Brain, Vol. 117, No. 6, 1357-1376, 1994
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Pathogenic factors underlying the lesions in Leigh's disease
Tissue responses to cellular energy deprivation and their clinico-pathological consequences
1Department of Neurology, King's College Hospital Medical School and Institute of Psychiatry Great Ormond Street, London, UK 2Department of Neuropathology, Hospital for Sick Children Great Ormond Street, London, UK
Correspondence to:
Correspondence to: Professor J. B. Cavanagh, Department of Neurology, Institute of Psychiatry, London SE5 8AF, UK
In a search for pathogenic factors that might play roles in the selective 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 examined. Attention was paid to the topography of the lesions, their nature and timing in the evolution of the disease, the clinico-pathological correlations and the ages of the subjects at onset and at death. The following observations would appear to be explicable in terms of the present understanding that impairment of cellular energy generation is known to be defective in some, and probably all, cases, (i) The characteristic lesion of this disease is symmetrical vasculo-necrotic damage affecting several brainstem centres, the topography of which is variable and may partly depend upon the age of the individual, (ii) Early features of this lesion are indistinguishable from a small partial infarction and progress similarly. The size of the damaged area is generally related to the size of the region affected. There is no haemorrhagic component and haemosiderin is not at any time found, unlike the lesions of Wernicke's disease. (Hi) The process is episodic and total tissue damage is thus cumulative. More than one episode of damage may be seen in a region, changes of clearly different ages being often present together, (iv) In some regions the lesions appear to be age dependent, e.g. inferior olivary nuclei, and may be related to behavioural development and neuronal activity. Other regions showdamage at any age, e.g. substantia nigra. (v) Myelin and sometimes axon loss in optic pathways is usually central, the periphery being spared. This occurred in more 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 infarction with secondary ascending degeneration, (vii) Massive myelin loss in the centra semiovalia occurred in one-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, infarct-like and analogous to Binswanger's disease, (viii) Selective neuronal loss, common in some mitochondrial disorders, is not a major feature of Leigh's disease. However, cases dying when more than 1 year old, where seizures were not a factor, showed Purkinje cell loss and gliosis in 12 out of 14 cases. This closely correlated with necrotic lesions in or near inferior olivary nuclei and may be an expression of excitotoxic damage secondary to loss of climbing fibres, (ix) The close metabolic association between Leigh's disease and other mitochondrial encephalomyopathies is emphasized by the essential similarity in every condition of each feature of the pathological changes; each disease entity is in fact defined by the topography of the changes as well as the genetic defect, although the determinant factors are unknown.
Leigh's disease; energy deprivation syndromes; mitochondrial defect; topography of lesions; Purkinje cell loss
Received May 17, 1994. Revised June 21, 1994. Accepted June 24, 1994.
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