Optical coherence tomography (OCT) is a noninvasive technique that allows for tissue-level in vitro imaging of the optic nerve head and retina. OCT provides a unique opportunity to image the unmyelinated axons arising from the retinal ganglion cells (axons not myelinated anterior to the lamina cribrosa). By measuring the thickness of the peripapillary RNFL (commonly referred to for simplicity as the RNFL), OCT provides the ability to quantitate the amount of axonal loss associated with optic nerve injury and is a means to monitor the neurodegenerative process. In addition, OCT can be used to measure total macular volume (TMV), which may provide an estimate of neuronal integrity (ganglion cell integrity) at the retinal level. The development of computerized OCT image segmentation techniques has added to the ability to image distinct neuronal populations including the ganglion cell layer (GCL).

Autopsy studies have shown that up to 94–99 % of patients with MS have detectable optic nerve lesions [23, 24]. The earliest application of OCT technology to the study of MSON was reported by Parisi et al. in 1999 [25]. In that study, which utilized first-generation OCT, RNFL thickness was reduced by an average of 46 % in the eyes with history of MSON as compared to control subjects and by an average of 28 % in comparison to fellow eyes of patients with a history of MSON. Even in the clinically unaffected eyes of patients with MS, there was a 26 % reduction in RNFL thickness when compared to disease-free control eyes (whose average RNFL thickness is approximately 100–110 microns). In 2005, Trip et al. [26] reported similar findings, with 33 % reductions in RNFL thickness in the eyes of the patients with a history of MSON compared with eyes of matched controls and a 27 % reduction when the MSON-affected and unaffected eyes of the same patients with MS were compared. They also showed total macular volume loss by 11 % in the eyes of patients with a history of MSON when compared to control eyes (p < 0.001) and by 9 % in the MSON-affected versus the unaffected eyes of the same patients (p < 0.001). Thus, OCT was able to show both RNFL thinning and macular retinal volume loss, suggesting the occurrence of both axonal and neuronal cell loss in the eyes of patients with MS with and without acute MSON (see Case Studies 1 and 2).

In 2010, Petzold et al. [27] performed a meta-analysis of OCT studies in the MS and MSON literature with available data (n = 63 studies). The authors found an average RNFL thinning of 20.38 μm (95 % CI 17.91–22.86, n = 2,063, p < 0.0001) in eyes with MSON, while thinning was 7.08 μm on average (5.52–8.65, n = 3,154, p < 0.0001) in MS eyes without MSON. The estimated degree of RNFL thinning in patients with MS was greater than the extent expected by normal aging. Normal RNFL thickness may be in the range of 110–120 μm by the age of 15 years, with an estimated physiological loss of only about 0.017 % per year in retinal thickness (approximately 10–20 μm loss over 60 years) [28]. RNFL thickness in the Petzold et al. meta-analysis [27] also was found to correlate with visual and neurological functioning.

In 2006, Costello et al. [29] reported that the majority of patients with acute MSON (approximately 75 %) will sustain 10–40 μm of RNFL loss within a period of approximately 3–6 months (see Case Study 3). Importantly, RNFL thinning down to a level of 75–80 μm was found to be a “threshold level” below which there was a corresponding decline in visual function, as measured by automated perimetry [29], and below which visual dysfuntion persisted.

In the acute setting of ON, Pro et al. [30] demonstrated mild OCT RNFL thickening in 8 subjects who were thought clinically to have retrobulbar ON (i.e., no obvious optic disk swelling on ophthalmoscopy). In most of these cases, increased RNFL thickness was subtle and not beyond the range of normal (100.7 μm in ON-affected eyes, versus 92.9 μm in unaffected fellow eyes). The unaffected eyes in this study remained stable, while thinning was demonstrated in the affected eyes with ON. This thinning was seen as early as 2–4 months after the onset of the visual loss. The findings of this study, as well as clinical experience, suggest that mild optic disk swelling is present even in cases of suspected retrobulbar ON based on ophthalmoscopic examination.

The time course of RNFL axonal loss following an episode of acute MSON may be important for determining the “window of opportunity” for potential intervention with neuroprotective or repair therapies. From the available data, it appears that most of the RNFL thinning occurs in MSON within the first 1–3 months. This observation suggests that significant and rapid axonal degeneration follows primary demyelination of the optic nerve [27, 29]. Stabilization of RNFL thickness is evident by 6 months following onset of MSON [29, 31].

Henderson et al. [31], in a study of 23 patients with acute clinically isolated unilateral MSON, performed comprehensive visual assessments. The mean time to 90 % loss of RNFL thickness from baseline values for MSON-affected eyes was 2.38 months. Ninety-nine percent of the RNFL thickness loss occurred by a mean of 4.75 months. The time of first OCT-detectable RNFL atrophy compared to the baseline fellow eye value was 1.64 months (95 % CI, 0.96–2.32; listed p < 0.05). Eyes with poor recovery had a significantly greater decline of RNFL thickness from baseline to 3 months (p = 0.002). Macular volumes also declined significantly to the time of last follow-up.

Costello et al. [32] demonstrated that the pattern of OCT RNFL thinning may be able to distinguish MS disease subtypes. They found that RNFL comparisons involving MS eyes with a history of ON (MSON eyes) yielded greater differences between MS subtypes than did comparisons of unaffected eyes. For MSON eyes in this study, patients with clinically isolated syndrome (CIS) had the highest overall RNFL thickness values (mean 87.8 μm), while patients with secondary progressive MS (SPMS) had the greatest degree of thinning compared to control reference values (mean RNFL thickness 70.8 μm). For MS non-MSON eyes, RNFL thickness was reduced in patients with primary progressive MS (PPMS, average 94.3 μm p = 0.04), relapsing remitting MS (RRMS, average 99.6 μm, p = 0.02), and SPMS (average 84.7 μm, p < 0.0001) relative to eyes of patients with CIS (average RNFL thickness 105.7 μm). RNFL thickness may thus represent an important structural marker of disease progression.

Galetta et al. [33] have shown that even patients with “benign MS” may have RNFL axonal loss that is similar to that of typical MS. In these studies, definitions of “benign MS” were an EDSS score of ≤3 and a ≥15-year disease duration. Importantly, those with benign MS had associated reductions of vision-specific QOL as well as impairments of low-contrast letter acuity. While overall neurologic impairment in benign MS may be mild, visual dysfunction may actually account for a substantial degree of disability.

One of the most important findings that have resulted from the use of OCT in MS is the correlation between RNFL thinning and visual loss, as measured by low-contrast letter acuity [22]. In 2006, Fisher et al. [34] published a cross-sectional study that compared RNFL thickness among MS eyes with a history of ON (MSON eyes), MS eyes without a history of ON (MS non-MSON eyes), and eyes of disease-free controls. They found that RNFL thickness was reduced significantly among MS patients (92 μm) versus controls (105 μm, p < 0.001, generalized estimating equation models, accounting for age) and particularly reduced in MSON eyes (85 μm, p < 0.001). Furthermore, lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every one line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 μm. These findings supported the validity of low-contrast visual assessment and suggested a potential role for OCT in MS trials that examine neuroprotective and other disease-modifying therapies [40]. Several other investigations have demonstrated correlations between RNFL thinning and visual loss [26, 41–43]. For example, Costello et al. [44] found that RNFL thickness after an episode of isolated ON cannot be used to predict the risk of MS.