Improving the visual outcome in Leber's hereditary optic neuropathy: Framework for the future

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease characterized by central vision loss and a poor visual prognosis.1 LHON remains without cure; however, recent advances in understanding the natural history of disease have led to new insights and approaches to therapy. Natural history of disease Various studies have advanced our understanding of LHON pathophysiology. Until recently, the contribution of the microvascular supply to the pathogenesis of LHON was poorly understood.1,2 Optical coherence tomography angiography (OCTA) has improved on previous imaging technologies through enhanced visualization of the optic disc and retinal microvasculature.3 Balducci and colleagues used OCTA to detect significant peripapillary microvascular changes over the disease course of LHON.4 Intriguingly, vessel attrition corresponded with loss of the retinal ganglion cell-inner plexiform layer (RGC-IPL) and preceded thinning of the retinal nerve fiber layer (RNFL).4 In addition to the peripapillary vasculature, recent OCTA studies conducted by our laboratory revealed vascular pathology also in the macula for both chronic and acute disease stages of LHON.1,5 Borrelli et al. showed quantitative differences in the macular retinal and choroidal circulation of chronic LHON patients. Specifically, vascular attenuation was localized to the macular region corresponding to the upstream portion of the papillomacular bundle (PMB).1 More recently, our group observed vascular pathology as early as the acute and subacute stages of LHON. Intriguingly, OCTA of the subacute stage showed vascular attrition with marked enlargement of the foveal avascular zone. In contradistinction, the acute stage exhibited increased vascular perfusion with evidence of microangiopathy and vascular telangiectasias.5 Similar to chronic LHON, these early vascular changes coincided with loss of the PMB,6,7 which contains the smallest RGC fibers that are the most vulnerable to mitochondrial dysfunction.8,9 Taken together, these studies provide new insight into the evolution of disease and introduce the clinical utility of vascular parameters as objective biomarkers for LHON.