Visual acuity changes in idebenone treatment‑naïve patients with Leber hereditary optic neuropathy: insights from the CRS-2 study

Objective Case Record Survey (CRS)-2 was an international, multicenter, retrospective study designed to characterize the natural history of vision loss and spontaneous recovery in patients with Leber hereditary optic neuropathy (LHON). Methods Case records of idebenone treatment-naïve patients aged ≥12 years, with mitochondrial DNA (mtDNA) variants m.3460G>A, m.11778G>A or m.14484 T>C, onset of symptoms (OoS) after 1999, and ≥2 visual acuity (VA) assessments within 5 years of OoS were analyzed. Disease phases were subacute/dynamic (≤1 year) or chronic (>1 year from OoS). Separate analyses were performed for eyes with VA assessments within 12 or 24±3 months from baseline (first VA assessment after OoS in each eye). Outcomes included: spontaneous clinically relevant recovery (sCRR; improvement from off-chart to ≤1.6 logMAR, or ≥0.2 logMAR if on-chart), sCR stabilization (sCRS; maintenance of VA <1.0 logMAR), sCR benefit (sCRB; eyes with a sCRR and/or sCRS), and sCR worsening (sCRW; worsening to off-chart, or loss of ≥0.2 logMAR if on-chart). The primary endpoint was the proportion of subacute/dynamic eyes 12 months from baseline with sCRB. Results Of 402 eligible eyes, 385 were subacute/dynamic at baseline, with 96 included in the 12-month analysis. Most patients were male (79.9%), with the m.11778G>A variant (71.7%). The primary endpoint was observed in 20.8% (n=20/96) of eyes. Spontaneous visual outcomes varied by disease phase, mtDNA variant, sex, and age at OoS. Conclusions CRS-2 provides insights into LHON natural history and suggests the disease course may be more dynamic than previously reported, with spontaneous VA changes occurring well into the chronic phase. Trial registration ClinicalTrials.gov NCT02796274, May 2016.