Reappraisal of the Retinal Cotton-Wool Spot: A Discussion Paper
Authors: David McLeod
Journal: Journal of the Royal Society of Medicine (1981)

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