P. Charbel Issa

Confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia

PURPOSE To report the characteristics of confocal blue reflectance imaging in type 2 idiopathic macular telangiectasia (type 2 IMT). METHODS In a prospective observational cross-sectional study, both eyes of 33 patients with type 2 IMT were examined by means of fundus biomicroscopy, fundus photography, fluorescein angiography, and optical coherence tomography (OCT). Confocal blue reflectance (CBR) imaging was performed using a confocal scanning laser ophthalmoscope (HRA2; Heidelberg Engineering, Heidelberg, Germany). To compare the results derived from different imaging modalities, an analysis was performed using image analysis software (Heidelberg Eye Explorer; Heidelberg Engineering). RESULTS CBR imaging revealed a parafoveal area of increased reflectance that was slightly larger than the area of hyperfluorescence in late-phase fluorescein angiography. The area usually encompassed an oval parafoveal area, but sectors could be spared. A parafoveal area of increased CBR was detected in 98% of eyes that showed angiographic evidence for type 2 IMT. CONCLUSIONS CBR imaging is a new, noninvasive, and sensitive method that may contribute to differentiate type 2 IMT from other diseases. Abnormalities of macular pigment distribution and Müller cell pathology may contribute to the phenomenon of increased CBR and thus the pathophysiology of type 2 IMT.

Eighteen-month follow-up of intravitreal bevacizumab in type 2 idiopathic macular telangiectasia

Aim: To evaluate the effects of intravitreal bevacizumab for non-proliferative type 2 idiopathic macular telangiectasia (type 2 IMT) within a mean follow-up period of 18 months. Methods: The authors retrospectively studied six eyes of five patients with type 2 IMT who received two doses of intravitreal bevacizumab (1.5 mg) at a 4-week interval, followed by further applications depending on disease activity. Examinations included biomicroscopy, standardised visual acuity (VA) testing, fluorescein angiography, retinal thickness analysis by optical coherence tomography and fundus-controlled microperimetry. Results: Mean follow-up time was 18 months (range 16–21 months). The mean VA at four selected time points (1 month after second treatment, 1 month and 3–4 months after last treatment, and at last visit) increased significantly (by 8.8, 6.3, 7.7 and 8.7 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, respectively; all p⩽0.05). Parafoveal leakage in fluorescein angiography and mean central retinal thickness decreased in all eyes following treatment. A rebound effect was observed after 3–4 months, and at the last visit, retinal thickness was increased in selected retinal sectors including the fellow eye. Conclusion: Inhibition of vascular endothelial growth factor (VEGF) by intravitreally injected bevacizumab may lead to functional improvement as well as a transient decrease in leakage and retinal thickness in patients with type 2 IMT. A VEGF-mediated active disease stage in which treatment might be most effective is discussed.

Characterisation of severe rod-cone dystrophy in a consanguineous family with a splice site mutation in the MERTK gene.

Aim: To characterise the ocular phenotype of a family segregating the splice site mutation c.2189+1G>T in the tyrosine kinase receptor gene MERTK. Methods: Five affected children of a consanguineous Moroccan family were investigated by ophthalmic examinations, including fundus photography, autofluorescence (FAF) imaging, optical coherence tomography (OCT), psychophysical and electrophysiological methods. Results: Affected children were between 5 and 19 years of age, allowing an estimation of disease progression. Electroretinography demonstrated loss of scotopic and photopic function in the first decade of life. Younger siblings showed drusen-like deposits with focal relatively increased FAF in the macular area. With increasing age, a yellowish lesion with relatively increased FAF and subsequent macular atrophy developed. Visual acuity deteriorated with age and ranged between 20/50 in the best eye of the youngest affected and 20/400 in the worst eye of the oldest affected sibling. Spectral-domain OCT revealed debris-like material in the subneurosensory space. Conclusion: The splice site mutation c.2189+1G>T in MERTK causes rod–cone dystrophy with a distinct macular phenotype. The debris in the subneurosensory space resembles that in the Royal College of Surgeons (RCS) rat being the mertk animal model. Patients might therefore benefit from advances in gene therapy that were previously achieved in the RCS rat.

Intravitreal bevacizumab for choroidal neovascularisation associated with pseudoxanthoma elasticum

Purpose: To investigate the efficacy of intravitreal bevacizumab injections for treating choroidal neovascularisation (CNV) secondary to pseudoxanthoma elasticum (PXE). Methods: Patients with active CNV due to PXE received intravitreal bevacizumab (1.5 mg) and were reviewed at monthly intervals. Further treatments were administered depending on disease activity (visual loss of 5 letters or one line, persistent leakage, persistent macular oedema). Baseline and 1–3 monthly follow-up examinations included best corrected visual acuity (BCVA), biomicroscopy, optical coherence tomography (OCT), fluorescein and indocyanine green angiography, fundus autofluorescence and digital fundus photography. Results: 15 patients (16 eyes) with CNV and PXE were treated. Mean (SD) age was 53 (12.3) years (range 24–72). Mean BCVA at baseline was 20/100 (mean (SD) LogMAR 0.68 (0.51)), improved to 20/63 after the first injection (LogMAR 0.49 (0.45); p = 0.028), and was 20/63 (LogMAR 0.48 (0.48); p = 0.126) at the last follow-up. The mean follow-up time was 8 months. Central retinal thickness decreased significantly from 252 μm at baseline to 214 μm at the last follow-up (p = 0.004) as measured by OCT. Eyes were injected an average of 2.4 times. Categorising patients into two groups (group 1 with only mild changes and group 2 with evident morphological changes in the central macula) revealed that group 1 improved significantly more (LogMAR range 0.41–0.06) than group 2 (LogMAR range 0.80–0.66) (p = 0.014). Conclusions: The results indicate that intravitreal bevacizumab is effective both functionally and morphologically in treating CNV due to PXE. Best recovery can be achieved in eyes with disease that has not progressed too far and if treatment is initiated at the earliest point possible.

Discrete arcs of increased fundus autofluorescence in retinal dystrophies and functional correlate on microperimetry.

PurposeTo describe the occurrence of discrete arcs of increased fundus autofluorescence (FAF) associated with various retinal dystrophies and to assess their functional significance by fundus-controlled microperimetry.MethodsSeven patients, three with pigmented paravenous retinochoroidal atrophy (PPRCA), one with sector retinitis pigmentosa (RP), one with typical RP, and two with macular dystrophy were assessed by retinal imaging including FAF imaging. Serial images were obtained within a review period of 6 and 10 years in a patient with PPRCA and macular dystrophy, respectively. Fundus-controlled microperimetry was performed in eight eyes of five patients to determine light increment sensitivity.ResultsA discrete arched line of increased FAF was observed without obvious correlate on fundus biomicroscopy. The orientation of this line differed from ring shape in RP and macular dystrophy, a semi-circle structure in sector RP to crescent shape with tiplike extensions towards branching retinal veins in PPRCA. Longitudinal investigation revealed slight migration of the arc in PPRCA and peripheral extension of the ring diameter in macular dystrophy. Microperimetry revealed that the arc of increased FAF sharply delineated areas of severely impaired retinal sensitivity.ConclusionsThe findings indicate that arcs of increased FAF in PPRCA and other retinal dystrophies demarcate areas of impaired retinal function and may migrate over time. FAF imaging may therefore reveal the exact extent of neurosensory dysfunction that may exceed the dimensions anticipated by conventional examinations.

Two-wavelength fundus autofluorescence and macular pigment optical density imaging in diabetic macular oedema

PurposeTo evaluate the application of 488 and 514 nm fundus autofluorescence (FAF) and macular pigment optical density (MPOD) imaging in diabetic macular oedema (DMO) and to demonstrate the typical imaging features.Patients and MethodsA hundred and twenty-five eyes of 71 consecutive patients with diabetic retinopathy who underwent examination at a specialist university clinic employing a modified Heidelberg Retina Angiograph, using two different light sources of 488 and 514 nm wavelength, were retrospectively reviewed. MPOD images were calculated using modified Heidelberg Eye Explorer software. All images were evaluated by two independent masked graders. Features from FAF and MPOD images were correlated with optical coherence tomography (OCT) imaging findings and inter-grader variability, sensitivity and specificity were calculated using OCT as reference.ResultsSixty-seven eyes had DMO on OCT. The inter-grader variability was 0.84 for 488 nm FAF, 0.63 for 514 nm FAF and 0.79 for MPOD imaging. Sensitivity and specificity for detection of DMO were 80.6 and 89.7% for 488 nm FAF; 55.2 and 94.8% for 514 nm FAF; and 80.6 and 91.4% for MPOD imaging. In 488 nm FAF and MPOD imaging, DMO was better visualised in comparison with 514 nm FAF imaging, P<0.01. MPOD revealed displacement of macular pigment by intraretinal cysts.ConclusionMPOD imaging, and particularly its combination with 488 nm and 514 nm FAF, provides a valuable addition to OCT in the evaluation of DMO and is clinically useful in rapid en-face assessment of the central macula.

Das Komplementsystem und dessen mögliche Beteiligung an der Pathogenese der altersabhängigen Makuladegeneration (AMD)

The discovery of the complement factor H (CFH) polymorphism in age-related macular degeneration (AMD) strongly suggests a causative role of the complement system in the pathogenesis of this disease. The complement system is part of the innate immune system and is closely associated with the cellular response and the adaptive immune system. This article provides an overview of the complement system and, taking the new data into account, of possible immunopathogenetic processes in AMD.ZusammenfassungSpätestens seit der Entdeckung der Rolle des Komplementfaktor-H- (CFH-) Polymorphismus bei der altersabhängigen Makuladegeneration (AMD) scheint eine Beteiligung des Komplementsystems an der Pathogenese dieser Erkrankung gesichert. Das Komplementsystem gehört zum unspezifischen Abwehrsystem und ist eng mit zellulären Immunantworten und dem spezifischen Abwehrsystem verknüpft. Anhand der derzeitigen Datenlage soll hier eine Übersicht über das Komplementsystem und mögliche immunpathogenetische Vorgänge bei der AMD gegeben werden.AbstractThe discovery of the complement factor H (CFH) polymorphism in age-related macular degeneration (AMD) strongly suggests a causative role of the complement system in the pathogenesis of this disease. The complement system is part of the innate immune system and is closely associated with the cellular response and the adaptive immune system. This article provides an overview of the complement system and, taking the new data into account, of possible immunopathogenetic processes in AMD.

Single residue AAV capsid mutation improves transduction of photoreceptors in the Abca4-/- mouse and bipolar cells in the rd1 mouse and human retina ex vivo.

Gene therapy using adeno-associated viral (AAV) vectors for the treatment of retinal degenerations has shown safety and efficacy in clinical trials. However, very high levels of vector expression may be necessary for the treatment of conditions such as Stargardt disease where a dual vector approach is potentially needed, or in optogenetic strategies for end-stage degeneration in order to achieve maximal light sensitivity. In this study, we assessed two vectors with single capsid mutations, rAAV2/2(Y444F) and rAAV2/8(Y733F) in their ability to transduce retina in the Abca4−/− and rd1 mouse models of retinal degeneration. We noted significantly increased photoreceptor transduction using rAAV2/8(Y733F) in the Abca4−/− mouse, in contrast to previous work where vectors tested in this model have shown low levels of photoreceptor transduction. Bipolar cell transduction was achieved following subretinal delivery of both vectors in the rd1 mouse, and via intravitreal delivery of rAAV2/2(Y444F). The successful use of rAAV2/8(Y733F) to target bipolar cells was further validated on human tissue using an ex vivo culture system of retinal explants. Capsid mutant AAV vectors transduce human retinal cells and may be particularly suited to treat retinal degenerations in which high levels of transgene expression are required.

Ätiologie und Pathogenese der altersabhängigen Makuladegeneration

ZusammenfassungDie altersabhängige Makuladegeneration (AMD) ist die häufigste Ursache für eine Erblindung in Deutschland. Aufgrund der demografischen Entwicklung ist zudem mit einer deutlichen Zunahme von Betroffenen zu rechnen. Neue Erkenntnisse zur Pathogenese der AMD wurden in den letzten Jahren durch molekularbiologische Methoden generiert, die insbesondere die Assoziation genetischer Faktoren mit der AMD herausstellten. Vor allem das Komplementfaktor-H-Gen sowie der zweite Hochrisiko-Locus ARMS2 sind maßgeblich am Risiko für die Erkrankung beteiligt. Normale Alterungsprozesse und Umwelteinflüsse wie Rauchen und erhöhte Lichtexposition modulieren das individuelle genetische Risikoprofil. Ein verbessertes Verständnis der komplexen AMD-Pathogenese ist auch in der augenärztlichen Praxis notwendig, um neue Therapien zu verstehen und den Patienten adäquat zu betreuen. In diesem Fortbildungsbeitrag soll eine Übersicht über das Zusammenspiel von Altern, externen Umwelteinflüssen und genetischen Faktoren bei der Entwicklung der AMD gegeben werden.AbstractAge-related macular degeneration (AMD) is the most common cause of blindness in Germany. Due to the demographic development a further increase of affected patients is to be expected. Improved understanding of AMD pathogenesis resulted from the molecular biological approaches in recent years and showed an association of genetic factors with AMD. The complement factor H gene and the second high-risk locus ARMS2 in particular were found to contribute a significant risk for development of the disease. Ageing and environmental factors, such as smoking, modulate the individual genetic risk profile. A detailed understanding of the complex AMD pathogenesis is also relevant in ophthalmological practice to understand new treatment strategies. In this review we aim to give an overview of the interplay of ageing, external environmental factors and genetic risk variants leading to AMD.Age-related macular degeneration (AMD) is the most common cause of blindness in Germany. Due to the demographic development a further increase of affected patients is to be expected. Improved understanding of AMD pathogenesis resulted from the molecular biological approaches in recent years and showed an association of genetic factors with AMD. The complement factor H gene and the second high-risk locus ARMS2 in particular were found to contribute a significant risk for development of the disease. Ageing and environmental factors, such as smoking, modulate the individual genetic risk profile. A detailed understanding of the complex AMD pathogenesis is also relevant in ophthalmological practice to understand new treatment strategies. In this review we aim to give an overview of the interplay of ageing, external environmental factors and genetic risk variants leading to AMD.

An integrated software solution for multi-modal mapping of morphological and functional ocular data

Various morphological and functional techniques for retina examination have been established in the recent years. Although many examination results are spatially resolved and can be mapped onto data originating from other modalities, usually only data from one modality is analyzed by a clinician at a time. This is mainly because there is no software available to the public that enables the registration of structure and function in the clinical setting. Therefore we developed an integrated mapping application that allows the registration and analysis of morphological data (fundus photography, optical coherence tomography, scanning laser ophthalmoscopy images, and GDx thickness profiles) and functional data (multifocal electroretinography, multifocal pattern electroretinography, perimetry, and microperimetry). To obtain quantitative data that can be used for clinical trials and statistical analyses, extraction routines for morphological parameters — such as retinal layer thicknesses and measures of the vascular network — have been integrated. Global, regional and point-specific data from registered modalities can be extracted and exported for statistical analyses. In this article we present the implementation and examples of use of the developed software.