Mathematically Modeling the Involvement of Axons in Leber's Hereditary Optic Neuropathy

Abstract

PURPOSE. Leber's hereditary optic neuropathy (LHON), a mitochondrial disease, has clinical manifestations that reflect the initial preferential involvement of the papillomacular bundle (PMB). The present study seeks to predict the order of axonal loss in LHON optic nerves using the Nerve Fiber Layer Stress Index (NFL-S I ), which is a novel mathematical model. METHODS.Optic nerves were obtained postmortem from four molecularly characterized LHON patients with varying degrees of neurodegenerative changes and three age-matched controls. Tissues were cut in cross-section and stained with pphenylenediamine to visualize myelin. Light microscopic images were captured in 32 regions of each optic nerve. Control and LHON tissues were evaluated by measuring axonal dimensions to generate an axonal diameter distribution map. LHON tissues were further evaluated by determining regions of total axonal depletion. RESULTS.A size gradient was evident in the control optic nerves, with average axonal diameter increasing progressively from the temporal to nasal borders. LHON optic nerves showed an orderly loss of axons, starting inferotemporally, progressing centrally, and sparing the superonasal region until the end. Values generated from the NFL-S I equation fit a linear regression curve (R 2 ¼ 0.97; P < 0.001).CONCLUSIONS. The quantitative histopathologic data from this study revealed that the PMB is most susceptible in LHON, supporting clinical findings seen early in the course of disease onset. The present study also showed that the subsequent progression of axonal loss within the optic nerve can be predicted precisely with the NFL-S I equation. The results presented provided further insight into the pathophysiology of LHON. (Invest Ophthalmol Vis Sci. 2012;53:7608-7617)

Drug-Related Mitochondrial Optic Neuropathies

“…A number of factors probably lead to selective vulnerability of the PMB axons. These include high energy needs coupled with low energy production, a high surface area to volume ratio, and absence of saltatory conduction due their unmyelinated structure (7).…”

The Optical Coherence Tomographic Profile of Leber Hereditary Optic Neuropathy

“…1,2 It has been reported that the axons in the papillomacular bundle are the most susceptible to injury in LHON due to preferential involvement of smaller axons. 3 Recent studies have detected subclinical ganglion cell dysfunction in asymptomatic carriers using pattern electroretinogram, and structural changes of the GCC on OCT. 4,5 High-definition optical coherence tomography (OCT) has shed some light on the events occurring at the optic nerve head in LHON, including a more clear depiction of axonal swelling, which occurs before and during the time of visual loss. Furthermore, OCT clearly detects atrophy of the nerve fibre layer (RNFL) following the acute event, which in most cases is confined to the maculopapillary bundle.…”

Diffusion Tensor Imaging Mapping of Brain White Matter Pathology in Mitochondrial Optic Neuropathies

“…1,2 DOA and LHON represent the so-called nonsyndromic mitochondrial optic neuropathies, characterized by optic nerve atrophy as the only or at least prevalent pathologic feature with an early and preferential involvement of the small fibers in the papillomacular bundle. 3,4 Recent MR imaging studies by using voxelbased morphometry, 5 DWI, 6 and DTI 7 have also indicated abnormalities of the optic radiation in patients with LHON, confirmed by postmortem investigation, 6 suggesting a trans-synaptic degeneration. A similar secondary involvement of the retrogeniculate visual pathway could also be hypothesized in patients with DOA.…”