulled-in-two syndrome of the contractured medial rectus muscle (MR) that occurred during strabismus surgery for strabismus fixus due to high myopia, and to describe a rescue of this complication. PATIENT CONCERNS: A woman in her 60s presented to our Ophthalmology Department with the main complaint of unilateral high myopia and severe myopic strabismus fixus. Esotropia exceeded 45° and hypotropia exceeded 15° in her right eye in the Hirschberg test. Right eye duction was markedly limited in every gaze direction. Orbital magnetic resonance images showed rupture of the superior rectus to lateral rectus band ligament and lengthening of the distance between the SR and LR muscles in the right eye. DIAGNOSIS: Due to the patient's ophthalmic examination and imaging results, she was diagnosed with high myopic strabismus fixus. INTERVENTIONS: We performed MR recession and Yokoyama surgery to correct right eye hypoesotropia. In the MR recession procedure, pulled-in-two syndrome (MR muscle tear) occurred. Thus, no additional procedure was performed on the MR. After the surgery, she presented 45 prism diopter exotropia and 18 prism diopter residual right hypotropia in a Krimsky test. We performed a second surgery, combining MR muscle advancement and inferior rectus (IR) muscle recession, 3 months after the first surgery. OUTCOMES: One and a half years after the second surgery, she presented exotropia of 14 prism diopters without hypotropia in the Krimsky test and was satisfied with her ocular position and improved motility. LESSONS: We experienced pulled-in-two syndrome in a case with severe myopic strabismus fixus and achieved a good outcome by performing additional surgery 3 months later, in which the lost MR muscle was advanced. This case underscores that, if the lost muscle cannot be found during surgery, one should maintain composure and perform a reoperation a few months after the initial surgery, if necessary. This case report can aid in making rescue treatment decisions when pulled-in-two syndrome occurs.

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.

Intravitreal tissue plasminogen activator to treat macular edema associated with branch retinal vein occlusion.

PURPOSE: To evaluate the efficacy of intravitreal tissue plasminogen activator (tPA) injection for branch retinal vein occlusion (BRVO). DESIGN: Retrospective, interventional case series. METHODS: Seventeen eyes presenting with macular edema caused by BRVO were treated with an intravitreal tPA (Monteplase, 40 k IU) injection. We assessed the visual acuity (VA) and foveal thickness measured with optical coherence tomography. RESULTS: The mean duration of symptoms before surgery was 3.6 +/- 3.8 weeks. The mean logMAR VA significantly improved from 0.603 +/- 0.327 at baseline to 0.388 +/- 0.248 (P < .01) at one month and 0.359 +/- 0.319 (P < .05) at six months. The mean foveal thickness significantly decreased from 738 +/- 156 microm at baseline to 454 +/- 213 microm (P < .001) at one month and 253 +/- 164 microm (P < .001) six months. CONCLUSION: Intravitreal tPA injection may be an effective treatment for resolving macular edema and improving the VA in BRVO.

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).

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 microm to 221 microm 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.

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, chi 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.

Delayed absorption of macular edema accompanying serous retinal detachment after grid laser treatment in patients with branch retinal vein occlusion.

PURPOSE: To study the detailed process of macular edema (ME) absorption after grid laser photocoagulation in patients with branch retinal vein occlusion (BRVO). The influence of pretreatment serous retinal detachment (SRD) at the fovea on patient outcome was also evaluated. DESIGN: Retrospective, interventional, comparative case series. PARTICIPANTS: Thirty-seven BRVO patients presenting with severe ME. METHODS: Patients were treated with grid laser photocoagulation with 6 months of follow-up examinations. Baseline and post-treatment examinations included measurements of visual acuity (VA), fluorescein angiography, and detailed imaging of ME by optical coherence tomography (OCT). Macular thickness was defined as the distance from the inner retinal surface to the outer border of the sensory retina (foveal retinal thickness) and also to the inner border of the retinal pigment epithelium including the SRD (total foveal elevation). MAIN OUTCOME MEASURES: Post-treatment macular thickness with OCT, VA converted to the logarithm of the minimum angle of resolution, and absorption of SRD, and correlations of macular thickness and VA both before and after treatment. RESULTS: Total foveal elevation and VA were significantly improved at 1, 3, and 6 months after treatment. There was also a significant correlation between reduction of total foveal elevation and increase in VA. Fourteen eyes (37.8%) displayed SRD, as evidenced by OCT at the baseline. In eyes without SRD, foveal retinal thickness and VA had significantly improved in a time-dependent manner. However, although SRD itself was almost absorbed 6 months after treatment, the improvement of both VA and total foveal elevation in eyes with pretreatment SRD was not significant compared with baseline conditions. Both post-treatment total foveal elevation and VA of eyes with SRD tended to be worse than eyes without SRD. CONCLUSION: The presence of subfoveal SRD retards the absorption of ME and recovery of VA after grid laser photocoagulation in patients with BRVO.

Analysis of choriocapillaris flow patterns by continuous laser-targeted angiography in monkeys.

PURPOSE: To investigate choriocapillaris flow patterns and its segmental distribution in monkeys by continuous laser-targeted angiography (LTA). METHODS: A slit lamp was modified to incorporate two kinds of lasers (argon and diode). Carboxyfluorescein (CF) was encapsulated in heat-sensitive liposomes and injected intravenously. Encapsulated CF was released locally by applying a continuous heat beam provided by the diode laser (810 nm). Video angiograms were generated with excitation illumination provided by the argon laser (488 and 514 nm), to observe selective images of the choriocapillaris. RESULTS: Continuous application of the diode laser disclosed three distinct phases (filling, plateau, and draining) of fluorescent images of the choriocapillaris. In the plateau phase, a cluster of lobules fed by a common arteriole was uniformly illuminated. This defined area did not change in size while a continuous diode laser was applied to the same spot. Only in posterior regions did the angiograms demonstrate that during the filling and draining phases each lobule was filled from a central spot and drained along a peripheral ring, showing honeycomb flow patterns. In peripheral regions, large choroidal vessels as well as choriocapillaris were observed. CONCLUSIONS: Continuous LTA demonstrated clusters of lobules fed by a common arteriole, and each cluster was found to be functionally independent. There were regional differences in choriocapillaris flow patterns, which suggests that the choriocapillaris provides a more highly efficient system of outflow in posterior regions than in peripheral regions. This modified LTA method appears to be useful in analyzing choroidal circulation in vivo.

In vivo analysis of choroidal circulation by continuous laser-targeted angiography in the rat.

PURPOSE: To obtain high-quality angiograms of the rat choriocapillaris with continuous laser-targeted angiography (LTA), for the purpose of assessing the choroidal circulation system in vivo by studying the patterns of the images. METHODS: A slit lamp was modified to incorporate two kinds of lasers (argon and diode). Carboxyfluorescein was encapsulated in heat-sensitive liposomes and injected intravenously. Encapsulated carboxyfluorescein was released locally by applying a continuous heat beam provided by diode laser (810 nm) with various powers. Video angiograms were generated with excitation illumination provided by argon laser (488 and 514 nm) to observe highly selective images of the choriocapillaris. RESULTS: Three distinct phases (filling, plateau, and draining) were observed in fluorescent images of choriocapillaris by applying the diode laser continuously. In the plateau phase, a lobe-shaped area of choriocapillaris peripheral to the laser site was illuminated, and this finite area did not change in size with continuous laser application to the same spot. When laser power was increased, a larger area of choriocapillaris was illuminated in the plateau phase. The filling and draining phases demonstrated the flow patterns in choriocapillaris lobules, which filled from a central spot and drained along a peripheral ring. CONCLUSIONS: This study showed that the rat choriocapillaris is divided into independent functional units and that the choroidal circulation is segmental under normal conditions. The results implied that in LTA, the diode laser warms up a choroidal artery and the released fluorescein flows downstream to an area of choriocapillaris fed by the same artery. LTA appeared to be a powerful method to analyze choroidal circulation in vivo.

Noninvasive technique for monitoring chorioretinal temperature during transpupillary thermotherapy, with a thermosensitive liposome.

PURPOSE: To develop a technique for noninvasive and real-time monitoring of chorioretinal temperature in transpupillary thermotherapy (TTT). METHOD: A modified slit lamp, which was equipped with two laser wavelengths (490 nm for illumination and fluorescein excitation and 810 nm for hyperthermia), was developed for TTT and temperature monitoring. Five types of liposomes were prepared, and their phase-transition temperatures were 40 degrees C, 46 degrees C, 47 degrees C, 48 degrees C, and 52 degrees C, respectively. Carboxyfluorescein was encapsulated in each liposome. After intravenous injection of each liposome, TTT with the modified slit lamp was performed on normal rat choroid or tissue with choroidal neovascularization (CNV). During TTT, chorioretinal temperature was monitored by observing release of fluorescein from circulating liposomes. RESULTS: Fluorescence from liposomes was initially observed around the heated lesion immediately after TTT began and disappeared rapidly when irradiation stopped. Choroidal and retinal temperatures were monitored separately. TTT for normal retina required higher power than that for normal choroid to observe fluorescence from a 40 degrees C, 46 degrees C, and 47 degrees C liposome. Retinal whitening was observed after TTT at a high-power setting. TTT for CNV required higher laser power than that for the normal choroid and retina. CONCLUSIONS: The results demonstrate the potential use of a noninvasive monitoring technique of chorioretinal temperature during TTT. The method should be useful to establish the TTT setting and achieve the optimal temperature increase in CNV.

Relation between retinal thickening and clinically visible fundus pathologies in mild nonproliferative diabetic retinopathy.

BACKGROUND AND OBJECTIVE: To determine the association of retinal thickening (RT) with clinically observable retinal pathologies in eyes with mild nonproliferative diabetic retinopathy. PATIENTS AND METHODS: Using an objective quantitative imaging method (Retinal Thickness Analyzer), the ratio relative to normal RT (RTI) was measured in 23 eyes with and 35 eyes without clinically observable diabetic fundus pathology. RTI was analyzed in relation to presence of mild diabetic retinal lesions in the +/-0.5 mm vicinity. RESULTS: The percent of eyes with RTI significantly above normal values did not differ significantly between eyes with and without retinopathy (30% vs 34%). Mean RTI was not associated with local presence of microaneurysms (P=0.92), soft exudates (P=0.55), or retinal hemorrhages (P=0.31). Areas without hard exudates had significantly greater mean RTI (1.10) than areas with exudates (0.97, P=0.009). CONCLUSION: In diabetic patients with mild retinopathy, areas with and without clinically observable retinal pathologies had similar retinal thickness. We conclude that clinical strategies for detection of retinal thickening should not be limited to areas with visible fundus pathologies.

Laser targeted photo-occlusion of rat choroidal neovascularization without collateral damage.

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), Bruch's 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.

Inflammatory response after scatter laser photocoagulation in nonphotocoagulated retina.

PURPOSE: Macular edema is one of the most serious adverse effects after retinal scatter laser photocoagulation. It has been suggested that the changes in the distribution of retinal blood flow or the inflammatory reaction after photocoagulation may be involved in the pathogenesis of macular edema, but little information is available about its exact mechanism. This study was designed to evaluate quantitatively leukocyte-endothelial cell interactions and vascular permeability in the nonphotocoagulated portions of the retina after partial scatter laser photocoagulation. METHODS: Argon laser photocoagulation was performed in one half of the retina in male pigmented rats (n = 90). In the other half of the retina, leukocyte dynamics after photocoagulation were evaluated in vivo with acridine orange digital fluorography. Retinal vessel permeability was quantified by using Evans blue dye. RESULTS: Scatter laser photocoagulation caused significant inflammatory leukocyte-endothelial interactions not only in the photocoagulated but also in the untreated half of the retina. In the nonphotocoagulated half of the retina, the number of leukocytes rolling along the major retinal veins increased after photocoagulation and peaked at 12 hours (14.3 +/- 4.5 cells/min per vessel). Leukocyte accumulation in the untreated half of the retina increased after photocoagulation, with a peak of 47.5 +/- 13.0 cells/mm(2) 24 hours after photocoagulation. Retinal vascular permeability in the untreated half of the retina gradually increased after photocoagulation. CONCLUSIONS: Scatter laser photocoagulation increased leukocyte rolling and subsequent accumulation in both the photocoagulated and the untreated portions of the retina. The accumulated leukocytes may be involved in the augmented vascular permeability in the untreated retina, resulting in retinal edema after photocoagulation.

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. METHODS: 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.

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 normotensive 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.