All studies including NMOSD patients and HC demonstrated that peripapillary retinal nerve fiber layer (pRNFL) and total macular volume (TMV)/macular thickness were significantly reduced after 1 or more clinical episodes of ON versus HC. Ratchford et al. reported that a single episode of ON in NMOSD causes an estimated decrease of 31 μm in pRNFL thickness compared to an estimated decrease of 10 μm in RRMS [20]. All studies reporting subanalysis of pRNFL quadrants reported significant atrophy in all quadrants for comparison of NMOSD and HC [18, 19, 24–26].

Most of the studies including NMOSD and MS patients demonstrated that global pRNFL and TMV/macular thickness were significantly reduced after ON in both diseases but with a significant greater extent in NMOSD [19–22, 24, 25, 27, 29, 33], which is in agreement with consideration that ON is clinically more severe in NMOSD than in MS [2, 3]. Moreover visual disability of NMOSD-ON eyes is worse than in MSON eyes [3, 20, 24, 25, 27, 29, 31]. One additional study highlighted no significance but only a trend toward significance about a decreased VA in NMOSD-ON eyes versus MSON eyes [28]. Most of the previous OCT studies in NMOSD did not adjust for the number of clinical ON [19–22, 24, 25, 28, 29, 31] and/or did not perform statistical analysis with generalized estimation equation (GEE) models. The number of ON episodes increases the retinal axonal loss [29] and GEE is the best adapted statistical test for data with hierarchical structure including clusters of eyes on an individual level. Nevertheless, 1 study involving NMOSD and MS patients with only 1 MSON episode showed a greater pRNFL decrease in NMOSD [20] and another one with adjustment to the number of ON episodes showed more global pRNFL in NMOSD [27].

If post-ON retinal axonal loss seems to be higher in NMOSD than in MS, it seems not to involve all pRNFL quadrants with the same magnitude or as in MS. Compared to MS patients, NMOSD patients present frequently an inferior [19, 22, 24, 25, 27, 29] and a superior [22, 24, 27, 29] pRNFL atrophy after ON. Since temporal pRNFL atrophy is predominant in MSON eyes, comparison of NMOSD-ON eyes and MSON eyes rarely found more marked temporal pRNFL atrophy in NMOSD-ON eyes [19, 24, 25]. Merle et al. found temporal pRNFL atrophy in NMOSD eyes versus MS eyes but ON and NON eyes were mixed for both populations [19]. Interestingly nasal/temporal (N/T) pRNFL ratio in NMOSD remains in normal range [24, 26] arguing in favor of a more overall atrophy in NMOSD than in RRMS.

Only three studies did not show significant difference in retinal atrophy between NMOSD and MS [23, 26, 34]. In the first study, the authors compared ON eyes affected by only 1 episode of ON between NMOSD and MS and showed no difference in macular RNFL and GCIP thicknesses. However, INL thickness of NMOSD population was significantly thicker than in the MS population, and the NMOSD population closed to that already published in another paper [22] presented significantly more pRNFL atrophy than MS. The second study [34] did not highlight significant pRNFL differences between ON eyes of NMOSD and MS (p = 0.46). Indeed, it seems that patients with NMOSD presented more ON episodes than MS patients. The third study [26] found pRNFL thinning in some nasal quadrants with a TMV decreasing in NMOSD versus MS, but after adjustment, notably including the number of ON episodes in GEE analysis, differences did not persist any longer.

It remains quite difficult to summarize all previously referenced NMOSD-OCT studies because all of them have not included MS patients or HC and because comparison sometimes included mixed MSON and NON eyes or specifically investigated MSON eyes or NON eyes or both.

For highlighting microcystic macular edema (MME), it is mandatory to perform OCT with a 4th-generation OCT (spectral-domain OCT). In MS, MME might occur in the absence of any clinical MSON episode [35–37]. However, these three studies did not report optic nerve imaging of the MME eye without MSON, and it is difficult to consider that MME and severe pRNFL thinning could be due to only retrograde transsynaptic degeneration. Five studies investigated specifically or reported MME in NMOSD. All these studies showed that NMOSD patients with MME have always presented at least 1 clinical episode of ON [24, 26, 30, 32, 36]. MME is most often located in the inner nuclear layer (INL) and sometimes the inner plexiform layer (IPL). It is not specific of neuroinflammatory diseases [38], but it is a marker of severe optic neuropathy as illustrated in an NMOSD patient in Fig. 6.2a–e.

The proportion of NMOSD patients presenting MME is ranged between 8.7 and 25.6 % and the proportion of NMOSD-ON eyes with MME between 6.3 and 29.8 % [24, 26, 30, 32, 36] (Table 6.1) [19, 21, 24, 26, 30, 32, 35–39]. MME seems more frequently observed in NMOSD than in MS [32, 36]. NMOSD patients with MME presented thinner pRNFL than NMOSD patients without MME [32]. In agreement with this last finding, it has been shown that patients with MME have presented more episodes of ON than those without, but these latter were younger [30]. All pathologies included MS, CRION, and Whatever the cause of ON (MS, NMOSD, Chronic Relapsing Inflammatory Optic Neuropathy) is, MME is associated with a thinner pRNFL than the contralateral eye not affected by ON, but not with a lower total macular volume [36]—probably because of the slight INL thickening observed on ON eyes in this cohort. In MS, INL thickening is observed in MME eyes but also in MSON eyes without MME compared to contralateral NON eyes [35]. Fernandes et al. did not report MME in their cohort but interestingly reported the same INL thickening in NMOSD eyes with only 1 episode of ON versus HC but also versus MS patients with only 1 episode of MSON [23]. INL thickening seems to be of greater magnitude in NMOSD versus MS. MME is not always highlighted on an OCT scan, whereas ocular fundus may show macular changes (Fig. 6.2c–e). Inner nuclear layer thickening may be the ultimate step before microcyst formation.

In MS, the “outer” retinal layers (ORL; INL to photo receptor layer) seem not to be involved in the retinal atrophic process [21, 26, 40]. Balk and coworkers discussed a potential retinal neuroplasticity [40, 41]. In NMOSD, the same external retinal conservation has been found [26] whereas the thickness of ONL, which takes part of ORL, has been reported significantly increased in NMOSD-ON eyes presenting MME [24]. A recent study coupling OCT and optic nerve imaging in a MS/NMOSD/idiopathic ON cohort suggested that optic nerve with clinical or subclinical T2 lesion might be associated with an INL and ONL thickening whatever the presence of MME [42]. If ORL in NMOSD-ON eyes did not suffer from a retinal atrophic process, a thickening process may be discussed.

If a large majority of OCT studies considered that NMOSD patients affected by ON presented a more severe retinal atrophy than MS patients, subclinical retinal axonal loss in NMOSD is more discussed. Only studies including HC [18–26] enable us to really discuss whether or not a subclinical retinal axonal loss in NMOSD exists. However, Park et al. [25] did not show interest in NMOSD-NON eyes, and in two other studies [22, 23], all NMOSD eyes presented past history of ON. Regardless of the very few patients without ON in the NMOSD group, the French collaborative work was not able to do a statistical comparison, but pRNFL values between HC and NMOSD-NON eyes were very comparable [18]. Global peripapillary RNFL [24, 34] and total macular volume [24] of NMOSD-NON eyes appear in some studies similar to HC eyes. In other studies, macular involvement in NMOSD-NON eyes is highlighted [21, 26, 30]. GCIP [21, 30], average macular thicknesses/TMV [21, 30], and GCL volume [26] are reduced in NMOSD-NON eyes versus HC. Merle et al. [19] showed that global pRNFL value was significantly reduced in NMOSD-NON eyes versus HC, and a recent work [26] only found significant atrophy in temporal and naso-inferior quadrants of pRNFL.

If subclinical retinal involvement may be discussed in NMOSD, it seems that it is probably of a lesser extent than in MS since it has been reported that there are lower global pRNFL [27] and temporal pRNFL [26] values in MS-NON eyes than in NMOSD-NON eyes.

Astroglial cells and Müller cells are AQP4-expressing cells. Müller cells are located inside the retina and astroglial cells inside the RNFL and the optic nerve [43, 44] but also in the chiasma, optic tract, and brain. Without any clinical ON episode, anti-AQP4 Ab may induce their pathological process directly on these cells inside the different retinal layers (astrocytes and Müller cells) and on the rest of the optic ways (astrocytes). Some NMOSD studies have already described extensive [8] or more located brain abnormalities [7, 10], particularly in the brainstem and near the lateral ventricules where the lateral geniculate nucleus and the posterior part of optic radiations (OR) are located, respectively. As it has been demonstrated in MS [45], a retrograde transsynaptic degenerative process cannot be excluded in NMOSD.

Firstly, we propose to focus on ON eyes and what could be in favor of NMOSD (versus MS) is the presence of more severe pRNFL atrophy in global analysis but more particularly in another quadrant than temporal quadrant and a more frequent maculopathy (more atrophy, more MMO) associated with worse visual disability. Secondly, we propose to focus on NON eyes and an absence of temporal pRNFL atrophy would be in favor of NMOSD. In Table 6.1, the main results of OCT studies in NMOSD and MS are summarized.

Kim recently proposed that after a first episode of ON, global pRNFL less than 78.9 μm associated with a high-contrast visual acuity of less than 0.4 logMar leads to a specificity of 100 % in favor of NMOSD diagnostic [33].

Further multicentric collaborative studies with spectral-domain OCT and larger cohorts would be able to examine the question in more detail and to confirm or not the results of all previous exploratory OCT studies in NMOSD.

Another imaging biomarker that may help to distinguish these two diseases is optic nerve magnetic resonance imaging (MRI). In NMOSD, demyelinating lesion seen on MRI may involve more frequently the posterior part of the optic nerve and the chiasma [46, 47] with a greater extent [47] than in MS. To date no study has coupled optic nerve MRI and OCT assessments in NMOSD. One could expect that T2 lesion length in NMOSD may be higher in NMOSD than in MS, but these 2 latter studies with semiquantitative measurements remain contradictory. It was recently shown that 3D Double Inversion Recovery (DIR) sequence was superior to coronal 2D Short Tau Inversion Recovery – Fluid Attenuated Inversion Recovery (STIR-FLAIR) sequence in the detection of T2 optic nerve lesion [48]. This 3D sequence allows a direct T2 hypersignal length measurement, strongly associated with retinal axonal loss in a MS/NMOSD/idiopathic ON cohort [42] as illustrated in an NMOSD patient in Fig. 6.3a–e.

If similar metabolic measurement by proton(H+)-magnetic resonance spectroscopy (H-MRS) in NMOSD and HC argued in favor of brain white matter (WM) sparing in NMOSD [49], many diffusion tensor imaging (DTI) studies [50] showed altered DTI parameters in NMOSD versus HC in many tracts and notably optic radiations [50–53]. In addition, voxel-based morphometry studies [50, 54–56] showed atrophic process in WM and grey matter of NMOSD patients. Recently, a Brazilian study group showed for the first time a high correlation between average pRNFL thickness and pericalcarine cortical thickness [56]. In this study, many other cortical areas were reduced in NMOSD versus HC. In MS associated ON, a relationship between retinal thicknesses and occipital cortex thickness seems to be weaker [40, 41].