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June 09, 2020; 94 (23) Article

Asymptomatic optic nerve lesions

An underestimated cause of silent retinal atrophy in MS

Jean-Baptiste Davion, Renaud Lopes, Élodie Drumez, Julien Labreuche, Nawal Hadhoum, Julien Lannoy, Patrick Vermersch, Jean-Pierre Pruvo, Xavier Leclerc, Hélène Zéphir, Olivier Outteryck
First published May 20, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009504
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Abstract

Objective To evaluate the frequency of asymptomatic optic nerve lesions and their role in the asymptomatic retinal neuroaxonal loss observed in multiple sclerosis (MS).

Methods We included patients with remitting-relapsing MS in the VWIMS study (Analysis of Neurodegenerative Process Within Visual Ways In Multiple Sclerosis) (ClinicalTrials.gov Identifier: 03656055). Included patients underwent optical coherence tomography (OCT), optic nerve and brain MRI, and low-contrast visual acuity measurement. In eyes of patients with MS without optic neuritis (MS-NON), an optic nerve lesion on MRI (3D double inversion recovery [DIR] sequence) was considered as an asymptomatic lesion. We considered the following OCT/MRI measures: peripapillary retinal nerve fiber layer thickness, macular ganglion cell + inner plexiform layer (mGCIPL) volumes, optic nerve lesion length, T2 lesion burden, and fractional anisotropy within optic radiations.

Results An optic nerve lesion was detected in half of MS-NON eyes. Compared to optic nerves without any lesion and independently of the optic radiation lesions, the asymptomatic lesions were associated with thinner inner retinal layers (p < 0.0001) and a lower contrast visual acuity (p ≤ 0.003). Within eyes with asymptomatic optic nerve lesions, optic nerve lesion length was the only MRI measure significantly associated with retinal neuroaxonal loss (p < 0.03). Intereye mGCIPL thickness difference (IETD) was lower in patients with bilateral optic nerve DIR hypersignal compared to patients with unilateral hypersignal (p = 0.0317). For the diagnosis of history of optic neuritis, sensitivity of 3D DIR and of mGCIPL IETD were 84.9% and 63.5%, respectively.

Conclusions Asymptomatic optic nerve lesions are an underestimated and preponderant cause of retinal neuroaxonal loss in MS. 3D DIR sequence may be more sensitive than IETD measured by OCT for the detection of optic nerve lesions.

Glossary

CIS=
clinically isolated syndrome;
CIS-NON=
clinically isolated syndrome without history of optic neuritis;
DIR=
double inversion recovery;
DTI=
diffusion tensor imaging;
EPI=
echoplanar imaging;
FA=
fractional anisotropy;
FLAIR=
fluid-attenuated inversion recovery;
FOV=
field of view;
IETD=
intereye retinal thickness differences;
INL=
inner nuclear layer;
IQR=
interquartile range;
mGCIPL=
macular ganglion cell + inner plexiform layer;
mINL=
macular inner nuclear layer;
MME=
microcystic macular edema;
MS=
multiple sclerosis;
MS-NON=
multiple sclerosis without history of optic neuritis;
MS-ON=
multiple sclerosis with history of optic neuritis;
OCT=
optical coherence tomography;
ON=
optic neuritis;
ORs=
optic radiations;
pRNFL=
peripapillary retinal nerve fiber layer;
RNFL=
retinal nerve fiber layer;
RRMS=
relapsing-remitting multiple sclerosis;
TE=
echo time;
TI=
inversion time;
TR=
repetition time;
VA=
visual acuity;
VEP=
visual evoked potential

Embedded Image

Long-term disability in multiple sclerosis (MS) is mainly related to axonal loss.1 Easily accessible to examination and composed solely of axons, the retinal nerve fiber layer (RNFL) is a promising imaging biomarker to study axonal degeneration in MS. RNFL atrophy in MS is mainly due to clinical episodes of optic neuritis (ON).2 ON causes axonal lesions of ganglion cells within the optic nerve, leading to retrograde axonal degeneration and RNFL atrophy. Anterograde axonal degeneration of ganglion cells can also drive a transsynaptic degeneration of postgeniculate neurons, leading to visual cortex atrophy. RNFL atrophy can also be found in eyes of patients with MS without history of ON (MS-NON).2 Three hypotheses have been mentioned: lesions of the optic radiations (ORs), primary retinal pathology, and asymptomatic lesions of the optic nerve.3 OR injury including MS lesions can induce RNFL atrophy.4 Retrograde axonal degeneration of the postgeniculate neuron can lead to a transsynaptic axonal degeneration of ganglion cells. Considering this latter mechanism, RNFL atrophy in MS-NON eyes may represent a window to the brain in MS but none of the studies focusing on this mechanism has simultaneously evaluated the possibility of asymptomatic optic nerve lesions with highly sensitive tools. A primary retinal degenerative process has also been discussed.5,6 Demyelinating lesions of the optic nerve without ON exist in MS. Pathology showed constant7 to frequent8 optic nerve inflammatory lesions in MS, whereas half of patients with MS experience ON during their lifetime.9 MRI displays inflammatory lesions of the optic nerve in 20%10 to 38.5%11 of MS-NON eyes, and in 22.1% of clinically isolated syndrome (CIS) NON eyes.12 Recently, we suggested that asymptomatic optic nerve lesion was the main cause of retinal neuroaxonal loss in CIS.13

It is unknown if these asymptomatic optic nerve lesions are associated with RNFL atrophy in relapsing-remitting MS (RRMS). Our main objective was to study retinal neuroaxonal loss and visual disability associated with asymptomatic optic nerve lesions in patients with RRMS.

Methods

Design, settings, and participants

We conducted a transversal pilot study (NCT 03656055) and included patients with RRMS fulfilling McDonald 2010 criteria, aged 18 to 65 years, treated by natalizumab for at least 6 months in our center and seronegative or with a low serum antibody index (<1.5) for JC virus. Natalizumab is associated with an early and sustained drop of new or enlarging T2 lesions.14 Therefore, our population comprised patients with MS without recent inflammation, but with disease that has been active enough to result in a moderate to marked lesion burden. Patients were not included if it was impossible to determine the existence or absence of history of ON or if they had signs of clinical activity in the last 6 months or any factor that could modify retinal thickness.

All included patients underwent clinical examination, retinal optical coherence tomography (OCT), contrast vision examination, and optic nerve/brain MRI. Each evaluation (OCT, MRI, contrast vision) was performed blind to any clinical or paraclinical data.

Clinical measures were recorded by interrogation and complete reading of the medical records: age, sex, date of the first relapse, and history of clinical episode of ON. Diagnosis of ON should have been documented by a neurologist or neuro-ophthalmologist. Absence of history of ON was reaffirmed only if there was no evocative history9 at interrogation and in medical records.

Data acquisition and analysis

Optical coherence tomography

Retinal OCT was performed with spectral-domain OCT (Spectralis; Heidelberg Engineering, Germany) and respected OSCAR-IB criteria.15 Our protocol has been detailed previously.16 Classification of peripapillary RNFL (pRNFL) thickness values according to Heidelberg Spectralis healthy control database (<1st percentile, <5th percentile) were reported. For the calculation of intereye retinal thickness difference, we considered the macular thickness within the 6-mm Early Treatment Diabetic Retinopathy Study disc.

Visual acuity (VA) measures

Monocular VA was measured at high (100%), low (2.5%), and very low (1.25%) contrasts with printed scales PRECISION-VISION-2180, using logarithm of the minimum angle of resolution (logMAR) unit.

MRI measures

Magnetic resonance images were acquired on a 3T Achieva scanner (Philips, the Netherlands) using a 32-channel array head coil. The imaging protocol included 3D T1 turbo field echo (repetition time [TR]/echo time [TE] = 9.9/4.6 ms, sagittal acquisition, voxel size 1.0 × 1.0 × 1.0 mm, field of view [FOV] 256 × 256 × 160, number of slices 160, sense 2), 3D double inversion recovery (DIR) (TR/TE = 5,500/252 ms, inversion time [TI]–dual 625/2,600, voxel size 1.2 × 1.2 × 1.3 mm, number of excitations 2, fat suppression spectral presaturation with inversion recovery, FOV 250 × 250 × 195, number of slices 150, sense 2), 3D fluid-attenuated inversion recovery (FLAIR) (TR/TE = 8,000/334 ms, TI = 2,500 ms, sagittal acquisition, voxel size 1.12 × 1.12 × 1.12 mm, FOV 250 × 250 × 180, number of slices 160, sense 3), diffusion tensor imaging (DTI) (32 directions, single shot, 2 b-factors, b-max = 1,000 s/mm2, TR/TE = 12,000/56 ms, axial acquisition, voxel size 2.0 × 2.0 × 2.0 mm, FOV 250 × 250 × 132, number of slices 66, sense 2), and 1 B0 with a reversed phase-encoding polarity.

Detection of demyelinating lesions on optic nerve/chiasma/optic tracts was performed by a reading of 3D DIR17 and 3D FLAIR sequences by a trained investigator (O.O.) who was blind of OCT and clinical data. Length of optic nerve DIR hypersignal was measured directly on MRI workstation.11 If several hypersignals were present on 1 nerve, length was defined as the sum of the length of each hypersignal. For the detection of demyelinating optic nerve lesions with 3D DIR sequence, sensitivity and specificity were 95% and 94%, respectively.17 Intraobserver and interobserver agreement was excellent and very good for optic nerve DIR hypersignal detection and length measurement, respectively.11 We provide the optic nerve imaging and the corresponding OCT scans of some patients in figure 1.

Figure 1
Figure 1 Optic nerve MRI and optical coherence tomography (OCT) of patients with multiple sclerosis (MS)

Patients 1–3: Patients with MS without optic neuritis (MS-NON) and without asymptomatic optic nerve double inversion recovery (DIR) hypersignal. Peripapillary retinal nerve fiber layer (pRNFL) thicknesses are in normal range without any significant intereye thickness difference (IETD). Patients 4–6: Patients with MS with optic neuritis (MS-ON) with unilateral symptomatic optic nerve DIR hypersignal (red arrows) and without asymptomatic involvement in the fellow eye (patient 4) or presenting asymptomatic optic nerve DIR hypersignal (yellow arrows) of the fellow eye (patients 5 and 6). pRNFL thicknesses of the eye associated with optic neuritis (ON) are lower than in the fellow eye. IETD are quite high. Patients 7–12: Patients with MS without ON but with unilateral (patients 7 and 8) or bilateral (patients 9–12) asymptomatic optic nerve DIR hypersignal (yellow arrows). pRNFL thicknesses are lower than normal and IETD are low or very low. Green disc: eyes without ON and without asymptomatic optic nerve DIR hypersignal. Yellow disc: eyes without ON but with asymptomatic optic nerve DIR hypersignal. Red disc: eyes with ON and with symptomatic optic nerve DIR hypersignal. Yellow arrows point to the asymptomatic optic nerve DIR hypersignals and the corresponding hyperintensities on 3D fluid-attenuated inversion recovery (FLAIR) sequence. Red arrows point to the symptomatic optic nerve DIR hypersignals and the corresponding hyperintensities on 3D FLAIR sequence.

T1-weighted images were processed using FreeSurfer software (v5.3, surfer.nmr.mgh.harvard.edu/). This included the preprocessing steps of nonuniform signal correction, signal and spatial normalizations, skull stripping, and brain tissues segmentation. The primary visual cortex (V1) was identified from Brodmann area atlas of the Martinos Center for Biomedical Imaging. The visual cortex volume was measured as the sum of left and right primary visual cortex, normalized on the intracranial volume estimated by FreeSurfer. To segment the ORs, we warped to the T1 space the Juelich histologic atlas, made from postmortem histologic examination of 10 human brains from patients without neurologic affection. T2 lesion volumes in the ORs were measured as follows: brain MS lesions were semiautomatically segmented on 3D FLAIR with ITK-SNAP (v3.6.0, itksnap.org) to create a lesion mask, which was warped into T1 space. Then, an OR lesion mask was created by keeping voxels of the warped lesion mask that were in the OR mask. Diffusion tensor images were corrected for eddy current and motion artifacts using FSL software (fsl.fmrib.ox.ac.uk/fsl/fslwiki/). Then the susceptibility-induced off-resonance field, inherent to echoplanar imaging (EPI) acquisition schemes and responsible for geometric and signal artifacts, was estimated using images with reversed phase-encode blips. This field was applied to correct all diffusion tensor images. OR segmentations defined in the T1 space were transformed into the DTI space to calculate a mean fractional anisotropy (FA) in the ORs. We provide images of the OR postprocessing analysis for one patient in figure 2.

Figure 2
Figure 2 Postprocessing MRI analysis

The primary visual cortex volume was measured using the atlas included in FreeSurfer (A). The lesions were semiautomatically segmented with ITK-SNAP on the fluid-attenuated inversion recovery (FLAIR) sequence (B), and warped in the T1 space using statistical parametric mapping (SPM) (C). The optic radiations mask was creating by warping the Juelich atlas to the T1 space with SPM (D). The optic radiations lesion volume was measured as the lesion volume inside the optic radiation mask (E). The mean fractional anisotropy was calculated inside the optic radiation mask warped in the double inversion recovery space (F).

Statistical analysis

Thickness and volume of different retinal layers and VA at different contrasts were first compared between eyes with asymptomatic lesions (i.e., eyes without history of ON with a homolateral optic nerve hypersignal on 3D DIR) and eyes without lesions (i.e., eyes without history of ON without homolateral optic nerve hypersignal on 3D DIR), and secondly, compared between eyes with asymptomatic lesions and eyes with symptomatic lesions (i.e., ON history with a homolateral optic nerve hypersignal on 3D DIR) using linear mixed models by including eye subgroups as fixed effect and patients as random effects, to account for the correlation between eyes in the same patient. Comparisons were adjusted further for prespecified confounding factors: age, sex, MS duration, lesion volume in ORs divided by intracranial volume, and mean FA in ORs (included as fixed effects into linear mixed models). We used multivariable linear mixed models to study the associations of the different retinal layer thicknesses and volumes with the length of the optic nerve lesions on MRI in eyes with asymptomatic or symptomatic lesion subgroups, with the normalized lesion volume in ORs, and with the mean FA in ORs, including prespecified confounding factors (age, sex, and MS duration) as fixed effects and patients as random effect. We also used a linear mixed model including a random patient effect to compare the length of the optic nerve DIR hypersignal between symptomatic and asymptomatic cases. Finally, we used an analysis covariance adjusted for age, sex, MS duration, normalized lesion volume, and mean FA in ORs to compare, in patients without history of ON, the primary normalized visual cortex volume between those with asymptomatic hypersignal on one or both optic nerves and those without hypersignal on either optic nerve. Normality of model residuals were checked using normal quantile–quantile plots.

Intereye retinal thickness differences (IETD) were compared between MS subgroups using variance analysis. Post hoc pairwise comparisons were performed using the Bonferroni correction. Considering a history of unilateral or bilateral ON as the gold standard, optimal IETD thresholds for the detection of optic nerve involvement were calculated from the receiver operating characteristic curve by maximizing the Youden index. Diagnostic values of the observed optimal IETD (expressed as absolute difference) thresholds were evaluated by calculating sensibility and specificity. Successively, we evaluated the ability of IETD and of 3D DIR MRI sequence to detect symptomatic optic nerve involvement within the whole cohort (occurrence of unilateral or bilateral clinical episode of ON as gold standard).

All statistical tests were done at the 2-tailed α level of 0.05. Data were analyzed using SAS software (version 9.4; SAS Institute Inc., Cary, NC).

Standard protocol approvals, registrations, and patient consents

The study is registered at Clinicaltrials.gov (NCT02766205). The study was approved by the independent ethics committee of Dijon, France, and was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Data availability

De-identified participant data are available upon reasonable request.

Results

Description of the population

Between March and December 2017, we included 98 patients (72 women) with a mean age at inclusion of 41.5 ± 11.7 years (range, 19.5–65.0), a median delay since first relapse of 11.6 years (interquartile range [IQR], 7.1–16.7; range, 0.8–28.0), and a median natalizumab treatment duration without interruption of 5.4 years (IQR, 2.0–8.4; range, 6 months–10.4 years). Delay from last ON episode was more than 6 months. No patient developed progressive multifocal leukoencephalopathy at 23 months follow-up. Lesion volume in ORs varied from a minor to a severe burden (extremes: 0.01–6.95 cm3). Over 196 eyes (figure 3), 73 presented at least 1 episode of ON (MS-ON eyes: 37.2% of all eyes, 54.1% of patients). Over these 73 eyes with ON, we found 60 homolateral optic nerve DIR hypersignals on MRI (MS-ON-DIRpositive eyes, 82.2%). Over 123 MS-NON eyes), 60 had at least 1 asymptomatic optic nerve DIR hypersignal on MRI (MS-NON-DIRpositive eyes, 48.8%) and 63 did not (MS-NON-DIRnegative eyes, 51.2%). These asymptomatic optic nerve hypersignals involved 42 patients (42.9% of our population), being bilateral in 18 patients. Among the 196 eyes, 120 had an optic nerve DIR hypersignal on MRI (MS-DIRpositive eyes, 61.2%). We found no patient with optic tract or chiasm involvement. We found microcystic macular edema (MME) on OCT of 2 MS-ON-DIRpositive eyes (2 different patients). MME was not found in any other eyes subgroup. In 196 eyes, 77 (39.3%) presented a global pRNFL <5th percentile and 44 (22.5%) a global pRNFL <1st percentile. In 98 patients, 49 (50%) presented at least on 1 side a global pRNFL <5th percentile, and 33 (33.7%) a global pRNFL <1st percentile. In patients with only asymptomatic optic nerve lesions (n = 25), 13 (52.0%) presented at least on 1 side a global pRNFL <5th percentile, and 8 (32.0%) a global pRNFL <1st percentile. In patients with only symptomatic optic nerve lesions (n = 36), 22 (61.1%) presented at least on 1 side a global pRNFL <5th percentile, and 15 (41.7%) a global pRNFL <1st percentile.

Figure 3
Figure 3 Flowchart of our population

DIR = double inversion recovery; MS = multiple sclerosis; MS-NON = multiple sclerosis without history of optic neuritis; MS-ON = multiple sclerosis with history of optic neuritis.

Asymptomatic optic nerve DIR hypersignal vs no optic nerve lesions

In MS-NON eyes, eyes with asymptomatic optic nerve DIR hypersignal had a significantly lower temporal (p < 0.0001) and global pRNFL (p < 0.0001) thicknesses and a lower macular ganglion cell + inner plexiform layer (mGCIPL) volume (p < 0.0001) compared to those with absence of hypersignal (table 1).

View this table:
Table 1

Measurement of different retinal layers and visual acuity at different contrasts in eyes without history of optic neuritis according to the presence or absence of an optic nerve lesion and in eyes with an optic nerve lesion on MRI according to their symptomatic or asymptomatic nature

Asymptomatic optic nerve DIR hypersignals were associated with a significantly worst contrast VA at 2.5% (p = 0.002) and 1.25% (p = 0.003).

Symptomatic vs asymptomatic optic nerve DIR hypersignal

Among MS-DIRpositive eyes (n = 120), eyes with symptomatic optic nerve DIR hypersignal had significantly lower temporal and global pRNFL, lower mGCIPL, and higher macular inner nuclear layer (mINL) volumes compared to asymptomatic hypersignal (table 1). Moreover, eyes with symptomatic optic nerve DIR hypersignal had a significantly worse VA at 1.25%, 2.5%, and 100% contrast. The mean length of the optic nerve hypersignal was significantly higher in symptomatic than in asymptomatic cases (20.55 mm ± 9.8 vs 13.32 mm ± 9.3, p < 0.0001).

Measures independently associated with retinal thickness/volume

Among MS-NON-DIRpositive eyes (n = 60, table 2), a higher length of optic nerve DIR hypersignal was significantly associated with a thinner temporal pRNFL (β = −0.43 µm/mm ± 0.18, p = 0.027) and mGCIPL (β = −0.002 mm3/mm ± 0.001, p = 0.022). The quantitative measures of injury within ORs (normalized lesion volume, mean FA) were associated with no retinal measures.

View this table:
Table 2

Association between the thickness or volume of different retinal layers and MRI measures in eyes with an asymptomatic optic nerve lesion (n = 60), in eyes with a symptomatic optic nerve lesion (n = 60), and in eyes without optic nerve lesion (n = 63) in multivariate analysis including age, sex, and multiple sclerosis duration as prespecified confounding factors

Among MS-ON-DIRpositive eyes (n = 60, table 2), a higher length of optic nerve DIR hypersignal was significantly associated with a thinner temporal (β = −0.93 µm/mm ± 0.17, p < 0.001) and global pRNFL (β = −0.86 µm/mm ± 0.14, p < 0.001), and with a lower mGCIPL volume (β = −0.007 mm3/mm ± 0.001, p < 0.001). The normalized lesion volume in ORs was significantly associated with a lower mGCIPL and a higher mINL volumes (β = −0.37 mm3/% ± 0.14, p = 0.018 and β = 0.19 mm3/% ± 0.06, p = 0.009, respectively). The mean FA in ORs was associated with none of the retinal measures.

Among MS-NON-DIRnegative eyes (n = 63, table 2), the quantitative measures of injury within ORs (normalized lesion volume, mean FA) were significantly associated with a higher mGCIPL volume (β = 0.34 mm3/% ± 0.12, p = 0.011 and β = 0.012 ± 0.0039, p = 0.003, respectively), but not with the other retinal measures.

Impact for optic nerve DIR hypersignal on primary visual cortex volume

Within MS-NON, the 25 patients with unilateral or bilateral asymptomatic optic nerve DIR hypersignal had a significantly lower normalized primary visual cortex volume, compared to the 20 patients without optic nerve DIR hypersignal (0.58% ± 0.09 vs 0.67% ± 0.14, p = 0.018). After adjustment for age, sex, MS duration, normalized lesion volume, and mean FA in ORs, this difference was not significant (p = 0.089).

Within the whole cohort, the 36 patients with unilateral or bilateral symptomatic optic nerve DIR hypersignal and without asymptomatic optic nerve involvement had a significantly lower normalized primary visual cortex volume compared to the 20 patients without optic nerve DIR hypersignal (0.60% ± 0.11 vs 0.67% ± 0.14, p = 0.039). After adjustment for age, sex, MS duration, normalized lesion volume, and mean FA in ORs, this difference remained significant (p = 0.029).

Intereye retinal thickness difference

Intereye retinal thickness differences according to different MS subgroups are described in tables 3 and 4. Patients with unilateral optic nerve DIR hypersignal presented a higher pRNFL and mGCIPL-IETD than patients without optic nerve DIR hypersignal (p = 0.0018 and p = 0.0008, respectively) and patients with bilateral optic nerve hypersignal (p = 0.0493 and p = 0.0317, respectively). There was no significant difference between IETD of patients with bilateral optic nerve DIR hypersignal and IETD of patients without optic nerve DIR hypersignal (p = 0.1863 for pRNFL and p = 0.1399 for mGCIPL).

View this table:
Table 3

Retinal thickness and intereye retinal thickness difference among patient subgroups classified according to unilateral/bilateral/no, symptomatic, or asymptomatic optic nerve involvement

View this table:
Table 4

Retinal thickness and intereye retinal thickness difference (IETD) among patient subgroups classified according to unilateral or bilateral or no optic nerve double inversion recovery (DIR) hypersignal (symptomatic or asymptomatic)

Among the whole cohort and by considering a history of unilateral or bilateral ON as the gold standard, optimal IETD thresholds for the detection of optic nerve involvement were ≥6 mm for global pRNFL and ≥2.83 mm for mGCIPL. Sensitivity of these optimal pRNFL and mGCIPL-IETD thresholds and sensitivity of optic nerve MRI (3D DIR) were 56.6%, 67.3%, and 84.9%, respectively. Specificity of these optimal pRNFL and mGCIPL-IETD thresholds and specificity of optic nerve MRI were 86.7%, 67.4%, and 44.4%, respectively.

Discussion

We found that asymptomatic optic nerve involvement in RRMS is significantly associated with asymptomatic retinal neuroaxonal loss and higher visual disability. As we adjusted to normalized T2 lesion volume and to microstructural integrity of ORs, these associations seems to be independent of demyelinating and degenerative processes in the brain, and of a possible transsynaptic degeneration. Evidence supports that asymptomatic optic nerve lesions induce retinal atrophy: the strength of the associations, their independence from another explanation, and the analogy with symptomatic lesions responsible for ON. The significant relation between the optic nerve lesion length and the temporal pRNFL and mGCIPL thicknesses argues for causality. Therefore asymptomatic optic nerve lesions seem to be an additional important explanation of retinal neuroaxonal loss in MS-NON eyes.

A thinning of retinal layers associated with lesions of the ORs is demonstrated experimentally in primates18 but also in MS with a methodology close to ours,19 explained by a retrograde transsynaptic degeneration. We observed a positive association of the mean FA within the ORs and the mGCIPL thickness in the eyes without optic nerve lesions (MS-NON-DIRnegative): a lower mean FA may reflect a poorer conservation of the microstructural architecture within the ORs, which might lead to a retrograde transsynaptic degeneration and thus to a greater retinal degeneration.20 Conversely, we also observed a positive association of the normalized OR lesion volume and the mGCIPL thickness in the same eyes without optic nerve lesion (MS-NON-DIRnegative), which is inconsistent with a retrograde transsynaptic degeneration induced by OR lesions. No significant association was observed between the normalized OR lesion volume and the pRNFL. These results may argue against an important role of OR T2 lesions in retinal neurodegeneration occurring in MS.

The significant association of asymptomatic lesions with low-contrast VA is consistent with previous data,11 showing low-contrast scales to be more prone to detecting post-ON visual impairment.21 We hypothesize that the asymptomatic nature of optic nerve lesions in MS results from a difference in size, insufficient to alter the 100% contrast VA. Our results suggest that asymptomatic optic nerve lesions induce the same morphologic and functional changes on optic ways, but to a lesser extent than symptomatic lesions. Asymptomatic optic nerve lesions were shorter and contrary to symptomatic lesions, we failed to demonstrate an anterograde transsynaptic degeneration associated with asymptomatic lesions.

Frequency of asymptomatic optic nerve lesions was high in our population. This frequency is higher than in previous studies, possibly because of differences in methods and population: Miller et al.10 found 20% in CIS and Hadhoum et al.11 found 38.5% in patients with less advanced MS. In MS, asymptomatic lesions are frequently observed in spinal cord, brainstem, and brain. Thus it seems unsurprising to find many asymptomatic lesions on optic nerves. Indeed, pathologic studies reported that optic nerve demyelinating lesions were near constant in MS.7,8 Some MRI studies contrast with our results and did not report any asymptomatic optic nerve lesion with T2-fat-sat4 and 3D DIR.22 Other studies tried to detect these asymptomatic lesions by searching for pRNFL asymmetry between the eyes.23 However, asymptomatic optic nerve lesions, which are frequently bilateral in our population, would probably make this method not sensitive enough. We cannot firmly demonstrate with our data that optic nerve MRI was better than OCT (IETD) for the detection of asymptomatic optic nerve lesions since we would need another gold standard. However, in case of bilateral optic nerve lesions, IETD was not different from IETD of patients without optic nerve involvement. Furthermore, optic nerve MRI (3D DIR) clearly presented a higher sensitivity to detect a history of clinical episode of ON than IETD. If not better, 3D DIR sequence can at least be considered as a sensitive tool for the detection of demyelinating optic nerve lesions in MS. In our study, specificity of 3D DIR sequence was clearly underestimated by the identification of multiple asymptomatic optic nerve lesions in eyes without history of ON. Recently, it has been shown that optic nerve imaging with 3D DIR sequence may be more sensitive than visual evoked potentials (VEPs).24

If we confirm the preponderant role of symptomatic optic nerve lesions noted by others4,20 and highlight the role of asymptomatic optic nerve lesions in the retinal neuroaxonal loss of patients with RRMS, we cannot exclude a concomitant primary retinal pathology, previously described as a macular thinning in the absence of retrograde degeneration of RNFL.5 Macular GCIPL atrophy without global pRNFL atrophy has been reported recently in eyes without history of ON in patients with early MS25 and in eyes without history of ON in patients with CIS (CIS-NON).13 In this latter study, asymptomatic retinal neuronal loss in CIS-NON was associated with a temporal pRNFL thinning and the presence of asymptomatic optic nerve lesion. Thus, the previously reported primary retinal neuronopathy might actually be due to an asymptomatic optic nerve lesion, itself responsible for macular and temporal pRNFL thinning without significant global pRNFL thinning. Temporal pRNFL values have not been studied in articles focusing on the potential existence of a primary retinal pathology.5,6

We reported MME in 2% of our population. This MME prevalence is in line with previous studies reporting MME in 0%–6% of patients with MS.16,26,–,29 Patients with symptomatic optic nerve lesions presented a thicker inner nuclear layer (INL) than patients with asymptomatic lesions and contrary to some previous studies,27,29 we did not observe MME in eyes without ON. mINL volume has been correlated with the optic nerve lesion length in CIS13 but this correlation is weaker than with inner retinal layers.11,13 In longitudinal OCT studies, baseline mINL volume has been correlated with annualized new T2 lesions.30 In our cross-sectional study, we have some clues in favor of correlation between T2 lesion load in ORs and mINL volume but this link seems weak and is not found in every eye subgroup.

Many studies have attempted to correlate nonvisual measures to retinal OCT in MS. In MS-NON eyes, retinal atrophy was well correlated with cerebral volume, cognitive impairment,3 or risk of disability worsening.31 Retinal OCT might be a reflection of the total axonal loss in the CNS, as a window to the brain. However, none of these studies looked at asymptomatic optic nerve lesions with a highly sensitive method. Our results are not contradictory with those, but it sheds the light on one additional important explanation for asymptomatic retinal neuroaxonal loss in RRMS. OCT seems to be a window to the optic nerve and every study trying to associate a nonvisual measure to retinal OCT should not only consider symptomatic but also asymptomatic optic nerve lesions.

Our study has several limitations. We could not exclude false-positive findings regarding multiple comparisons. Our population may not be representative of patients with mildly active MS, or of patients with primary or secondary progressive MS. Nevertheless, the characteristics of the patients were varied. Our method of detection of ON history was retrospective. Sensitivity of the 3D DIR sequence is not perfect. In our population, 3D DIR showed 61.2% of optic nerve lesions (symptomatic or not), whether histology showed up to 100%.7 It is therefore possible that some asymptomatic lesions were not identified, and difficult to certify that all optic nerve hypersignals correspond to inflammatory demyelinating lesions, and not to lesions of another type. OR location was obtained from an anatomical atlas, constituted from healthy subjects; MS-related cerebral atrophy can make this localization imprecise. Finally, we did not present exhaustive visual function measurements (i.e., visual field testing) and did not perform VEP, which would have helped us to look for optic nerve demyelinating lesions.

Frequency of asymptomatic optic nerve lesions has been underestimated in MS-NON eyes. Asymptomatic optic nerve lesions in MS are associated with structural changes and functional changes of the optic ways. Asymptomatic optic nerve lesions may be the main explanation of retinal atrophy in eyes without ON, before transsynaptic degeneration induced by OR lesions. Our results demonstrate the importance of studying the optic ways as a whole. Finally, we also suggest that optic nerve MRI may be more sensitive than IETD for the detection of optic nerve lesions in MS, because of the bilateral optic nerve involvement we frequently observed.

Study funding

No targeted funding reported.

Disclosure

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Acknowledgment

The authors thank the In-vivo Imaging and Functions core facility (ci2c.fr) for its help with data analysis: Romain Viard, Julien Dumont, Matthieu Vanhoutte, and Clément Bournonville; Maxime Thoor and Chloé Crinquette for MRI acquisition; and Julie Petit for help with data management.

Appendix Authors

Table

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • CME Course: NPub.org/cmelist

  • Received June 6, 2019.
  • Accepted in final form January 14, 2020.

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