PATHOGENIC FACTORS UNDERLYING THE LESIONS IN LEIGHS DISEASE - TISSUE RESPONSES TO CELLULAR-ENERGY DEPRIVATION AND THEIR CLINICOPATHOLOGICALCONSEQUENCES

In a search for pathogenic factors that might play roles in the select ive vulnerability of brain regions to the lesions of Leigh's disease, archival material from 20 cases of this condition, dying between 1975 and 1992 and aged from 4 days to 11.75 years at death, have been exami ned Attention was paid to the topography of the lesions, their nature and timing in the evolution of the disease, the clinico-pathological c orrelations and the ages of the subjects at onset and at death. The fo llowing observations would appear to be explicable in terms of the pre sent understanding that impairment of cellular energy generation is kn own to be defective in some, and probably all, cases. (i) The characte ristic lesion of this disease is symmetrical vasculonecrotic damage af fecting several brainstem centres, the topography of which is variable and may partly depend upon the age of the individual. (ii) Early feat ures of this lesion are indistinguishable from a small partial infarct ion and progress similarly. The size of the damaged area is generally related to the size of the region affected. There is no haemorrhagic c omponent and haemosiderin is not at any time found, unlike the lesions of Wernicke's disease. (iii) The process is episodic and total tissue damage is thus cumulative. More than one episode of damage may be see n in a region, changes of clearly different ages being often present t ogether: (iv) In some regions the lesions appear to be age dependent, e.g. inferior olivary nuclei, and may be related to behavioural develo pment and neuronal activity. Other regions show damage at any age, e.g . substantia nigra. (v) Myelin and sometimes axon loss in optic pathwa ys is usually central, the periphery being spared. This occurred in mo re than half the cases and may represent a partial infarct-like change . (vi) The characteristic dorsal spinal column degeneration is always associated with focal necrosis of central grey and white matter; this also resembles a partial intraction with secondary ascending degenerat ion. (vii) Massive myelin loss in the centra semiovalia occurred in on e-third of the cases, with or without cavitation, often in association with spongy myelin changes elsewhere. A mild general spongy change in myelin alone occurred in two cases. The massive lesions are focal, in farct-like and analogous to Binswanger's disease. (viii) Selective neu ronal loss, common in some mitochondrial disorders, is not a major fea ture of Leigh's disease. However cases dying when more than I year old , where seizures were not a factor; showed Purkinje cell loss and glio sis in 12 out of 14 cases. This closely correlated with necrotic lesio ns in or near inferior olivary nuclei and may be an expression of exci totoxic damage secondary to loss of climbing fibres. (ix) The close me tabolic association between Leigh's disease and other mitochondrial en cephalomyopathies is emphasized by the essential similarity in every c ondition of each feature of the pathological changes; each disease ent ity is in fact defined by the topography of the changes as well as the genetic defect, although the determinant factors are unknown.