Clinical Trials to Clinical Use: Using Vision as a Model for MS and Beyond - Case Study

Just over a decade ago, clinical trials for multiple sclerosis (MS) did not include visual outcomes. Experts recognized the need for more sensitive measures of visual function, and low-contrast letter acuity emerged as a leading candidate to measure visual impairment. While lowcontrast acuity was quickly shown to correlate well with MRI lesion burden, visual-evoked potentials (VEPs), quality of life (QOL) in MS, it was the introduction of optical coherence tomography (OCT) to the field of MS that allowed for the direct assessment of structure-function correlations in the anterior visual pathway. This unique capacity to link axonal and neuronal loss with specific impairment (vision) in MS makes the anterior visual pathway and acute optic neuritis (ON) ideal models for testing novel agents for neuroprotection and repair. The latest OCT investigations involve high-resolution spectraldomain (SD) OCT with segmentation (measurement) of specific retinal layers using computerized algorithms. These methods allow quant ation of both retinal nerve fiber layer (RNFL, axonal) and ganglion cell layer (GCL, neuronal) loss in vivo. New therapies that reduce axonal and neuronal loss by neuroprotective or myelin repair mechanisms can now be assessed non-invasively by OCT and coupled with visual function data. Most MS clinical trials now include both OCT and visual function testing, and new clinical trials that use acute ON as a model will examine the capacity for OCT measures in particular to demonstrate structural evidence for neuroprotection in patients with MS and other neurologic disorders. In this syllabus, we examine the data from observational studies and ongoing trials, presenting representative group data for visual function, OCT measures, and QOL scales in patients with MS, ON, and disease-free controls. These data, as well as those from meta-analyses within the past five years, may be used to provide reference values for the development of clinical trial protocols.