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Brain Advance Access originally published online on October 13, 2004
Brain 2005 128(1):35-41; doi:10.1093/brain/awh310
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Brain Vol. 128 No. 1 © Guarantors of Brain 2004; all rights reserved

Neuropathology of white matter disease in Leber's hereditary optic neuropathy

Gábor G. Kovács1,*, Romana Höftberger4,*, Katalin Majtényi1, Rita Horváth6, Péter Barsi1, Sámuel Komoly2, Hans Lassmann5, Herbert Budka4 and Gábor Jakab3

1 National Institute of Psychiatry and Neurology, H-1021 Budapest, Hüvösvölgyi út 116, 2 Department of Neurology, F. Jahn Teaching Hospital and 3 Department of Neurology, Uzsoki Hospital, Budapest, Hungary, 4 Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18–20, POB 48, A-1097 Vienna, 5 Brain Research Institute, Division of Neuroimmunology, A-1090 Vienna, Austria and 6 Metabolic Disease Center Munich-Schwabing, Institutes of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, Academic Hospital Schwabing, Kölner Platz 1, D-80804 Munich, Germany

Correspondence to: Professor Herbert Budka, Institute of Neurology, AKH 4J, Währinger Gürtel 18–20, POB 48, A-1097 Vienna, Austria E-mail: Herbert.Budka{at}kin.at

Leber's hereditary optic neuropathy (LHON) is associated with point mutations in the mitochondrial DNA (mtDNA), coding for a mitochondrial respiratory chain complex I subunit. It is characterized by bilateral, usually sequential, optic neuropathy and may co-occur with multiple sclerosis-like white matter lesions. Despite repeated clinical reports including MRI and histopathological examination of the visual system, neuropathological descriptions of LHON associated with multiple sclerosis-like syndrome are lacking. We present here the case of a female patient with a point mutation at nucleotide position T14484C, who suffered from relapsing episodes of visual loss of both eyes and consecutively developed Hashimoto thyroiditis as well as widespread demyelinating CNS lesions outside the visual system. She died of bronchopneumonia at the age of 44 years, after a disease duration of 19 years, with progressive deterioration, epileptic seizures and immobility. Immunohistochemical analysis on formalin-fixed and paraffin-embedded tissue reveals a spectrum of neuropathological changes, including actively and inactively demyelinating plaques in the white matter and optic nerve, vacuolation and cystic necrosis with CD8-positive T cells in the frontal lobe, axonal damage, and vacuolation of white matter. Tissue destruction is associated with upregulation of mitochondrial manganese superoxide dismutase within the lesions and an increase in the expression of inducible nitric oxide synthase within macrophages and microglia. This variable phenotype of extraoptic LHON disease suggests that mtDNA mutations may affect the nervous system on a common metabolic basis and occasionally may aggravate or initiate autoimmune pathology.

* These authors contributed equally to this work


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