Francis A. Billson

Axonal loss and myelin in early ON loss in postacute optic neuritis

To investigate the relation between retinal nerve fiber layer (RNFL) thickness and latency and amplitude of multifocal visual‐evoked potentials (mfVEPs) in the postacute stage of optic neuritis in patients with early or possible multiple sclerosis.

Autoantibodies to retinal astrocytes associated with age-related macular degeneration*

Sera from 128 patients with age-related macular degeneration (AMD) were examined and profiles of a variety of serum constituents, including immunoglobulins, alpha and beta globulins and autoantibodies, were tabulated. A similar series of tests were carried out on 20 control sera. The results indicate a higher incidence of serum abnormalities, particularly involving alpha-2 globulin, in patients with disturbance of pigmentation of the retinal pigment epithelium (RPE). The sera were further tested for the presence of autoantibodies with specificity for retinal tissue, and five major staining patterns were observed. Many sera produced patterns of labelling on human retina identical to that observed using labelled monoclonal anti-glial fibrillary acid protein (GFAP) antibodies, which are an established marker of retinal astrocytes. Although anti-retinal autoantibodies have been reported in association with a number of ocular pathologies, the observation of anti-astrocyte autoantibodies is new. Astrocytes are involved in the maintenance of the blood-retinal barrier (BRB) and also appear to be the facultative antigen-presenting cells of neural tissue. The present results indicate that the formation of anti-astrocyte autoantibodies may be an early feature of the pathogenesis of AMD.

Age-related macular degeneration: ultrastructural studies of the relationship of leucocytes to angiogenesis

We describe the ultrastructural features of subretinal neovascularisation associated with the pathogenesis of age-related macular degeneration (AMD). The choroidal origin of new vessels was confirmed, and ultrastructural details are presented. Serial sectioning of new vessels revealed a relationship between leucocytes and neovascular structures. The results are discussed in the context of the previously established role of leucocytes in angiogenesis. Our results provide circumstantial evidence, based on morphological observations, for the involvement of leucocytes in the promotion of neovascular proliferation and exudation from new vessels.

Effects of triamcinolone acetonide on microglial morphology and quantitative expression of MHC-II in exudative age-related macular degeneration

Animal models, in vitro assays and pilot clinical studies suggest that intravitreal triamcinolone acetonide may be useful in the treatment of age‐related macular degeneration. The present case study reports the effect of intravitreal triamcinolone acetonide injection on a subretinal neovascular lesion, microglial morphology and quantitative expression of MHC‐II antigens. Triamcinolone acetonide significantly decreased MHC‐II expression consistent with immunocytochemical observations which revealed condensed microglial morphology. The modulation of subretinal oedema and microglial morphology correlates with in vitro observations suggesting that downregulation of inflammatory markers and endothelial cell permeability are significant features of the mode of action of triamcinolone acetonide.

Differential expression of GFAP in early v late AMD: a quantitative analysis

Background/aims: Glial fibrillary acidic protein (GFAP) is an established indicator of retinal stress; its expression in retinal astrocytes and Müller cells has been demonstrated to be modulated by cytokines and retinal pathology, including age related macular degeneration (AMD). This study aims to quantify the modulation of GFAP expression in retinas with drusen and atrophic AMD versus normal age matched controls. Methods: Following a histopathological survey, 17 donor retinas were classified into four groups: drusen (n=5), geographic atrophy (GA) (n=6), aged normal (n=3), and young normal (n=3). Paramacular cryosections were immunolabelled with GFAP antibody, examined by confocal microscopy, and quantified by NIH digital image analysis. Groups were matched for potential confounding factors including age, sex, and postmortem delay. Results: A significant increase in GFAP immunolabelling of macroglia was noted in aged normal compared with young normal retinas (p<0.04). Upregulation of GFAP immunoreactivity involving astrocytes was observed in drusen retinas compared with control retinas (p<0.03). GFAP was also upregulated in retinas with GA compared with controls (p<0.05) and in retinas with GA compared with drusen (p<0.04), both involving Müller cells. Discrete regions of GFAP upregulation in Müller cells were associated with drusen formation. In GA specimens atrophied retinal pigment epithelium (RPE) was substituted by GFAP immunoreactive Müller cell processes (gliosis). Conclusion: This study provides a quantitative assessment of GFAP modulation in ageing and AMD affected retinas. Morphological observations were consistent with quantitative analyses indicating differential modulation of GFAP immunoreactivity in inner and outer retina. Upmodulation of GFAP in inner retina and astroglial processes was predominantly associated with drusen, while in outer retina Müller glia upmodulation of GFAP was associated with disruption of the RPE and blood-retinal barrier.

Angiogenesis in normal human retinal development the involvement of astrocytes and macrophages

Recent studies have suggested a role for mononuclear phagocytes series (MPS) cells in neovascularisation associated with retinal pathology and experimentally induced subretinal neovascularisation. The present study is concerned with the normal development of the human retinal vasculature. Morphological details are provided of developing vascular structures including the formation of tight junctions and canalisation of angioblast cords. The relationships of astrocytes and pericytes to developing structures and the presence of a perivascular collagenous matrix are described. Ultrastructural and histochemcal analyses reveal an association between MPS cells and developing vascular structures. It is suggested that MPS cells may influence angiogenesis in normal retinal development, as well as in retinal pathology.

Intermediate filament expression in human retinal macroglia. Histopathologic changes associated with age-related macular degeneration.

Purpose Intermediate filament expression by retinal macroglia was studied in normal eyes, normal eyes of older subjects, and eyes of subjects with age-related macular degeneration (AMD), classified on the basis of histopathologic assessment of the retinal pigment epithelium (RPE), choroid, and donor age. Methods. Adult human retinae (N = 43) were divided into three groups: normal (< 50 years of age, with normal RPE and choroid); normal eyes of older subjects (> 50 years with normal RPE and choroid); and eyes of subjects with AMD (>50 years with histopathologic findings indicative of AMD), on the basis of histopathologic assessment of the RPE/choroid and donor age. Intermediate filament expression by retinal macroglia was studied in cryostat sections and in retinal flatmounts using avidin-biotinperoxidase immunolabeling of antibodies to glial fibrillary acidic protein (GFAP) and vimentin. Results. Analyses of immunohistochemically labeled retinal sections revealed similar distributions of vimentin reactivity in retinae of each group. Distributions of GFAP in normal and normal aged retinae were similar, but sections of AMD-affected retinae showed evidence of GFAP expression by Müller cells. In flatmounts, vimentin distribution was similar in the three groups, but GFAP labeling revealed hypertrophic astrocytes, which were absent from normal retinae, in 17% of aged retinae and 55% of AMD-affected retinae. Deeply penetrating, GFAP-positive processes were observed in 17%, 27%, and 55% of normal, normal aged, and AMD-affected retinae, respectively. Conclusions Variation in GFAP and vimentin expression in retinal macroglia is affected by increasing age, and a distinctive variation of intermediate filament expression in retinal macroglia is associated with the pathogenesis of AMD.

Secondary glaucoma after paediatric cataract surgery

Aim: To determine the prevalence and risk factors associated with secondary glaucoma postcongenital cataract surgery. Methods: All children diagnosed as having congenital cataracts in a major children’s hospital between 1985 and 2005 were included in a retrospective case series. Medical records of 423 eyes among 283 patients who underwent cataract surgery with or without intraocular lens implantation at age ⩽16 for congenital cataract were reviewed. The main outcome measure was presence or absence of secondary glaucoma and time to glaucoma postsurgery. The following risk factors were evaluated: age at cataract surgery, presence of systemic anomalies, microcornea, persistent hyperplastic primary vitreous (PHPV), primary capsulotomy/anterior vitrectomy, primary intraocular lens implantation, secondary membrane surgery and duration of postoperative observation. Results: The statistical methods were the use of Kaplan–Meier survival analysis and Multivariate Cox hazards regression analysis. The mean follow-up was 6.3 (SD 5.0) years (median 4.6 years; range 0.5 to 20.3 years). Glaucoma developed in 36 of 234 patients (15.4%). Multivariate Cox proportional hazards regression analysis identified age less than 9 months at time of surgery (RR 2.9, 95% CI 1.3 to 7.7; p = 0.03), microcornea (RR 3.7, 95% CI 2.0 to 7.0; p<0.001), and follow-up time as important predictors of glaucoma. PHPV (RR 1.4, 95% CI 0.7 to 2.7; p = 0.41) and primary posterior capsulotomy/anterior vitrectomy (RR 2.2, 95% CI 0.9 to 5.5; p = 0.17) were not significantly associated with secondary glaucoma in the multivariate model. The mean time to glaucoma after congenital cataract surgery was 4.9 years (range 2 weeks to 16.8 years). Conclusion: Secondary glaucoma is an important sequela in patients who undergo surgery for congenital cataracts. It is imperative that these patients get lifelong surveillance, as glaucoma can occur years after the initial operation.

Specific Unwillingness to Donate Eyes: The Impact of Disfigurement, Knowledge and Procurement on Corneal Donation

Although willingness, attitudes and beliefs surrounding solid‐organ donation have been extensively investigated, much less is known about corneal donation. Despite evidence that a substantial number of families who agree to multiorgan donation also specifically refuse corneal donation, it is unclear why this occurs and what can be done to increase rates of corneal donation. We conducted a survey of 371 Australian adults regarding their views on corneal donation. Although willingness to donate corneas generally reflected a persons willingness to donate all of ones organs, unwillingness to donate corneas appeared to be due to other factors. Specifically, decisions not to donate appear to be driven by a range of concerns surrounding disfigurement. The survey also provides eye banks with reassurance about the acceptability of whole globe procurement, and recognition that research into blindness is a highly valued part of corneal donation. Finally, the survey identifies that many individuals see benefit in having their family engaged in the decision‐making process, suggesting that decisions about donation are more complex than a simple appeal to the autonomy of the deceased.

Consent for corneal donation: the effect of age of the deceased, registered intent and which family member is asked about donation.

Aim: To determine whether consent to corneal donation is related to which next of kin is asked to consent, the age of the potential donor and the indication about donation made by the deceased on their driving licence. Method: The Lions New South Wales Eye Bank (Sydney, New South Wales, Australia) provides the corneal transplantation service for Australia’s most populous state. Over the 18-month period from 1 July 2004 to 31 December 2005 for all requests for donation, records were kept of which next of kin was asked for consent, the age of the deceased and the indication about donation by the deceased on their driving licence. Results: Over the 18-month study period, 841 people were approached about corneal donation. 63.2% of those people approached gave their consent to donation. Increasing age of the deceased was significantly positively associated with consent to donation (p = 0.006). Multivariable univariate analysis adjusting for age of deceased showed that relative type was strongly associated with consent (p<0.001), with mothers and fathers more likely to donate than siblings, and siblings more likely to donate than children and spouses. An indication of willingness to donate on a driving licence was strongly associated with consent (p<0.001). Conclusions: Higher consent rates from older donors have implications for policies to maximise corneal procurement. The decision to donate on behalf of a deceased family member is complex and influenced by social context. Research should investigate individualised strategies to be used when seeking consent from particular categories of next of kin.