Interpreting Relative Afferent Pupillary Defect in Leber Hereditary Optic Neuropathy Using Interocular Visual Acuity Difference.

Abstract

Introduction: The aims of this study were to clarify how relative afferent pupillary defect (RAPD) relates to interocular visual acuity asymmetry in Leber hereditary optic neuropathy (LHON), and to derive clinically interpretable thresholds of absolute interocular best-corrected visual acuity difference (|ΔBCVA|) for RAPD interpretation.

Methods: This retrospective study included patients with genetically confirmed LHON (one of the three primary mitochondrial DNA mutations: m.11778G>A, m.14484T>C, or m.3460G>A) who presented within 6 months of symptom onset and underwent RAPD assessment at the initial visit. The absolute |ΔBCVA| (logarithm of the minimum angle of resolution [logMAR]) was analyzed using multivariable logistic regression. Discrimination was assessed by receiver operating characteristic (ROC) analysis. In unilateral-onset cases, time to fellow-eye involvement was compared by the Kaplan-Meier analysis.

Results: Ninety-two patients were included; 23 (25%) were RAPD-positive. In multivariable logistic regression, |ΔBCVA| was independently associated with RAPD (adjusted odds ratio 1.20 per 0.1 logMAR, 95% confidence interval [CI] 1.08-1.35; p < 0.001). ROC analysis showed good discrimination (area under the curve 0.791, 95% CI 0.672-0.910). The Youden-optimal cutoff was 0.88 logMAR (sensitivity 56.5%, specificity 92.8%); additional thresholds were 0.47 logMAR for higher sensitivity (87.0%, 58.0%) and 1.14 logMAR for higher specificity (52.2%, 97.1%). In the Kaplan-Meier analysis, fellow-eye involvement occurred earlier in RAPD-negative than RAPD-positive cases (log-rank p = 0.020), with an estimated median time to involvement of 2 months and 4 months, respectively.

Conclusion: In LHON, RAPD is largely driven by interocular acuity asymmetry. Quantitative |ΔBCVA| thresholds can support interpretation of RAPD without prematurely excluding LHON and may help plan diagnostic work-up and follow-up while confirmatory testing is pending.