Longitudinal Anterior Visual Pathway Evaluation of Patients with Multiple Sclerosis Using Multifocal Visual Evoked Potential and Optical Coherence Tomography

Purpose: Multiple sclerosis (MS) is a chronic disease of the central nervous system involving inflammation, demyelination and neurodegeneration. Optic neuritis (ON) is acute inflammatory, demyelination of the optic nerve. The anterior visual pathway serves as a good model to track MS related disease changes. Multifocal visual evoked potential (mfVEP) is an objective, non-invasive technique that provides spatially localized, topographic information on visual function. MfVEP response amplitude and latency reflects integrity of axons and myelin, respectively. Optical coherence tomography (OCT), provides high-resolution, cross-sectional images of the retina and is a sensitive technique for assessing neurodegeneration. The purpose of this dissertation was to assess functional and structural changes over time in the visual system of relapsing-remitting MS (RRMS) patients.

Methods: 1) In the first experiment, to assess reproducibility, mfVEP was recorded twice within a month in 40 normals and 40 RRMS patients (25 eyes with last ON ≥ 6 months (mo), 34 non-ON). Global and 9 regional mfVEP amplitudes (logSNR) and latency (ms) were calculated. Traditional pattern VEP (TVEP) was recorded (15’, 60’, 120’ checks) in subsets of 34 normals and 30 RRMS patients. Reproducibility was evaluated using intraclass correlation coefficient (ICC) and test-retest variability (TRV) to establish 95% tolerance limits. 2) In the second experiment to evaluate longitudinal changes in visual function, mfVEP, contrast sensitivity (CS) and Humphrey visual fields (HVF) were obtained at two different visits (mean follow-up: 1.5 ± 0.9 years) in 57 RRMS patients (53 eyes with optic neuritis (ON): 14 with ON within 6 months (mo) of first visit (ON < 6mo), 39 with ON ≥ 6mo, 57 non-ON). Longitudinal changes were assessed using mfVEP amplitude, latency, log CS and HVF mean deviation (MD) based on 95% tolerance limits of TRV established in experiment 1. 3) In the third experiment, to assess neurodegenerative changes over time in MS eyes, retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus OCT in 133 RRMS patients (149 non-ON, 97 ON ≥ 6 mo eyes). 93 patients were scanned at two visits. Percents of abnormal GCIPT vs RNFLT (< 5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed.

Results: 1) ICCs for global and regional mfVEP amplitude and latency were all > 0.80 indicating good intervisit agreement. ICCs for tVEP ranged from 0.52 to 0.86, being lowest for ON latency (0.52 to 0.68). TRV for amplitude (mfVEP and tVEP) was similar across groups. TRV for latency, greater for tVEP than mfVEP in all groups, was larger in ON (5.3/9.2 ms for mfVEP global/60’ tVEP) compared to non-ON (3.1/5.6, p = 0.003/p = 0.02) and normals (2.3/4.1, p = 0.0001/p < 0.01). 2) A significant percentage of ON < 6mo eyes exceeded 95% tolerance limits for mfVEP amplitude (21%, p < 0.05), latency (35%, p < 0.01) and for CS (31% p < 0.001); more improved than worsened. MfVEP latency shortened in 11% non-ON, 10% ON ≥ 6mo, lengthened in 21%, and 10%, respectively (p < 0.01 for all). Latency changes correlated negatively with baseline latency (r = - 0.43, - 0.45 for non-ON, ON ≥ 6mo; p = 0.0008). Although an insignificant number of non-ON and ON ≥ 6mo eyes exceeded tolerance limits for amplitude, CS or HVF; amplitude and latency changes were correlated, and both measures correlated with changes in CS (r = 0.47 to 0.79, p < 0.01). 3) GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p = 0.004 in non-ON, 82% vs 72% p = 0.007 in ON ≥ 6 mo). RNFLT and GCIPT decreased with MS duration by - 0.49 μm/yr (p = 0.0001) and - 0.36 (p = 0.005) for non-ON; - 0.52 (p = 0.003) and - 0.41 (p = 0.007) for ON ≥ 6 mo. RNFLT and GCIPT decreased with follow-up time by - 1.49 μm/yr (p < 0.0001) and - 0.53 (p = 0.004) for non-ON, - 1.27 (p = 0.002) and - 0.49 (p = 0.04) for ON ≥ 6 mo.

Conclusions: MfVEP showed better reproducibility than tVEP in normals and RRMS patients. MfVEP, and particularly latency, can be used to track visual functional changes in individual RRMS eyes. Progressive loss of RNFLT and GCIPT occurs even in the absence of clinically-evident inflammation in RRMS. MfVEP and OCT are potentially useful for assessing therapeutic effects of novel remyelinating and neuroprotective strategies in RRMS.