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August 11, 2020; 95 (6) Article

Optical coherence tomography for detection of asymptomatic optic nerve lesions in clinically isolated syndrome

Olivier Outteryck, Renaud Lopes, Élodie Drumez, Julien Labreuche, Julien Lannoy, Nawal Hadhoum, Julie Boucher, Patrick Vermersch, Mickaël Zedet, Jean-Pierre Pruvo, Hélène Zéphir, Xavier Leclerc
First published July 28, 2020, DOI: https://doi.org/10.1212/WNL.0000000000009832
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Abstract

Objective To evaluate the ability of intereye retinal thickness difference (IETD) measured by optical coherence tomography (OCT) to detect asymptomatic optic nerve involvement in clinically isolated syndrome (CIS).

Methods We conducted a cross-sectional study of patients who recently presented a CIS (≤4.5 months). All patients underwent OCT and brain/optic nerve MRI. Optic nerve involvement was defined clinically (episode of optic neuritis [ON] or not) and radiologically (optic nerve hypersignal on 3D double inversion recovery [3D-DIR]). We evaluated the sensitivity and specificity of previously published IETD thresholds and report the observed optimal thresholds for identifying symptomatic optic nerve involvement but also for identifying asymptomatic optic nerve involvement (optic nerve hypersignal without ON history). Primary outcomes were ganglion cell–inner plexiform layer (GC-IPL) and peripapillary retinal nerve fiber layer IETD.

Results The study group consisted of 130 patients. In the CIS with ON group, 3D-DIR showed a hypersignal in all 41 symptomatic optic nerves and in 11 asymptomatic optic nerves. In the CIS without ON group, 3D-DIR showed a unilateral optic nerve hypersignal in 22 patients and a bilateral optic nerve hypersignal in 7 patients. For the detection of symptomatic and asymptomatic optic nerve lesion, GC-IPL IETD had better performance. We found an optimal GC-IPL IETD threshold ≥2.83 µm (sensitivity 88.2, specificity 83.3%) for the detection of symptomatic lesions and an optimal GC-IPL IETD ≥1.42 µm (sensitivity 89.3%, specificity 72.6%) for the detection of asymptomatic lesions.

Conclusions Detection of asymptomatic optic nerve lesions in CIS requires lower IETD thresholds than previously reported. GC-IPL IETD represents an alternative biomarker to MRI for the detection of asymptomatic optic nerve lesions.

Classification of evidence This study provides Class I evidence that OCT accurately identifies asymptomatic optic nerve involvement in patients with CIS.

Glossary

AUC=
area under the receiver operating characteristic curve;
CDMS=
clinically definite multiple sclerosis;
CI=
confidence interval;
CINOCIS=
Clinical Monitoring, MRI and Neuro-Ophthalmology of a Cohort of Patients With a Clinically Isolated Syndrome;
CIS=
clinically isolated syndrome;
CIS-NON=
clinically isolated syndrome without optic neuritis;
CIS-ON=
clinically isolated syndrome with optic neuritis;
DIR=
double inversion recovery;
DIS=
dissemination in space;
GC-IPL=
ganglion cell layer coupled to the inner plexiform layer;
HC=
healthy control;
IEPD=
intereye percentage difference;
IETD=
intereye retinal thickness difference;
LCMVA=
low contrast monocular visual acuity;
MAGNIMS=
Magnetic Resonance Imaging in Multiple Sclerosis;
MOG=
myelin oligodendrocyte glycoprotein;
MS=
multiple sclerosis;
NMOSD=
neuromyelitis optica spectrum disorder;
OCT=
optical coherence tomography;
ON=
optic neuritis;
pRNFL=
peripapillary retinal nerve fiber layer;
ROC=
receiver operating characteristic;
VEP=
visual evoked potential

Symptomatic1 and asymptomatic2,3 optic nerve lesions are very frequent at the clinically isolated syndrome (CIS) stage but the optic nerve is not part of typical location for dissemination in space (DIS) criteria for multiple sclerosis (MS).4 In a recent analysis comparing the performance of the 2010 McDonald and 2016 Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) criteria for multiple sclerosis diagnosis, the MAGNIMS network showed a slight improvement in sensitivity of predicting occurrence of second relapse by adding optic nerve as a fifth location for DIS criteria, but with a reduced specificity.1 However, it has been shown recently that the presence of asymptomatic optic nerve hypersignal may be associated with the presence of gadolinium-enhanced lesions.3 The overall performance of 2017 diagnostic criteria for MS may be improved by inclusion of symptomatic optic nerve involvement, but inclusion of asymptomatic optic nerve involvement on visual evoked potentials (VEPs) might be of limited value.5 However, the subset of patients without optic neuritis (ON) and with available VEPs was small.

Optical coherence tomography (OCT), VEP, and optic nerve MRI represent potential tools for identifying asymptomatic optic nerve demyelinating lesions. 3D double inversion recovery (3D-DIR) MRI sequence may be more sensitive than VEP for the detection of optic nerve demyelinating lesions.6 Sensitivity of VEP may be equal to7 or higher than that of OCT when considering normative OCT values.8 Another interesting and probably more sensitive way to detect an optic nerve lesion by OCT is to consider the intereye retinal thickness difference (IETD) rather than the raw thicknesses data.

Our study objective was to evaluate the diagnostic accuracy of the IETD measured by OCT in a cohort of patients with CIS for the diagnosis of symptomatic as well as asymptomatic optic nerve involvement.

Methods

This is an ancillary study of CINOCIS (Clinical Monitoring, MRI and Neuro-Ophthalmology of a Cohort of Patients With a Clinically Isolated Syndrome), a prospective cohort study conducted between June 2013 and December 2018, and enrolled 134 patients with CIS at the Lille MS Center (France).

Participants

Included patients presented with a CIS (with or without clinical episode of ON) in the previous 2.5–4.5 months. Patients with CIS developing clinically definite MS soon after their CIS and before the inclusion period were excluded. Data on sex, age at CIS onset, type of onset, and presence of oligoclonal bands were collected. No patient was treated at the time of MRI/OCT evaluation. Consenting adults (18–65 years) diagnosed with history of CIS in the last 4.5 months were prospectively recruited. Patients with other retinal pathology or severe ametropia (≥6 D) were excluded.

Standard protocol approvals, registrations, and patient consents

This study (CINOCIS; NCT03541226) was approved by our local ethical committee of Lille University Hospital. Written informed consent was obtained for all participants. Patient consent was obtained according to the Declaration of Helsinki.

Data acquisition and analysis

Each patient underwent brain MRI and OCT. Brain MRI were performed on a 3T MRI (Achieva; Philips, Best, the Netherlands) with the use of a 32-channel array head coil. Brain MRI protocol included a 3D-DIR MRI sequence with the following parameters: sagittal acquisition, voxel size 1.2 × 1.2 × 1.3 mm, repetition time 5500, echo time 252, dual inversion time 625/2600, number of excitations 2, fat suppression spectral presaturation with inversion recovery, matrix size 208 × 208, field of view 250 × 250 × 195, number of slices 300, sense 2. During the 3D-DIR acquisition, patients were asked to close their eyes and avoid eye movements as much as possible. Signal abnormality was defined as increased signal intensity within the optic nerve compared with the normal white matter signal intensity. Each optic nerve DIR hypersignal was identified on axial and coronal planes to exclude partial volume contamination and to avoid uncertainty on the differentiation of the nerve from the meningeal sheath (figure, A–D). For each optic nerve, the presence or absence of DIR hypersignal was recorded. Intraobserver and interobserver agreement for detection of optic nerve lesion on 3D-DIR had been previously reported as excellent.9,10

Figure
Figure Optic nerve MRI and optical coherence tomography findings in patients with clinically isolated syndrome (CIS) without optic neuritis (CIS-NON)

(A–D) Patients with CIS-NON presenting asymptomatic optic nerve lesion (red arrows) detected on 3D double inversion recovery MRI sequence associated with corresponding peripapillary retinal nerve fiber layer thicknesses. (E) Flowchart of Clinical Monitoring, MRI and Neuro-Ophthalmology of a Cohort of Patients With a Clinically Isolated Syndrome (CINOCIS) cohort and patients with CIS included in our analysis. ON = optic neuritis.

OCT examination was performed with spectral-domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany) on the same day as the MRI. Our OCT protocol included a peripapillary scan for measuring peripapillary retinal nerve fiber layers (pRNFLs; 12°, 3.4- mm circular scan around the optic nerve with a minimum of 50 ART) respecting OSCAR-IB criteria11 and a macular scan consisting of 25 vertical scans centered on the fovea (minimum of 25 ART). A macular segmentation was performed with HEYEX software (multilayer segmentation algorithm, Heidelberg Engineering, version 6.0.0.3) in an anonymized manner. The mean thickness (Early Treatment Diabetic Retinopathy Study 6-mm disc) was calculated for the macular ganglion cell layer coupled to the macular inner plexiform layer (GC-IPL).

Low contrast monocular visual acuity (LCMVA) (2.5%) was measured with printed scales (PRECISION-VISION no. 2180) using the number of correctly identified letters (from 0 to a maximum of 60).

Statistical analysis

Qualitative variables were reported as the number or the percentage and continuous variables as mean ± SD in case of normal distribution or median (interquartile range) otherwise. Normality was assessed graphically and using the Shapiro-Wilk test. Retinal layer thickness and visual disability were compared among CIS eyes without optic nerve lesion, CIS eyes with asymptomatic optic nerve lesion, and CIS eyes with symptomatic optic nerve lesion using a linear mixed model to take into account the correlation between eyes within the same patient. Post hoc pairwise comparisons were performed using Bonferroni correction. Intereye differences of retinal layers and visual acuity were compared between groups using the Mann-Whitney U test. For the parameters that were significant between the 2 study groups, we calculated the optimal threshold values from the receiver operating characteristic (ROC) curve by maximizing the Youden index. Diagnostic values (and their 95% confidence intervals [CIs]) of the observed optimal and published intereye difference (expressed as absolute and relative differences) thresholds were evaluated by calculating sensibility, specificity, positive predictive value, negative predictive value, relative risk, and the area under the ROC curve (AUC). Successively, we evaluated the ability of IETD and intereye percentage difference (IEPD) thresholds described previously in the literature for the detection of symptomatic lesions12,–,15 to identify symptomatic optic nerve involvement in our CIS cohort and we reported our optimal IETD and IEPD thresholds (occurrence of clinical episode of ON as gold standard). Finally, we investigated the ability of IETD and IEPD thresholds described previously for the detection of symptomatic lesions in the literature12,–,15 to identify asymptomatic optic nerve involvement and we reported our optimal IETD and IEPD thresholds (presence of asymptomatic optic nerve DIR hypersignal as gold standard). All statistical tests were done at the 2-tailed α level of 0.05 using SAS software, release 9.4 (SAS Institute, Cary, NC).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Results

Population

Among the 134 patients with CIS included in the CINOCIS study, we excluded 4 patients from our analysis: 1 because of unilateral eye agenesis, 2 because of presence of anti–myelin oligodendrocyte glycoprotein (MOG) antibodies (1 patient with myelitis and 1 patient with unilateral ON), and 1 because of a previously unknown associated retinal pathology. Patients were included in a period of 3.31 ± 0.51 months after their first relapse.

Among 130 patients with CIS included in our analysis, 100 (76.9%) had oligoclonal bands in CSF. Three patients refused the lumbar puncture. All patients presented typical MS lesions outside the optic nerve. Among our 130 patients with CIS, 117 presented dissemination in space, 112 dissemination in time, according to MS diagnostic criteria revised in 2017. A total of 105 patients fulfilled the MS diagnostic criteria revised in 2017.

Among the 130 remaining patients, 39 presented a unilateral (n = 37) or bilateral (n = 2) clinical episode of ON. Patients with bilateral ON were seronegative for anti-MOG and anti–aquaporin-4 antibodies. We defined 2 groups of patients: patients with ON (CIS-ON) and patients without ON (CIS-NON). In table 1, we summarize the clinical, contrast vision, and OCT characteristics in the overall study population and according to CIS subgroups. We report the flowchart of our cohort in the figure, E.

View this table:
Table 1

Population characteristics

Optic nerve imaging results of patients with CIS

We found a symptomatic optic nerve DIR hypersignal in all CIS-ON eyes. Among the CIS-ON patients, we considered 3 subgroups: patients with unilateral symptomatic optic nerve lesion and without any lesion on the fellow eye (n = 26), patients with unilateral symptomatic optic nerve lesion and asymptomatic optic nerve lesion on the fellow eye (n = 11), and patients with bilateral symptomatic optic nerve lesions (n = 2). Among CIS-NON patients, we considered 3 patient subgroups: patients without any optic nerve lesion (n = 62), patients with unilateral asymptomatic optic nerve lesion (figure, A–D; n = 22), and patients with bilateral asymptomatic lesion (n = 7). Symptomatic optic nerve involvement were found in 39 patients (30%) and asymptomatic optic nerve involvement was found in 40 patients (30.8%).

Retinal neuroaxonal loss and visual disability among CIS eye subgroups

We defined 3 groups: eyes without optic nerve lesion (n = 172), eyes with asymptomatic optic nerve lesion (n = 47), and eyes with symptomatic optic nerve lesion (n = 41). Results are summarized in table 2. Eyes with symptomatic optic nerve lesion presented lower retinal thickness/volume and lower LCMVA score than eyes with asymptomatic optic nerve lesion (p < 0.001) or eyes without optic nerve lesion (p < 0.001). Eyes with asymptomatic optic nerve lesion presented lower retinal thickness/volume and lower LCMVA score than eyes without optic nerve lesion (p < 0.001).

View this table:
Table 2

Comparison of retinal layer thickness and visual disability in clinically isolated syndrome (CIS) eyes without optic nerve lesion, CIS eyes with asymptomatic optic nerve lesion, and CIS eyes with symptomatic optic nerve lesion

Intereye difference in CIS subgroups

We summarize intereye differences for the different CIS subgroups in table 3, expressed as IETD (IETD = absolute difference [thickness of right eye − thickness of left eye])12,–,15 or IEPD (IEPD = 100 − [lower thickness/upper thickness] × 100).12 Patients with CIS-ON presented greater IETD and IEPD (p < 0.001) and intereye LCMVA difference (p < 0.001) compared to patients with CIS-NON (table 4). Patients with CIS-NON with asymptomatic optic nerve lesion presented greater IETD and IEPD (p < 0.001) compared to patients with CIS-NON without optic nerve lesions but intereye LCMVA difference was not significantly different (table 4). Patients with CIS-NON with bilateral asymptomatic lesions presented greater GC-IPL IETD than did patients with CIS-NON without lesions but their pRNFL IETD was similar (table 5).

View this table:
Table 3

Intereye differences in clinically isolated syndrome (CIS) subgroups

View this table:
Table 4

Comparison of intereye retinal layer thickness differences and intereye contrast visual acuity difference in clinically isolated syndrome (CIS) for differentiating patients with and without symptomatic lesion (n = 128) and with and without asymptomatic lesion (n = 91)

View this table:
Table 5

Comparison of intereye retinal thickness differences and visual acuity between clinically isolated syndrome (CIS) subgroups without clinical history of optic neuritis

Diagnostic values of IETD thresholds in patients with CIS for differentiating patients with and without symptomatic optic nerve lesions

Diagnostic values of IETD or IEPD for the detection of symptomatic optic nerve lesion, previously reported in the literature, are summarized in the upper part of table 6. As in previous studies,13,–,15 we excluded patients with bilateral symptomatic ON.

View this table:
Table 6

Diagnostic values of intereye peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell layer coupled to the inner plexiform layer (GC-IPL) thickness differences and intereye contrast visual acuity difference in previously published studies and in clinically isolated syndrome (CIS) for differentiating patients with and without symptomatic lesion (n = 128) and with and without asymptomatic lesion (n = 91)

Peripapillary retinal nerve fiber layers

Considering pRNFL IETD threshold ≥5 µm,14,15 we found sensitivities and specificities close to previously published results. For the pRNFL IETD threshold ≥9 µm, we found a clearly lower sensitivity (46.0%; 95% CI, 29.9%–62.0%) compared to the previously published results (73%) (table 6).13

In our CIS cohort, an optimal pRNFL IETD threshold ≥4 µm (sensitivity 81.1%, specificity 69.2%) and an optimal pRNFL IEPD threshold ≥5% (sensitivity 75.7%, specificity 78.0%) were found. We found the same optimal IEPD threshold as Coric et al.12 and a lower optimal pRNFL IETD threshold than those described previously.13,–,15

Macular GC-IPL

Considering GC-IPL IETD threshold ≥4 µm,15 we found a relatively higher sensitivity and a higher specificity than previously published results. Considering GC-IPL IETD threshold ≥6 µm,13 we found a clearly lower sensitivity (67.7%; 95% CI, 51.9%–83.4%) compared to previously published results (96%).

In our CIS cohort, an optimal GC-IPL IETD threshold of ≥2.83 µm (sensitivity 88.2%, specificity 83.3%) and an optimal GC-IPL IEPD threshold ≥8% (sensitivity 73.5%, specificity 95.6%) were found. We found an optimal GC-IPL IEPD threshold closed to that reported by Coric et al.12 and a lower GC-IPL IETD threshold than described previously.13,15

Concerning the detection of symptomatic optic nerve lesions, our optimal pRNFL IETD and GC-IPL IETD thresholds were, most often, lower than those previously described but seem to have similar diagnostic values. GC-IPL IETD seems more relevant than pRNFL IETD.

Low contrast vision acuity

A reduction of 7 letters in 2.5% LCMVA has been considered clinically significant.15 For an intereye LCMVA difference ≥7 letters, sensitivity was 58.3% (95% CI, 42.2%–74.4%) and specificity was 70.1% (95% CI, 60.5%–79.7%).

An optimal intereye LCMVA difference threshold of ≥12 letters and ≥16% (sensitivity 52.7%, specificity 89.7% and sensitivity 80.0%, specificity 61.6%, respectively) was found.

Diagnostic values of IETD in patients with CIS-NON for differentiating patients with and without asymptomatic lesion

pRNFL

Considering previous pRNFL IETD thresholds (≥5 µm,14,15 ≥9 µm13 and pRNFL IEPD threshold ≥5%12), we found low sensitivities (<50%) and high specificities (>80%) (table 6).

An optimal pRNFL IETD threshold ≥4 µm and an optimal pRNFL IEPD ≥4% (both with sensitivity 58.6% and specificity 82.3%) were found. Both optimal thresholds were lower than those described previously for the detection of symptomatic optic nerve lesions.12,–,15

Macular GC-IPL

Considering previous GC-IPL IETD thresholds (≥4 µm,15 ≥6 µm13) and GC-IPL IEPD ≥9%,12 we found very low sensitivities (<40%) and very high specificities (>95%).

An optimal GC-IPL IETD threshold ≥1.42 µm and an optimal GC-IPL IEPD threshold ≥2% (sensitivity 89.3%, specificity 72.6% and sensitivity 89.3%, specificity 69.4%, respectively) were found. Both optimal thresholds were lower than those described previously for the detection of symptomatic optic nerve lesions.12,13,15

Concerning the detection of asymptomatic optic nerve lesions, our optimal pRNFL IETD and GC-IPL IETD were lower than those described previously. Whereas pRNFL IETD had similar diagnostic values, our optimal GC-IPL IETD (≥1.42 µm) performed clearly better than others.

Low contrast vision acuity

ROC curve analysis was not possible because there was no significant difference in terms of intereye difference of LCMVA between patients with CIS-NON with and without asymptomatic optic nerve lesions.

Discussion

In this study, we confirmed the high frequency of asymptomatic optic nerve lesions and demonstrated that their detection during the CIS diagnosis workup would require lower IETD threshold than those enabling detection of symptomatic lesions. We confirmed that GC-IPL IETD seems more relevant than pRNFL IETD for the detection of optic nerve lesions, symptomatic or asymptomatic. Finally, we showed that intereye difference on LCMVA was not an interesting biomarker for the detection of asymptomatic optic nerve lesions.

OCT is considered a window to the optic nerve in CIS or MS eyes with ON (CIS-ON or MS-ON eyes). Retinal thickness significantly decreased in the 3–12 months period following a clinical episode of ON.16 Therefore, IETD to identify symptomatic optic nerve lesions can be measured in a period ≥3 months following ON. In the absence of past clinical episode of ON, OCT has been considered as a potential window to the brain because of the retrograde trans-synaptic degenerative process related to the inflammatory lesions within the optic radiations.17,18 Because of optic ways anatomical structure, this process is supposed to involve both eyes homogeneously and not to induce any real retinal thickness asymmetry. In agreement with postmortem studies in MS,19 and owing to the high sensitivity of 3D-DIR to detect optic nerve inflammatory lesions, our group recently reported the high frequency of asymptomatic optic nerve involvement in CIS3 and relapsing-remitting MS20 and the significant association between the length of optic nerve DIR hypersignal and the retinal neuroaxonal loss.20,21 Thus IETD may appear as an interesting biomarker enabling the detection of asymptomatic optic nerve lesions. IETD has been correlated previously with optic nerve atrophy at a chronic post-ON phase22 but also investigated as a marker of optic nerve remyelination at distance from acute ON,23 and more recently as a potential diagnostic marker of symptomatic optic nerve involvement in MS12 and various demyelinating CNS disorders affecting the optic nerve.13 Based on a physiologic slight IETD observed in healthy controls (HCs),14,15 it has been proposed that a large difference might be a good biomarker for assessing the presence of optic nerve lesion. An international multicenter OCT study evaluated a large cohort of patients with MS to discern the optimal IETD threshold in order to detect unilateral symptomatic optic nerve lesions.15

Asymptomatic lesions are very common in MS. They have been observed frequently within the brain and brainstem of patients with CIS and have been implemented in various MRI criteria assessing the risk of developing clinically definite MS (CDMS).24 Asymptomatic spinal cord lesions have also been reported frequently in MS, CIS, and radiologically isolated syndrome, and associated with a higher risk of developing CDMS.25,–,27 More recently, it has been suggested that optic nerve is no exception to the rule. If we consider postmortem studies13 and studies suggesting the existence of optic nerve atrophy, microstructural optic nerve abnormalities, and abnormal P100 latency values among MS-NON eyes,22,28,29 frequency of asymptomatic optic nerve lesions in MS has probably been underestimated. In fact, asymptomatic optic nerve lesions seem to occur frequently in CIS (3.5%–31.8%)2,3,21,30,–,32 and very frequently in MS (20%–72%).6,10,33 Although some other studies in CIS34,–,36 and MS18,36,37 reported no asymptomatic optic nerve involvement, we confirm in our CINOCIS cohort that asymptomatic optic nerve involvement is frequent at the earliest clinical stage of MS. These conflicting results may be due to the use of optic nerve MRI sequence with lower sensitivity for the detection of optic nerve lesions, in some cases. Few studies in CIS-ON eyes did not analyze the fellow eyes of ON eyes.38,–,40

There are no longitudinal study data clearly demonstrating that symptomatic or asymptomatic optic nerve lesions may be a risk factor of CDMS. Thus it is important to develop reliable biomarkers available in clinical routine for the detection of optic nerve involvement. IETD measured by OCT has been proposed as one of them. The diagnosis of symptomatic optic nerve involvement does not require OCT. At the acute phase, ON diagnosis is based on clinical and other neuro-ophthalmologic findings. However, in some unclear cases, a progressive unilateral retinal thinning or a significant increase of IETD may be helpful. Peripapillary RNFL IETD would only be observed beyond 3 months.16 Intereye GC-IPL thickness difference (GC-IPL IETD) may be observed earlier and would be a more interesting biomarker for this use.16,18,41 In the recent OCT studies focusing on IETD, the gold standard for optic nerve involvement was the occurrence of a clinical episode of ON.12,–,15 Thus we could consider that the thresholds reported previously may be applicable to the confirmatory diagnosis of clinical episode of ON but not strictly applicable to the diagnosis of asymptomatic optic nerve lesion. No study has evaluated what may be the optimal IETD threshold to detect asymptomatic optic nerve lesions in MS or CIS with other gold standards (VEPs, MRI, others) than the presence or absence of a clinical history of ON. In MS42 and CIS,21,43,–,47 asymptomatic retinal neuroaxonal loss is lower than symptomatic retinal neuroaxonal loss. Asymptomatic retinal neuroaxonal loss represents less than half of that observed in post-ON.42 In the same way, few studies suggested that asymptomatic optic nerve lesion length is lower in asymptomatic cases compared to symptomatic cases.20,–,22 Thus IETD in case of unilateral asymptomatic optic nerve lesion would probably be lower than in case of unilateral symptomatic optic nerve lesion. Interestingly, we demonstrated in our study that IETD and IEPD thresholds for the detection of asymptomatic optic nerve lesions need to be lower than those for the detection of symptomatic optic nerve involvement.12,–,15 The highest IETD thresholds have been reported by Xu et al.13 Applied on our CIS-NON cohort, these thresholds were highly specific but the sensitivity was very low. All patients included in this study had a remote history of unilateral ON but half of them presented a demyelinating disease different from MS, where symptomatic retinal thinning is classically greater (neuromyelitis optica spectrum disorder [NMOSD])48 or asymptomatic contralateral optic nerve lesion very scarce (NMOSD, idiopathic ON).8,10,42 Heterogeneity of the disease associated with ON may be the reason why higher IETD thresholds had been found.

Compared to previous published IETD/IEPD thresholds, our optimal IETD/IEPD thresholds for detecting asymptomatic optic nerve lesions on 3D-DIR MRI sequences were associated with a higher sensitivity and a lower specificity concerning pRNFL and with a much higher sensitivity and a lower specificity concerning GC-IPL. When directly comparing models, GC-IPL IETD seems to perform better than pRNFL IETD (best AUC). This point has already been raised.12,–,15 Fluctuations in pRNFL thickness possibly due to residual edema have been advanced as a possible confusing factor.15 Conversely, macular GC-IPL is not involved in case of acute or residual papillary edema. Indeed, our patients with CIS were included shortly after relapse and it is not possible to know the timing of asymptomatic lesion occurrence. Bilateral asymptomatic optic nerve involvement is not rare in our CIS cohort. It may decrease IETD and its ability to detect optic nerve lesions. Interestingly, in our study, we better detected bilateral asymptomatic optic nerve lesions with GC-IPL IETD than with pRNFL IETD.

In this study, we reported lower GC-IPL and pRNFL IETD thresholds than reported previously to identify symptomatic as well as asymptomatic optic nerve lesions. These thresholds have been identified in a CIS population and from a statistical point of view are supposed to be applicable only to CIS populations. These thresholds could appear low and closed to IETD values observed in an HC population.15 Our GC-IPL and pRNFL IETD thresholds need to be evaluated and confirmed in other CIS cohorts.

Whereas intereye LCMVA difference might be able to differentiate patients with CIS with and without symptomatic optic nerve lesions, it does not demonstrate any ability to differentiate patients with CIS with and without asymptomatic optic nerve lesions. Although LCMVA is a good biomarker of post-ON residual visual disability and is associated with optic nerve lesion length, intereye LCMVA difference does not seem to be a good surrogate marker for detection of asymptomatic optic nerve lesions at the CIS stage.

The best MRI diagnostic strategy to detect optic nerve demyelinating lesions is T2-weighted MRI sequences including both fat and water suppression. 3D-DIR MRI sequence, a turbo spin echo acquisition that combines fat, white matter, and fluid suppression, has been shown to be one of the most sensitive MRI sequences to detect optic nerve demyelinating lesions.9

Our study has some limitations. We did not evaluate the prognostic value of asymptomatic or symptomatic optic nerve involvement for the risk of developing CDMS but a clinical and MRI follow-up of patients included in the CINOCIS study is warranted. We performed retinal thickness measurements with only one type of OCT device and thus the optimal IETD thresholds we reported might be restricted to the use of this specific OCT device. However, whereas thickness measurements may differ between OCT devices, IETD seems to be comparable.15 For other OCT devices, it may be better to use IEPD. We did not include patients with early primary progressive MS and cannot extrapolate our conclusions to the detection of symptomatic or asymptomatic optic nerve involvement in this clinical form of the disease. We acknowledge that applying lower IETD threshold values than reported previously increases the risk of false-positive results because such IETD values may be close to those observed in some HCs.15 However, applying higher threshold values permits the use of a nonsensitive diagnostic tool. Spectral-domain OCT resolution is about 4–5 µm. Future improvement of this resolution should help clinicians to better use OCT for the detection of asymptomatic optic nerve lesions. Optic nerve MRI remains a challenge and interscanner variability might be an additional difficulty in finding or developing a highly sensitive optic nerve MRI sequence for routine clinical care. Recent publications argue in favor of the development of various MRI sequences sensitive for the detection of optic nerve demyelinating lesions.9,33,36,49,50

OCT is the tool of choice for the assessment of retinal neuroaxonal loss following ON, at CIS stage, but is not necessary for the diagnosis of symptomatic optic nerve involvement. In absence of optic nerve imaging with a sensitive MRI sequence for the detection of optic nerve lesions, GC-IPL IETD measured by OCT may represent a sensitive and specific alternative biomarker for the detection of asymptomatic optic nerve demyelinating lesions in routine practice. Applying lower IETD thresholds than for the detection of symptomatic lesions enables better detection of asymptomatic lesions. Prospective studies using OCT and optic nerve MRI may help to confirm the validity of our thresholds and to evaluate the added value of optic nerve inclusion in the next version of MS diagnostic criteria.

Study funding

This work was supported by Bayer and Novartis. Bayer provided research funding for performing MRIs. Novartis provided research funding for the acquisition of the OCT device. Bayer and Novartis had no role in study design, data collection, analysis, interpretation, or writing of the report.

Disclosure

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

Acknowledgment

The authors thank Julie Petit for help and technical support; the In-vivo Imaging and Functions core facility (ci2c.fr) for help; Maxime Thoor and Chloé Crinquette for MRI acquisitions; and Bayer for support.

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.

  • Editorial, page 239

  • Class of Evidence: NPub.org/coe

  • Received August 16, 2019.
  • Accepted in final form February 6, 2020.

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