Differential diagnosis of endophthalmitis after intravitreal drug injection for age related macular degeneration: sterile vs. infectious.

The recent release of brolucizumab and the development of new antiangiogenic molecules as abicipar pegol has increased the interest towards inflammatory complications after intravitreal drug injection. Those drugs are associated to a higher rate of inflammatory adverse events compared to classic drugs. In this context it is essential to differentiate between sterile and infectious cases for a fast and effective treatment. The clinical similarities between infectious and sterile cases, the high rate of culture negative patients and the heterogeneity in the terminology used are obstacles for a correct diagnosis and report of these complications. Sterile cases appear early after the injection, before 48 h; or 20 days after in brolucizumab-related vasculitis cases. Infectious cases show up around the third day after injection and up to a week after it. A severe visual impairment, severe pain, severe hyperemia, hypopyon and a more severe intraocular inflammatory process are signs of a likely infectious origin. If the cause of the inflammation is uncertain we must follow up the patient closely or "tap and inject" antimicrobial agents in order to prevent the eventual complications of an infectious endophthalmitis. On the other hand, sterile endophthalmitis might be observed in mild cases or treated with steroids according to the severity of the inflammation.

Evaluation of non-exudative tomographic signs in cases of exudative age-related macular degeneration.

OBJECTIVE: To analyse the prevalence of non-exudative tomographic signs (onion sign, pseudoswelling, external retinal tubulation, pseudocysts, subretinal clefts and macular atrophy) in patients with neovascular age-related macular degeneration. MATERIAL AND METHODS: A total of 174 eyes of patients with neovascular age-related macular degeneration who had not received previous treatment were included in the study. Visual acuity, neovascularization activity, and the appearance or not of the different signs under study were assessed at times 0 (initial visit), 4 months, one year, year and a half, and at 2 and 3 years of follow-up. The following were also evaluated: age, sex, affected eye and type of neovascularization (1, 2, 3, polypoid or mixed). The analysis were performed using the statistical software R (version 3.3.2) and the glmmADMB package (version 0.8.3.3). RESULTS: The presence of pseudocysts and external retinal tubulation increases throughout the follow-up. The onion sign begins with an ascending frequency up to 12 months, then decreases at 18 months and increases again at 24 months. Regarding pseudowelling, it maintains an increase until 18 months to finally decrease. Subretinal clefts is the rarest sign, presenting in 1.1% on the first visit. Finally, macular atrophy, present in 12.6% of the eyes initially, is found in 25% after 2 years. CONCLUSION: Pseudocysts, external retinal tubulation and macular atrophy were the most prevalent signs, while subretinal clefts were the most infrequent.

Guidance on brolucizumab management recommendations.

PURPOSE: Brolucizumab, a new generation anti-VEGF, has demonstrated efficacy and safety in AMD in the pivotal HAWK and HARRIER trials. Post-marketing, previously undetected adverse events related to intraocular inflammation have been reported. An independent post hoc review of the pivotal trials puts the rate of IOI at 4.6%. The aim of this paper is to propose a set of recommendations for implementing the management of brolucizumab in clinical practice. METHODS: The recommendations made by the authors are based on their clinical experience, critical review of (i) the pivotal trials, the post-hoc analysis of the Safety Review Committee, (ii), and (iii) the published literature. RESULTS: In the pivotal trials, brolucizumab showed sustained functional gains, superior anatomical outcomes with potentially longer intervals between injections and a well-tolerated overall safety profile. Adverse events reported post-marketing include retinal vasculitis and retinal vascular occlusion. Based on the available information, experts recommend (i) ruling out non-recommended patient profiles (prior history of ORI), (ii) screening the patient prior to each injection to rule out active ORI, (iii) monitoring the patient for early warning signs, and (iv) treating immediately should any adverse events develop. CONCLUSIONS: The adverse events reported are rare, but may be associated with severe and irreversible loss of visual acuity. The recommendations made are intended to facilitate the management of brolucizumab in the routine practice of retinologists, to ensure patient safety and, should any adverse events occur, to minimise their impact on vision.

Vogt-Koyanagi-Harada: treatment of recurrence after administration of 3 intravenous bolus of 1 g of corticosteroids and mycophenolate mofetil.

The case is presented on a young Honduran female with no medical history of note, who presented with multiple areas of exudative retinal detachment (RD), and a best-corrected visual acuity of 1.3 logMAR in both eyes. She was diagnosed with incomplete Vogt-Koyanagi-Harada syndrome, and treated early with a combination of intravenous therapy with 1 g of prednisolone per day for 3 days, as recommended by published evidence, as well as mycophenolate mofetil (2 g per day). During the corticosteroids tapering, there was a recurrence of exudative retinal detachments, and megadoses of 1 g of intravenous corticosteroids per day were reintroduced for 6 days until the complete resolution of the fluid of the exudative RD, and cyclosporine (100 mg per day), subtenon triamcinolone (40 mg/mL), and intravitreal ranibizumab once a month in the both eyes were added to the treatment, with a great control of choroidal inflammation that resulted in the remission of symptoms and signs.

Vogt-Koyanagi-Harada: treatment of recurrence after administration of 3 intravenous bolus of 1g of corticosteroids and mycophenolate mofetil. / Vogt-Koyanagi-Harada: tratamiento de la recurrencia tras la administración de 3 bolos intravenosos de 1g de corticoides y micofenolato de mofetilo.

The case is presented on a young Honduran female with no medical history of note, who presented with multiple areas of exudative retinal detachment (RD), and a best-corrected visual acuity of 1.3logMAR in both eyes. She was diagnosed with incomplete Vogt-Koyanagi-Harada syndrome, and treated early with a combination of intravenous therapy with 1g of prednisolone per day for 3 days, as recommended by published evidence, as well as mycophenolate mofetil (2g per day). During the corticosteroids tapering, there was a recurrence of exudative retinal detachments, and megadoses of 1g of intravenous corticosteroids per day were reintroduced for 6 days until the complete resolution of the fluid of the exudative RD, and cyclosporine (100mg per day), subtenon triamcinolone (40mg/mL), and intravitreal ranibizumab once a month in the both eyes were added to the treatment, with a great control of choroidal inflammation that resulted in the remission of symptoms and signs.

Retinal pigment epithelial tears.

A retinal pigment epithelial (RPE) tear is a well-known complication of retinal pigment epithelial detachments (PED) and may cause a significant visual impairment. The most common cause is a vascularized PED in patients with exudative age-related macular degeneration (AMD). The development of diagnostic imaging techniques brings us closer to the etiology and pathophysiological mechanisms of this entity, offering us new strategies for treatment and follow-up. The advent of intravitreal antiangiogenic treatment (anti-VEGF) has led to an increase in the number of reported cases of RPE tears, which are an important vision-limiting factor during treatment. However, RPE tears may occur spontaneously or as a consequence of thermal laser treatment, photodynamic therapy or anti-VEGF therapy. It is accepted that the mechanism of RPE tears is multifactorial. The optimization of the functional outcome of this complication has been described with continuous treatment with antiangiogenic drugs. The goal of the present review is to evaluate the incidence, risk factors and treatment of RPE tears.

[Choroideremia: one-year follow-up with scanning laser polarimetry examination]. / Coroideremia: seguimiento durante un año con polarimetría láser.

CASE REPORT: We report the follow-up of a case of choroideremia who underwent three white-on-white automated visual field and three scanning laser polarimetry (SLP) examinations by means of a GDx VCC in the course of one year. A bilateral perimetric deterioration in indices and scotomas was found. As a result, retinal nerve fiber layer retardation parameters and maps changed on GDx VCC advanced serial analyses in both eyes. DISCUSSION: Serial analyses with GDx VCC may be used as objective and quantitative tests to assess the progression of chorioretinal dystrophies like choroideremia

[Biochemical characterization of the optic nerve in mice overexpressing the P53 gen. Oxidative stress assays]. / Caracterización bioquímica del nervio óptico en el ratón que sobreexpresa el gen P53. Análisis de estrés oxidativo.

PURPOSE: The tumour inhibitor p53 gene has the ability of triggering proliferation arrest and cellular death by apoptosis subsequent to several factors, among them oxidative stress. The p53 protein is a major regulator of gene expression. Using genetically manipulated mice carrying an extra copy of gene p53 (transgenic mice super p53) versus control mice, we have investigated the generation of reactive oxygen species and antioxidant activity in the optic nerve of mice in relation to p53 availability. METHODS: We studied two groups of 12-month-old mice of the strain C57BL/6: 1) super p53 group (Sp53) and 2) wild-type control group (CG). Mice were anesthetized in ether atmosphere and the eyeball and retrobulbar optic nerves were excised, washed, soaked in PBS, and stored in liquid nitrogen at -85 degrees C until processing. Three-four optic nerves from the same group were placed in an eppendorf tube, homogenized and enzymatic-colorimetric methods used to determine oxidative and antioxidant activities and the nitric oxide synthesis. RESULTS: A significant increase in free radical formation (via lipid peroxidation; p<0.001), antioxidant activity (p<0.001) and nitric oxide synthesis (p<0.001) was found in the optic nerves from transgenic super p53 mice compared to respective controls. CONCLUSION: The presence of an extra copy of the p53 gene correlated with redox status in the mouse optic nerve. This transgenic mouse could be useful as an experimental model to study cell resistance to neurodegenerative processes in relation to oxidative stress and to apoptosis induction, such as glaucomatous optic neuropathy or age-related macular degeneration.

[Study of apoptosis and mitosis mechanisms in the eye. Experimental model of gestational toxic syndrome]. / Estudio de los mecanismos de apoptosis y mitosis en el globo ocular. Modelo experimental del síndrome tóxico gestacional.

OBJECTIVE: To improve knowledge of the mechanisms of cellular differentiation and proliferation during retinal development, by studying cellular and molecular damage in a rat model of prenatal ethanol exposure. METHODS: Female, juvenile Wistar rats (200g body weight) and their offspring were divided into two groups, which were fed a liquid diet: 1) ethanol-exposed group (5% ethanol weight/vol as 35% of daily total calories) and 2) isocaloric control group (maltose/dextrin as 35% of daily total calories). Eyeballs were obtained at 21 days of gestation, embedded in paraffin, and immunodetection procedures performed on apoptotic (TUNEL) and mitotic profiles, which were observed and photographed using a confocal microscope. RESULTS: Analysis of the microphotographs revealed a statistically significant increase of apoptotic profiles and a decrease in mitotic profiles in the ethanol exposed group compared to controls (p<0.05). Ganglion cells and photoreceptors showed more changes than other retinal cell phenotypes. These findings suggest that abnormalities in the differentiation and proliferation processes of the retina were caused by the alcohol exposure. CONCLUSIONS: Alcohol abuse during pregnancy alters development of the visual system by inducing developmental changes in the mitotic and apoptotic processes of the retina. These latter changes may be the result of changes in the expression of regulatory genes as well as the result of alteration in signalling pathways for both differentiation-proliferation and apoptotic events.

[Involvement of nitric oxide and other molecules with redox potential in primary open angle glaucoma]. / Implicaciones del óxido nítrico y otras moléculas con potencial redox en el glaucoma primario de ángulo abierto.

PURPOSE: Nitric oxide (NO) and other molecules with redox potential are involved in cell signalling, including endothelial-dependent relaxation and the maintenance of vascular homeostasis. We investigated the availability of NO and the formation of reactive oxygen species (ROS) in the aqueous humour and its relationship to the pathogenic mechanisms of primary open-angle glaucoma (POAG). METHODS: We analysed biochemically aqueous humour samples from patients having anterior segment surgery that were divided into two separate groups: 1) patients having a Watson's trabeculectomy because of worsening of the glaucoma evolution (GG; n=60), and 2) a comparative group of individuals having phacoemulsification for non-complicated cataracts (CG; n=60). Enzymatic-colorimetric methods were used to analyse the NO concentration, the lipid peroxidation by-product malondialdehyde (MDA) and the total antioxidant status (TAS). Statistical analysis was carried out in the two groups by means of the SPSS 15.0 programme. RESULTS: A significant increase in both the NO concentration (p<0.05) and MDA levels (p<0.05), and a significant decrease of the TAS (p<0.05) were detected in the GG versus the CG samples. CONCLUSIONS: Changes in NO availability and the concomitance of oxidative stress in the aqueous humour of the POAG patients may be useful markers for identifying those at risk of glaucoma progression and visual loss.

Idiopathic macular telangiectasia type 2: Prevalence and a morphometric and phenotypic study. / Telangiectasias maculares idiopáticas de tipo 2: prevalencia en nuestra área y estudio morfométrico y fenotípico.

OBJECTIVE: Type 2 idiopathic macular telangiectasia (MacTel2) is a rare retinal disease that has still not been well-defined. The aim of the present manuscript is to describe the clinical features by multimodal retinal imaging, to present the functional characteristics, and to estimate the prevalence of the disease. METHODS: A retrospective study was conducted on the 12 eyes of 6 patients with MacTel2. Fundus colour photographs, fundus autofluorescence, fluorescein angiography, optical coherence tomography (OCT), and OCT-angiography were performed and subsequently analysed. Visual acuity (VA) was prospectively recorded. The prevalence was established based on the patients referred to a specialised macular diseases unit. Minimum follow-up period was 18 months. RESULTS: Prevalence of MacTel 2 in our study was 0.12%. Clinical features were presented using multimodal retinal imaging. VA remained stable during follow-up. Three patients developed choroidal neovascularisation (CNV), requiring intravitreal treatment with antiangiogenic agents. CONCLUSIONS: The prevalence of the disease found was 0.12%. The study using multimodal imaging allows a more accurate diagnosis and follow-up of this pathology. The VA is maintained during the 18-month follow-up (P=.492). Patients who develop CNV and are treated with antiangiogenic agents appear to respond adequately to them. More studies are needed to establish these conclusions.

Geographic atrophy: Etiopathogenesis and current therapies. / Atrofia geográfica: etiopatogenia y terapias actuales.

Geographic atrophy is characterized by severe visual deficit whose etiology and pathophysiology are yet to be elucidated. As a working hypothesis, oxidative damage could trigger a chronic inflammation in Bruch's membrane-RPE-choriocapillaris complex, mostly due to complement pathway overactivation. Some individuals with mutations in the complement system and other factors have diminished capacity in the modulation of the inflammatory response, which results in cell damage and waste accumulation. This accumulation of intracellular and extracellular waste products manifests as drusen and pigmentary changes that precede the atrophy of photoreceptors, RPE, choriocapillaris with an ischemic process with decreased choroid flow. All these processes can be detected as tomographic findings and autofluorescence signals that are useful in the evaluation of patients with atrophic AMD, which helps to establish an individualized prognosis. Anti-inflammatory, antioxidant and therapies that decrease the accumulation of toxins for the preservation of the RPE cells and photoreceptors are being investigated in order to slow down the progression of this disease.

Incidence and clinical outcomes of the different neovascular forms of age-related macular degeneration in Valencia (Spain). / Incidencia y resultados clínicos de las distintas formas neovasculares de degeneración macular asociada a la edad en Valencia (España).

OBJECTIVE: To analyse the incidence and outcomes of the different neovascular subtypes in age-related macular degeneration (AMD). MATERIAL AND METHODS: A retrospective review was carried out on patients with neovascular AMD treated in the University and Polytechnic Hospital la Fe in Valencia by the same retinal physician (RGP) between December 2012 and July 2015. The anatomic classification of the neovascular lesions was recorded, as well as the number of intravitreal treatments administered and the change in visual acuity (VA) obtained throughout the follow-up. RESULTS: A total number of 174 eyes of 156 patients (mean age: 79.9years) with a minimum follow-up of 4 months were included. The anatomic classification of choroidal neovascularisation (CNV) showed the presence of type1 lesions in 40,8%, type2 lesions in 12%, type3 lesions in 31%, and mixed lesions in 14.4%, with 1.7% showing polypoidal choroidal vasculopathy features. Overall, the mean baseline VA was 0,32, improving to 0,38 at 24months, after having received a mean of 9.3 injections. Type2, 3, and mixed forms showed a visual result significantly lower than type1, but there was no significant difference in the polypoidal vasculopathy. CONCLUSIONS: Type 1 CNV was the most common finding, and was associated with a better visual prognosis, compared to the other neovascular lesions.

[Dacryocystitis caused by Candida lusitaniae]. / Dacriocistitis por Candida Lusitaniae.

CASE REPORT: We report the case of a 60-year-old woman with recurrent dacryocystitis of the right lacrimal sac. She did not recover after medical treatment, nor after dacryocystorhinostomy with canalicular intubation. She also had dacryocystitis on the left side. The material that was obtained during surgery was grown in a culture medium and Candida Lusitaniae was identified as the responsible organism. All symptoms disappeared after topical treatment with amphotericin B and dacryocystorhinostomy. DISCUSSION: Dacryocystitis caused by Candida Lusitaniae is very rare. We should always consider whether Candida Lusitaniae is responsible for the primary infection or is the agent resulting from a superadded infection caused by previous antibiotic therapy.

[Optic neuropathy induced by prenatal drug or alcohol exposure]. / Neuropatía óptica inducida por exposición prenatal a drogas o alcohol.

PURPOSE: The main aim of this work was to analyse the cellular and molecular mechanisms involved in retinal and optic nerve development, and the consequences of methamphetamine "ice" (MA) or alcohol (EtOH) abuse during pregnancy on the developing visual system. MATERIAL AND METHODS: Wistar rats were exposed to MA or EtOH during gestation and lactation and their offspring studied. Control isocaloric rats were maintained in parallel. The eyes and optic nerves from pups (at 7, 14 and 21 postnatal days) were processed using morphologic, morphometric and western blot approaches using antibodies against glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and neurofilament protein (NFP). RESULTS: Statistically significant differences were observed between the methamphetamine-exposed and the alcohol-exposed rats, as compared to the controls. The optic nerve cross-sectional area was smaller in the drug or alcohol-exposed animals. The expression of developmental protein markers (GFAP and MBP) in the retina and optic nerve displayed striking alterations related to drug or alcohol abuse during gestation and lactation. CONCLUSIONS: Psychostimulant and alcohol exposure alters the development of the retina and optic nerve.

Cardiovascular involvement in patients with diabetic macular oedema treated with intravitreal ranibizumab in routine clinical practice. / Afectación cardiovascular en pacientes con edema macular diabético tratados con ranibizumab intravítreo en la práctica clínica habitual.

OBJECTIVE: To determine the cardiovascular events in naïve patients with diabetic macular oedema, before and after being treated with intravitreal ranibizumab. MATERIAL AND METHODS: A retrospective and descriptive study was conducted on patients with diabetic macular oedema and foveal involvement, who started treatment with intravitreal ranibizumab in 2014 in the Hospital Universitario Nuestra Señora de Candelaria and the Hospital Universitario y Politécnico La Fe. During the follow-up until August 2015, a record was made of parameters, including the prevalence and incidence of stroke and myocardial infarction. RESULTS: Among the 1,324 intravitreal ranibizumab injections administered in 2014, only 159 of them corresponded to treatment initiation in 99 patients, with more than half requiring treatment of both eyes. The study patients included 58.4% males, in the 6th decade of life (Mean=65.93±11.24 years), non-smokers (86.7%), type 2 diabetes (91.9%), hypertension (70.7%), and with dyslipidaemia (65.7%). Prior to treatment initiation, it was found that 6 patients (6.1%) suffered from an acute myocardial infarction, and 8 (8.1%) from stroke, and only one (1%) with post-stroke (P=.039). CONCLUSION: In our experience it seems that the intravitreal ranibizumab in diabetic macular oedema could be a safe alternative in patients with a history of stroke and myocardial infarction.

Implications of the anatomical classification of the neovascular form of age-related macular degeneration. / Implicaciones de la clasificación anatómica de la forma neovascular de la degeneración macular asociada a la edad.

OBJECTIVE: To present the clinical relevance of the anatomical classification of the neovascular form of Age-Related Macular Degeneration (AMD). METHODS: Critical analysis of the current situation in the management of patients with neovascular AMD, by reviewing the available scientific evidence with regards to the classification of the types of neovascular lesion by angiography and optical coherence tomography (OCT). RESULTS: The classification of the neovascular lesion type secondary to AMD by OCT in type 1 lesions (under the pigment epithelium), type 2 (subretinal), and type 3 (retinal angiomatous proliferation), provides an added value in allowing to establish a long-term visual prognosis, an estimate of the number of treatments that a certain case may require, and a stratification of the risk for secondary geographic atrophy. CONCLUSIONS: Incorporating OCT to the initial qualitative analysis of cases with neovascular AMD offers an added value superior to that provided by the angiography, with the relevant clinical implications.

Functional impact of treatment with ranibizumab under a reactive strategy in patients with neovascular age-related macular degeneration. / Impacto funcional del tratamiento con ranibizumab bajo una estrategia reactiva en pacientes con degeneración macular asociada a la edad exudativa neovascular.

OBJECTIVE: To analyse the functional recovery using a pro re nata (PRN) dosing strategy with intravitreal injections of ranibizumab for patients with neovascular age-related macular degeneration (AMD). MATERIAL AND METHODS: An observational, retrospective, single-centre study, was conducted on patients with neovascular AMD managed with a PRN strategy with ranibizumab, and were followed-up for a minimum of 18 months. Sociodemographic and clinical data were collected from medical records. The percentage of visual acuity (VA) recovered after losing 5 or more letters was calculated taking into account the previous visit, as well as considering the best VA recorded prior to the retreament. RESULTS: The analysis included 128 patients. The mean (SD) follow-up period was 18.9 (2.3) months. The mean (SD) elapsed days between onset of symptoms and diagnosis, and between prescription and administration of treatment was 50.2 (57.4) and 10.9 (16.0), respectively. Only 108 patients were prescribed ranibizumab after losing 5 or more letters of VA. The mean (SD) VA recovery compared to the previous VA was 70.3% (114.4). On the other hand, the mean (SD) VA recovery when considering the best VA registered before the retreatment was 43.5% (112.9), with 59.4% of re-treatments having a VA recovery below 75%, and with 11.7% not presenting any VA recovery. CONCLUSIONS: A PRN dosing strategy with intravitreal ranibizumab for neovascular AMD may not be efficient in preserving and/or recovering VA in the long-term, due to a cumulative irreversible VA loss.

Intravitreal therapies for non-neovascular age-related macular degeneration with intraretinal or subretinal fluid. / Terapias intravítreas en degeneración macular asociada a la edad no neovascular con fluido intrarretiniano o subretiniano.

OBJECTIVE: To evaluate the efficacy of intravitreal therapies in cases of atrophic age-related macular degeneration (AMD) with subretinal or intraretinal fluid. METHODS: A retrospective review was made of the clinical charts of patients diagnosed with atrophic AMD with subretinal or intraretinal fluid. Fundus photographs and spectral-domain optical coherence tomography images were examined, and an analysis was made on the presence of fluid and its density. Neovascularisation was ruled out by fluorescein and/or indocyanine green angiography. RESULTS: The study included 14 eyes from 13 patients with a mean age of 72.64 years and a mean follow-up of 80.5 weeks. Intraretinal fluid was observed in 6 eyes (42.9%), while subretinal fluid was shown in 8 eyes (57.1%), with high density in 4 eyes (28.5%), and low density in 4 eyes (28.5%). Snellen best-corrected visual acuity improved from 0.37 at baseline to 0.56 at the final visit (P=.002). Central subfield thickness (microns) significantly decreased (P<.001) from 291.0 at baseline to 228.9 at the final visit. Eight eyes received ranibizumab, 5eyes received bevacizumab, and one case received triamcinolone. CONCLUSIONS: Cases of atrophic AMD may present with subretinal or intraretinal fluid in the absence Neovascularisation. Further studies are required to analyse the value of this finding as a risk factor of developing advanced forms of AMD, as well as the efficacy of intravitreal therapies.