An electrophysiological biomarker for the classification of cataract-reversal patients: A case-control study

Background: Untreated congenital blindness through cataracts leads to lasting visual brain system changes, including substantial alterations of extrastriate visual areas. Consequently, late-treated individuals (> 5 months of age) with dense congenital bilateral cataracts (CC) exhibit poorer visual function recovery compared to individuals with bilateral developmental cataracts (DC). Reliable methods to differentiate between patients with congenital and developmental cataracts are often lacking, impeding efficient rehabilitation management and introducing confounds in clinical and basic research on recovery prognosis and optimal timing of surgery. A persistent reduction of the P1 wave of visual event-related potentials (VERPs), associated with extrastriate visual cor-tical activity, has been reported in CC but not in DC individuals. Using two experiments, this study developed and validated P1-based biomarkers for diagnosing a history of congenital blindness in cataract-reversal individuals. Methods: Congenital and developmental cataract-reversal individuals as well as typically sighted matched controls took part in a first experiment used for exploring an electrophysiological biomarker (N[CC] = 13, N[DC] = 13, N[Control] = 26). Circular stimuli containing gratings were presented in one of the visual field quadrants while visual event-related potentials (VERPs) were recorded. Two biomarkers were derived from the P1 wave of the VERP: (1) The mean of the normalized P1 amplitude at posterior electrodes, and (2) a classifier obtained from a linear support vector machine (SVM). A second experiment with partially new CC/DC individuals and their matched controls (N[CC] = 14, N[DC] = 15, N[Control] = 29) was consecutively used to validate the classification based on both biomarkers. Performance of the classifiers were evaluated using receiver operating characteristic (ROC) curve analyses. All cataract-reversal individuals were tested after at least one year of vision recovery. Findings: The normalized P1 amplitude over posterior electrodes allowed a successful classification of the CC from the DC individuals and typically sighted controls (area under ROC curve, AUC = 0.803 and 0.929 for the normalized P1 amplitude and the SVM-based biomarker, respectively). The validation for both biomarkers in experiment 2 again resulted in a high classification success (AUC = 0.800 and 0.883, respectively for the normalized P1 amplitude and the SVM-based biomarker). In the most conservative scenario involving classification of CC from DC individuals in a group of only cataract-reversal individuals, excluding typically sighted controls, the SVM-based biomarker was found to be superior to the mean P1 amplitude based biomarker (AUC = 0.852 compared to 0.757 for the mean P1 based biomarker in validation). Minimum specificity obtained was 80% across all biomarkers. Interpretation: A persistent reduction of the P1 wave provides a highly specific method for classifying cataract patients post-surgically as having suffered from bilateral congenital vs. bilateral developmental cataracts. We suggest that using the P1 based non-invasive electrophysiological biomarker will augment existing clinical classification criteria for individuals with a history of bilateral congenital cataracts, aiding clinical and basic research, recovery prognosis, and rehabilitation efforts.