David McLeod

Age-Related Cellular Proliferation at the Vitreoretinal Juncture

Clinical and pathological features of non-vascularised epiretinal membranes are reviewed with special attention to focal epimacular fractional lesions in the elderly. The role of immunohistochemistry in elucidating the nature of component cells of complex epiretinal membranes is emphasised. Clinicopathological correlation establishes the ‘fibroglial membrane’ as the causative lesion of age-related epimacular traction. The pathogenesis of this process is discussed, including relevant animal models, and chronic inflammation and ischaemia (rather than acute posterior vitreous detachment) are implicated. Vitrectomy and epimacular membrane peeling results in significant visual improvement in most patients.

Inflammation and the formation of epiretinal membranes

In this review of the literature evidence is provided from clinical, histological and experimental sources that inflammatory processes play a central role in the pathogenesis of contractile epiretinal membranes and proliferative vitreoretinopathy.

Indentation microsurgery: Internal searching for retinal breaks

Breaks responsible for rhegmatogenous retinal detachments in 78 eyes could not be seen preoperatively owing to opacities in the media, previous buckling or other causes. Deep kinetic indentation of the sclera combined with endoillumination enabled retinal breaks to be identified during closed microsurgery in 95% of these eyes, and retinal reattachment was eventually achieved in 85%.

Silicone-oil injection during closed microsurgery for diabetic retinal detachment.

A beneficial visual outcome was achieved in 16 (38%) of 42 eyes into which silicone oil was injected after difficulties were encountered during closed microsurgery for severe diabetic retinal detachment. Without recourse to oil injection, most if not all of the eyes would have remained blind and many would have deteriorated into rubeotic glaucoma or phthisis. The main cause of failed surgery was rhegmatogenous retinal detachment associated with residual or reparative epiretinal fibrosis, and silicone oil appeared to be of value in preventing rubeosis iridis in such cases. Cataract was a significant problem in the successfully treated eyes.

The role of inflammation in the development of epiretinal membranes

Single or multiple (3) injections of Shigella endotoxin were administered into the rabbit vitreous body to investigate the development of epiretinal membranes following intraocular inflammation. The evaluation included clinical assessment of the resulting traction retinal detachments, together with histological, autoradiographic, immunohistochemical and ultrastructural studies. Traction retinal detachments were found beneath fibroglial epiretinal membranes (being more extensive in eyes which had received 3 endotoxin injections) in the vicinity of the medullary rays, while purely glial membranes occurred over attached peripheral retina. The primary change at the vitreoretinal interface was an elevation of the inner limiting lamina of the retina followed by the extension of glial cells onto the retinal surface. It is postulated that glial cells breach the inner limiting lamina as a sequel to inflammation involving the vitreoretinal interface and form a scaffold upon which fibroblast-like cells migrate.

Which cells are involved in the formation of epiretinal membranes

SCAR TISSUE in the vitreous and contractile epiretinal membranes (ERM) produce Pactional detachment of the retina and complicate retinal reattachment surgery. Membranous proliferations are associated with a wide range of disorders including diabetic eye disease, trauma, inflammation, and ischaemic retinopathies.1 For the purpose of this presentation, we would like to limit our observations to events associated with nondiabetic proliferations. An essential difference between diabetic and nondiabetic ERM formation is that whereas posterior vitreal detachment provides protection against further development of vascularised diabetic membranes, posterior vitreal detachment may be an integral part of the aetiology of nonvascular membranogenesis.

CLINICAL SIGN OF OBSTRUCTED AXOPLASMIC TRANSPORT

Orthograde and retrograde axoplasmic transport in retinal ganglion-cell axons can be interrupted by axonal ischaemia. This report is believed to be the first to illustrate how this phenomenon can be obserbed clinically in man in cases of retinal vascular disease. The intense retinal whiteness of small cottonwool spots and at the periphery of larger areas of retinal ischaemia represents gross localised axonal distension secondary to the cessation axoplasmic flow.

Reappraisal of the retinal cotton-wool spot: a discussion paper.

In 1969, Professor Norman Ashton discussed the then current views on retinal cotton-wool spots at the Section of Ophthalmology of the Royal Society of Medicine. It is appropriate now to reappraise the nature of cotton-wool spots since our thoughts on this subject have changed significantly in the intervening years. Cotton-wool spots are localized areas of dense white swelling of the retinal nerve fibre layer. They often have a zigzag internal structure, a feathered edge but an otherwise well-delineated form and an approximately 1 mm dimension; they project slightly into the vitreous and sometimes deflect retinal vessels. For many years it had been widely held that these lesions represented microinfarcts of the inner retina. There were, however, several objections to this microinfarction hypothesis. Firstly, although the relationship between arteriolar occlusion and cotton-wool spots was well established for hypertensive retinopathy, local obstruction of the feeding vessel was not a universal accompaniment of cotton-wool spots, e.g. in anaemic retinopathy and carotid artery occlusion (Ashton 1970). Secondly, a fundamental difference was observed between both the clinical and the histopathological appearances of cotton-wool spots and retinal infarction. Cotton-wool spots essentially involve just the nerve fibre layer of the retina, and their dense whiteness appears to result from an accumulation of organelles in the distended axon terminals (cytoid bodies) contained within the lesions (Ashton 1970). On the other hand, retinal infarction produces a grey translucent swelling with ischaemic necrosis and vacuolation of the whole of the inner half of the retina. Ashton emphasized that the essential determinant of the cotton-wool spot organelle aggregation in axon terminals was not a feature of necrosis but was predominantly a living reaction in the axon. How, then, could this aggregation of organelles in axon terminals be explained both in terms of axonal physiology and retinal circulatory pathology? The experiments ofAshton and coworkers (1966) went some way towards providing an answer. The retinal circulation of pigs was focally occluded by injection of glass microspheres into the external carotid artery with resulting embolism of small retinal arterioles. Areas of grey retinal swelling up to 6 mm in diameter appeared within a few minutes and corresponded to zones of vascular nonperfusion on fluorescein angiography. Ischaemic damage was identified histologically throughout the inner half of the retina and, even at only one hour following occlusion, nerve fibres at the borders of the lesions showed increased granularity. In the following days, the ischaemic areas became more densely white, smaller lesions becoming whiter than larger areas. Furthermore, an enormous accumulation of organelles (often showing degeneration) appeared in grossly distended axon terminals especially at the periphery of the lesions. Two possible mechanisms of intra-axonal organelle aggregation were considered: (1) proliferation of organelles in situ; (2) migration of preformed organelles by axoplasmic flow. For reasons which have been critically reviewed elsewhere (McLeod 1976), Shakib & Ashton (1966) came down in favour of the former mechanism. They suggested that a nonspecific reactive proliferation of organelles occurred in axons arising from ganglion cells which had survived at the hypoxic periphery of ischaemic (anoxic) areas. Stimulated by informal discussions with Professor Ashton, I re-evaluated retinal cottonwool spots by reviewing hundreds of fundus photographs of patients with ischaemic retinopathies. It was immediately evident that cotton-wool spots and retinal infarcts

Retinal patching: A new approach to the management of selected retinal breaks

Restoration of retinal continuity by a patching technique is proposed as a new means of treating selected rhegmatogenous retinal detachments where established techniques frequently fail. The patch consists of a substrate and adhesive applied to the inner surface of the retina surrounding the retinal break. Bovine eye cup experiments have been performed to explore the effectiveness of a range of adhesives, and cyanoacrylates and Tisseel have been found to be effective. Studies of these adhesives on confluent cultures of bovine retinal pigment epithelial cells and glia revealed temporary cyanoacrylate toxicity and stimulation of proliferation by Tisseel. Substrate biocompatability was investigated by observing the growth of cells on various substrates in tissue culture; biological substrates such as lens capsule supported cell growth whereas synthetic membranes only did so if pretreated with fibronectin.

Human retinal pigment epithelial cells in the vitreous of the owl monkey

Cultured human retinal pigment epithelium was injected into the vitreous of owl monkeys. The epithelial cells were derived from either a foetal or an adult cell line. The five monkeys which were injected with cultured foetal cells developed substantial vitreal membranes and had retinal detachment by 2 weeks, whereas the five monkeys with cultured adult cells did not develop detachments within the period of investigation, and vitreal membranes were insubstantial. An electron-microscopic, immunohistochemical and autoradiographic study was conducted on these eyes to investigate in detail the behaviour and intraocular effects of the injected cells.