Optic Nerve Histopathology in Two Affected Brazilian Cases of 11778 Leber's Hereditary Optic Neuropathy Reveals a Specific Pattern of Axonal Loss

Abstract

Purpose: : To examine the postmortem histopathology of four optic nerves from two subjects with Leber's Hereditary Optic Neuropathy (LHON) with a homoplasmic 11778 mtDNA mutation, J–haplogroup.

Methods: : Two men, ages 62 and 54, came to autopsy in 2005 after being part of a prospective study of a large Brazilian LHON pedigree. Enucleation with retrobulbar optic nerves attached was performed within a post–mortem time of 24 hours for both patients. Two age–matched control optic nerves were used for comparison. Tissues were initially fixed in neutral buffered formalin. After the optic nerves were oriented into superior–inferior and nasal–temporal quadrants, they were dissected into cross–sectional profiles and processed for both paraffin and plastic embedding. Various standard, special, and immunohistochemical stains were performed.

Results: : At the time of their initial examinations in 2001, both men had visual acuities of hand motions. Both had devastating impairments of all psychophysical measures including loss of all visual fields except the far periphery for the first patient. However, GDx exams identified preservation of nerve fibers, especially on the nasal side. The first subject showed moderate and the second severe optic atrophy with complete loss of the papillomacular bundle. Histopathological examination of their optic nerves revealed a severe loss of axons most pronounced on the temporal side. Most of the spared axons were on the nasal side, especially of the superior nasal quadrant. The examination of each nerve from the two LHON patients demonstrated a pattern of axonal loss consistent with the clinical and psychophysical measures of their prospective investigations.

Conclusions: : Collectively, the LHON optic nerves appear to demonstrate a common spectrum of axonal loss which begins on the temporal side, then progresses to the central region. From there, diffuse to severe degeneration seems to spread radially outward with relative sparing of most of the superior nasal rim, suggesting involvement of the smallest caliber fibers first and relative preservation of the largest fibers.

Keywords: neuro-ophthalmology: optic nerve • microscopy: light/fluorescence/immunohistochemistry • mitochondria