Optic nerve lesion length is a biomarker of visual disability in the pre-chronic phase of Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON; OMIM 535,000) is characterized by an, initially, subacute vision loss in one eye while the fellow eye becomes similarly involved, usually within a couple of months [1]. Given that p.Tyr51Cys DNAJC30 founder mutation accounts for over 20% of molecularly diagnosed LHON patients, LHON is suggested to be subdivided as LHON due to mitochondrial DNA mutations and LHON with autosomal recessive mode of inheritance [2]. However, the m.11778 G>A/MT-ND4, m.3460 G>A/MT-ND1, and m.14484 T > C/MT-ND6 mutations still account for the majority of LHON cases worldwide [3]. Other mitochondrial DNA mutations such as m.10197 G>A, m.14502 T > C, m.3736 G>A, m.3866 T > C, and m.11696 G>A are considered as rare causes of LHON [4], [5], [6], [7]. Missense mutations in the mitochondrial DNA can cause mitochondrial dysfunction with drastic defects in complex I subunits of the respiratory chain, and result in the progressive degeneration of retinal ganglion cells at the axonal region of the optic nerve (ON) [8].

Retinal ganglion cell axons exit the eye through the lamina cribrosa. The unmyelinated prelaminar axons have higher energy demands with larger numbers of mitochondria in comparison to the myelinated retrolaminar axons [9]. Herein, theoretically, conventional orbital magnetic resonance imaging (MRI) is normal in the majority of LHON patients. However, hyperintensities on T2-weighted images have been revealed in the pregeniculate visual pathway in some patients with LHON [10], [11]. Our previous study also showed T2-weighted short tau inversion recovery (T2-STIR) hyperintensities in 81.19% of the afflicted eyes with predominant involvement of the intraorbital and intracanalicular segments [11]. Herein, a hyperintense signal may be common on T2-weighted images in LHON.

Quantitative evaluation with reduced field of view diffusion tensor imaging revealed a significant correlation of fractional anisotropy (FA) value with visual acuity and mean deviation (MD), indicating that the damage progression of optic neuropathy was related to visual field and visual acuity in LHON[12]. Our previous study indicated the gradual decrease in measurements of best corrected visual acuity (BCVA) with the extension of T2-STIR hyperintensities on the ON, albeit no statistical differences were detected in BCVA among various affected segments [11]. These studies suggested a possible relationship between the imaging abnormalities and visual function, and more studies on LHON with MRI are needed to provide a better understanding of these imaging findings.

Conventional MRI studies of the ON typically use a STIR sequence. Although 3D double inversion recovery sequence is more sensitive for the detection of ON signal abnormalities [13], it is not pre-programmed on all MR systems and is time-consuming in its acquisition. Consequently, it is not available in both clinical routine and most clinical trials. Recently, new imaging techniques such as Zero Echo Time MRI sequence have been developed to enable precise and clinically effective visualization of the visual systems in optic neuritis or LHON [14]. However, it is still difficult for them to be widely used in clinical practice. Herein, it is reasonable to argue that orbital MRI is challenging but remains a performing tool to detect ON involvement in optic neuropathy. For this reason, our current research aims to investigate the relationships between the length of retrobulbar optic nerve T2-STIR hyperintensity and visual function in patients with LHON. The present study, although preliminary, may offer a deeper understanding of imaging abnormalities on conventional MRI in LHON.

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