This study demonstrates that 1) retinal axonal thinning begins early in the course of MS and independently of the occurrence of symptomatic optic neuritis and 2) that in the absence of symptomatic optic neuritis, RNFL thickness is nearly identical between progressive MS subtypes.
Previous studies using time-domain OCT to examine retinal axonal degeneration in CIS found no differences in retinal nerve fiber layer thickness or macular volumes between CIS patients and controls. 
This may reflect differences in study populations, differences in methodology or the lower spatial resolution of the time-domain OCT technique used in these previous studies. Other studies have reported greater retinal axonal thinning in patients with MS compared to patients with CIS. 
Temporal-predominant peripapillary retinal nerve fiber layer thinning is characteristic in MS, 
and the prominence of this pattern of RNFL thinning in CIS patients indicates that temporal-predominant RNFL loss begins early in the disease course. The cause of temporal-predominant RNFL thinning in MS is unknown. The RNFL is made up primarily of retinal ganglion cell axons. There are three main types of retinal ganglion cells that synapse in the lateral geniculate nucleus – 1) smaller parvocellular cells, which are distributed overwhelmingly in the macula, 2) larger magnocellular cells, which are distributed primarily in the retinal periphery, and 3) koniocellular cells, which are distributed more diffusely and sparser in number. 
On the standard peripapillary OCT scan, the RNFL temporal to the optic disc consists primarily of parvocellular axons within the papillomacular bundle that subserve central vision. 
Autopsy studies of the lateral geniculate nucleus in people who died with late stage MS have demonstrated a selective loss of parvocellular (smaller-sized) axons in the lateral geniculate nucleus in MS with relative preservation of magnocellular (larger-sized) axons. 
Autopsy studies of the spinal cord in patients who died with MS have also revealed a loss of smaller-sized axons in the lateral cortical spinal tracts of the cervical and thoracic spinal cord, with relative preservation of larger-sized axons. 
Whether smaller sized axons are more vulnerable to injury in MS is unknown. It is also possible that smaller sized axons may remyelinate less efficiently than larger sized axons following demyelinating injury, given evidence from in vitro
models of remyelination in which axonal scaffold size appears to be a critical determinant of oligodendrocyte precursor cell differentiation. 
More research is needed to understand the cause of temporal-predominant thinning in MS.
In the absence of prior symptomatic optic neuritis, RNFL thickness was nearly identical between patients with progressive MS subtypes. These results differ from previous studies using time-domain OCT that found no significant retinal thinning in PPMS 
and no difference in retinal thickness between PPMS and other types of MS 
, and are consistent with the findings of another study using time-domain OCT that found prominent RNFL and macular volume loss in progressive MS. 
These results add to the mounting evidence of phenotypic similarities between PPMS and SPMS. Measures of genetic susceptibility to MS are similar between patients with primary and secondary progressive phenotypes of disease, 
as are measures of global brain tissue damage and magnetization transfer imaging. 
The median age at time of disease progression was also indistinguishable between primary and secondary progressive MS patients in a large French population-based study, as was the time it took to reach major disability milestones. 
In our study, macular volumes were slightly lower in patients with primary MS compared to eyes without prior ON in secondary progressive MS patients. One possible interpretation of this result is that there may be a proportionally greater loss of other neuronal elements in the inner and outer retina in primary progressive disease. Future studies using segmentation algorithms will be helpful in exploring this possibly further.
Strengths of our analysis include the large sample size, which allows for more reliable point estimates for the observed values of retinal thickness at different stages of MS and the higher spatial resolution of the spectral domain OCT technique used in this study compared to time-domain OCT techniques used in some previous studies. 
While the cross-sectional study design precludes comparison of differential rates of change over time across MS subtypes, it is also advantageous for examining associations with retinal thickness and disease stage over the lifetime of disease, as MS typically evolves over decades. One possible limitation of our analysis is that the control group was slightly younger than the disease group, which could bias the results, although we attempted to adjust for age using regression models.
This study demonstrates that retinal axonal thinning is detectable in patients with a CIS; that retinal thinning is nearly identical in patients with primary and secondary progressive MS in eyes without prior symptomatic optic neuritis; and that RNFL thinning is increasingly prominent in more advanced stages of disease, even in eyes with prior symptomatic optic neuritis. These findings support the possible utility of OCT as a marker of axonal injury for trials of neuroprotective and neurorestorative therapies in MS and support the idea that prevention of axonal injury is relevant from the earliest clinical stages of disease.