Anita Leys

EXTERNAL BEAM RADIOTHERAPY (20 Gy, 2 Gy FRACTIONS) FAILS TO CONTROL THE GROWTH OF CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION: A Review of 111 Cases

Background: Control of the natural course of choroidal neovascularization (CNV) in age‐related macular degeneration (ARMD) is difficult, and laser photocoagulation is recommended in only a subset of patients. Alternative modalities of treatment are under investigation. Methods: We have used external beam radiotherapy (20 gray radiation units [Gy], 2 Gy fractions) to treat CNV in ARMD. A total of 111 patients have been followed for 12‐30 months after radiotherapy. This study evaluates the effect of radiotherapy on the size of CNV, which was digitally measured on serial fluorescein angiograms. Results: Analysis of results in the classic (or mixed classic and occult) CNV group was conclusive for fast growth of CNV and continuous increase of size during follow up. In the occult CNV group, a slowly progressive growth of CNV was demonstrated. In patients with vascularized pigment epithelium detachments, “hot spots„ persisted; in a few patients, flattening of the macula was observed. Nearly all treated patients experienced further loss of vision. CNV growth in the radiotherapy treated eye was usually similar to growth in the untreated fellow eye, and in some, even worse. Conclusion: External beam radiotherapy (20 Gy, 2 Gy fractions) failed to control growth of CNV and was ineffective in stabilizing vision.

ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a hereditary disease characterized by progressive dystrophic mineralization of the elastic fibres. PXE patients frequently present with skin lesions and visual acuity loss. Recently, we and others showed that PXE is caused by mutations in the ABCC6/MRP6 gene. However, the molecular pathology of PXE is complicated by yet unknown factors causing the variable clinical expression of the disease. In addition, the presence of ABCC6/MRP6 pseudogenes and multiple ABCC6/MRP6-associated deletions complicate interpretation of molecular genetic studies. In this study, we present the mutation spectrum of ABCC6/MRP6 in 59 PXE patients from the Netherlands. We detected 17 different mutations in 65 alleles. The majority of mutations occurred in the NBF1 (nucleotide binding fold) domain, in the eighth cytoplasmatic loop between the 15th and 16th transmembrane regions, and in NBF2 of the predicted ABCC6/MRP6 protein. The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. The second most frequent mutation, an intragenic deletion from exon 23 to exon 29 in ABCC6/MRP6, was detected in 11 (18.6%) of the patients. Our data include 11 novel ABCC6/MRP6 mutations, as well as additional segregation data relevant to the molecular pathology of PXE in a limited number of patients and families. The consequences of our data for the molecular pathology of PXE are discussed.

Hereditary retinal dystrophies and choroidal neovascularization

Abstract Background: Choroidal neovascularization infrequently occurs in patients affected by hereditary retinal dystrophies. Methods: We studied eight patients suffering from different hereditary retinal dystrophies (Best’s disease, reticular dystrophy, butterfly-shaped dystrophy, gyrate atrophy, and retinitis pigmentosa) who developed choroidal neovascularization. All patients underwent complete ophthalmic evaluation, electrophysiology, colour vision testing, and fluorescein angiography. In some patients, ICG video-angio- graphy was also performed. Laser treatment was carried out in only one patient. Results: The mean duration of follow-up was 41.7 months (range 6–148 months). At CNV diagnosis, the mean VA was 0.23 (range 0.02–0.6). At the last follow-up, mean VA was 0.34 (range HM to 0.9). At the last follow-up, fluorescein angiography showed a focal, atrophic scar in seven eyes, a fibrotic membrane in two eyes and a still active membrane in two cases. Conclusion: We emphasize the relatively favourable visual prognosis in patients suffering from inherited retinal dystrophies complicated with choroidal neovascularization. Therapeutic approaches other than laser treatment could be attempted in these patients.

Fundus changes in membranoproliferative glomerulonephritis type II

A total of 23 patients aged between 11 and 64 years who had biopsy-proven membranoproliferative glomerulonephritis type 11 (dense deposit disease) were studied using fluorescein angiography of the retina. With the exception of two adolescents, all patients exhibited small subretinal nodules that were similar to basal laminar drusen. Subjects with a long history of renal disease displayed more numerous and larger nodules as well as atrophic changes. Four subjects presented with subretinal neovascular membranes.

Missense mutation and hexanucleotide duplication in the PAX2 gene in two unrelated families with renal-coloboma syndrome (MIM 120330)

We present a family with autosomal-dominant inheritance of renal insufficiency caused by renal hypoplasia in six individuals. In all affected individuals, signs of optic disk dysplasia were detected, but most patients were asymptomatic. A heterozygous missense mutation in the PAX2 gene causing a Gly75 to Ser substitution was present in all affected individuals. A second, unrelated patient presented with ocular complaints related to optic disk dysplasia, and had a history of vesico-ureteral reflux. A heterozygous hexanucleotide duplication in the PAX2 gene was detected leading to the duplication of GluThr at positions 74 and 75. The mutations in these two families are the first mutations in the PAX2 gene that do not lead to a truncated protein. Mechanistically, these mutations are expected to result in abnormal folding of the PAX2 protein. These observations further expand the spectrum of clinical features associated with PAX2 mutations, and suggest that a distinct genetic disorder can be identified in patients with renal dysplasia through a careful eye examination. As the ocular manifestations in this syndrome are variable anomalies of retinal and optic disk dysplasia, we prefer the term “papillo-renal syndrome”.

Subretinal neovascular membranes associated with chronic membranoproliferative glomerulonephritis type II

Subretinal neovascular membranes were observed in three patients with chronic membranoproliferative glomerulonephritis type II (dense deposit disease). The first signs of glomerulonephritis occurred at respective ages of 13, 10 and 10 years; subretinal neovascular membranes were noted at respective ages of 25, 32 and 32 years. All patients had bilateral, widespread retinal pigment epithelial abnormalities. Our findings indicate that subretinal neovascularization is a complication of dense deposit disease. In one patient, the early recognition and laser treatment of an extrafoveal subretinal neovascular membrane prevented further loss of vision.

Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study

Introduction The aim of this study was to examine ranibizumab treatment patterns in “real-world” practice and clinical settings, as well as to assess quality of life outcomes over a 24-month period. Materials and methods This was a prospective, observational, multicenter, open-label study of 0.5 mg of ranibizumab administered intravitreally. Patients were followed over 24 ± 3 months with intermediate data points at 6 ± 2 months and 12 ± 2 months, and a limited data point at 2.5 ± 1 month that coincided with the end of the loading phase. Outcomes included visual acuity (Early Treatment Diabetic Retinopathy Study), visual function (National Eye Institute Visual Function Questionnaire-25 [NEI VFQ-25]), quality of life (Health Utilities Index Mark III [HUI3]), and safety. Results A total of 267 patients with wet age-related macular degeneration (mean ± standard deviation [SD] age = 78.5 ± 7.3 years; 62.4% were female; 34.5% with dual eye involvement; 74.9% were treatment-naïve) were treated (309 eyes were treated). The mean ± SD Early Treatment Diabetic Retinopathy Study score at baseline was 56.3 ± 14.3 letters. The mean ± SD number of injections over 24 months was 7.6 ± 4.1, including 2.5 ± 0.7 and 5.9 ± 3.6 during the loading and maintenance phases, respectively, with corresponding treatment intervals of 4.8 ± 1.4 weeks and 11.5 ± 9.5 weeks, respectively. Improvements in visual acuity over baseline were reached at 2.5 months and maintained at 6 months (both P < 0.0001). The mean visual acuity increase over baseline at 12 months was not significant (P = 0.08); the decline over baseline at 24 months statistically significant (P = 0.02). Overall, 94.3% of patients showed stable or improved disease at 6 months and 81.5% of patients showed stable or improved disease at 24 months. At 6 months, improvements over baseline were significant for VFQ-25 (P = 0.03) and HUI3 (P = 0.02), but not at 12 months and 24 months. Improvements in VFQ-25 and HUI3 were maintained at 24 months in 38% and 34% of patients, respectively. In total 78 serious adverse events were reported in 40 patients and 77 nonserious adverse events in 34 patients. Nine serious adverse events and nine nonserious adverse events in 14 patients were suspected to be related to ranibizumab treatment. Conclusion The “real-world” clinical effectiveness of ranibizumab was evidenced by the initial improvements over baseline in visual acuity and quality of life, as well as the maintenance of these outcomes at baseline levels at 24 months, and this was observed under variable treatment conditions. The findings underscore the need for individualized treatment with regular monitoring to achieve optimal vision and quality of life outcomes.

Photodynamic therapy with verteporfin in the treatment of exudative idiopathic polypoidal choroidal vasculopathy

Purpose To determine the safety and efficacy of photodynamic therapy with verteporfin (V-PDT) in the treatment of exudative idiopathic polypoidal choroidal vasculopathy (IPCV) lesions that were not suitable for laser photocoagulation. Methods This was a prospective, open label study in two centers involving 30 consecutive patients (31 eyes) diagnosed with exudative IPCV using fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). All patients underwent complete ophthalmologic examination including best-corrected visual acuity (VA) measurement, contrast sensitivity (CS) testing, FA, ICGA, and OCT. OCT was used to assess the stage of the polypoidal dilations (active or scarred) and the evolution of the signs associated with exudation. Study patients were treated with V-PDT and followed up at 6 weeks and 3, 6, and 12 months. Re-treatment was applied, at an interval of 3 months, until there was an absence of leakage on FA and hyperfluorescence on ICGA. Results Thirty eyes (29 patients) completed the 12 months post-treatment visit and were retained for further analysis. The mean number of V-PDT treatments was 2.5 (SD 1.1). At 12 months post-treatment, the mean foveal thickness had significantly (p<0.03) decreased to 224 (SD 104) μm from the baseline 292 (SD 124) μm while the mean VA had significantly (p<0.02) improved to 0.50 (SD 0.38) from the baseline 0.38 (SD 0.24). Serous detachment of the macula completely resolved in 83.3% of the eyes while 73.3% of the polypoidal dilations were occluded at 12 months. Conclusions The results suggest that V-PDT is effective and relatively safe in treating exudative IPCV.

Specific eye fundus lesions in type II membranoproliferative glomerulonephritis.

In three adolescents, suffering from membrano-proliferative glomerulonephritis type II, ophthalmoscopy and fluorescein angiography revealed retinal pigment epithelium lesions, referred to as basal laminar drusen. The patient with the longest renal history had the most pronounced fundus changes. These lesions, earlier described in adult patients, are believed to be specific for this particular form of chronic glomerulonephritis.

Fundus changes in chronic membranoproliferative glomerulonephritis type II

Chronic membranoproliferative glomerulonephritis type II (dense deposit disease) is a renal disease characterized by dense deposits in the glomerular and tubular basement membranes. We report a retinopathy with diffuse retinal pigment alterations in 11 out of 12 patients with this disease. Four of the eleven patients also presented disciform macular detachment and choroidal neovascularisation. The lesions were observed at the earliest 1 year after the diagnosis of the renal disease. In a control group of 17 patients with chronic membranoproliferative glomerulonephritis type I none of the patients presented similar fundus lesions.