Choroidal Metastasis with Adenocarcinoma of the Lung Treated with Gefitinib

To evaluate macular morphology and function in diabetic macular edema (DME) over the course of intravitreal anti-vascular endothelial growth factor (VEGF) treatment with Ranibizumab. A consecutive series of 39 study eyes with centre-involving DME were included in this study. In all subjects, best-corrected visual acuity (BCVA) according ETDRS protocol, fluorescein angiography (FA), microperimetric macular sensitivity (MP) and Spectral Domain optical coherence tomography (SD-OCT) cross-sectional scans were obtained before treatment and after 3 monthly applied intravitreal Ranibizumab injections. Six different morphological qualities [IS/OS layer integrity, outer nuclear layer (ONL) cysts, ONL cyst size, inner nuclear layer (INL) cysts, blocking phenomenon and subretinal fluid] were graded of each cross-sectional OCT scan before and over the course of treatment by two experienced graders. Correlation analyses between functional and morphological parameters were obtained. Mean BCVA increased from 26 ± 14 to 33 ± 13 letters after 3 consecutive monthly applied Ranibizumab injections (p < 0.001). Central retinal thickness (CRT) decreased from 504 ± 144 to 387 ± 122 μm (p < 0.001). Over the course of treatment, IS/OS continuity improved (index: 0.56 ± 0.52 to 0.43 ± 0.49, Z = -1.415, p = 0.157), ONL cyst prevalence and size decreased significantly (index: 0.61 ± 0.44 to 0.56 ± 0.35, Z = -3.41, p = 0.001 and 1.75 ± 0.88 to 1.17 ± 1.05, Z = -4.02, p < 0.001), INL cyst prevalence decreased (index: 0.35 ± 0.52 to 0.28 ± 0.52, Z = -1.60, p = 0.109), blocking phenomenon did not change significantly (index: 00.12 ± 0.16 to 0.13 ± 0.15, Z = -0.45, p = 0.656) and subretinal fluid almost disappeared (index: 0.10 ± 0.24 vs. 0.00 ± 0.01, Z = -2.56, p = 0.011). Correlation analyses revealed highest significant correlations between ONL cyst prevalence and their size and CRT as well as BCVA and MP before treatment and over the course of treatment. ONL cysts and their size as morphological parameters correlate with retinal function measured with BCVA and microperimetry before and over the course of anti-VEGF therapy with Ranibizumab in patients with DME.

To assess the interobserver variability (IOV) in indicating retreatment for neovascular Age-related macular degeneration 4 weeks after three Ranibizumab loading doses using spectral domain OCT (SD-OCT) as the primary objective diagnostic tool. Four observers decided for or against 4th Ranibizumab injection in 108 patients by six different rating rounds (RR) based on the SD-OCT findings after the loading doses. Postoperative OCT images were supplemented consecutively with information from a chart review as the 'patients subjective estimation of vision (SE)', the course of best-corrected visual acuity (BCVA) and the preoperative OCT as well as all information collectively. Agreement rates (AR) and Kappa statistics were calculated. Based on post-treatment OCT findings only (RR1), mean reinjection rate of all observers was 37.5%. Adding supplementary information, mean reinjection rate decreased to 20% when all information was available reflecting the 'real' situation (RR 6). Interobserver agreement rates varied from 66.7% to 90.7% depending on rating rounds and interobserver pairs. Mean AR and Kappa values (KV) were as following: AR 81.6%, KV 0.61 (RR1: 'only post-OP OCT'); AR 76.7%, KV 0.33 (RR2: post-OP OCT + SE); AR 80.3%, KV 0.45 (RR3: post-OP OCT + BCVA); AR 80.7%, KV 0.46 (RR4: pre- and post-OP OCT); AR 82.2%, KV 0.49 (RR5: post-OP OCT + SE + BCVA); and finally AR 83.6%, KV 0.47 (RR6: pre- and post-OP OCT + SE + BCVA). The overall mean agreement rate was 80.9% with a Kappa of 0.47. IOV for indicating retreatment after three Ranibizumab loading doses reveals only moderate agreement in Kappa statistics, which seems to be too low considering the high costs for retreatments. More concise guidelines based on the post-treatment OCT scans as the presumably most sensitive and noninvasive objective tool to follow choroidal neovascularization activity by judging the course of sub- and intraretinal fluid are necessary.

A 21-year-old man experienced unilateral vision loss associated with multiple atrophic chorioretinal lesions. He was treated for a presumptive diagnosis of acute retinal necrosis, but his vision did not improve with antiviral therapy. Over the course of several weeks, his symptoms progressed to involve both eyes. The fellow eye showed characteristic yellow-white placoid lesions, prompting treatment with oral corticosteroids for acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Despite high-dose therapy with prednisone 80 mg daily, the patient developed the acute onset of mental status changes within the next several days. Neuroimaging revealed multifocal large-vessel strokes associated with cerebral edema; these infarcts led to herniation and death. Postmortem histopathologic examination confirmed granulomatous inflammation in both ocular and cerebral vasculatures. Together with findings from multimodal imaging obtained throughout this patient's clinical course, our findings support the notion that granulomatous choroiditis is the mechanism of the ocular lesions seen in APMPPE. This granulomatous inflammation can also affect cerebral vessels, leading to strokes.

Choroideremia Gene Therapy

To report new indocyanine green angiographic (ICGA) findings after intravitreal bevacizumab (IVB) for myopic choroidal neovascularization (mCNV). Three eyes of three patients with mCNV were examined with fluorescein angiography (FA) and ICGA using Heidelberg Retinal Angiograph 2 and the conventional fundus camera before and after IVB. The cessation of angiographic leakage on FA was achieved in all eyes (100%) after IVB, however the hypofluorescent line delineating the margin of the neovascular tissue appeared in ICGA seemingly according to the contraction of mCNV. It was not detected either on FA or ICGA with the conventional camera. This hypofluorescence line enlarged over the time. The contraction-associated hypofluorescence line, namely marginal crack line, indicates the early damage of retinal pigment epithelium and seems to lead to expanding macular chorioretinal atrophy typically seen in mCNV.

With interest we read the article by Tsai and colleagues (Tsai et al. 2013) describing an increased risk of being diagnosed with erectile dysfunction in males with central serous chorioretinopathy (CSC). In this article, it is hypothesized that vascular obstruction due to endothelial dysfunction may be an underlying mechanism in CSC. Strikingly, an inappropriate activation of the mineralocorticoid receptor, found in the choroidal vasculature (endothelial and smooth muscle cells), has also been recently suggested to underlie the pathogenesis of CSC (Zhao et al. 2012). This study also suggested a reduction in subretinal fluid (SRF) level in two patients by systemic use of eplerenone, a selective mineralocorticoid receptor antagonist, implying that eplerenone could be a promising treatment. Here we report the treatment outcome with oral eplerenone in five patients suffering from chronic CSC, who experienced persistent SRF on spectral-domain optical coherence tomography (OCT) for at least 9 months and responded insufficiently to previous treatments. Oral administration of eplerenone 25 mg/day was started at baseline. At the start of week 2, eplerenone was increased to 50 mg/day and completely stopped at the end of week 5, according to the previously described protocol (Zhao et al. 2012). A fixed follow-up protocol was used with visits scheduled at baseline, 1, 3, 5 weeks and a final examination after 10 weeks. The five patients (three males) had a mean age of 55 years (range 41–64 years), and two patients had bilateral active chronic CSC. None of the patients had a history of steroid use. A full reduction of SRF on OCT was seen in patient 1 (Fig. 1A). In this patient, there was only a minor increase in visual acuity (VA), which is most likely the result of the prolonged detachment of the neurosensory retina, causing irreversible damage to the photoreceptors (Wang et al. 2002). Patient 2 initially had a decrease in SRF but then relapsed after cessation of the eplerenone treatment (Fig. 1B). Patient 3 showed a decrease in subfoveal SRF, but showed an increase in SRF inferior of the fovea (Fig. 1C). Patient 4 had no change in SRF, nor a clear effect on VA (Fig. 1D). Patient 5 had bilateral active disease, in which one eye first had a decrease in SRF which then returned to baseline-level, whereas an increase in SRF occurred in the other eye (Fig. 1E). The use of eplerenone did not influence the hyperfluorescent pattern, typical for chronic CSC, that was seen in all patients on fluorescein angiography and indocyanine green angiography. None of the patients showed a change in subfoveal choroidal thickness on enhanced-depth-imaging-OCT during the course of the study, and systemic parameters remained within normal range in all patients. Curative therapeutic options for chronic CSC are scarce and the current leading options consist of photodynamic therapy treatment, conventional laser treatment, or micropulse laser treatment, with anatomical success rates in photodynamic therapy treatment ranging from 60 up to 100% (Quin et al. 2013). A lack of response to these treatment modalities is not uncommon. Zhao and colleagues (Zhao et al. 2012) described that an overstimulation of the mineralocorticoid receptor in a rat model caused dilation of the choroidal vasculature and choroidal thickening, similar to clinical observations in chronic CSC. The same group recently presented promising results in 13 patients with CSC, showing a full reduction of SRF in 25% of the patients at 1 month and 67% at 3 months after use of eplerenone (Bousquet et al. 2013). However, the current pilot study indicates that eplerenone has a beneficial effect only in a minority of patients with long-standing treatment-resistant chronic CSC. The precise role of an inappropriate activation of the mineralocorticoid receptor in chronic CSC therefore remains controversial. This study was supported by the following foundations: 'Stichting MD Fonds', 'Gelderse Blindenstichting', 'Landelijke Stichting voor Blinden en Slechtzienden' and 'Oogfonds' that contributed through 'UitZicht' and the 'JANIVO Stichting'. The funding organizations had no role in the design or conduct of this research. No author has any financial/conflicting interests in the products mentioned in the article.

To assess and correlate fundus autofluorescence (FAF) characteristics with photoreceptor morphology and functional features in eyes with retinitis pigmentosa (RP). Thirty-four eyes of 17 patients with RP were examined. We compared FAF images obtained by confocal scanning laser ophthalmoscopy with Spectral-domain optical coherence tomography (SD-OCT) and retinal function assessed by microperimetry. Normal FAF surrounded by a ring of increased FAF at the macular area was detected in 32 (94%) eyes. The diameter of the normal FAF was correlated significantly with the preserved area of the photoreceptor inner segment and outer segment (IS/OS) junction on SD-OCT (R=0.939, p<0.001). The area outside the ring was associated with loss of IS/OS junction and external limiting membrane (ELM). The ring of increased FAF demarcated the border between the central retina with preservation of the IS/OS junction and ELM, and the adjacent eccentric retina with loss of these bands. In two eyes of one patient, there was no preservation of normal FAF at the macula and the photoreceptor IS/OS junction was not detected on SD-OCT. The mean retinal sensitivity derived from microperimetry was correlated significantly with the area of normal FAF (R=0.929, p=0.007) and the preserved area of the IS/OS junction (R=0.851, p=0.032). Ten eyes had progressive reduction in size of the normal FAF inside the ring accompanied by decreased area of preserved IS/OS during 3.1 years. FAF appears to reflect the integrity of the photoreceptor layer. It may serve as a secondary outcome measure for novel therapeutic strategies for RP.

To describe visual function and ocular manifestations in patients with onset of cholestasis during the neonatal period. Patients with neonatal cholestasis, either transitory or chronic, who came for assessment to our tertiary referral centre were included in a cross-sectional study and underwent ophthalmological examinations including fundus photography. A total of 57 patients (24 girls and 33 boys), aged 0.4-18.0 years, were included. Of these, 28 patients had biliary atresia, 11 had Alagille's syndrome, five had progressive familiar intrahepatic cholestasis and nine had different disorders such as pituitary insufficiency, alpha-1-antitrypsin deficiency, mitochondriopathy, congenital infections or cholestasis caused by unknown reasons. Visual dysfunction and/or one or several ocular manifestations occurred in 39 out of 57 patients. Major ocular malformations occurred in five patients. Out of three patients with biliary atresia, one patient had severe visual impairment caused by microphthalmia and chorioretinal coloboma, one patient with Cat Eye syndrome had bilateral uveochorioretinal coloboma and one patient had Rieger's anomaly. Two patients, both with pituitary deficiency and transient cholestasis, had severe unilateral visual impairment caused by optic nerve hypoplasia. The majority (68%) of the patients with cholestasis had ocular manifestations. Although the severity of ocular complications varied with diagnosis, and was most apparent among patients with biliary atresia or pituitary deficiency, no conclusion can be drawn regarding the connections between these conditions from the present study. Nevertheless, ocular assessment is important for diagnostic purposes and for early intervention in patients with cholestasis.

Objective: To describe the development of retinal pigment epithelium (RPE) atrophy after uncomplicated pars plana vitrectomy (PPV) with epiretinal membrane (ERM) and/or internal limiting membrane (ILM) peeling in 2 patients.Cases description:Case 1: A 79-years-old female with diagnosis of a full-thickness macular hole in her right eye (OD) with best corrected visual acuity (BCVA) of: 20/100 and left eye (OS): 20/70. After surgery she developed large RPE hyperplasia and presented hand movement that did not improve with pinhole. Case 2: A 69-years-old female patient who had ERM in her OS with BCVA of 20/30 in both eyes (OU). PPV was assisted with brilliant blue (BB) to better visualize the ILM. During follow-up visits we evidenced RPE atrophy in the zone where peeling was done. In the last control after 2-years, her visual acuity was 20/40 that did not improve with pinhole.Discussion: There are three possible mechanisms to explain this complication: toxic damage, mechanical trauma during the membrane removal with forceps, or a combination of both. In our cases, a combination of them is probably the cause of the presence of RPE atrophy.Conclusion: Vitrectomy with membrane removal is successful in most cases with low rate of complications. Because RPE atrophy is infrequent, our suggestion is to continue performing this technique and if possible, it should be done without dye staining to minimize risks.Abbreviations: ERM = epiretinal membrane, ILM = internal limiting membrane, MH = macular hole, RPE = Retinal pigment epithelium, OD = right eye, BCVA = Best corrected visual acuity, OS = left eye, OU = both eyes, IOL = intraocular lens, OCT = Optical coherence tomography, BB = Brilliant blue, TB = Trypan blue, ICG = indocyanine green

To report a case of choroidal neovascularization (CNV) associated with rubella retinopathy (RR) treated with intravitreal aflibercept. A 15-year-old girl presented a complaint of visual decrease in her left eye. She had a history of hearing decrease since she was 1year old in addition to patent ductus arteriosus. On ocular examination, the best corrected visual acuity (BCVA) was 20/20 in the right eye and 20/400 in the left eye. Dilated fundus examinations revealed a classic salt-and-pepper appearance in both eyes and a whitish subretinal lesion with retinal hemorrhages in the left macula. Fundus fluorescein angiography (FFA) of the left eye illustrated a pattern of diffuse spotty fluorescence with an active subfoveal CNV lesion, that hyperfluoresces in the early phases of the FFA, maintains well-demarcated borders, and leaks. Spectral domain optical coherence tomography (SD-OCT) revealed thickened and elevated retinal layers at the macula due to the subretinal and intraretinal fluid with foveal and extrafoveal protruding hyper-reflective lesion in the left eye. Single dose of intravitreal aflibercept was performed to the left eye and at the first month after the injection, the BCVA improved to 20/100 and the OCT revealed scar formation. At the follow-up visits, the macula was similar to those at the first month post-injection, and the BCVA was preserved. No additional injections were needed. Intravitreal aflibercept may be a treatment alternative, which provides satisfactory anatomical and functional results and leads to a better visual acuity in cases with RR complicated by CNV.

To report long-term follow-up of patients with pigmented paravenous retinochoroidal atrophy (PPRCA) and to assess the involvement of the choroid and retinal pigment epithelium (RPE) in PPRCA. Clinical features of PPRCA were studied retrospectively in four patients followed for 6-26 years. Retinal pigment epithelium and choroidal changes were analysed with fluorescein and indocyanine green (ICG) angiography. The two younger patients, aged 16 and 28 years and followed for 6 and 18 years, respectively, showed stationary RPE atrophy and pigmentation. Indocyanine green angiography visualized slight to modest atrophy of the choriocapillaris. The two older patients, aged 69 and 70 years and each followed for 26 years, showed slow progression of disease during follow-up. Indocyanine green angiography revealed choriocapillaris atrophy partly extending into the areas shown as hyperfluorescent in fluorescein angiography. Pigmented paravenous retinochoroidal atrophy is probably a slowly progressive disease, particularly in older patients. The choriocapillaris atrophy in this disease is more properly evaluated by ICG angiography and can be underestimated by fluorescein anigiography.

Neurofibromatosis Type 1 Vasculopathy Presenting as Impending Central Retinal Artery Occlusion

Neurofibromatosis Type 1 Vasculopathy Presenting as Impending Central Retinal Artery Occlusion.

To report the effectiveness of subthreshold transpupillary thermotherapy (TTT) in the early resolution of subretinal fluid at the fovea in solitary choroidal metastasis. : Three consecutive patients who had adenocarcinoma of the lung with choroidal metastasis and macular subretinal fluid were treated by subthreshold TTT. Tumor response and fluorescein angiographic and visual results were recorded. Fluorescein angiography revealed solitary choroidal metastasis at the posterior pole with subretinal fluid in all patients. Initial best-corrected visual acuity in Patient 1, a 57-year-old man, was 40/200. Instead of usual high laser intensity, three applications of TTT, 400-mW power, 3-mm size, and 1-minute duration, were performed over the tumor mass. Repeated treatment with the same regimen was performed after 1 week. Visual acuity improved to 20/25 2 months after treatment. Best-corrected visual acuity in Patient 2, a 68-year-old woman, was 10/200 in the right eye before treatment. Visual acuity improved to 80/200 after treatment and remained stable for 14 months. Visual acuity improved from 20/100 to 20/60 in a third patient 2 months after treatment. The disappearance of subretinal fluid over the fovea was noted by fluorescein angiography 2 months after laser treatment and remained stable until the end of follow-up. Improvement of visual acuity and cessation of fluorescein leakage in the tumor showed that subthreshold (i.e., biomicroscopically invisible laser effect) TTT served as an effective treatment modality in the early resolution of macular subretinal fluid in choroidal metastasis. Multiple sessions of subthreshold TTT are safe to apply very close to the macula.

Super-dose Anti-VEGF (SAVE) Trial: 2.0 mg Intravitreal Ranibizumab for Recalcitrant Neovascular Macular Degeneration–Primary End Point