Retinal axonal loss begins early in the course of multiple sclerosis and is similar between progressive phenotypes

Abstract

Background: To determine whether retinal axonal loss is detectable in patients with a clinically isolated syndrome (CIS), a first clinical demyelinating attack suggestive of multiple sclerosis (MS), and examine patterns of retinal axonal loss across MS disease subtypes.

Methodology/principal findings: Spectral-domain Optical Coherence Tomography was performed in 541 patients with MS, including 45 with high-risk CIS, 403 with relapsing-remitting (RR)MS, 60 with secondary-progressive (SP)MS and 33 with primary-progressive (PP)MS, and 53 unaffected controls. Differences in retinal nerve fiber layer (RNFL) thickness and macular volume were analyzed using multiple linear regression and associations with age and disease duration were examined in a cross-sectional analysis. In eyes without a clinical history of optic neuritis (designated as "eyes without optic neuritis"), the total and temporal peripapillary RNFL was thinner in CIS patients compared to controls (temporal RNFL by -5.4 µm [95% CI -0.9 to--9.9 µm, p = 0.02] adjusting for age and sex). The total (p = 0.01) and temporal (p = 0.03) RNFL was also thinner in CIS patients with clinical disease for less than 1 year compared to controls. In eyes without optic neuritis, total and temporal RNFL thickness was nearly identical between primary and secondary progressive MS, but total macular volume was slightly lower in the primary progressive group (p<0.05).

Conclusions/significance: Retinal axonal loss is increasingly prominent in more advanced stages of disease--progressive MS>RRMS>CIS--with proportionally greater thinning in eyes previously affected by clinically evident optic neuritis. Retinal axonal loss begins early in the course of MS. In the absence of clinically evident optic neuritis, RNFL thinning is nearly identical between progressive MS subtypes.

Figure 1. Retinal Axonal Degeneration in Multiple Sclerosis is Increasingly Prominent in More Advanced Stages of Disease and Proportionally Greater in Eyes Previously Affected by Symptomatic Optic Neuritis.

Retinal Nerve Fiber Layer thickness (A, B, C) and macular volume (D), as measured by spectral-domain optical coherence tomography (Heidelberg Spectralis) in a cross sectional sample of patients with high-risk Clinically Isolated Syndromes (CIS) (n = 45), Relapsing-Remitting MS (RRMS) (n = 403), Secondary-Progressive MS (SPMS) (n = 60), Primary-Progressive MS (PPMS) (n = 33) and unaffected controls (n = 54). Both the total and temporal peripapillary RNFL were thinner in CIS patients compared to controls in eyes without prior symptomatic optic neuritis. RNFL measures were nearly identical between SPMS and PPMS patients in eyes without optic neuritis, but macular volumes were lower in PPMS compared to SPMS patients in eyes without optic neuritis (p<0.05). The black dots denote the median, and the bars signify the interquartile range. *p<0.05, **p<0.001 refers to the comparison with unaffected controls using linear regression to adjust for age and sex.

Figure 2. Associations of Temporal Retinal Nerve Fiber Layer Thickness by Disease Stage and Subtype with Age and Disease Duration in MS.

Temporal quadrant peripapillary retinal nerve fiber layer (RNFL) thickness by age (A) and disease duration (B) in MS patients in eyes without a history of symptomatic optic neuritis. Note that temporal RNFL thickness is nearly identical between patients with primary and secondary progressive MS, but disease durations tend to be greater in SPMS and shorter in PPMS for the same degree of RNFL loss. The solid line indicates the slope as fitted by linear regression, and the dotted lines denote 95% confidence intervals. CIS = Clinically Isolated Syndrome; RRMS = Relapsing-Remitting MS; PPMS = Primary Progressive MS; SPMS = Secondary Progressive MS.