Baseline Retinal Nerve Fiber Layer Thickness and Macular Volume Quantified by OCT in the North American Phase 3 Fingolimod Trial for Relapsing–Remitting Multiple Sclerosis

Abstract

Background Patients with multiple sclerosis (MS) demonstrate thinning of peripapillary retinal nerve fiber layer (RNFL) and decreased macular volume as measured by optical coherence tomography (OCT). To our knowledge, there are no previous reports from a large MS OCT database with strict quality control measures that quantitate RNFL and macula in patients with relapsing–remitting multiple sclerosis. Methods The University of California Davis OCT Reading Center gathered OCT data at baseline as part of the North American phase 3 trial of fingolimod (Gilenya). Average RNFL thickness (RNFLT) and macular volume (TMV) were measured using time domain OCT (TD-OCT). RNFL quadrants, clock hours, and macular subfields were included. With strict quality control and accounting for signal strength differences, scans were categorized as “reduced” or “not reduced” for each field, based on being less than 5th percentile for age-matched controls derived from the normative database in the scanner software. Patients were deemed “abnormal” if at least 1 eye had reduced values for a given parameter. Patients with abnormalities in corresponding RNFL and macular subfields were compared by cross-tabulation. Results The TD-OCT data were prospectively collected from 939 of the 1,083 trial patients, 712 of whom met all final quality and data inclusion criteria. Of the final cohort, 242 (34.0%) demonstrated reduced (less than 5th percentile) average RNFLT in at least 1 eye. One hundred seventy-eight (25.0%) patients had reduced TMV. One hundred twenty-eight (18.0%) demonstrated both reduced TMV and RNFLT in the same eye, whereas 42 (5.8%) had reduced TMV and RNFLT in both eyes. Of the 242 patients with reduced average RNFL thickness, 128 (52.9%) also had reduced TMV. Fifty patients had reduced TMV in the absence of reduced RNFLT in at least 1 eye, a cohort prevalence of 7.0%. Quadrant and subfield analysis showed a predominance of temporal and inferior RNFL thinning, with inferior macular thinning corresponding best to RNFL thinning. Conclusion RNFL and macular thinning/volume loss is common at baseline in relapsing–remitting multiple sclerosis, as measured by TD-OCT. When the RNFL is thin, the macular volume is reduced in more than half of the patients. There is a population of reduced TMV without any reduction in RNFLT. Documenting the prevalence and distribution of these structural abnormalities supports recent reports and suggests new retinal areas to probe for functional vision changes in MS.

Optical Coherence Tomography in Multiple Sclerosis

“…A rare 7% of these patients had reduced macular volume with normal pRNFL. 33 While this trial used the older time-domain version of OCT, other studies with spectral domain OCT have also reported approximately 10% of subjects having isolated macular thinning. 31,33 Another research group from Germany could not identify a similar phenotype in their cohort, however.…”

“…33 While this trial used the older time-domain version of OCT, other studies with spectral domain OCT have also reported approximately 10% of subjects having isolated macular thinning. 31,33 Another research group from Germany could not identify a similar phenotype in their cohort, however. 34 Decreased macular volumes are associated with decreased visual function, reduced brain volumes, and disability scores in patients with MS. 35 Baseline macular volume has been shown to predict 10-year disability in MS patients, demonstrating significant relevance for prognosis.…”

“…32 In a large dataset of 712 patients from a baseline analysis of a phase-3 trial of fingolimod, Winges et al reported that 25% of MS patients had at least one eye with abnormally reduced total macular volume. 33 Most of these patients also had reduced pRNFL. A rare 7% of these patients had reduced macular volume with normal pRNFL.…”

Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients

“…However, the usefulness of RNFL for monitoring disease progression and neurodegeneration longitudinally in MS clinical trials is not well established. Recently, baseline RNFLT and macular volume data from the prospective longitudinal phase 3 fingolimod trial were published . A potential criticism of our study is that PRVEP latency, visual acuity and LCLA data were not available.…”

Clinical Trials to Clinical Use

“…The University of California Davis Reading Center recently published the results of Stratus (TD) OCT quality control in 2 multicenter MS clinical trials (40). The University of California Davis Reading Center recently published the results of Stratus (TD) OCT quality control in 2 multicenter MS clinical trials (40).…”