Havla et al. Journal of Neuroinflammation (2021) 18:121 https://doi.org/10.1186/s12974-021-02160-9 RESEARCH Open Access Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well? Joachim Havla1,2*† , Thivya Pakeerathan3†, Carolin Schwake3, Jeffrey L. Bennett4, Ingo Kleiter3,5, Ana Felipe-Rucián6, Stephanie C. Joachim7, Amelie S. Lotz-Havla8, Tania Kümpfel1, Markus Krumbholz9, Eva M. Wendel10, Markus Reindl11, Charlotte Thiels12, Thomas Lücke12, Kerstin Hellwig3, Ralf Gold3, Kevin Rostasy13† and Ilya Ayzenberg3,14*† Abstract Background: To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). Methods: All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation < 18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. (Continued on next page) * Correspondence: joachim.havla@med.lmu.de; ilya.ayzenberg@rub.de † Joachim Havla, Thivya Pakeerathan, Kevin Rostasy, and Ilya Ayzenberg contributed equally to the manuscript. 1 Institute of Clinical Neuroimmunology, LMU Hospital, Ludwig-Maximilians Universität München, Munich, Germany 3 Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 2 of 10 (Continued from previous page) Results: Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8± 1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 μm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4± 9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA- logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. Conclusion: Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes. Keywords: Optical coherence tomography, Optic neuritis, Myelin oligodendrocyte glycoprotein IgG, MOGAD Introduction adults with MOGAD. The latter is especially interesting Myelin oligodendrocyte glycoprotein antibody-associated as pediatric MS and MOGAD patients generally demon- disease (MOGAD) is a newly defined autoimmune dis- strate better relapse recovery than adults [18–22]. Here, order of the central nervous system (CNS) [1]. While we compared the outcomes of MOGADped and MOGA- immune responses targeting myelin oligodendrocyte Dadult ON including age-related (1) severity and patterns glycoprotein (MOG) have been extensively studied in ex- of retinal structural damage and (2) functional visual perimental autoimmune encephalomyelitis [1], the clin- recovery. ical relevance of MOG-immunoglobulin (Ig)G was only recently appreciated following the identification of auto- Subjects and methods antibodies targeting conformational epitopes of full- Study population length MOG in humans [2]. MOGAD patients may de- We conducted an analysis of prospectively collected data velop any combination of monophasic or relapsing acute from MOGADped and MOGADadult patients with or disseminated encephalomyelitis (ADEM), non-ADEM without ON. The inclusion criteria included the acute encephalitis, neuromyelitis optica spectrum disorder presentation of demyelinating disease, MOG-IgG sero- (NMOSD), optic neuritis (ON), transverse myelitis positivity, availability of OCT, visual acuity data, and (TM), brainstem encephalitis, or rarely multiple sclerosis clinical information. If one or multiple ON events were (MS)-like demyelinating disease [3–5]. Clinical manifes- known, visits could be considered at least 6 months after tations seem to be age-dependent: children < 10 years the last ON. During the study period (2018–2020), all are more likely to develop an ADEM phenotype, while patients tested positive for MOG-IgG were included those ≥10 years are more likely to present with an who met the inclusion criteria and who were seen at five NMOSD- or MS-like phenotype similar to adults [6]. In academic university centers specialized in neuroimmu- both pediatric and adult patients, isolated, bilateral, or nological diseases (Department of Pediatric Neurology, recurrent ON are common clinical presentations [3, 5, 7, Children’s Hospital Datteln, University Witten/Her- 8]. High levels of MOG expression and enhanced blood- decke, Germany, N=9; Department of Neuropediatrics brain barrier permeability in the optic nerve may explain and Social Pediatrics University Hospital of Pediatrics its frequent involvement [9, 10]. Although the histopath- and Adolescent Medicine, Ruhr-University Bochum, N= ology of cerebral lesions in MOGAD patients demon- 3; Neurology Department, St. Josef Hospital Bochum, strates relative preservation of axonal structures, severe Bochum, Germany, N=16; Institute of Clinical Neuroim- visual impairment or functional blindness have been re- munology, LMU Hospital, Munich, Germany, N=29, and ported in >30% of MOGADadults ON patients, and OCT Institute of Pediatrics, University Hospital Vall d’Heb- studies repeatedly demonstrated profound axonal degen- ron, Barcelona, Spain, N=2) [total N=59]. Five patients eration with loss of retinal ganglion cells [11–14]. Al- were excluded due to incomplete examination data (n= though MOG-IgG antibodies have been frequently 2) or an acute ON at the time of examination (n=3) (see reported in children with ON, there are only a few stud- supplementary Figure 3). A part of the MOGAD cohort ies investigating retinal changes and visual outcomes in of the Institute of Clinical Neuroimmunology (13/29 pa- this population [5, 15–17]. Moreover, there are no stud- tients) has already been published as a subset of other ies comparing ON course and outcome in children and cohort analyses [12, 13]. Written informed consent was Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 3 of 10 obtained from all patients participating in the study. The letters). Characteristic pRNFL scans in a pediatric and local ethics committees approved the study protocol in an adult MOGAD patient are shown in Fig. 1. accordance with the Declaration of Helsinki (1964) in its currently applicable version. Two groups of patients Visual evoked potentials (VEP) were evaluated depending on the age at disease mani- VEP data (Keypoint.net, Neurolite Software, Natus, festation: group 1 with 20 MOG-IgG-positive children Switzerland) were collected from occipital midline re- with initial manifestation < 18 years (MOGADped) and ferred to a mid-frontal electrode according to the Inter- group 2 with 39 MOG-IgG-positive adult patients with national Society for Clinical Electrophysiology of Vision initial manifestation ≥ 18 years (MOGADadult). Demo- standards. Pattern reversal VEP was produced by high- graphic (gender and age at initial manifestation) and contrast, black and white checks. Each check has the size clinical (disease duration, number and side of clinical of 171.6 arc minute. The examination was performed in ON episodes) data were collected for all patients. For a dark room in a 1-m distance. P100 latency and the the detection of MOG-IgG, serum samples were ana- P100-P125 amplitude were collected. All VEP examina- lyzed during the initial workup at least once by estab- tions were performed in Bochum (data available for 15 lished cell-based assays at the discretion of each center MOGADped and 12 MOGADadult patients). using the laboratory’s cutoffs (MOG IFT, EUROIM- MUN, Laboratory Stöcker, Germany; Reindl Lab, Med- Statistical methods ical University of Innsbruck, Innsbruck, Austria; Meinl Clinical data, OCT, VEP, and VA results were compared Lab, LMU Hospital, Munich, Germany) [1, 2, 23]. between MOGADped and MOGADadult patients. The mean and standard deviation were calculated for continu- Optical coherence tomography (OCT) and visual acuity ous variables, frequency, and proportion for categorical All centers used spectral-domain optical coherence tom- variables. The non-parametric Mann-Whitney U test and ography (SD-OCT, SPECTRALIS, Heidelberg Engineer- chi-square test were used to compare two independent ing, Heidelberg, Germany) with automatic real-time groups. Statistical significance was defined as p < 0.05. (ART) averaging. A scan around the optic nerve with an SD-OCT data, VEP data, and HCVA/LCVA in the activated eye tracker (12°, 3.5 mm ring, 50≤ ART ≤100) eyes with and without ON were analyzed within and be- and a macular volume scan (20° × 20°, 25 vertical B-scans, tween the MOGADped and MOGADadult cohorts using 20 ≤ ART ≤ 49) were performed as cylinders of 3 mm generalized estimating equation models (GEE) to ac- diameter around the fovea based on local protocols. The count for within-patient inter-eye correlation. The cor- thickness of the peripapillary retinal nerve fiber layer relation matrix parameter was set to “exchangeable.” (pRNFL) and the volumes of the macular retinal nerve Further, we performed a Spearman correlation to iden- fiber (mRNFL), the combined ganglion cell and inner tify the possible factors determining the visual outcome plexiform layer (GCIPL), the inner nuclear layer (INL), the in MOGAD ON. Age at ON, number of ON episodes combined outer plexiform layer and outer nuclear layer per eye, the extent of retinal degeneration (pRNFL and (OPONL), and the total macular volume (TMV) were GCIPL thickness), and VEP P100 latency were included analyzed. The segmentation of all layers was performed in the analysis. For cases of recurrent ON, we calculated semi-automatically using software from the SD-OCT an average age at ON onset. Due to a relatively small manufacturer (Eye Explorer 1.9.10.0 with viewing module sample size, both groups were pooled. All factors that 6.3.4.0, Heidelberg Engineering, Heidelberg, Germany). significantly correlated with visual outcome were in- Experienced evaluators carefully checked all scans for suf- cluded in GEE analysis. Data were analyzed with SPSS ficient quality and segmentation errors and corrected version 26 (IBM SPSS Statistics). them if necessary. The SD-OCT data in this study are ana- lyzed and reported according to the recommendations of Results APOSTEL and OSCAR-IB [24, 25]. Cohort description In addition, at the time of OCT examination, habit- We enrolled 20 MOG-IgG-positive children ually corrected high-contrast and low-contrast monocu- (MOGADped patients, female:male 13:7, mean age 10.3± lar visual acuity (VA) was acquired using high contrast 3.7 years) and 39 MOG-IgG-positive adults (MOGADa- dult and 2.5% low-contrast Sloan letter charts placed in a patients, female: male 20:19, mean age 34.9±11.6 retro-illuminated light box at 2 m distance. Each chart years). From the medical history, 2 patients had no ON, consists of 14 lines with 5 letters per line that are stan- 6 had unilateral ON, and 12 had bilateral ON in the dardized with equal difficulty per line and equal spacing MOGADped patient cohort (total 30 ON affected eyes). between the lines. The total number of correct letters Accordingly, in the MOGADadult patient cohort, 15 had identified on each chart was tested to determine high- no ON, 6 had unilateral ON, and 18 had bilateral ON and low-contrast VA (HCVA, LCVA; maximum, 70 (total 42 ON affected eyes). The main clinical data of all Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 4 of 10 Fig. 1 Representative pediatric and adult retinal OCT scans after recurrent MOGAD-ON. Despite almost identical neuroaxonal retinal atrophy, functional vision is notably better in children than adults. Abbreviations: OD oculus dexter, G global pRNFL, N nasal pRNFL, I inferior pRNFL, T temporal pRNFL, PMB paillo-macular-bundle, TMV total macular volume, GCIPL combined ganglion cell and inner plexiform layer patients are described in Table 1. Eight of 20 MOG-IgG- MOGADadult patients (12 azathioprine, 7 rituximab, 1 oral positive children were diagnosed with recurrent prednisone as an add-on therapy, 3 methotrexate, 2 toci- NMOSD, 6 children with recurrent ON (rON), 3 chil- lizumab, 2 teriflunomide, 2 glatiramer acetate, 1 monother- dren with ADEM + rON, and 3 children with encephalo- apy with oral prednisone, and 1 long-term IVIG). myelitis. Three of 39 MOG-IgG-positive adults were diagnosed with monophasic NMOSD, 12 with recurrent Pediatric and adult MOGAD ON cause profound NMOSD, 14 with encephalomyelitis, 9 adults with rON, neuroaxonal retinal atrophy and 1 adult with ADEM. There were no differences in The main SD-OCT results are shown in Table 2 (for gender, disease duration, or number of previous ON epi- more detailed results, see supplementary Table 3 and sodes between the two groups. Eighteen (94.7%) of the supplementary Figure 4). The thickness of pRNFL was MOGADped patients were on long-term immunotherapy significantly reduced in MOGADped- and MOGADadult- at the time of SD-OCT (8 monotherapy with oral pred- ON eyes compared to non-ON eyes globally as well as nisone, 5 intravenous long-term immunoglobulin/sub- in all segments (pRNFL S, pRNFL I, pRNFL T, pRNFL cutaneous immunoglobulin (IVIG/SCIG), 3 glatiramer N, pRNFL PMB); the pRNFL N/T ratio remained un- acetate, 1 rituximab, 1 azathioprine, 1 oral prednisone as changed (see Fig. 1 for illustrating OCT images). The an add-on therapy) compared with 30 (76.9%) of total macular volume (TMV), as well as combined GCIP Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 5 of 10 Table 1 Demographic and main clinical characteristics of pediatric and adult cohorts MOGADped (n=20) MOGADadult (n=39) p Age at initial manifestation, median (range) 10.5 (4–15) 35.0 (19–64) <0.001 Females, n (%) 13 (65.0%) 20 (51.3%) 0.157 Ethnicity 20 Caucasians 36 Caucasians 0.081 3 Asians Disease duration (years), median (range) 4.5 (0–22) 6.5 (0–24) 0.084 Patients with a clinical history of ON, n (%) 18 (90.0%) 24 (61.5%) 0.001 Patients with unilateral ON, n (%) 6 (30.0%) 6 (15.4%) 0.062 Patients with bilateral ON, n (%) 12 (60.0%) 18 (46.2%) 0.154 Patients with a simultaneous bilateral ON, n (%) 8 (40.0%) 14 (35.9%) 0.663 Total ON eyes, n (%) 30 (75.0%) 42 (53.8%) 0.029 Number of ON episodes per eye, mean (SD) 1.8 (1.3) 2.0 (1.7) 0.864 Time between ON and examination in months, median (range) 7 (6–129) 10 (6–155) 0.2 Abbreviations: MOGAD myelin oligodendrocyte glycoprotein antibody-associated disease, ON optic neuritis, SD standard deviation L volume, were also significantly decreased in ON eyes microcysts were observed in 10% of MOGADped-ON of both pediatric and adult patients compared to non- and 7.7% of MOGADadult-ON eyes. ON eyes. In contrast, the volume of the inner nuclear layer (INL) was increased in ON eyes of both groups. Peripapillary retinal atrophy patterns are similar Comparing MOGADped-ON and MOGADadult-ON independently of age eyes, we found no differences in pRNFL thickness or There was no difference in the pattern of neuroaxonal volumes of the macular GCIPL, INL, and OPONL, while retinal atrophy between MOGADped and MOGADadult macular RNFL was significantly lower in MOGADped- ON eyes (Table 3, supplementary results). MOGAD ON ON eyes compared to MOGADadult-ON eyes. Macular eyes showed no temporal predominance of pRNFL Table 2 Comparison of OCT and VEP measures as well as visual acuity between MOGAD-ON and MOGAD-NON eyes in pediatric and adult MOGAD patients Parameter Pediatric patients Adult patients Pediatric Adult patients MOGAD- MOGAD- patients ON eyes NON eyes MOGAD-ON MOGAD-NON MOGAD-ON MOGAD-NON MOGAD-ON MOGAD-ON Pediatric Pediatric eyes (30 eyes, eyes (10 eyes, eyes (42 eyes, eyes (36 eyes, vs. MOGAD- vs. MOGAD- vs. adult vs. adult mean± SD) mean± SD) mean± SD) mean± SD) NON eyes, p NON eyes, p patients, p patients, p pRNFL G 63.12 ± 18.74 90.30 ± 13.40 64.26 ± 22.85 96.64 ± 20.67 < 0.001 0.001 0.997 0.292 TMV 2.19 ± 0.11 2.30 ± 0.13 2.22 ± 0.12 2.31 ± 0.11 0.021 0.048 0.484 0.718 mRNFL 0.12 ± 0.02 0.14 ± 0.01 0.13 ± 0.02 0.14 ± 0.03 < 0.001 0.537 0.012 0.278 mGCIPL 0.42 ± 0.09 0.57 ± 0.08 0.44 ± 0.13 0.57 ± 0.08 < 0.001 0.012 0.555 0.853 mINL 0.28 ± 0.03 0.26 ± 0.02 0.29 ± 0.04 0.26 ± 0.02 0.001 0.017 0.793 0.994 mOPONL 0.77 ± 0.07 0.74 ± 0.08 0.77 ± 0.05 0.75 ± 0.05 0.307 0.949 0.779 0.589 VEP P100 117.86 ± 10.67 112.44 ± 9.59 117.99 ± 14.51 118.15 ± 9.84 0.324 0.790 0.946 0.115 latency VEP 10.57 ± 6.12 8.52 ± 4.47 5.76 ± 2.79 7.61 ± 5.21 0.235 0.049 – – amplitude HC VA 51.36 ± 9.33 55.60 ± 8.88 34.97 ± 20.57 52.03 ± 8.67 0.245 0.002 < 0.0001 0.325 2.5% LC VA 22.83 ± 14.62 25.60 ± 13.94 13.54 ± 16.44 29.52 ± 13.89 0.963 0.017 0.028 0.451 GEE analysis: p value: significant results p < 0.05 are indicated in bold Abbreviations: MOGAD-ON eyes with a history of ON, MOGAD-NON eyes without a history of ON, pRNFL peripapillary retinal nerve fiber layer (G global), TMV total macular volume, mRNFL macular RNFL, mGCIPL macular ganglion cell and inner plexiform layer, mINL macular inner nuclear layer, mOPONL macular outer plexiform and outer nuclear layer, HC high-contrast, LC low-contrast, VA visual acuity, pRNFL thickness in μm, macular volumes in mm3, VEP P100 latency in ms, VEP amplitude in uV, VA number of correctly stated letters Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 6 of 10 atrophy after 1.8±1.3 vs. 2.0±1.7 ON episodes per eye in unaffected eyes in both cohorts (Table 2). Interestingly, children and adults respectively. The N/T ratio was the VEP latencies were also almost identical in affected comparable in affected eyes of pediatric and adult eyes in MOGADped and MOGADadult patients. Signifi- patients. cant reduction of the VEP amplitudes was observed in the affected eyes of MOGADadult patients only. VEP Children demonstrate significantly better visual outcome amplitude varies with age and was not compared be- after MOGAD ON tween MOGADped and MOGADadult patients. VA testing revealed significantly worse HCVA and LCVA in affected MOGADadult-ON eyes (Table 2, sup- Age at onset correlates with visual outcome in MOGAD plementary Figure 4). This was not the case for affected ON MOGADped-ON eyes. Complete visual recovery (defined We next evaluated the effects of the number of previous as HCVA logMAR 0.0) occurred in 73.3% of ON attacks, age at ON onset, extent of neuroaxonal ret- MOGADped-ON eyes vs. 31.0% MOGADadult-ON eyes. inal atrophy and optic nerve signal transmission (P100 Only 3.3% of MOGADped-ON eyes vs. 31.0% of MOGA- latency) on the HCVA, and LCVA in the entire study Dadult-ON eyes showed moderate to severe (HCVA log- population (Fig. 2 and supplementary Figure 5). Neither MAR > 0.5) visual impairment. HCVA and LCVA were the number of previous ON nor P100 latency correlated significantly worse in affected eyes of MOGADadult ver- with HCVA or LCVA. Neuroaxonal retinal atrophy sus MOGADped patients; there was no difference noted weakly correlated with HCVA (rho=0.311 CI95% 0.080– in unaffected non-ON eyes. 0.510, p=0.014 [pRNFL] and rho=0.282 CI95% 0.049– 0.486, p=0.036 [GCIPL]) and more closely with a LCVA VEP are not different in affected eyes in pediatric and reduction (rho=0.498 CI95% 0.288 0.662, p<0.001 adult MOGAD patients [pRNFL] and rho=0.448 CI95% 0.230 0.623, p=0.001 VEP latencies were only moderately prolonged and [GCIPL]) (Fig. 2). We observed a stronger correlation showed no significant differences between affected and with the age at ON onset (rho=−0.565 CI95% −0.713– Fig. 2 Scatterplots of age at ON onset (a), pRNFL G thickness (b), and GCIPL volume (c) against visual outcome (HCVA and 2.5% LCVA). HCVA correlated modestly with neuroaxonal retinal atrophy and more strongly with age at ON onset, whereas LCVA correlated moderately with both parameters Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 7 of 10 0.368, p<0.001 [HCVA] and rho=−0.460 CI95% −0.632– MOGAD ON has been reported, in general, to have a 0.244, p<0.001 [LCVA]). more favorable visual prognosis when compared to AQP-4 IgG-seropositive NMOSD ON [30–35]. Study re- sults, however, varied significantly, probably due in part Discussion to MOGAD clinical heterogeneity [11, 12, 27, 30–32, 34, In this study, we were able to demonstrate a significantly 36–38]. Our adult MOGAD cohort, being partly in- better visual recovery after ON in pediatric versus adult cluded in previous multicenter studies, showed signifi- MOGAD patients. Interestingly, substantial differences cant visual impairment in a relatively high proportion of in the functional outcome in these two groups were in- patients after MOGAD ON [12, 13]. Nevertheless, other dependent of structural neuroaxonal retinal atrophy and studies also reported functional blindness in MOGAD signal transmission in the optic nerve, so that other age- ON patients, with a VA below logMAR 1.0 in 13% of dependent mechanisms are likely to be responsible. Our MOGAD ON eyes [11, 13]. In contrast, we observed a results thus add nicely to the recently published work on very good functional recovery in the pediatric cohort clinical features and risk of relapse in children and adults despite similar levels of neuroaxonal retinal atrophy. with MOGAD [22]. In this study, overall better remis- Interestingly, another study also demonstrated a more sion of general relapses was reported in MOGADped favorable functional outcome in MOGAD ON compared compared to MOGADadult patients, although the under- to AQP4-IgG seropositive NMOSD ON despite similar lying mechanisms remained unclear [22]. structural pRNFL degeneration [37]. HCVA in our On a structural level, we clearly observed both pRNFL MOGADped-ON cohort was similar to that reported by and GCIPL atrophy in the affected eye compared with Wan et al. (complete recovery in 85% of affected eyes the unaffected eyes in MOGADped and MOGADadult pa- [n=59, mean age 12.6, range 3.9–18.8]) [36]. In contrast, tients, indicating combined neuroaxonal retinal atrophy. Eyre et al. showed that only 65% of children from the The extent of degeneration was comparable across both mixed cohort recovered completely; microstructural cohorts and in line with recent studies. Previously, we damage of the retina was the only factor correlating with and others have shown that pRNFL parameters, TMV, visual recovery [38]. mRNFL, mGCL, and mIPL are significantly reduced in The association of better visual recovery with younger MOGADadult-ON eyes compared to healthy controls age at ON onset is a central finding of this study. The [11–13]. There is little data on structural changes after better visual recovery in younger patients was independ- MOGAD ON in children. Two other groups have re- ent of the number of previous ON attacks per eye, ported significant neuroaxonal retinal atrophy following microstructural retinal changes, or optic nerve signal MOGADped-ON with an average and median pRNFL transmission. This is generally consistent with previous thickness of 68.7 ± 12.6 μm and 58 μm, respectively [26, observations of better visual recovery in younger patients 27]. These findings are comparable to our pRNFL mea- with AQP4-abs-positive NMOSD-ON and MS-ON, al- sures (mean 63.1±18.7 μm). Data on GCIPL thickness though these studies did not control for the number of are only available from one Chinese cohort. Similar to previous ON episodes, optic nerve signal transmission, our study, the combined GCIPL volume in MOGADped- and neuroaxonal retinal atrophy [21, 33, 34]. In a re- ON was significantly reduced [26]. cently published analysis of the relapse recovery of chil- The volume of the INL was increased in ON eyes of dren versus adults with MS, the probability of both MOGADped and MOGADadult patients. It has been incomplete recovery increased 1.33-fold with each dec- suggested that the INL may serve as a biomarker for in- ade of life [39]. flammatory processes, since an increase in INL volume We propose that an active age-dependent neuroplasti- is associated with MS-ON and risk for clinical relapse city of the visual system, most likely at a cortical level, [28]. However, the meaning of the INL volume change may explain our findings. First, there is evidence for the in MOGAD remains uncertain and may occur in com- existence of immature neural visual circuits in children pensation to neuroaxonal retinal atrophy. We could not enabling further development of visual acuity in child- confirm an association between INL volume and relapse hood and adolescence [40]. Indeed, the HCVA of healthy rate in our cohort (data not shown). Microcystic macular children up to the age of 8–10 years is inferior to that of edema (MME) in the INL has been documented in healthy adults, and the age of 6–8 years is widely ac- MOGAD ON [12, 13]. We observed INL-MME in 10% cepted as a “sensitive period” for the development of vs. 7.7% of MOGADped- and MOGADadult-ON, but not amblyopia [40–42]. Second, animal studies have shown in unaffected eyes. In contrast to MS, we did not observe that contrast sensitivity is less promoted by retinal integ- predominant temporal atrophy or any other specific pat- rity than by the maturation of visual circuits [43]. In tern of RNFL loss. We found a high rate of RNFL atro- children, contrast sensitivity matures between the age of phy in all optic nerve head segments [29]. 8 and 19 [41]. Accordingly, visual system maturation is Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 8 of 10 likely to be ongoing in our MOGADped cohort (mean age Supplementary Information 10.3±3.7 years). Indeed, we observed only minimal differ- The online version contains supplementary material available at https://doi. org/10.1186/s12974-021-02160-9. ences in HCVA and LCVA between affected and non- affected- MOGADped-ON eyes, regardless of the profound Additional file 1: Supplementary Figure 3: Flow chart of patients neuroaxonal retinal atrophy. Third, a large functional mag- included in the study. During the study period 64 MOGAD patients were netic resonance imaging (fMRI) study demonstrated a clear identified in participating centers. Five patients were excluded due to incomplete examination data (n=2) or an acute ON at the time of association between fMRI activity in the lateral occipital examination (n=3). Depending on the age of manifestation patients were cortex (as a marker of early adaptive neuroplasticity) and divided into 2 groups: group (1) 20 MOG-IgG-positive patients with initial visual outcome in young adults (mean age 32 years) with manifestation < 18 years (MOGADped) and group (2) 39 MOG-IgG-positive patients with initial manifestation ≥ 18 years (MOGADadult). Supplemen- acute ON. Interestingly, the fMRI activity was the strongest tary Figure 4: Beeswarm plots showing the distribution of pRNFL G thick- predictor of the visual outcome in this study and was also ness (A), GCIPL volume (B), HCVA (C) and 2,5% LCVA (D) in MOGADped- independent of other structural or electrophysiological pa- ON and MOGADadult-ON. Despite profound neuroaxonal retinal atrophy in both groups, MOGADadult-ON eyes showed significantly worse visual rameters at baseline or 12 months follow-up [44]. outcome (HCVA and 2,5% LCVA) in comparison to MOGADped-ON. Sup- Given the heterogeneity of MOGAD, we cannot ex- plementary Figure 5: Scatterplots of VEP P100 latency (A) and number of clude that age- or disease-dependent differences in the previous ON (B) against visual outcome (HCVA and 2,5% LCVA). Neither the number of previous ON nor P100-latency correlated with HCVA (rho= MOGAD autoimmunity contribute to the noted differ- 0.030 CI95% -0.288 -0.152, p=0.840 [number of previous ON] and rho=- ences in ON recovery. Indeed, the role of MOG-IgG in 0.028 CI95% -0.354 -0.290, p=0.851 [VEP P100 latency]) or LCVA (rho=- disease pathogenesis is not clear, and the titer and epi- 0.237 CI95% -0.422 -0.106, p=0.104 [number of previous ON] and rho=- 0.263 CI95% -0.503 -0.078, p=0.071 [VEP P100 latency]). Supplementary tope specificity of MOG-IgG may drive distinct effects Table 3: Demographic and main clinical characteristics of pediatric and during injury and recovery [34, 35]. Additionally, other adult cohorts with ON history (MOGAD-ON). Abbreviations: MOGAD mye- cellular mechanisms, including T cell and microglial re- lin oligodendrocyte glycoprotein-antibody-associated disease, ON optic neuritis, SD standard deviation. Supplementary Table 4. Comparison of all sponse, need to be further characterized [2, 14]. Never- OCT and VEP measures as well as visual acuity between in ON- and non- theless, in our cohorts, these immunologic variables did ON-eyes in pediatric and adult MOGAD patients. Abbreviations: MOGAD- not impact structural or electrophysiologic metrics. ON eyes with a history of ON, MOGAD-NON eyes without history of ON, pRNFL peripapillary retinal nerve fibre layer (G global, S superior, l inferior, Our study has several limitations. Due to the limited T temporal, N nasal, PMB papillomacular bundle, N/T nasal/temporal ra- dataset, the extent of visual impairment before the onset tio), TMV total macular volume, mRNFL macular RNFL, mGCIPL macular of ON and at nadir remains unknown and cannot be ganglion cell and inner plexiform layer, mINL macular inner nuclear layer, mOPONL macular outer plexiform and outer nuclear layer, HCVA high- compared between the groups. Visual acuity was cor- contrast, LCVA low-contrast visusal acuity. pRNFL thickness in μm and rected habitually, and there is no visual field or color vi- macular volumes in mm3, VEP P100 latency in ms, VEP amplitude in uV, sion data. In addition, our study lacks MRI data on the VA in number of correctly stated letters. GEE analysis: B regression coeffi- cient, p-value: significant results p < 0.05 are indicated in bold letters. extent and volume of optic nerve lesions and accom- panying lesions in the post-geniculate visual pathways or occipital cortex. A prospective study combining longitu- dinal clinical data, OCT and neuro-imaging, visual field Acknowledgements data, electrophysiology, and fMRI would be important to We would like to thank all patients and their families for participating in the study. We would like to thank Inga Sedleckiene, Yvonne Skrzypiec, Ute confirm our findings. Furthermore, studies in MS or Rüther, Stefanie Stüwe (Bochum), Angelika Bamberger, and Luise Böhm aquaporin-4-IgG-positive NMOSD are needed to clarify (Munich) for their excellent technical support. if the demonstrated age-dependent VA improvement is universal or disease-specific. Authors’ contributions JH, TP, KR, and IA: conception and design of the study, acquisition and Conclusion analysis of the data, drafting of a significant portion of the manuscript or figures, and analysis or interpretation of the data. IK: conception and design In summary, a comparison of pediatric and adult of the study, acquisition and analysis of the data, and revision of the MOGAD cohorts demonstrates age-dependent effects manuscript for content. CS, JLB, AKK, AFR, SCJ, ALH, TK, MK, EW, MR, CT, TL, on visual recovery after ON. Despite almost identical KH, and RG: acquisition and analysis of the data, analysis or interpretation of the data, and revision of the manuscript for content. The authors read and neuroaxonal retinal atrophy, functional vision is notably approved the final manuscript. better in children than in adults. Age-dependent cortical neuroplasticity seems to be the most plausible mechan- ism explaining this dissociation. Future studies, combin- Funding JH is (partially) funded by the German Federal Ministry of Education and ing precise analysis of the anterior and posterior visual Research (Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H] (DIFUTURE)). system, are needed to confirm the leading role of central Open Access funding enabled and organized by Projekt DEAL. neuroplasticity in determining visual recovery after MOGAD-ON. Identification of a functionally relevant Availability of data and materials cutoff age for the visual recovery in MOGAD-ON could The data that support the findings of this study are available from the be of high relevance for the prognosis and care. corresponding author upon reasonable request. Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 9 of 10 7 Declarations Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany. 8Dr. von Hauner Children’s Hospital, LMU Ethics approval and consent to participate Hospital, Ludwig-Maximilians Universität München, Munich, Germany. 9 Written informed consent was obtained from all patients participating in the Department of Neurology & Stroke and Hertie Institute for Clinical Brain study. The local ethics committees approved the study protocol in Research, University Hospital of Tübingen, Tübingen, Germany. 10Department accordance with the Declaration of Helsinki (1964) in its currently applicable of Pediatric Neurology, Olgaspital Stuttgart, Stuttgart, Germany. 11Clinical version. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. 12 Department of Neuropaediatrics and Social Pediatrics, University Hospital of Consent for publication Pediatrics and Adolescent Medicine, Ruhr-University, Bochum, Germany. 13 Not applicable. Department of Pediatric Neurology, Children’s Hospital Datteln, University Witten/Herdecke, Witten, Germany. 14Department of Neurology, Sechenov First Moscow State Medical University, Moscow, Russia. Competing interests J. Havla reports grants for OCT research from the Friedrich-Baur-Stiftung and Received: 18 January 2021 Accepted: 29 April 2021 Merck; personal fees and non-financial support from Celgene, Merck, Alexion, Novartis, Roche, Santhera, Biogen, Heidelberg Engineering, and Sanofi Gen- zyme; and non-financial support of the Guthy-Jackson Charitable Foundation, all outside the submitted work. References T. Pakeerathan has no conflicts of interest. C. Schwake has no conflicts of interest. 1. Jarius S, Paul F, Aktas O, Asgari N, Dale RC, de Seze J, et al. MOG J.L. Bennett reports payment for study design/consultation from encephalomyelitis: international recommendations on diagnosis and MedImmune/Viela Bio; personal fees from AbbVie, Alexion, Chugai, Clene antibody testing. J Neuroinflammation. 2018;15(1):134. https://doi.org/10.11 Nanomedicine, Mitsubishi-Tanabe, Reistone Bio, Genentech, and Roche; 86/s12974-018-1144-2. grants and personal fees from Novartis, Mallinckrodt, and the National Insti- 2. Spadaro M, Winklmeier S, Beltran E, Macrini C, Höftberger R, Schuh E, et al. tutes of Health; and has a patent for Aquaporumab issued. Pathogenic mechanisms of human autoantibodies against myelin I. Kleiter has received speaker honoraria or travel funding from Alexion, oligodendrocyte glycoprotein. Mult Scler J. 2017;23:976–1023. Biogen, Novartis, Merck, Mylan, Sanofi Genzyme, and Roche; travel funding 3. Cobo-Calvo A, Ruiz A, Maillart E, Audoin B, Zephir H, Bourre B, et al. Clinical from the Guthy-Jackson Charitable Foundation; and consulted for Alexion, spectrum and prognostic value of CNS MOG autoimmunity in adults: the Biogen, Celgene, Chugai, IQVIA, Novartis, Merck, and Roche. MOGADOR study. Neurology. 2018;90(21):e1858–69. https://doi.org/10.1212/ A. Felipe-Rucián has no conflicts of interest. WNL.0000000000005560. S.C. Joachim received travel funding and/or speaker honoraria from Bayer, 4. Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, et al. MOG- Novartis, and Roche and received research support from Bayer, Novartis, IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Roche, and Ursapharm. Epidemiology, clinical presentation, radiological and laboratory features, A. S. Lotz-Havla has received travel expenses from BioMarin. treatment responses, and long-term outcome. J Neuroinflammation. 2016; T. Kümpfel received speaker and/or consultation honoraria from Bayer 13(1):280. https://doi.org/10.1186/s12974-016-0718-0. Healthcare, Merck, Novartis Pharma, Roche Pharma, and Biogen as well as 5. Wegener-Panzer A, Cleaveland R, Wendel EM, Baumann M, Bertolini A, grant support from Novartis. Hausler M, et al. Clinical and imaging features of children with autoimmune M. Krumbholz received travel funding and/or speaker honoraria from Merck, encephalitis and MOG antibodies. Neurol Neuroimmunol Neuroinflamm. Novartis, and Roche and research support from Merck. 2020;7(4):e731. https://doi.org/10.1212/NXI.0000000000000731. E. Wendel has nothing to declare. 6. Hacohen Y, Banwell B. Treatment approaches for MOG-Ab-associated M. Reindl (the University Hospital and Medical University of Innsbruck demyelination in children. Curr Treat Options Neurol. 2019;21(1):2. https:// (Austria); employer of M. Reindl) receives payments for antibody assays doi.org/10.1007/s11940-019-0541-x. (MOG, AQP4, and other autoantibodies) and for antibody validation 7. Ramanathan S, Mohammad S, Tantsis E, Nguyen TK, Merheb V, Fung VSC, experiments organized by Euroimmun and research grants from Euroimmun et al. Clinical course, therapeutic responses and outcomes in relapsing MOG and Roche. antibody-associated demyelination. J Neurol Neurosurg Psychiatry. 2018; C. Thiels has no conflicts of interest. 89(2):127–37. https://doi.org/10.1136/jnnp-2017-316880. T. Lücke has no conflicts of interest. 8. Reindl M, Rostasy K. MOG antibody-associated diseases. Neurol K. Hellwig has received travel grants from Biogen, Novartis, and Merck and Neuroimmunol Neuroinflamm. 2015;2(1):e60. https://doi.org/10.1212/NXI. received speaker and research honoraria from Biogen Idec Germany, Teva, 0000000000000060. Sanofi Genzyme, Novartis, Bayer Healthcare, Merck Serono, and Roche 9. Hofman P, Hoyng P, vander Werf F, Vrensen GF, Schlingemann RO. Lack of R. Gold received speaker’s and board honoraria from Baxter, Bayer Schering, blood-brain barrier properties in microvessels of the prelaminar optic nerve Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Stendhal, head. Invest Ophthalmol Vis Sci. 2001;42(5):895–901. Talecris, and Teva. His department received grant support from Bayer 10. Bettelli E, Pagany M, Weiner HL, Linington C, Sobel RA, Kuchroo VK. Myelin Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, and Teva. All are oligodendrocyte glycoprotein-specific T cell receptor transgenic mice not related to the content of this manuscript. develop spontaneous autoimmune optic neuritis. J Exp Med. 2003;197(9): K. Rostasy has no conflict of interest related to this article. 1073–81. https://doi.org/10.1084/jem.20021603. I. Ayzenberg has received travel grants from Biogen Idec and Guthy-Jackson 11. Pache F, Zimmermann H, Mikolajczak J, Schumacher S, Lacheta A, Oertel FC, Charitable Foundation, served on scientific advisory boards for Roche and et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 Alexion, and received research support from Diamed, not related to this patients. Part 4: Afferent visual system damage after optic neuritis in MOG- manuscript. IgG-seropositive versus AQP4-IgG-seropositive patients. J Neuroinflammation. 2016;13(1):282. https://doi.org/10.1186/s12974-016-072 Author details 0-6. 1 Institute of Clinical Neuroimmunology, LMU Hospital, Ludwig-Maximilians 12. Havla J, Kumpfel T, Schinner R, Spadaro M, Schuh E, Meinl E, et al. Universität München, Munich, Germany. 2Data Integration for Future Myelin-oligodendrocyte-glycoprotein (MOG) autoantibodies as potential Medicine (DIFUTURE) Consortium, LMU Hospital, Ludwig-Maximilians markers of severe optic neuritis and subclinical retinal axonal Universität München, Munich, Germany. 3Department of Neurology, St. degeneration. J Neurol. 2017;264(1):139–51. https://doi.org/10.1007/s0041 Josef-Hospital, Ruhr-University Bochum, Bochum, Germany. 4Departments of 5-016-8333-7. Neurology and Ophthalmology, Programs in Neuroscience and Immunology, 13. Oertel FC, Outteryck O, Knier B, Zimmermann H, Borisow N, Bellmann-Strobl University of Colorado Anschutz Medical Campus, Denver, USA. J, et al. Optical coherence tomography in myelin-oligodendrocyte- 5 Marianne-Strauß-Klinik, Behandlungszentrum Kempfenhausen für Multiple glycoprotein antibody-seropositive patients: a longitudinal study. J Sklerose Kranke, Berg, Germany. 6Department of Pediatric Neurology, Vall Neuroinflammation. 2019;16(1):154. https://doi.org/10.1186/s12974-019-1 d’Hebron Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 521-5. Havla et al. Journal of Neuroinflammation (2021) 18:121 Page 10 of 10 14. Hoftberger R, Guo Y, Flanagan EP, Lopez-Chiriboga AS, Endmayr V, of 61 patients. Eur J Neurol. 2021;28(5):1659–64. https://doi.org/10.1111/ Hochmeister S, et al. The pathology of central nervous system inflammatory ene.14746. demyelinating disease accompanying myelin oligodendrocyte glycoprotein 32. Jitprapaikulsan J, Chen JJ, Flanagan EP, Tobin WO, Fryer JP, Weinshenker BG, autoantibody. Acta Neuropathol. 2020;139(5):875–92. https://doi.org/10.1 et al. Aquaporin-4 and myelin oligodendrocyte glycoprotein autoantibody 007/s00401-020-02132-y. status predict outcome of recurrent optic neuritis. Ophthalmology. 2018; 15. Ramanathan S, Prelog K, Barnes EH, Tantsis EM, Reddel SW, Henderson AP, 125(10):1628–37. https://doi.org/10.1016/j.ophtha.2018.03.041. et al. Radiological differentiation of optic neuritis with myelin 33. Akaishi T, Nakashima I, Takeshita T, Mugikura S, Sato DK, Takahashi T, et al. oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and Lesion length of optic neuritis impacts visual prognosis in neuromyelitis multiple sclerosis. Mult Scler. 2016;22(4):470–82. https://doi.org/10.1177/13 optica. J Neuroimmunol. 2016;293:28–33. https://doi.org/10.1016/j. 52458515593406. jneuroim.2016.02.004. 16. Wendel EM, Baumann M, Barisic N, Blaschek A, Coelho de Oliveira Koch E, 34. Bruijstens AL, Breu M, Wendel EM, Wassmer E, Lim M, Neuteboom RF, et al. Della Marina A, et al. High association of MOG-IgG antibodies in children E.U. Paediatric MOG Consortium Consensus: Part 4 - Outcome of paediatric with bilateral optic neuritis. Eur J Pediatr Neurol. 2020;27:86–93. https://doi. myelin oligodendrocyte glycoprotein antibody-associated disorders. Eur J org/10.1016/j.ejpn.2020.04.002. Paediatr Neurol. 2020;29:32–40. https://doi.org/10.1016/j.ejpn.2020.10.007. 17. Jonzzon S, Suleiman L, Yousef A, Young B, Hart J, Peschl P, et al. Clinical 35. Armangue T, Capobianco M, de Chalus A, Laetitia G, Deiva K, consortium features and outcomes of pediatric monophasic and recurrent idiopathic EUpM. E.U. Paediatric MOG Consortium Consensus: Part 3 - Biomarkers of optic neuritis. J Child Neurol. 2020;35(1):77–83. https://doi.org/10.1177/0883 paediatric myelin oligodendrocyte glycoprotein antibody-associated 073819877334. disorders. Eur J Paediatr Neurol. 2020;29:22–31. https://doi.org/10.1016/j. 18. Rocca MA, Absinta M, Ghezzi A, Moiola L, Comi G, Filippi M. Is a preserved ejpn.2020.11.001. functional reserve a mechanism limiting clinical impairment in pediatric MS 36. Wan MJ, Adebona O, Benson LA, Gorman MP, Heidary G. Visual outcomes patients? Hum Brain Mapp. 2009;30(9):2844–51. https://doi.org/10.1002/ in pediatric optic neuritis. Am J Ophthalmol. 2014;158(3):503–7 e502. hbm.20712. https://doi.org/10.1016/j.ajo.2014.05.036. 19. Banwell B, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M. Multiple sclerosis in 37. Zhao G, Chen Q, Huang Y, Li Z, Sun X, Lu P, et al. Clinical characteristics of children: clinical diagnosis, therapeutic strategies, and future directions. myelin oligodendrocyte glycoprotein seropositive optic neuritis: a cohort Lancet Neurol. 2007;6(10):887–902. https://doi.org/10.1016/S1474-4422 study in Shanghai, China. J Neurol. 2018;265(1):33–40. https://doi.org/10.1 (07)70242-9. 007/s00415-017-8651-4. 20. Confavreux C, Vukusic S, Adeleine P. Early clinical predictors and progression 38. Eyre M, Hameed A, Wright S, Brownlee W, Ciccarelli O, Bowman R, et al. of irreversible disability in multiple sclerosis: an amnesic process. Brain. 2003; Retinal nerve fibre layer thinning is associated with worse visual outcome 126(4):770–82. https://doi.org/10.1093/brain/awg081. after optic neuritis in children with a relapsing demyelinating syndrome. 21. Lana-Peixoto MA, Andrade GC. The clinical profile of childhood optic Dev Med Child Neurol. 2018;60(12):1244–50. https://doi.org/10.1111/ neuritis. Arq Neuropsiquiatr. 2001;59(2B):311–7. https://doi.org/10.1590/ dmcn.13757. S0004-282X2001000300001. 39. Chitnis T, Aaen G, Belman A, Benson L, Gorman M, Goyal MS, et al. 22. Cobo-Calvo A, Ruiz A, Rollot F, Arrambide G, Deschamps R, Maillart E, et al. Improved relapse recovery in paediatric compared to adult multiple Clinical Features and Risk of Relapse in Children and Adults with Myelin sclerosis. Brain. 2020;143(9):2733–41. https://doi.org/10.1093/brain/awaa199. Oligodendrocyte Glycoprotein Antibody-Associated Disease. Ann Neurol. 40. Liu R, Zhou J, Zhao H, Dai Y, Zhang Y, Tang Y, et al. Immature visual neural 2021;89(1):30–41.https://doi.org/10.1002/ana.25909. Epub 2020 Oct 15. system in children reflected by contrast sensitivity with adaptive optics 23. Reindl M, Schanda K, Woodhall M, Tea F, Ramanathan S, Sagen J, et al. correction. Sci Rep. 2014;4:4687. International multicenter examination of MOG antibody assays. Neurol 41. Leat SJ, Yadav NK, Irving EL. Development of visual acuity and contrast Neuroimmunol Neuroinflamm. 2020;7(2):e674. https://doi.org/10.1212/NXI. sensitivity in children. Journal of Optometry. 2009;2(1):19–26. https://doi. 0000000000000674. org/10.3921/joptom.2009.19. 24. Cruz-Herranz A, Balk LJ, Oberwahrenbrock T, Saidha S, Martinez-Lapiscina 42. Castaldi E, Lunghi C, Morrone MC. Neuroplasticity in adult human visual EH, Lagreze WA, et al. The APOSTEL recommendations for reporting cortex. Neurosci Biobehav Rev. 2020;112:542–52. https://doi.org/10.1016/j. quantitative optical coherence tomography studies. Neurology. 2016;86(24): neubiorev.2020.02.028. 2303–9. https://doi.org/10.1212/WNL.0000000000002774. 43. Kiorpes L, Tang C, Hawken MJ, Movshon JA. Ideal observer analysis of the 25. Schippling S, Balk LJ, Costello F, Albrecht P, Balcer L, Calabresi PA, et al. development of spatial contrast sensitivity in macaque monkeys. J Vis. 2003; Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR- 3(10):630–41. https://doi.org/10.1167/3.10.6. IB criteria. Mult Scler. 2015;21(2):163–70. https://doi.org/10.1177/1352458514 44. Jenkins TM, Toosy AT, Ciccarelli O, Miszkiel KA, Wheeler-Kingshott CA, 538110. Henderson AP, et al. Neuroplasticity predicts outcome of optic neuritis 26. Song H, Zhou H, Yang M, Xu Q, Sun M, Wei S. Clinical characteristics and independent of tissue damage. Ann Neurol. 2010;67(1):99–113. https://doi. outcomes of myelin oligodendrocyte glycoprotein antibody-seropositive org/10.1002/ana.21823. optic neuritis in varying age groups: a cohort study in China. J Neurol Sci. 2019;400:83–9. https://doi.org/10.1016/j.jns.2019.03.014. Publisher’s Note 27. Narayan RN, McCreary M, Conger D, Wang C, Greenberg BM. Unique Springer Nature remains neutral with regard to jurisdictional claims in characteristics of optical coherence tomography (OCT) results and visual published maps and institutional affiliations. acuity testing in myelin oligodendrocyte glycoprotein (MOG) antibody positive pediatric patients. Mult Scler Relat Disord. 2019;28:86–90. https:// doi.org/10.1016/j.msard.2018.11.026. 28. Balk LJ, Coric D, Knier B, Zimmermann HG, Behbehani R, Alroughani R, et al. Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis; a longitudinal OCT study. Mult Scler J Exp Transl Clin. 2019;5:2055217319871582. 29. Outteryck O, Majed B, Defoort-Dhellemmes S, Vermersch P, Zephir H. A comparative optical coherence tomography study in neuromyelitis optica spectrum disorder and multiple sclerosis. Mult Scler. 2015;21(14):1781–93. https://doi.org/10.1177/1352458515578888. 30. Chen JJ, Flanagan EP, Jitprapaikulsan J, Lopez-Chiriboga ASS, Fryer JP, Leavitt JA, et al. Myelin oligodendrocyte glycoprotein antibody-positive optic neuritis: clinical characteristics, radiologic clues, and outcome. Am J Ophthalmol. 2018;195:8–15. https://doi.org/10.1016/j.ajo.2018.07.020. 31. Deschamps R, Pique J, Ayrignac X, Collongues N, Audoin B, Zephir H, et al. The long-term outcome of MOGAD: an observational national cohort study