In this study, we demonstrate that MS-related subclinical optic neuropathy, and the neurodegeneration associated with this process, occurs more significantly in patients exhibiting classic evidence of clinical and/or radiologic disease activity. This suggests that clinical trials enriched with patients with active MS may have better power to detect neuroprotective effects of novel therapeutic agents. Moreover, our findings suggest that the basis for subclinical optic neuropathy/subclinical optic nerve neurodegeneration may at least be partially related to microscopic optic nerve inflammatory disease. GCIP thinning was accelerated in patients exhibiting evidence of disease activity such as non-ON relapses, new T2 lesions, and new gadolinium-enhancing lesions. Patients exhibiting disability progression also were found to have faster rates of GCIP thinning. Furthermore, rates of GCIP thinning were faster in those with disease duration <5 years, which may reflect a greater availability of retinal ganglion cells for neurodegeneration earlier in the disease course, or a greater tendency for inflammatory disease activity earlier in the disease course. Rates of GCIP thinning were also augmented when these independent factors were present in combination. For example, patients with new T2 lesions, new enhancing lesions, and disease durations <5 years exhibited 70% faster rates of GCIP thinning. These results provide evidence that longitudinal GCIP changes in MS may be clinically meaningful and associated with more aggressive inflammatory disease. In addition, GCIP thinning was observed in all MS subtypes, suggesting GCIP neurodegeneration occurs throughout the disease course, perhaps related to microscopic inflammation. Although overall rates of GCIP thinning were significantly greater in patients with MS than in HCs, the rate of GCIP thinning observed in patients with MS is relatively modest. However, the mean duration of this study was short and presented results are expressed as annualized rates of thinning, rather than total thickness reduction between study beginning and study end.
Although baseline RNFL results in this study are consistent with prior studies,10–14
the rate of RNFL thinning in this study (−0.21 μm/year) was lower than that observed in some other studies, and was not significantly different from HCs. In one study, the rate of RNFL thinning in MS was −2.0 μm/year,19
and in another it was −2.7 μm/year.20
In the latter study, a rate of RNFL thinning of −1.4 μm/year was also observed in HCs. Our results, however, are more in line with 2 other studies in which no significant decrease was observed in RNFL thickness during follow-up.30,31
Discrepancies in RNFL change across studies may relate to differences in cohort characteristics. Our results raise the possibility that rates of RNFL thinning may be greater in cohorts with larger proportions of patients with prior ON. Also, another source of potential difference is that the rates we report control for several disease characteristics, whereas some other studies have reported unadjusted rates. Differences in the use of disease-modifying medication could also account for different results. Although all studies excluded patients who developed ON during follow-up, an important factor still bearing consideration is the differential effect of optic nerve inflammation on RNFL and GCIP thicknesses.17
Our finding that rates of GCIP thinning are accelerated in those with nonocular disease activity suggests that retinal changes in MS may be reflective of more global CNS processes, consistent with cross-sectional observations.32,33
However, the mechanism by which retinal changes may reflect global CNS processes is unclear. One plausible explanation is that disruption of the blood-brain barrier in one part of the CNS (reflected for example by an enhancing lesion) may represent a susceptibility for the blood-brain barrier to become disrupted elsewhere, such as in the optic nerves (even though it may be subclinical). If this was the case, it could imply that microinflammatory processes may be occurring within the optic nerves of patients with MS. Because optic nerve inflammation is associated with RNFL swelling but not GCIP swelling,17
these processes could result in the pseudonormalization or swelling of the RNFL, thus underestimating the true rates of RNFL thinning. The absence of GCIP swelling during optic nerve inflammation, as well as the absence of astroglial influence on GCIP thickness measures (the retinal astrocytes are predominantly located in the RNFL),16,34
may help explain the superiority of GCIP thickness measures over RNFL thickness measures, cross-sectionally and longitudinally. These factors may contribute toward the better reproducibility and lower variance of GCIP over RNFL thickness measures.16
It was surprising in this study that expected associations between worsening vision and changes in OCT measures were not observed, because these measures correlate well cross-sectionally.8,9
However, changes in visual acuity can have multiple causes in MS (e.g., posterior visual pathway lesions, refractive changes, temporary changes due to Uhthoff phenomenon), potentially weakening the association between changes in OCT and changes in vision in a cohort. Also, much of the change in vision that correlates with change in OCT measures comes from ON episodes. Because data after acute ON episodes were excluded in this study, this likely also weakened the ability to identify an association between change in low-contrast vision and change in OCT. Although patients with other known ocular diseases were excluded, the patients in this cohort were not systematically examined by an ophthalmologist, which limits our ability to correlate the OCT findings with aspects of visual function other than high- and low-contrast vision.
Given the potentially slow rate of change in OCT measures in non-ON MS eyes and nonactive MS, it is possible that a long timeframe may be needed to identify a neuroprotective therapeutic effect in a clinical trial using OCT as an outcome measure (such as in progressive MS). Nonetheless, if used as a secondary outcome, a finding of slower OCT change in treated relative to untreated patients may provide compelling evidence for neuroprotection. OCT has already shown promise as an outcome measure in acute ON, whereby a 10% to 20% change in RNFL thickness occurs within months.14
As discussed above, GCIP thickness may be a more sensitive measure to detect clinical change in MS than RNFL thickness. Because patients exhibiting active MS in this study, particularly early on in their disease course, had greater rates of GCIP thinning, a clinical trial using OCT as an outcome measure could potentially be enriched by the recruitment of patients with early, active MS. Our results suggest that researchers planning future trials incorporating OCT should consider the inclusion of macular-GCIP thickness measures (which will be commercially available soon), in addition to conventional peripapillary RNFL thickness measures.