400
1. Marignier R, Hacohen Y, Cobo-Calvo A, Probstel AK, Aktas O, Alexopoulos H, Amato MP, et al.
401
(2021) Myelin-oligodendrocyte glycoprotein antibody-associated disease. Lancet Neurol 20:762-
402
772
403
2. Armangue T, Olive-Cirera G, Martinez-Hernandez E, Sepulveda M, Ruiz-Garcia R, Munoz-
404
Batista M, Arino H, Gonzalez-Alvarez V, Felipe-Rucian A, Jesus Martinez-Gonzalez M,
405
Cantarin-Extremera V, Concepcion Miranda-Herrero M, Monge-Galindo L, Tomas-Vila M,
406
Miravet E, Malaga I, Arrambide G, Auger C, Tintore M, Montalban X, Vanderver A, Graus F,
407
Saiz A, Dalmau J, Spanish Pediatric anti MOGSG (2020) Associations of paediatric
408
demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies:
409
a multicentre observational study. Lancet Neurol 19:234-246
410
3. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger
411
EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142-
412
1149
413
414
415
416
4. Asseyer S, Cooper G, Paul F (2020) Pain in NMOSD and MOGAD: A Systematic Literature
Review of Pathophysiology, Symptoms, and Current Treatment Strategies. Front Neurol 11:778
5. Reindl M, Waters P (2019) Myelin oligodendrocyte glycoprotein antibodies in neurological
disease. Nat Rev Neurol 15:89-102
417
6. Jarius S, Paul F, Aktas O, Asgari N, Dale RC, de Seze J, Franciotta D, Fujihara K, Jacob A, Kim
418
HJ, Kleiter I, Kumpfel T, Levy M, Palace J, Ruprecht K, Saiz A, Trebst C, Weinshenker BG,
419
Wildemann B (2018) MOG encephalomyelitis: international recommendations on diagnosis and
420
antibody testing. J Neuroinflammation 15:134
421
7. Bruijstens AL, Breu M, Wendel EM, Wassmer E, Lim M, Neuteboom RF, Wickstrom R,
422
consortium EUpM, Baumann M, Bartels F, Finke C, Adamsbaum C, Hacohen Y, Rostasy K
423
(2020) E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin
424
oligodendrocyte glycoprotein antibody-associated disorders. Eur J Paediatr Neurol 29:32-40
425
8. Baumann M, Bartels F, Finke C, Adamsbaum C, Hacohen Y, Rostasy K, consortium EUpM
426
(2020) E.U. paediatric MOG consortium consensus: Part 2 - Neuroimaging features of paediatric
427
myelin oligodendrocyte glycoprotein antibody-associated disorders. Eur J Paediatr Neurol 29:14-
428
21
429
9. Baumann M, Sahin K, Lechner C, Hennes EM, Schanda K, Mader S, Karenfort M, Selch C,
430
Hausler M, Eisenkolbl A, Salandin M, Gruber-Sedlmayr U, Blaschek A, Kraus V, Leiz S,
431
Finsterwalder J, Gotwald T, Kuchukhidze G, Berger T, Reindl M, Rostasy K (2015) Clinical and
15
Ichimiya Y.
MOGAD and pain
432
neuroradiological differences of paediatric acute disseminating encephalomyelitis with and
433
without antibodies to the myelin oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry
434
86:265-272
435
10. Satukijchai C, Mariano R, Messina S, Sa M, Woodhall MR, Robertson NP, Ming L, Wassmer E,
436
Kneen R, Huda S, Jacob A, Blain C, Halfpenny C, Hemingway C, O'Sullivan E, Hobart J,
437
Fisniku LK, Martin R, Dopson R, Cooper SA, Williams V, Waters PJ, Ramdas S, Leite MI,
438
Palace J (2022) Factors Associated With Relapse and Treatment of Myelin Oligodendrocyte
439
Glycoprotein Antibody-Associated Disease in the United Kingdom. JAMA Netw Open
440
5:e2142780
441
11. Akaishi T, Himori N, Takeshita T, Misu T, Takahashi T, Takai Y, Nishiyama S, Fujimori J, Ishii
442
T, Aoki M, Fujihara K, Nakazawa T, Nakashima I (2021) Five-year visual outcomes after optic
443
neuritis in anti-MOG antibody-associated disease. Mult Scler Relat Disord 56:103222
444
12. Ogawa R, Nakashima I, Takahashi T, Kaneko K, Akaishi T, Takai Y, Sato DK, Nishiyama S,
445
Misu T, Kuroda H, Aoki M, Fujihara K (2017) MOG antibody-positive, benign, unilateral,
446
cerebral cortical encephalitis with epilepsy. Neurol Neuroimmunol Neuroinflamm 4:e322
447
448
13. Bartels F, Lu A, Oertel FC, Finke C, Paul F, Chien C (2021) Clinical and neuroimaging findings
in MOGAD-MRI and OCT. Clin Exp Immunol 206:266-281
449
14. Fernandez-Carbonell C, Vargas-Lowy D, Musallam A, Healy B, McLaughlin K, Wucherpfennig
450
KW, Chitnis T (2016) Clinical and MRI phenotype of children with MOG antibodies. Mult Scler
451
22:174-184
452
15. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher
453
AI, Munger KL, Ascherio A (2022) Longitudinal analysis reveals high prevalence of Epstein-
454
Barr virus associated with multiple sclerosis. Science 375:296-301
455
16. Nakamura Y, Nakajima H, Tani H, Hosokawa T, Ishida S, Kimura F, Kaneko K, Takahashi T,
456
Nakashima I (2017) Anti-MOG antibody-positive ADEM following infectious mononucleosis
457
due to a primary EBV infection: a case report. BMC Neurol 17:76
458
17. Dubey D, Pittock SJ, Krecke KN, Morris PP, Sechi E, Zalewski NL, Weinshenker BG, Shosha
459
E, Lucchinetti CF, Fryer JP, Lopez-Chiriboga AS, Chen JC, Jitprapaikulsan J, McKeon A,
460
Gadoth A, Keegan BM, Tillema JM, Naddaf E, Patterson MC, Messacar K, Tyler KL, Flanagan
461
EP (2019) Clinical, Radiologic, and Prognostic Features of Myelitis Associated With Myelin
462
Oligodendrocyte Glycoprotein Autoantibody. JAMA Neurol 76:301-309
16
Ichimiya Y.
MOGAD and pain
463
18. Oliveira LM, Apostolos-Pereira SL, Pitombeira MS, Bruel Torretta PH, Callegaro D, Sato DK
464
(2019) Persistent MOG-IgG positivity is a predictor of recurrence in MOG-IgG-associated optic
465
neuritis, encephalitis and myelitis. Mult Scler 25:1907-1914
466
19. Di Pauli F, Berger T (2018) Myelin Oligodendrocyte Glycoprotein Antibody-Associated
467
Disorders: Toward a New Spectrum of Inflammatory Demyelinating CNS Disorders? Front
468
Immunol 9:2753
469
20. Nanishi E, Hoshina T, Sanefuji M, Kadoya R, Kitazawa K, Arahata Y, Sato T, Hirayama Y, Hirai
470
K, Yanai M, Nikaido K, Maeda A, Torisu H, Okada K, Sakai Y, Ohga S (2019) A Nationwide
471
Survey of Pediatric-onset Japanese Encephalitis in Japan. Clin Infect Dis 68:2099-2104
472
21. Chong PF, Kira R, Mori H, Okumura A, Torisu H, Yasumoto S, Shimizu H, Fujimoto T,
473
Hanaoka N, Kusunoki S, Takahashi T, Oishi K, Tanaka-Taya K, Acute Flaccid Myelitis
474
Collaborative Study I (2018) Clinical Features of Acute Flaccid Myelitis Temporally Associated
475
With an Enterovirus D68 Outbreak: Results of a Nationwide Survey of Acute Flaccid Paralysis
476
in Japan, August-December 2015. Clin Infect Dis 66:653-664
477
22. Schneier AJ, Shields BJ, Hostetler SG, Xiang H, Smith GA (2006) Incidence of pediatric
478
traumatic brain injury and associated hospital resource utilization in the United States. Pediatrics
479
118:483-492
480
23. Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, Ghezzi A, Hintzen R,
481
Kornberg A, Pohl D, Rostasy K, Tenembaum S, Wassmer E, International Pediatric Multiple
482
Sclerosis Study G (2013) International Pediatric Multiple Sclerosis Study Group criteria for
483
pediatric multiple sclerosis and immune-mediated central nervous system demyelinating
484
disorders: revisions to the 2007 definitions. Mult Scler 19:1261-1267
485
24. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, et al.
486
(2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol
487
17:162-173
488
25. Torisu H, Kira R, Ishizaki Y, Sanefuji M, Yamaguchi Y, Yasumoto S, Murakami Y, Shimono M,
489
Nagamitsu S, Masuzaki M, Amamoto M, Kondo R, Uozumi T, Aibe M, Gondo K, Hanai T,
490
Hirose S, Matsuishi T, Shirahata A, Mitsudome A, Hara T (2010) Clinical study of childhood
491
acute disseminated encephalomyelitis, multiple sclerosis, and acute transverse myelitis in
492
Fukuoka Prefecture, Japan. Brain Dev 32:454-462
493
26. Yamaguchi Y, Torisu H, Kira R, Ishizaki Y, Sakai Y, Sanefuji M, Ichiyama T, Oka A, Kishi T,
494
Kimura S, Kubota M, Takanashi J, Takahashi Y, Tamai H, Natsume J, Hamano S, Hirabayashi S,
495
Maegaki Y, Mizuguchi M, Minagawa K, Yoshikawa H, Kira J, Kusunoki S, Hara T (2016) A
17
Ichimiya Y.
MOGAD and pain
496
nationwide survey of pediatric acquired demyelinating syndromes in Japan. Neurology 87:2006-
497
2015
498
27. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K,
499
Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee
500
AL, Waters P, Wellik KE, Weinshenker BG, International Panel for NMOD (2015) International
501
consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177-189
502
28. Torio M, Iwayama M, Sawano T, Inoue H, Ochiai M, Taira R, Yonemoto K, Ichimiya Y, Sonoda
503
Y, Sasazuki M, Ishizaki Y, Sanefuji M, Yamane K, Yamashita H, Torisu H, Kira R, Hara T,
504
Kanba S, Sakai Y, Ohga S (2021) Neurodevelopmental Outcomes of High-Risk Preterm Infants:
505
A Prospective Study in Japan. Neurol Clin Pract 11:398-405
506
29. Akaishi T, Himori N, Takeshita T, Misu T, Takahashi T, Takai Y, Nishiyama S, Kaneko K,
507
Fujimori J, Ishii T, Aoki M, Fujihara K, Nakazawa T, Nakashima I (2022) Follow-up of retinal
508
thickness and optic MRI after optic neuritis in anti-MOG antibody-associated disease and anti-
509
AQP4 antibody-positive NMOSD. J Neurol Sci 437:120269
510
30. Boesen MS, Blinkenberg M, Thygesen LC, Ilginiene J, Langkilde AR (2022) Magnetic
511
resonance imaging criteria at onset to differentiate pediatric multiple sclerosis from acute
512
disseminated encephalomyelitis: A nationwide cohort study. Mult Scler Relat Disord 62:103738
513
31. Tetsuhara K, Kaku N, Watanabe Y, Kumamoto M, Ichimiya Y, Mizuguchi S, Higashi K,
514
Matsuoka W, Motomura Y, Sanefuji M, Hiwatashi A, Sakai Y, Ohga S (2021) Predictive values
515
of early head computed tomography for survival outcome after cardiac arrest in childhood: a
516
pilot study. Sci Rep 11:12090
517
32. Jurynczyk M, Messina S, Woodhall MR, Raza N, Everett R, Roca-Fernandez A, Tackley G,
518
Hamid S, Sheard A, Reynolds G, Chandratre S, Hemingway C, Jacob A, Vincent A, Leite MI,
519
Waters P, Palace J (2017) Clinical presentation and prognosis in MOG-antibody disease: a UK
520
study. Brain 140:3128-3138
521
33. Ramanathan S, Prelog K, Barnes EH, Tantsis EM, Reddel SW, Henderson AP, Vucic S, Gorman
522
MP, Benson LA, Alper G, Riney CJ, Barnett M, Parratt JD, Hardy TA, Leventer RJ, Merheb V,
523
Nosadini M, Fung VS, Brilot F, Dale RC (2016) Radiological differentiation of optic neuritis
524
with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple
525
sclerosis. Mult Scler 22:470-482
526
34. Tenembaum S, Yeh EA, Guthy-Jackson Foundation International Clinical C (2020) Pediatric
527
NMOSD: A Review and Position Statement on Approach to Work-Up and Diagnosis. Front
528
Pediatr 8:339
18
Ichimiya Y.
MOGAD and pain
529
35. de Mol CL, Wong YYM, van Pelt ED, Ketelslegers IA, Bakker DP, Boon M, Braun KPJ, et al.
530
(2018) Incidence and outcome of acquired demyelinating syndromes in Dutch children: update
531
of a nationwide and prospective study. J Neurol 265:1310-1319
532
533
534
535
536
537
538
36. Beiske AG, Pedersen ED, Czujko B, Myhr KM (2004) Pain and sensory complaints in multiple
sclerosis. Eur J Neurol 11:479-482
37. Rae-Grant AD, Eckert NJ, Bartz S, Reed JF (1999) Sensory symptoms of multiple sclerosis: a
hidden reservoir of morbidity. Mult Scler 5:179-183
38. Osterberg A, Boivie J, Thuomas KA (2005) Central pain in multiple sclerosis--prevalence and
clinical characteristics. Eur J Pain 9:531-542
39. Fabri TL, O'Mahony J, Fadda G, Gur RE, Gur RC, Yeh EA, Banwell BL, Till C (2022)
539
Cognitive function in pediatric-onset relapsing myelin oligodendrocyte glycoprotein antibody-
540
associated disease (MOGAD). Mult Scler Relat Disord 59:103689
541
40. Marta CB, Oliver AR, Sweet RA, Pfeiffer SE, Ruddle NH (2005) Pathogenic myelin
542
oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb
543
oligodendrocyte physiology. Proc Natl Acad Sci U S A 102:13992-13997
544
41. Zackowski KM, Smith SA, Reich DS, Gordon-Lipkin E, Chodkowski BA, Sambandan DR,
545
Shteyman M, Bastian AJ, van Zijl PC, Calabresi PA (2009) Sensorimotor dysfunction in multiple
546
sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord.
547
Brain 132:1200-1209
548
549
550
42. Ding YQ, Qi JG (2022) Sensory root demyelination: Transforming touch into pain. Glia 70:397413
43. Sechi E, Krecke KN, Pittock SJ, Dubey D, Lopez-Chiriboga AS, Kunchok A, Weinshenker BG,
551
Zalewski NL, Flanagan EP (2021) Frequency and characteristics of MRI-negative myelitis
552
associated with MOG autoantibodies. Mult Scler 27:303-308
553
554
44. Absoud M, Greenberg BM, Lim M, Lotze T, Thomas T, Deiva K (2016) Pediatric transverse
myelitis. Neurology 87:S46-52
555
45. Silwal A, Pitt M, Phadke R, Mankad K, Davison JE, Rossor A, DeVile C, Reilly MM, Manzur
556
AY, Muntoni F, Munot P (2018) Clinical spectrum, treatment and outcome of children with
557
suspected diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy.
558
Neuromuscul Disord 28:757-765
559
46. Rinaldi S, Davies A, Fehmi J, Beadnall HN, Wang J, Hardy TA, Barnett MH, Broadley SA,
560
Waters P, Reddel SW, Irani SR, Brilot F, Dale RC, Ramanathan S, Australian, New Zealand
19
Ichimiya Y.
MOGAD and pain
561
MOGSG (2021) Overlapping central and peripheral nervous system syndromes in MOG
562
antibody-associated disorders. Neurol Neuroimmunol Neuroinflamm 8
563
47. Tanaka S, Hashimoto B, Izaki S, Oji S, Fukaura H, Nomura K (2020) Clinical and
564
immunological differences between MOG associated disease and anti AQP4 antibody-positive
565
neuromyelitis optica spectrum disorders: Blood-brain barrier breakdown and peripheral
566
plasmablasts. Mult Scler Relat Disord 41:102005
567
48. Kitley J, Waters P, Woodhall M, Leite MI, Murchison A, George J, Kuker W, Chandratre S,
568
Vincent A, Palace J (2014) Neuromyelitis optica spectrum disorders with aquaporin-4 and
569
myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 71:276-283
570
49. Doukas SG, Santos AP, Mir W, Daud S, Zivin-Tutela TH (2022) A Rare Case of Myelin
571
Oligodendrocyte Glycoprotein Antibody-Associated Transverse Myelitis in a 40-Year-Old
572
Patient With COVID-19. Cureus 14:e23877
573
50. Onouchi K, Koga H, Yokoyama K, Yoshiyama T (2014) An open-label, long-term study
574
examining the safety and tolerability of pregabalin in Japanese patients with central neuropathic
575
pain. J Pain Res 7:439-447
576
51. Kaneko K, Sato DK, Nakashima I, Ogawa R, Akaishi T, Takai Y, Nishiyama S, Takahashi T,
577
Misu T, Kuroda H, Tanaka S, Nomura K, Hashimoto Y, Callegaro D, Steinman L, Fujihara K,
578
Aoki M (2018) CSF cytokine profile in MOG-IgG+ neurological disease is similar to AQP4-
579
IgG+ NMOSD but distinct from MS: a cross-sectional study and potential therapeutic
580
implications. J Neurol Neurosurg Psychiatry 89:927-936
581
52. Dong Y, D'Mello C, Pinsky W, Lozinski BM, Kaushik DK, Ghorbani S, Moezzi D, Brown D,
582
Melo FC, Zandee S, Vo T, Prat A, Whitehead SN, Yong VW (2021) Oxidized
583
phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are
584
neutralized by microglia. Nat Neurosci 24:489-503
585
53. Kihara Y, Matsushita T, Kita Y, Uematsu S, Akira S, Kira J, Ishii S, Shimizu T (2009) Targeted
586
lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. Proc Natl Acad
587
Sci U S A 106:21807-21812
588
54. Masuda T, Sankowski R, Staszewski O, Bottcher C, Amann L, Sagar, Scheiwe C, Nessler S,
589
Kunz P, van Loo G, Coenen VA, Reinacher PC, Michel A, Sure U, Gold R, Grun D, Priller J,
590
Stadelmann C, Prinz M (2019) Spatial and temporal heterogeneity of mouse and human
591
microglia at single-cell resolution. Nature 566:388-392
592
593
55. Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, Walker AJ, Gergits
F, Segel M, Nemesh J, Marsh SE, Saunders A, Macosko E, Ginhoux F, Chen J, Franklin RJM,
20
Ichimiya Y.
MOGAD and pain
594
Piao X, McCarroll SA, Stevens B (2019) Single-Cell RNA Sequencing of Microglia throughout
595
the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes. Immunity
596
50:253-271 e256
597
56. Sugimoto K, Mori M, Liu J, Tanaka S, Kaneko K, Oji S, Takahashi T, Uzawa A, Uchida T,
598
Masuda H, Ohtani R, Nomura K, Hiwasa T, Kuwabara S (2019) The accuracy of flow cytometric
599
cell-based assay to detect anti-myelin oligodendrocyte glycoprotein (MOG) antibodies
600
determining the optimal method for positivity judgement. J Neuroimmunol 336:577021
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602
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MOGAD and pain
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Statements and Declarations
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Funding
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This study was supported by JSPS KAKENHI grant numbers JP17K16271 (Ichimiya), JP22K07893
606
(Sonoda), JP19K10613 (Chong), and JP21K07464 (Isobe); research grants from the Ministry of
607
Health, Labour and Welfare of Japan (JP22HA1003: Chong, JP21FC1005 and JP20FC1054: Sakai);
608
a research grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of
609
Health, Labour and Welfare of Japan (JP20FC1030: Isobe); AMED under the grant number
610
JP20ek0109411, JP20wm0325002h (Sakai) and JP21zf0127004 (Isobe); The Japan Epilepsy
611
Research Foundation, and Kawano Masanori Memorial Public Interest Incorporated Foundation for
612
Promotion of Pediatrics (Sakai).
613
614
Competing interests
615
The authors have no relevant financial or non-financial interests to disclose.
616
617
Ethics statement
618
This study was conducted in compliance with our institutional guidelines for clinical studies.
619
Research protocol was approved by the institutional review board at Kyushu University (21046-00).
620
For the presentation of cases, written informed consent was obtained from the parents.
621
622
Author contributions
623
All authors read and approved the final manuscript. Yuko Ichimiya: Data collection, formal
624
analysis, original draft preparation; Pin Fee Chong: Reviewing and editing, funding acquisition.
625
Yuri Sonoda: Data curation, investigation; Vlad Tocan: Investigation, reviewing and editing;
626
Toshiyuki Takahashi: Investigation; Mitsuru Watanabe: Validation; Hiroyuki Torisu: Data
627
collection, reviewing and editing; Ryutaro Kira: Data collection, reviewing and editing; Noriko
628
Isobe: Supervision, Reviewing and editing, funding acquisition; Junichi Kira: Supervision,
629
Reviewing and editing; Yasunari Sakai: Conceptualization, original draft preparation, reviewing and
630
editing; Shouichi Ohga: Conceptualization, funding acquisition, reviewing and editing.
631
632
Acknowledgments
633
We thank all the patients and parents for cooperatively participating in study; Dr. Toshiro Hara
634
(President, Fukuoka Children’s Hospital) and laboratory members for their helpful discussions.
635
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Ichimiya Y.
MOGAD and pain
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Figure legends
637
Figure 1. A selection flowchart for eligible subjects in this study
638
Patients were searched on International Statistical Classification of Diseases and Related Health
639
Problems 10th Revision (ICD-10) in our hospital. Among 108 patients, 31 met the inclusion criteria
640
(age <18 years and a diagnosis of acquired demyelinating syndrome [ADS]). Twenty-two received
641
cell-based tests for MOG-Ab (positive, n = 13; negative, n = 9). Nine patients with unknown
642
serostatus were removed from the analysis. ADEM, acute disseminated encephalomyelitis; CIS,
643
clinically isolated syndrome; ON, optic neuritis; MS, multiple sclerosis; Ab, antibody; +, positive; -,
644
negative.
645
646
Figure 2. Age, sex, diagnosis, and the follow-up periods of patients with MOGAD and MOG-Ab-
647
negative results
648
Age at the onset (vertical scale) and the duration of follow-up (horizontal scale) are shown for 13
649
patients with MOGAD (left) and 9 patients with MOG-Ab-negative results. Color codes indicate the
650
diagnostic categories of patients with acquired demyelinating syndromes (ADS).
651
Ab, antibody; ADEM, acute disseminated encephalomyelitis; CIS, clinically isolated syndrome;
652
MS, multiple sclerosis; ON, optic neuritis.
653
654
Figure 3. Somatosensory disturbances in the clinical course of the 22 patients
655
The presence and duration of somatosensory disturbances (red) are shown for each patient. The
656
types of ADS (ADEM, CIS, ON) at the disease onset are indicated by color.
657
658
Figure 4. Neuroimaging features of childhood-onset ADS and MOGAD
659
(A) Axial slices of fluid-attenuated inversion recovery (FLAIR). Patients with MOGAD (#1 to 13)
660
and those with MOG-Ab-negative results (#14 to 22) showed variable degrees of T2-
661
hyperintense lesions. Red font indicates patients with somatosensory disturbances.
662
(B) Violin-dot plots show the MRI scores of patients with MOGAD and MOG-Ab-negative results.
663
Red circles denote the patients with somatosensory disturbances. *P<0.05 (Wilcoxon’s rank sum
664
test).
665
(C) Pie charts indicate the composition (%) of affected brain regions in patients with MOGAD and
666
those with MOG-Ab-negative results. CTX/WM, cerebral cortex and white matter; HP/TH,
667
hippocampus and thalamus; SP/BS, spinal cord and brainstem; BG/CN, basal ganglia and
668
caudate nucleus; CB, cerebellum; and ON, optic nerve.
23
Table S1. Timepoints, methods and results of MOG-antibody tests for the present cases
MOG-Ab test†
Age at
(Years or months after the onset, Method-sample, Titer)
ID onset Diagnosis
st
(year)
2nd
3rd
2.5
MOGAD Onset, CBA-serum, 512
years, CBA-serum, 128
4.1
MOGAD 44 years,
5 years, CBA-serum, negative
CBA-CSF, 32
6.0
MOGAD
Onset, CBA-serum, 1024
7.3
MOGAD
Onset, CBA-serum,128
7.6
MOGAD
Onset, CBA-serum,1024
9.1
MOGAD
Onset, CBA-serum, 4096
10.8
MOGAD
Onset, CBA-serum, 256
13.8
MOGAD
Onset, CBA-serum, 8192
11.7
MOGAD
Onset, CBA-serum, 128
10
1.7
MOGAD
Onset, CBA-serum, 2048
11
8.8
MOGAD
Onset, CB-serum, Y
12
12.3
MOGAD
13
13.2
MOGAD
14
7.5
MS
Onset, CB-serum, Y
Onset, CBA-serum, 128
Onset, CBA-CSF, 4
Onset, CB-serum, -
15
9.3
MS
Onset, CB-serum, -
16
0.6
CIS
Onset, CB-serum, -
17
1.3
ADEM
Onset, CB-serum, -
18
3.2
CIS
Onset, CB-serum, -
19
4.4
ADEM
Onset, CB-serum, -
20
5.6
ADEM
Onset, CB-serum, -
21
10.3
ADEM
Onset, CB-serum, -
4 months, CBA-serum, 128
4th
42 months, CBA-serum, 128
47 month, CBA-serum,
negative
10 months, CBA-serum, 8192
26 months, CBA-serum, 4096
14 months, CBA-serum, 2048
30 months, CBA-serum,
negative
1 month, CBA-serum, 8192
3 months, CBA-serum,128
3 months, CBA-CSF, 4
22
15.0
ON
Onset, CB-serum, CB = cell-based binary test (commercially provided); CBA = cell-based semiquantitative assay. Data represent Y (yes, present) and - (absent) in CB tests.
Ab = antibody; ADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; MOGAD = MOG-Ab-associated disorder; MS = multiple
sclerosis; NMOSD = neuromyelitis optica spectrum disorder; and ON = optic neuritis.
Table S2. Demographics of 22 subjects and 9 patients with unknown serostatus
Participants, n = 22
Age at onset, median year [range]
Female (%)
MOGAD
n = 13
MOG-Ab negative
n=9
Serostatus unknown
(excluded)
n=9
8 [1.7-13.8] †
9 (69)
5 [0.6-15.0]
4 (44)
8 [0.6-16.7]
4 (44)
0.257 ‡
0.693 §
5 (38)
5 (38)
3 (23)
0 (0)
5 (56)
2 (22)
2 (22)
0 (0)
2 (22)
5 (55)
0 (0)
2 (22)
0.418 §
0.253 §
0.286 §
0.077 §
13 (100)
7 (54)
3 (23)
3 (23)
8 (89)
2 (22)
0 (0)
2 (22)
9 (100)
1 (11)
2 (22)
2 (22)
1.0 §
0.205 §
0.613 §
1.0 §
P-value
Participants vs. excluded
ADS type at onset
ADEM (%)
CIS (%)
ON (%)
NMOSD (%)
Treatment
IMP (%)
IVIG (%)
PE (%)
DMT (%)
Follow-up period, median months [range]
44 [5-134]
69 [5-167]
63 [1-198]
0.500 ‡
Number of recurrences, median [range]
6 [0-9]
1 [0-2]
6 [0-9]
0.843 ‡
Sensory problems (%)
12 (92)
3 (33)
2 (22)
0.0439 §
Age represents years; ‡ Wilcoxon’s rank sum test; and § Fisher’s exact test
Ab = antibody, ADEM = acute disseminated encephalomyelitis, MS = multiple sclerosis, CIS = clinically isolated syndrome, ON = optic neuritis, NMOSD =
neuromyelitis optica spectrum disorder, MOGAD = MOG-Ab-associated disorder, IMP = intravenous methylprednisolone pulse, IVIG = intravenous
immunoglobulin, PE= plasma exchange, DMT = disease-modifying therapy
Table S3. The diagnosis, clinical signs and MOG-Ab status of patients in the present study
ID
Age
at onset†
Sex
2.5
Diagnosis
Onset
Last visit
CIS
MOGAD
4.1
ADEM
6.0
7.3
Prodromal sign
Sensory problems
Headache
Somatosensory
Gait disturbance
MOGAD
Seizure
ADEM
MOGAD
Fever, coma
ADEM
MOGAD
Fever, coma
7.6
CIS
MOGAD
Fever
Systemic pain
Dysesthesia of
tongue
Dysesthesia of
penile to perineal
region
Chest pain
Hypesthesia,
Headache
9.1
ON
MOGAD
10.8
CIS
MOGAD
13.8
CIS
MOGAD
11.7
ON
MOGAD
10
1.7
ADEM
MOGAD
11
8.8
ON
MOGAD
12
12.3
ADEM
MOGAD
13
13.2
CIS
MOGAD
14
7.5
ON
MS
15
9.3
CIS
MS
16
17
18
19
20
21
0.6
1.3
3.2
4.4
5.6
10.3
ADEM
ADEM
CIS
ADEM
ADEM
ADEM
ADEM
ADEM
CIS
ADEM
ADEM
ADEM
22
15.0
ON
ON
years;
Visual
impairment
Visual
impairment
Visual
impairment
Visual
impairment
Seizure
Visual
impairment
Coma
Visual
impairment
Visual
impairment
Follow-up
(months)
134
Presence or absence of MOG Ab‡
Onset
Peak
Last
512
Not
tested
512 (onset)
NA
Treatment
IMP, IVIG
128 (84 mo)
Negative
IMP, SCIG
55
1024
1024 (onset)
Negative
IMP, IVIG
35
1024
1024 (onset)
Negative
92
1024
2048 (12 mo)
IMP, IVIG, PE
IMP, IFN, DMT,
SCIG, RTX
128
Relapse,
Type of
ADS
MS
r-ADEM
Ophthalmalgia
75
4096
4096 (onset)
Negative
IMP
Dysesthesia
44
256
256 (onset)
Negative
IMP
Hypesthesia
36
8192
8192 (onset)
4096
IMP, IVIG, PE,
DMT
r-ON
47
128
128 (onset)
NA
IMP
Ophthalmalgia,
Dysesthesia
24
2048
2048 (onset)
NA
IMP, IVIG
NA
NA
IMP
49
NA
NA
IMP, IVIG
20
128
128 (1 mo)
128 (3 mo)
Ophthalmalgia
105
IMP, IFN
Paralysis
Dysesthesia
167
IMP, IFN
Paralysis
Fever, coma
Paralysis
Fever, Seizure
Fever, Seizure
Fever, coma
Visual
impairment
69
13
34
71
91
46
IMP
IMP
IMP, IVIG
IMP, IVIG
IMP
IMP
Y, yes (present) or MOG Ab-positive; -, absent or MOG Ab-negative; NA, not available
IMP, IVIG, PE
r-ADEM
r-ON
MS
Ab = antibody; ADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; DMT = disease-modifying therapy; IFN = interferon-β1;
IMP = intravenous methylprednisolone pulse; IVIG = intravenous immunoglobulin; MOGAD = MOG-Ab-associated disorder; MS = multiple sclerosis;
NMOSD = neuromyelitis optica spectrum disorder; ON = optic neuritis; PE = plasma exchange; r-ADEM/ON = recurrent ADEM/ON; RTX = rituximab; SCIG
= subcutaneous infusion of immunoglobulin.
Table S4. Summary of laboratory test results
Blood test
Cerebrospinal fluid
ID
Age at
onset,
year
Diagnosis
Leukocyte, µl
(Neutrophil, %)
C-reactive protein,
mg/dl
Cell count, µl
Protein, mg/dl
IgG index
MBP, ng/ml
2.5
MOGAD
10540
0.07
17
26
0.62
352
4.1
MOGAD
17380
0.84
22
0.51
352
6.0
MOGAD
6720
0.35
10
24
0.26
＜31.3
7.3
MOGAD
16120
0.33
410
366
0.77
275
7.6
MOGAD
16400
0.38
17
27
NA
7010
9.1
MOGAD
13630
0.09
19
0.53
130
10.8
MOGAD
5700
0.01
10
39
0.42
40
13.8
MOGAD
7090
0.01
32.5
0.62
<40
11.7
MOGAD
10210
0.01
10
57
0.64
＜31.3
10
1.7
MOGAD
15810
0.28
15
0.69
1750
11
8.8
MOGAD
6820
0.07
NA
NA
NA
571
12
12.3
MOGAD
6580
0.03
35
70
0.62
1750
13
13.2
MOGAD
7150
0.02
17
47
0.67
60.1
14
7.5
MS
10060
0.10
31
28
0.43
56.6
15
9.3
MS
9180
0.01
15
0.5
405
16
0.6
CIS
16670
0.03
51
0.56
450
17
1.3
ADEM
2230
0.24
23
0.88
436
18
3.2
CIS
11210
0.63
20
0.5
＜31.3
19
4.4
ADEM
18420
0.08
17
NA
932
20
5.6
ADEM
4150
0.72
NA
NA
21
10.3
ADEM
6040
0.01
10
48
0.29
< 31.3
22
15.0
ON
6130
MBP = myelin basic protein, NA = not available
0.01
27
0.46
< 31.3
Table S5. Summary of neuroimaging features
BS
CB
HIP+TH
ON
ID
11
12
15
16
19
20
10
11
12
13
14
15
16
BG
ROI
CTX
Sum
17
18
10
13
14
13
13
11
11
13
13
13
13
10
10
10
105
53
104
10
119
92
55
76
10
11
91
13
13
12
12
12
12
107
96
10
96
27
98
11
11
13
13
24
23
22
21
62
30
17
18
19
20
21
22
...
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