Journal of Neurology (2022) 269:6366–6376 https://doi.org/10.1007/s00415-022-11256-y ORIGINAL COMMUNICATION Characteristic retinal atrophy pattern allows differentiation between pediatric MOGAD and MS after a single optic neuritis episode T. Pakeerathan1 · J. Havla2,3 · C. Schwake1 · A. Salmen4 · S. Bigi4,5,6 · M. Abegg7 · D. Brügger7 · T. Ferrazzini7 · A.‑K. Runge4 · M. Breu8 · B. Kornek9 · G. Bsteh9 · A. Felipe‑Rucián10 · M. Ringelstein11,12 · O. Aktas11 · M. Karenfort13 · E. Wendel14 · I. Kleiter1,15 · K. Hellwig1 · T. Kümpfel2 · C. Thiels16 · T. Lücke16 · R. Gold1 · K. Rostasy17 · I. Ayzenberg1 Received: 16 May 2022 / Revised: 22 June 2022 / Accepted: 23 June 2022 / Published online: 23 July 2022 © The Author(s) 2022 Abstract Background Optic neuritis (ON) is the most prevalent manifestation of pediatric multiple sclerosis (­ MSped) and myelin- oligodendrocyte glycoprotein antibody-associated disease ­(MOGADped) in children > 6 years. In this study, we investigated retinal atrophy patterns and diagnostic accuracy of optical coherence tomography (OCT) in differentiating between both diseases after the first ON episode. Methods Patients were retrospectively identified in eight tertial referral centers. OCT, VEP and high/low-contrast visual acuity (HCVA/LCVA) have been investigated > 6 months after the first ON. Prevalence of pathological OCT findings was identified based on data of 144 age-matched healthy controls. Results Thirteen ­MOGADped (10.7 ± 4.2 years, F:M 8:5, 21 ON eyes) and 21 ­MSped (14.3 ± 2.4 years, F:M 19:2, 24 ON eyes) patients were recruited. We observed a significantly more profound atrophy of both peripapillary and macular retinal nerve fiber layer in ­MOGADped compared to ­MSped (pRNFL global: 68.2 ± 16.9 vs. 89.4 ± 12.3 µm, p < 0.001; mRNFL: 0.12 ± 0.01 vs. 0.14 ± 0.01 ­mm3, p < 0.001). Neither other macular layers nor P100 latency differed. ­MOGADped developed global atrophy affecting all peripapillary segments, while ­MSped displayed predominantly temporal thinning. Nasal pRNFL allowed differentiation between both diseases with the highest diagnostic accuracy (AUC = 0.902, cutoff < 62.5 µm, 90.5% sensitivity and 70.8% specificity for ­MOGADped). OCT was also substantially more sensitive compared to VEP in identifica- tion of ON eyes in MOGAD (pathological findings in 90% vs. 14%, p = 0.016). Conclusion First MOGAD-ON results in a more severe global peripapillary atrophy compared to predominantly temporal thinning in MS-ON. Nasal pRNFL allows differentiation between both diseases with the highest accuracy, supporting the additional diagnostic value of OCT in children with ON. Keywords Optical coherence tomography · Visual evoked potential · Optic neuritis · Myelin-oligodendrocyte-glycoprotein IgG · MOGAD · Multiple sclerosis · Pediatric patients · Children Introduction same time, ON is the most prevalent clinical manifestation of MOGAD in children > 6 years of age, while up to 45% of Multiple sclerosis (MS) and myelin-oligodendrocyte glyco- all children with isolated ON and 73% of those with bilateral protein (MOG) antibody-associated disease (MOGAD) are ON are seropositive for MOG immunoglobulin(Ig)G [4–6]. two major autoimmune-inflammatory demyelinating dis- The overlapping clinical manifestation makes an early and eases of the central nervous system (CNS) associated with precise recognition of the underlying disease difficult. How- optic neuritis (ON) in children. ON represents the onset ever, a correct diagnosis is therapeutically highly relevant. symptom of pediatric MS in 20–25% of cases, while 42% of Pathophysiological mechanisms and recommended immu- all children with isolated ON later develop MS [1–3]. At the notherapies differ between both entities and classical MS medications can be ineffective or even worsen the course of MOGAD [7]. Testing for specific conformation-dependent * I. Ayzenberg ilya.ayzenberg@rub.de autoantibodies, targeting MOG, requires transfected cell- based assays (CBA) and can be challenging. Low titers of Extended author information available on the last page of the article 13 Vol:.(1234567890) Journal of Neurology (2022) 269:6366–6376 6367 MOG-IgG in serum have low positive predictive value and Children’s Hospital Datteln, N = 7, Institute of Clinical Neu- can be found in a number of other neurological conditions roimmunology, LMU Hospital, Munich, Germany, N = 2, and even in healthy persons [8, 9]. At the same time a Japa- Department of Neurology, Medical Faculty, Heinrich- nese group recently reported a cohort with an intrathecal Heine-University, Düsseldorf, Germany, N = 3, Pediatric origin of MOG-IgG, in which 29% of patients were sero- Neurology, Medical University of Vienna, Austria, N = 3, positive in CSF only [10, 11]. Considering these limitations Departments of Neurology and Neuropediatrics, Inselspi- and the unavailability of MOG-IgG CBA in many countries, tal, Bern University Hospital, Bern, Switzerland, N = 4 and an additional paraclinical biomarker for MOGAD could be Institute of Paediatrics, University Hospital Vall d’Hebron, diagnostically valuable. Barcelona, Spain, N = 2, Fig. 1 with flow chart visualizing ON results in a thinning of the retinal nerve fiber layer the recruitment process). Serum samples from all patients (RNFL) and the ganglion cell layer (GCL), that can be were analyzed for MOG-IgG and aquaporin-4-IgG during precisely evaluated by spectral-domain optical coherence initial workup at least once by established cell-based assays tomography (OCT). While a moderate RNFL thinning, at the discretion of each center using the laboratory’s cutoffs occurring predominantly in the temporal peripapillary seg- (MOG IFT, EUROIMMUN, Laboratory Prof. Stöcker, Ger- ment, is typical for MS-ON, no specific atrophy pattern many; Laboratory Prof. Reindl, Medical University of Inns- has been identified in MOGAD-ON, so far [12]. Available bruck, Innsbruck, Austria; Laboratory Prof. Meinl, LMU studies mostly reported profound retinal changes, probably Hospital, Munich) [7, 17]. Demographical (sex and age at due to a highly recurrent course of MOGAD-ON [13, 14]. initial manifestation) and main clinical data (disease dura- Given the relative rarity and novelty of MOGAD, there are tion, number and side of clinical ON episode) were acquired no studies directly comparing structural retinal changes for all patients. In addition, habitually corrected high-con- and functional integrity of the visual pathway in pediatric trast and low-contrast monocular visual acuity (VA) was MOGAD-ON and MS-ON. acquired using high-contrast and 2.5% low-contrast Sloan Main objectives of this study were as follows: (1) to letter charts placed in a retro-illuminated light box at 2 m investigate pattern of the retinal neuroaxonal damage and distance. Each chart consists of 14 lines with 5 letters per persisting visual evoked potential (VEP) changes after a line that are standardized with equal difficulty per line and single ON episode in pediatric MOGAD, and (2) to evalu- equal spacing between the lines. The total number of correct ate the sensitivity and specificity of OCT and VEP param- letters identified on each chart was tested to determine high eters in differentiating between MOGAD-ON and MS-ON and low-contrast VA (HCVA, LCVA; maximum: 70 letters). in children. LCVA is data available for 11 MOGAD-ON eyes and 14 MS-ON eyes. Ethics approval was obtained from the Insti- tutional Review Board of the Ruhr-University Bochum (#18- Subjects and methods 6397). The study was performed according to the Declara- tion of Helsinki (1964) in its currently applicable version. Study population Optical coherence tomography (OCT) In our multi-center, retrospective cross-sectional study, following Strengthening the Reporting of Observational The spectral-domain optical coherence tomography (SD- Studies in Epidemiology (STROBE) statement guidelines OCT, SPECTRALIS, Heidelberg Engineering, Heidelberg, [15], we analyzed the clinical and imaging data of pedi- Germany) with automatic real-time (ART) averaging was atric MOGAD (­MOGADped) and pediatric MS patients used in all participating centers. Based on local protocols ­(MSped) after the first ON episode, unilateral or bilateral a scan around the optic nerve head with an activated eye ON, fulfilling the following inclusion criteria: (1) MOG- tracker (12°, 3.5 mm ring, 50 ≤ ART ≤ 100) and a macular IgG positive status (> 1:32 in fixed or > 1:160 in live CBA) volume scan (20° × 20°, 25 vertical B-scans, 20 ≤ ART ≤ 49) or diagnosis of MS based on McDonald criteria 2017 [16]; as a cylinder of 3 mm diameter around the fovea were per- (2) age at first ON < 18 years of age;. 3. OCT and VEP per- formed. In the analysis, the thickness of the peripapillary formed > 6 months after the first ON episode. Patients with retinal nerve fiber layer (pRNFL) and the volumes of the concomitant ophthalmological diseases, with positive aqua- macular retinal nerve fiber layer (mRNFL), the combined porin-4 IgG or with subsequent ON episodes before OCT ganglion cell and inner plexiform layer (GCIPL), the inner were excluded from the analysis. Patients were recruited nuclear layer (INL), the combined outer plexiform and outer from 2018 to 2021 at eight specialized neuroimmuno- nuclear layer (OPONL), as well as the total macular vol- logical university and non-university tertiary care centers ume (TMV) were included. The segmentation of all layers (Department of Neurology, St. Josef-Hospital Bochum and was performed semi-automatically using software from the University Children’s Hospital Bochum, Germany, N = 17, SD-OCT manufacturer (Eye Explorer 1.9.10.0 with viewing 13 6368 Journal of Neurology (2022) 269:6366–6376 Fig. 1  Flow chart of patients included in the study. During the study period, 38 pediatric MOGAD or MS patients after the first ON attack were identi- fied in the participating centers. Four patients were excluded due to second ON attack during the first 6 months after the initial event. Depending on the diagno- sis, the pediatric patients were divided into 2 groups: group (1) 13 MOG-IgG-patients with initial manifestation < 18 years ­(MOGADpaed) and group (2) 21 MS patients with initial mani- festation < 18 years ­(MSped) module 6.3.4.0, Heidelberg Engineering, Heidelberg, Ger- To describe pattern of retinal changes after ON precisely, many). All scans were carefully checked by experienced we also reported frequencies of significant atrophy in differ- evaluators for sufficient quality and segmentation errors ent pRNFL quadrants and macular sectors in every group, and were corrected if necessary. The SD-OCT data were defined as a decrease below 2SD, compared to a group analyzed and reported according to the recommendations of age-matched healthy controls (N = 144, f:m 32:40, age of APOSTEL and OSCAR-IB [18, 19]. 12.49 ± 2.18). Healthy controls have been investigated in St. Josef-Hospital Bochum previously and will be reported sep- arately [21]. VEP latency delay was defined as 2SD below Visual evoked potentials (VEP) mean (105 ± 8 ms, cutoff: 121 ms). SD-OCT data, VEP data and HCVA/LCVA in eyes with ON were compared between VEP data (Keypoint.net, Neurolite Software, Natus, Swit- the ­MOGADped and M ­ Sped cohorts using generalized esti- zerland) were acquired according to International Society mating equation models (GEE) to account for within-patient for Clinical Electrophysiology of Vision standards [20]. The inter-eye correlation. The correlation matrix parameter was data were collected from occipital midline referred to the set to “exchangeable”. Significant parameters were further mid-frontal electrode. Pattern reversal VEP was produced included into receiver operating characteristic analysis (ROC by high-contrast, black and white checks. The examination analysis) to determine their sensitivity and specificity in dif- was performed in a dark room in 2 m distance. P100 latency ferentiating ­MOGADped from M ­ Sped. Parameters with an and the P100-N125 amplitude were collected (latency in area under the curve (AUC) > 0.700 were suitable param- milliseconds, amplitude in mV). VEP data are available for eters. We used Youden index analysis to find optimal cutoff patients who were seen in Bochum (data available for 11 values. To compare the sensitivity of OCT and VEP regard- MOGAD-ON eyes and 16 MS-ON eyes). ing the identification of eyes with a history of MOGAD-ON, we used the McNemar Test. Data were analyzed with SPSS Statistical methods version 28 (IBM SPSS Statistics). Clinical data, OCT and VEP results were compared between both groups (­ MOGADped vs M ­ Sped). Mean and standard Results deviation (SD) were calculated for continuous variables, frequency, and proportion for categorial variables. The non- Cohort description parametric Mann–Whitney-U-Test and Chi-square-test were used to compare two independent groups. Statistical signifi- Thirteen MOG-IgG-positive children ­(MOGAD ped , cance was defined as p < 0.05. female:male 8:5, mean age at ON 10.7 ± 4.2 years, 21 ON 13 Journal of Neurology (2022) 269:6366–6376 6369 eyes) and 21 MS children (­ MSped, female: male 19:2, mean was in different pRNFL segments as following: temporal age at ON 14.3 ± 2.4 years, 24 ON eyes) with a single uni- ­ OGADped vs 45.8% for M (T; 81.0 for M ­ S ped), temporal lateral or bilateral ON episode in their history were included superior (TS; 71.4 vs 38.1%), temporal inferior (TI; 81.0 into analysis. The main demographic and clinical data of vs 37.5%), nasal (N; 52.4 vs 0%), nasal superior (NS; 38.1 both groups are depicted in Table 1. Aquaporin-4 IgG was vs 8.3%) and nasal inferior (NI; 42.9 vs 0%) for MOGAD- negative in all patients. All 21 MS children tested negative ON and MS-ON eyes, accordingly. A direct comparison for MOG-IgG in serum and positive oligoclonal bands in of both groups confirmed significantly more profound CSF. ­MOGADped patients were younger at ON onset com- pRNFL atrophy in M ­ OGAD ped globally (pRNFL G) as pared to M­ Sped, whereas there was no significant difference well as in following segments (pRNFL TS, pRNFL TI, in disease duration till OCT investigation in both groups. pRNFL N, pRNFL NS, pRNFL NI), whereas pRNFL T Simultaneous bilateral ON were significantly more preva- and the papillomacular bundle (PMB) were comparable ­ OGADped compared to M lent in M ­ Sped (p < 0.001). Seven (Fig. 2 with exemplary OCT images). Taken altogether, of 13 MOG-IgG-positive children were initially diagnosed there was a mild-to-moderate temporal pRNFL thinning in with ON only, 3 children with ADEM + ON, 2 children with MS-ON and a substantial global atrophy in MOGAD-ON NMOSD, and 1 child with encephalomyelitis + ON. Three already after the first ON episode. patients in each group received plasma exchange, due to ster- oid refractory ON (5 MOGAD-ON eyes, 3 MS-ON eyes). A long-term immunotherapy was administered in 7 of 13 Comparable changes in macular OCT, visual evoked (53.8%) of ­MOGADped (4 intravenous immunoglobulin/sub- potential, and visual acuity cutaneous immunoglobulin (IVIG/SCIG), 1 monotherapy with oral prednisone, 1 rituximab, 1 dimethyl fumarate) and There were neither significant difference in the total macu- 18 of 21 (85.7%) M ­ Sped (6 ocrelizumab, 3 fingolimod, 2 lar volume no in the GCIPL, the INL and the OPONL rituximab, 2 interferon beta, 2 monotherapy with oral pred- between both patient groups (Table 2). Similarly, the fre- nisone, 1 dimethyl fumarate, 1 natalizumab, 1 glatiramer quencies of significant pathological findings compared to acetate). healthy controls did not differ between ­MOGADped and ­MSped. The macular RNFL volume was the only param- Different patterns of peripapillary retinal atrophy eter demonstrating a significant more profound thinning in ­MOGADped and ­MSped in ­MOGADped vs ­MSped. VEP P100 latencies were also comparable in both We observed a difference in the pattern of peripapillary groups, while a significant delay could be found in only retinal axonal degeneration between M ­ OGAD ped and 14.3% and 29.2% of ­M OGAD ped and M ­ S ped ON eyes, ped ­M S in ON affected eyes (Table 2). The frequency of respectively. There were no differences in the visual acu- marginal to severe atrophy comparing to healthy controls ity between the groups (Table 2). Table 1  Demographic and main clinical characteristics of pediatric MOGAD and MS cohorts MOGADped (n = 13) MSped (n = 21) p-value Age at initial disease manifestation, mean ± SD 9.0 ± 3.28 14.1 ± 2.5 < 0.001 Age at ON, mean ± SD 10.7 ± 4.2 14.3 ± 2.4 < 0.001 ON as first event, n (%) 8 (61.5%) 20 (95.2%) < 0.001 Females, n (%) 8 (61.5%) 19 (90.5%) 0.010 Disease duration (in years), median (range) 3 (1–15) 3 (1–13) 0.382 Ethnicity, n 13/13 Caucasians 21/21 Caucasians – Patients with a simultaneous bilateral ON, n (%) 8 (61.5%) 3 (14.3%) < 0.001 Total ON eyes, n (%) 21 (80.8%) 24 (57.1%) 0.045 Positive OCB, n (%) 0 (0%) 21 (100%) – HCVA, number of correctly stated letters, mean ± SD 54.3 ± 5.4 54.8 ± 7.7 0.483 2.5% LCVA, number of correctly stated letters, mean ± SD 24.3 ± 10.0 27.4 ± 11.0 0.472 MOGAD myelin oligodendrocyte glycoprotein-antibody-associated disease, MS multiple sclerosis, MOGADped pediatric MOGAD patients, MSped pediatric MS patients, ON optic neuritis, OCB oligoclonal bands, HCVA high-contrast visual acuity, LCVA low-contrast visual acuity, SD standard deviation 13 6370 Journal of Neurology (2022) 269:6366–6376 ­ OGADped and ­MSped: direct comparison and prevalence of moderate to severe atrophy in Table 2  OCT and VEP measures after a single ON in M each group compared to healthy controls Parameter MOGADped with MSped with MOGADped Cutoff value MOGADped with MSped with ON = 1 ON = 1 (21 eyes, ON = 1 (24 eyes, vs. ­MSped with (mean-2 SD, for ON = 1 (21 eyes, (24 eyes, number of mean ± SD) mean ± SD) ON = 1, p-value VEP P100 latency: number of patho- pathological results) mean + 2SD) logical results) G pRNFL 68.2 ± 16.9 89.4 ± 12.3 < 0.001 85.7 19 (90.5%)* 10 (41.7%) T pRNFL 47.7 ± 14.2 56.8 ± 17.0 0.096 54.3 17 (81.0%) 11 (45.8%) TS pRNFL 98.0 ± 22.7 127.5 ± 36.0 0.003 114.5 15 (71.4%) 8 (38.1%) TI pRNFL 99.7 ± 32.5 125.6 ± 23.2 0.017 117.9 17 (81.0%) 9 (37.5%) N pRNFL 46.7 ± 11.1 66.9 ± 10.8 < 0.001 43.1 11 (52.4%) 0 (0.0%) NS pRNFL 81.7 ± 26.5 109.4 ± 20.3 < 0.001 76.6 8 (38.1%) 2 (8.3%) NI pRNFL 75.3 ± 24.9 102.7 ± 16.5 < 0.001 67.3 9 (42.9%) 0 (0.0%) PMB 39.1 ± 14.3 42.4 ± 10.7 0.446 40.7 14 (66.7%) 11 (45.8%) N/T Ratio 1.06 ± 0.34 1.28 ± 0.35 0.039 0.42 < x < 1.12 7 (33.3%) 14 (58.3%)* TMV 3 mm 2.17 ± 0.15 2.25 ± 0.13 0.154 2.21 7 (33.3%) 9 (37.5%) mRNFL 3 mm 0.12 ± 0.01 0.14 ± 0.01 < 0.001 0.13 13 (61.9%) 4 (16.7%) GCIPL 3 mm 0.48 ± 0.09 0.54 ± 0.1 0.113 0.55 11 (52.4%) 13 (54.2%) INL 3 mm 0.27 ± 0.03 0.27 ± 0.03 0.742 0.23 2 (10.0%) 1 (4.2%) OPONL 3 mm 0.77 ± 0.06 0.74 ± 0.05 0.212 0.63 0 (0.0%) 0 (0.0%) VEP P100 latency 118.7 ± 9.3 124.6 ± 15.2 0.249 121 3 (14.3%) 7(29.2%) *Most sensitive parameters confirming history of the ON in each group MOGAD myelin oligodendrocyte glycoprotein-antibody-associated disease, MS multiple sclerosis, MOGADped pediatric MOGAD patients, MSped pediatric MS patients, ON optic neuritis, MOGAD-ON MOGAD patient’s eyes with a history of ON, MS-ON MS patient’s eyes with a his- tory of ON, pRNFL peripapillary retinal nerve fiber layer (G global, T temporal, TS temporal superior, TI temporal inferior, N nasal, NS nasal superior, NI nasal inferior, PMB papillomacular bundle, N/T nasal/temporal ratio), TMV total macular volume, mRNFL macular retinal nerve fiber layer, mGCIPL macular ganglion cell and inner plexiform layer, mINL macular inner nuclear layer, mOPONL macular outer plexiform and outer inner nuclear layer pRNFL thickness in µm and macular volumes in ­mm3, VEP P100 latency in ms p-value: significant results p < 0.05 are indicated in bold letter Nasal pRNFL demonstrated highest accuracy 16 MOGAD-ON and 20 MS-ON eyes, the same 3 param- in distinguishing ­MOGADped and ­MSped eters had the best diagnostic accuracy, demonstrating even higher sensitivity and specificity in distinguishing between All parameters demonstrating significant differences both diseases (nasal pRNFL AUC = 0.946, cutoff 58.5 µm, between both groups were included into the ROC analysis sensitivity of 93.8%, specificity of 84.2%; global pRNFL (Table 3). In the analysis of pRNFL segments nasal pRNFL AUC = 0.860, cutoff 82.6 µm, sensitivity of 81.3%, speci- demonstrated the highest diagnostic accuracy (area under the ficity of 84.2%; mRNFL AUC = 0.837, cutoff 0.125 m ­ m3 curve (AUC) = 0.902), followed by global pRNFL. Using a sensitivity of 72.7%, specificity of 89.5% for ­MOGADped nasal pRNFL cutoff of 62.5 µm, we were able to distinguish vs. ­MSped, Fig. 3 with scatter plots showing the distribution between ­MOGADped and M ­ Sped with a sensitivity of 90.5% of these three parameters). The McNemar test showed that and a specificity of 70.8%. Global pRNFL (AUC = 0.833, OCT is more sensitive in comparison to VEP in MOGAD- cutoff 67.9 µm) allowed a differentiation with a 61.9% sen- ON to identify eyes with history of ON (p = 0.016). sitivity and 95.8% specificity accordingly. In the analysis of macular layers, only mRNFL (AUC = 0.839, cutoff 0.125 ­mm3) enabled a diagnostic distinction between both groups Discussion with a sensitivity of 81.3% and a specificity of 83.3%. Concerning potential selection bias (recruitment of In this study, we investigated structural retinal and functional patients with most severe refractory ON in specialized neu- optic nerve changes after the first ON in pediatric MOGAD roimmunological in-patient departments) and probable role and MS and evaluated the eligibility of OCT and VEP to of so far unknown autoantibodies, we performed an addi- differentiate between these two clinical entities. Optic tional ROC analysis excluding patients treated with plasma neuritis was the first disease manifestation in the major- exchange from both groups. In this subgroup, including ity of patients in both groups. As expected, children with 13 Journal of Neurology (2022) 269:6366–6376 6371 Fig. 2  Substantial global pRNFL atrophy in MOGAD- ON compared to moderate predominantly temporal atrophy in MS-ON after a single ON episode Table 3  Sensitivity and Parameter/segment AUC​ Cutoff (µm, ­mm3) Sensitivity for Specificity for specificity of RNFL-parameters ­MOGADped vs ­MSped ­MOGADped vs M ­ Sped in distinguishing between (%) (%) pediatric MOGAD-ON and MS-ON pRNFL G 0.833 67.9 61.9 95.8 pRNFL TS 0.799 118.5 81.0 66.7 pRNFL TI 0.775 110.5 81.0 70.8 pRNFL N 0.902 62.5 90.5 70.8 pRNFL NS 0.791 88.0 61.9 87.5 pRNFL NI 0.801 85.5 66.7 87.5 mRNFL 0.839 0.125 81.3 83.3 MOGAD myelin oligodendrocyte glycoprotein-antibody-associated disease, MS multiple sclerosis, MOGA- Dped pediatric MOGAD patients, MSped pediatric MS patients, ON optic neuritis, MOGAD-ON MOGAD patient’s eyes with a history of ON, MS-ON MS patient’s eyes with a history of ON, pRNFL peripapillary retinal nerve fiber layer (G global, TS temporal superior, TI temporal inferior, N nasal, NS nasal superior, NI nasal inferior), mRNFL macular RNFL, AUC​area under the curve pRNFL thickness in µm and macular volume in ­mm3 Only parameters with AUC > 0.700 were suitable parameters which are listed in the table. Parameter with the highest sensitivity and specificity indicated in bold letter 13 6372 Journal of Neurology (2022) 269:6366–6376 Fig. 3  Scatterplot showing the distribution of a pRNFL N thickness, b pRNFL G thickness and c mRNFL volume. Optimal cutoff values for each feature were defined via the Youden Index in the ROC curves. Cutoffs are demonstrated for the whole group and adapted (dashed line) after excluding patients with plasma exchange from both groups MOGAD developed significantly more often simultaneous plasma exchange due to the steroid refractory ON, confirm- bilateral ON, while 86% of those with MS had an unilateral ing results of earlier studies [14, 22–24]. High age-related involvement [5, 22]. The functional outcome was excel- cortical neuroplasticity may account for this exceptional lent in both groups, including the patients who underwent 13 Journal of Neurology (2022) 269:6366–6376 6373 visual recovery in children, as previously reported by us and negative oligoclonal bands in cerebrospinal fluid) could be others [14, 22, 25]. another even more promising approach. Further studies with We observed a significantly more profound global peri- a larger number of patients are needed to evaluate the diag- papillary atrophy in ­MOGADped in comparison to ­MSped. nostic accuracy of such a score precisely. The average pRNFL thickness in both groups corresponded We suppose that the observed differences in the atrophy well with previous studies of MS-ON with 80.8–95.0 µm patterns reflect different etiopathogenesis in both diseases. and MOGAD-ON with 63.1–76.8 µm. [13, 14, 26–32]. Sub- Previous studies have indicated that the temporal predomi- stantial neuroaxonal retinal atrophy in MOGAD has been nance in MS may be explained by mitochondrial dysfunc- reported previously; however, due to an actively relapsing tion, especially critical for smaller and thinly myelinated par- course of MOGAD-ON, most of the patients were inves- vocellular axons of the PMB that are more vulnerable to the tigated after several ON episodes [13, 28, 33]. To investi- oxidative stress [14, 35, 39]. In contrast, these mechanisms gate a potential predominant atrophy pattern, we focused seem to be less relevant for MOGAD-ON, while a massive this study on patients after the first ON attack. Similar to acute primary MOG-IgG related inflammation involves all adults a predominantly temporal atrophy could be seen in distal parts of the optic nerve, additionally resulting in a ­MSped, while M ­ OGADped showed a moderate to profound papilledema and often more severe retroorbital pain [34, pRNFL thinning in all peripapillary segments already after 40, 41]. Further research on immunopathogenesis and neu- the first ON [13, 34–36]. Differences in the pRNFL thin- ropathological data is needed to investigate the MOG-IgG ning were most obvious in the nasal peripapillary segments, related optic nerve inflammation and a role of mitochondrial remaining within normal range in almost all MS-ON eyes. dysfunction in MS precisely. Macular OCT revealed no significant differences in any layer Due to the retrospective approach, the study is prone to but for mRNFL. This contrasts with several earlier stud- several kinds of potential biases, including selection and ies showing significant differences in GCIPL thickness, reporting bias, especially regarding ON history, as well as probably due to accumulation of neuroaxonal degeneration heterogeneity of treatment schedules and incomplete data. after several ON in relapsing disease. VEP latency delay The sample size was limited due to recruitment difficulties was more pronounced in our MS cohort in comparison to a in pediatric patients at a predefined timepoint after the first previous study conducted in pediatric MS (124.6 ± 15.2 for ON. However, the inclusion of patients after several ON our cohort vs. 115.0 ± 20.0 ms in a previous study) prob- episode could confound data on disease specific atrophy ably due to a selection bias and recruitment of patients with pattern in MOGAD. There were significant differences in more aggressive disease course, mostly requiring highly the age and sex distribution, as expected based on the differ- effective immunotherapies [37]. Nevertheless, we found a ent natural course of diseases. Previous studies revealed no significant P100 latency delay (> 2SD) in only 14% and 29% age- or sex-dependent difference in the pRNFL thickness in of MOGAD and MS-ON eyes, demonstrating its relative children from 5 to 15 years old [42]. The time between ON low diagnostic sensitivity in children during a stable disease and examination was also slightly different between pedi- stage (> 6 months after first acute ON). In contrast, OCT atric MOGAD and MS patients. However, considering the was substantially more informative in our cohort, among all observed substantial differences in OCT findings between parameters, significant global pRNFL decrease in MOGAD- groups, we suggest that possible minor variations should ON (90%) and N/T ratio increase in MS-ON (66%) revealed not be critical for the study results and can be neglected. to be most sensitive for the history of ON which corresponds A real prevalence of the steroid refractory ON in pediatric well with a similar study comparing adult NMOSD and MS MS and MOGAD is unknown, but we suppose that it could patients [38]. be increased in our cohort due to patients’ recruitment in High diagnostic accuracy of the nasal pRNFL (followed specialized neuroimmunological departments. To evaluate by macular RNFL and global pRNFL) in distinguishing a possible effect of this selection bias, we performed a sub- between MOGAD and MS is the most important and clini- group analysis, by excluding plasma exchange patients. We cally relevant finding of our study. OCT can be applied as a could confirm the best diagnostic accuracy of three already rather simple and feasible additional diagnostic tool, espe- identified parameters (pRNFL N, pRNFL G, mRNFL), cially in patients with a borderline result of antibody testing moreover, its sensitivity and specificity turned out to be or those with an unclear disease history, as OCT changes are even higher in this subgroup of patients. VEP data were stable after the initial attack without fluctuations. In contrast, not available for all patients and sample size was limited. the MOG antibody titer may decrease in the course of the Further larger studies with comparable age and sex distribu- disease. tion are needed to confirm our findings. Moreover, studies In our study, we specifically focused on the OCT changes. in adult MOGAD and MS patients are needed to clarify if A composite score, including additional parameters char- the observed disease-dependent retinal atrophy pattern and acteristic for MOGAD (e.g., simultaneous bilateral ON, the applicability of nasal pRNFL as the parameter with the 13 6374 Journal of Neurology (2022) 269:6366–6376 highest accuracy in distinguishing between MOGAD and honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Mer- MS is universal or age-specific. ck, Novartis, Roche, Sanofi-Genzyme and Teva, and received hono- raria for consulting Biogen, Celgene/BMS, Novartis, Roche, Sanofi- Genzyme and Teva. He has received financial support in the past 12 months by unrestricted research grants (Celgene/BMS, Novartis). Conclusion A. Felipe-Rucián reports no disclosures relevant to the manuscript. M. Ringelstein received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion and Ipsen and travel reimbursement from Bay- After a single ON pediatric MOGAD, patients develop er Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, and Merck, severe global atrophy of the peripapillary RNFL compared none related to this study. O. Aktas received speaker and/or consulta- to predominantly moderate temporal pRNFL thinning in tion honoraria or travel funding from Alexion, Bayer Healthcare, Bio- gen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, VielaBio. M. pediatric MS. Nasal pRNFL enables a diagnostic differen- Karenfort received personal honoraria from Novartis, not related to tiation between MOGAD-ON and MS-ON in children with the content of this manuscript. E. Wendel reports no disclosures rel- a high accuracy and may be used as a supportive diagnostic evant to the manuscript. I. Kleiter received personal compensation for tool. Moreover, OCT seems to be more sensitive compared consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Biogen, Celgene, Hexal, Horizon, Merck and to VEP in identification of eyes with a history of ON. Fur- Roche/Chuqai. K. Hellwig received speaker’s, board honoraria, and ther studies are needed to confirm applicability of OCT in research support from Bayer Schering, Biogen Idec, Genzyme, Merck in distinguishing between MOGAD and MS. Serono, Novartis, and Teva. Her department received grant support from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, Acknowledgements We would like to thank all patients and their Roche, and Teva. T. Kümpfel has received speaker honoraria and/or families for participation in the study. We would like to thank Inga personal fees for advisory boards from Novartis Pharma, Roche Phar- Sedleckiene, Yvonne Skrzypiec, Ute Rüther, Stefanie Stüwe (Bochum) ma, Alexion and Biogen as well as grant support from Novartis and Angelika Bamberger and Luise Böhm (Munich) for their excellent tech- Chugai Pharma in the past. All not related to the content of this manu- nical support. script. C. Thiels reports no disclosures relevant to the manuscript. T. Lücke has received speaker and board honoraria from Infectopharm, Novartis La Roche Ltd., Sanofi Genzyme, Proveca, Chiesi. His depart- Author contributions IA, JH, and TP: conception and design of the ment received grant support from Takeda. All not related to this manu- study, acquisition and analysis of data, drafting a significant portion of script. R. Gold received speaker’s and board honoraria from Baxter, the manuscript or figures, analysis or interpretation of data. CS, AS, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, SB, MA, DB, TF, A-KR, MB, BK, GB, AF-R, MR, OA, MK, EW, Novartis, Stendhal, Talecris, and Teva. His department received grant IK, KH, TK, CT, TL, RG, and KR: acquisition and analysis of data, support from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, analysis or interpretation of data, revision of the manuscript for content. Novartis, and Teva. All not related to the content of this manuscript. K. Rostasy served as a consultant for the Operetta-Study/Roche and Funding Open Access funding enabled and organized by Projekt received honoraria for lectures given for MERCK. I. Ayzenberg has DEAL. No. received travel grants from Biogen Idec and Guthy-Jackson Charita- ble Foundation, served on scientific advisory boards for Roche and Availability of data and materials The data that support the findings Alexion and received research support from Diamed, none related to of this study are available from the corresponding author upon reason- this manuscript. able request. Ethics approval and consent to participate Written informed consent was obtained from all patients and their legal representatives partici- Declarations pating in the study. The local ethics committees approved the study protocol in accordance with the Declaration of Helsinki (1964) in its Conflicts of interest T. Pakeerathan reports no disclosures relevant currently applicable version. to the manuscript. J. Havla reports grants for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees and financial and non-financial support from Celgene, Merck, Alexion, Novartis, Roche, Open Access This article is licensed under a Creative Commons Attri- Santhera, Biogen, Heidelberg Engineering, Sanofi Genzyme and non- bution 4.0 International License, which permits use, sharing, adapta- financial support of the Guthy-Jackson Charitable Foundation, all out- tion, distribution and reproduction in any medium or format, as long side the submitted work. C. Schwake reports no disclosures relevant as you give appropriate credit to the original author(s) and the source, to the manuscript. A. Salmen reports speaker honoraria and/or travel provide a link to the Creative Commons licence, and indicate if changes compensation for activities with Bristol Myers Squibb, CSL Behring, were made. The images or other third party material in this article are Novartis, and Roche, and research support by Baasch Medicus Foun- included in the article's Creative Commons licence, unless indicated dation and the Swiss MS Society, all outside the submitted work. S. otherwise in a credit line to the material. If material is not included in Bigi reports no disclosures relevant to the manuscript. M. Abegg re- the article's Creative Commons licence and your intended use is not ports no disclosures relevant to the manuscript. D. Brügger reports no permitted by statutory regulation or exceeds the permitted use, you will disclosures relevant to the manuscript. T. Ferrazzini reports no disclo- need to obtain permission directly from the copyright holder. To view a sures relevant to the manuscript. A-K. Runge reports no disclosures copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. relevant to the manuscript. M. Breu received speaker honoraria from Sanofi Genzyme. B. Kornek received speaker honoraria from Bayer, Biogen, Celgene-BMS, Merck, Novartis, Roche, Sanofi Genzyme, and Teva and participated in advisory boards from Celgene-BMS, Merck, Novartis, Sanofi Genzyme, and Roche. No COIs related to this study. G. Bsteh has participated in meetings sponsored by, received speaker 13 Journal of Neurology (2022) 269:6366–6376 6375 References 20. Odom JV, Bach M, Brigell M et al (2016) ISCEV standard for clini- cal visual evoked potentials: (2016 update). Doc Ophthalmol Adv Ophthalmol 133:1–9 1. Chang MY, Pineles SL (2017) Pediatric optic neuritis. Semin 21. Runge A-K, Remlinger J, Abegg M, et al (2022) Retinal layer seg- Pediatr Neurol 24:122–128 mentation in a cohort of healthy children via optical coherence 2. Tonagel F, Wilhelm H, Kelbsch C (2020) Optic neuritis in German tomography. Preprint, in review. Epub ahead of print 15 March children: clinical findings and association with multiple sclerosis. 2022. 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Ayzenberg1 1 10 Department of Neurology, St. Josef‑Hospital, Ruhr- Department of Pediatric Neurology, Universitat Autònoma de University Bochum, 44791 Bochum, Germany Barcelona, Vall d’Hebron Hospital, Barcelona, Spain 2 11 Institute of Clinical Neuroimmunology, LMU Hospital, Department of Neurology, Medical Faculty, Ludwig-Maximilians Universität München, Munich, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany Germany 12 Department of Neurology, Center for Neurology 3 Data Integration for Future Medicine (DIFUTURE) and Neuropsychiatry, LVR‑Klinikum, Consortium, LMU Hospital, Ludwig-Maximilians Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany Universität München, Munich, Germany 13 Department of General Paediatrics, Neonatology 4 Department of Neurology, Inselspital, Bern University and Paediatric Cardiology, Heinrich-Heine-University Hospital, University of Bern, Bern, Switzerland Düsseldorf, Düsseldorf, Germany 5 14 Institute for Social and Preventive Medicine, University Department of Pediatric Neurology, Olgahospital, Stuttgart, of Bern, Bern, Switzerland Germany 6 15 Division of Child Neurology, Department of Pediatrics, Marianne‑Strauß‑Klinik, Behandlungszentrum University Children’s Hospital Bern, University of Bern, Kempfenhausen für Multiple Sklerose Kranke, Berg, Bern, Switzerland Germany 7 16 Department of Ophthalmology, Inselspital, Bern University Department of Neuropediatrics, University Children’s Hospital, University of Bern, Bern, Switzerland Hospital, Ruhr-University, Bochum, Germany 8 17 Division of Pediatric Pulmonology, Allergology Department of Pediatric Neurology, Children’s Hospital and Endocrinology, Department of Pediatrics and Adolescent Datteln, University Witten/Herdecke, Witten, Germany Medicine, Medical University of Vienna, Vienna, Austria 9 Department of Neurology, Medical University of Vienna, Vienna, Austria 13