Leber's hereditary optic neuropathy with diffuse white matter changes mimicking gliomatosis cerebri: illustrative case

Abstract

Backgrouind: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by bilateral severe subacute central vision loss and a mutation in the mitochondrial DNA (mtDNA). The findings on cranial magnetic resonance imaging of patients with LHON vary from subtle to multiple white matter changes. However, they rarely present with diffuse infiltrative white matter changes.

Observations: The authors reported a case with diffuse white matter changes mimicking gliomatosis cerebri (GC). The histological findings included only mild glial hyperplasia without immunohistochemical positivity, supporting the diagnosis of glial tumors. Analysis of mtDNA obtained from the blood and brain tissue revealed mutation of m.11778G>A in the NADH dehydrogenase 4 gene, which confirmed the case as LHON. Immunohistochemistry of the brain tissue revealed 8-hydroxy-2'-deoxyguanosine positivity, suggesting the presence of oxidative stress.

Lessons: LHON is extremely difficult to diagnose unless one suspects or knows the disease. The present case brings attention not only to LHON but also to other mtDNA-mutated diseases that need to be considered with diffuse white matter changes or GC.

Keywords: 18F-FDG = 18F-fluorodeoxyglucose; FLAIR = fluid-attenuated inversion recovery; GC = gliomatosis cerebri; LHON = Leber’s hereditary optic neuropathy; Leber’s hereditary optic neuropathy; MRI = magnetic resonance imaging; ND = NADH dehydrogenase; PCR = polymerase chain reaction; PET = positron emission tomography; WHO = World Health Organization; gliomatosis cerebri; mitochondrial DNA; mitochondrial disease; mtDNA = mitochondrial DNA.

FIG. 1.

A: FLAIR MRI shows a high-intensity area at the right temporal, occipital, and parietal lobes; right insula; basal ganglia; right peduncle of the midbrain; splenium of the corpus callosum; optic chiasm; and bilateral optic tracts. B: Gadolinium-enhanced T1-weighted MRI did not demonstrate an enhanced lesion. C: ¹⁸F-FDG PET did not have uptake corresponding to the FLAIR high-intensity lesion. D: FLAIR MRI demonstrates slight enlargement of high-intensity area at the splenium of the corpus callosum without any atrophic changes and clinical worsening. Arrow indicates the biopsied region as a small hole.

FIG. 2.

Histological findings. A and B: Hematoxylin and eosin staining showing mild glial hyperplasia. C and D: Negative for immunohistochemical staining of IDH1R132H and TP53. E: MIB1 labeling index is less than 1%. F: Positive for immunohistochemical staining of 8-hydroxy-2′-deoxyguanosine. (Original magnifications: A: ×100; B, C, and F: ×400; D and E: ×200.)

FIG. 3.

The result of Sanger sequencing from the blood, brain tissue, and reference as a normal control (arrows). mtDNA from the blood and brain tissue showed m.11778G>A mutation.