The retinal cotton-wool spot.

The retinal cotton-wool spot has for many years excited the interest of ophthalmologists and histopathologists alike, and together they have defined through decades of careful work its clinical features, its associated diseases, and its structure and ultrastructure and have sought to explain its pathogenesis. Familiar to generations of students of ophthalmology, the cytoid body has been the structure of dominant interest in the histology of cotton-wool spots, and indeed it can now be seen that the elucidation of the ultrastructure of this body, a century after its first description, was the turning point from the period of purely descriptive morphology to the more dynamic concepts of today. Cytoid bodies were first described by Heymann in 1856 (in collaboration with Zenker in a case of Bright's disease) and were thought to be degenerate ganglion cells, a view with which Virchow (1856) agreed. Muller (1858), however, claimed that they were swollen varicose nerve fibres, and this was subsequently proved by Leber (1915); so that over 60 years ago it was suspected that varicose nerve fibres were basic components of the cotton-wool spot. Unfortunately, subsequent work tended to confuse rather than clarify this issue, it being suggested that cytoid bodies were 'moulded exudates' or 'non-specific deposits of acellular origin', the outer zone being precipitated ground substance and the inner zone fibrin or fibrinoid material. A further suggestion was that they represented glial degeneration (Verhoeff, 1921). A return to the correct line of thought, however, was provided by Wolter (1959) when by silver staining of the retina he again showed cytoid bodies as terminal swellings of interrupted nerve fibres, and he pointed out their location on the distal stump in connection with the ganglion cell, whereas the proximal axon soon became atrophic. He also emphasised that the damage causing the interruption may be of any kind-a cut, compression, or ischaemia, for example. This was soon followed by a study of the pathology of cotton-wool spots and cytoid bodies in hypertensive retinopathy (Ashton and Harry, 1963), wherein it was established that the cotton-wool spot was causally related to focal ischaemia from arteriolar occlusion. The presence of localised axonal swellings in the affected zone was demonstrated and cytoid bodies proved to be sited at terminal axonal bulbs, which, in agreement with Wolter (1959), were thought to correspond to the bulbs of injured nerve fibres as described by Cajal (1913), who believed them to represent a combined process of degeneration and regeneration. Further advances were made by Ashton and Harry (1963), who showed for the first time that the swollen nerve fibre of the cotton-wool spot contained aggregations of mitochondria, dense bodies, vesicles, and granules and that the fully formed cytoid body additionally contained a 'pseudonucleus' consisting of an electron-dense mass of ill-defined particles, probably deriving from degenerate elements in the axonal bulb. The nature of the cytoid body now seemed clear, but the pathogenesis of the cotton-wool spot itself was still obscure, although focal ischaemia was almost certainly involved. It was then found that cotton-wool spots could be produced experimentally by emboli, by injecting either latex spheres (Gay et al., 1964) or glass ballotini (Ashton and Henkind, 1965) into the carotid artery. These findings led to an extensive clinicopathological study in which cotton-wool spots were produced in the pig's retina by similar injections of glass ballotini, thus providing perfect experimental conditions for correlating the clinical evolution of the lesions with their ultrastructural changes as seen in suitably fixed material (Dollery et al., 1966; Shakib and Ashton, 1966). Their crucial finding in the present context was that the injured axons in the ischaemic area rapidly became swollen, and after a few hours those swollen axons at the periphery of the lesion became packed with mitochondria, dense bodies, and membranous whorls; a break then occurred in the axon, and the distal stump attached to the ganglion cell formed a bulblike swelling ('torpedo' formation) which developed into a cytoid body, while the proximal fibre atrophied. The swollen axons in the centre of the lesion did not develop this aggregation of organelles, only those axons at its periphery. These authors concluded that axons from irreparably injured ganglion cells within the ischaemic zone underwent complete degeneration, whereas axons of unaffected or surviving ganglion cells developed the 'torpedoes'. The fundamental question arose as to the origin of the massive aggregates of mitochondria and other organelles within the terminal axonal swellings, and it seemed likely that proliferation beyond the normal turnover of organelles had taken place. It was well established at that time that mitochondria, for instance, can replicate (De Robertis and Bleichmar, 1962), but whether they could proliferate 161 coright.