- Open Access
MOG encephalomyelitis: international recommendations on diagnosis and antibody testing
Journal of Neuroinflammationvolume 15, Article number: 134 (2018)
Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM (“red flags”) that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.
Over the past few years, the role of immunoglobulin G serum antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) in patients with inflammatory CNS demyelination has been revisited. While antibodies to MOG were originally thought to be involved in multiple sclerosis (MS), based on results from enzyme-linked immunosorbent assays employing linearized or denatured MOG peptides as antigen, more recent studies using new-generation cell-based assays have demonstrated a robust association of antibodies to full-length, conformationally intact human MOG protein with (mostly recurrent) optic neuritis (ON), myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations, rather than with classic MS [1,2,3,4,5,6,7,8,9,10,11].
Based on evidence from (a) immunological studies suggesting a direct pathogenic impact of MOG-IgG, (b) neuropathological studies demonstrating discrete histopathological features, (c) serological studies reporting a lack of aquaporin-4 (AQP4)-IgG in almost all MOG-IgG-positive patients, and (d) cohort studies suggesting differences in clinical and paraclinical presentation, treatment response and prognosis, MOG-IgG is now considered to denote a disease entity in its own right, distinct from classic MS and from AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD), which is now often referred to as MOG-IgG-associated encephalomyelitis (MOG-EM) [11,12,13].
Importantly, however, MOG-EM and MS show a relevant phenotypic, i.e., clinical as well as radiological, overlap [3, 14]: like MS, MOG-EM follows a relapsing course in most cases [3, 6], at least in adults, and 33 and 15% of adult patients with MOG-EM meet McDonald’s and Barkhof’s criteria for MS, respectively, at least once over the course of disease [3, 14]. Accordingly, many patients with MOG-EM were falsely classified as having MS in the past [3, 4]. However, such misclassification has potential therapeutic implications: (a) similar to what has been observed in AQP4-IgG-positive NMOSD, some drugs approved for MS might be ineffective or even harmful in MOG-EM owing to differences in immunopathogenesis [3, 4, 15,16,17]; (b) MOG-EM is associated with a high risk of flare-ups after cessation of steroid treatment for acute attacks and may thus require close monitoring and careful steroid tapering [3, 18,19,20,21,22]; and (c) patients positive for MOG-IgG might be particularly responsive to antibody-depleting treatments for acute attacks such as plasma exchange or immunoadsorption [3, 4, 9, 14, 23, 24], to B cell-targeted long-term therapies such as rituximab, to treatment with intravenous immunoglobulins (IVIG) (especially in children ), and to immunosuppressive treatments [3, 6, 14, 25, 26]. Therefore, increasing numbers of patients with suspected or established MS are currently being screened for MOG-IgG.
However, screening of large unselected populations for rare biomarkers generally decreases the positive predictive value of diagnostic tests by increasing the rate of false-positive results [27, 28]. Even if assays with high specificity (≥99%) are used, true-positive (TP) results can easily be outnumbered by false-positive (FP) results if the prevalence of a marker is low and the number of samples tested is high. This also applies to MOG-IgG testing. Based on a hypothetical prevalence of 1% genuinely MOG-IgG-positive cases among all patients currently diagnosed with MS, testing of 100,000 patients with an almost flawless, 99% specific and 100% sensitive assay would result in an unacceptable ratio of 990 FP results to 1000 TP results. Therefore, unselected screening of all patients with suspected or established MS for MOG-IgG should be discouraged and more specific criteria for MOG-IgG testing are urgently needed.
In this paper, we propose for the first time indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions considered atypical for MOG-EM (“red flags”) that should prompt physicians to challenge the validity of a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling, and data interpretation.
PubMed was searched for articles published between February 2007 and February 2017 using the following search term: (“myelin oligodendrocyte glycoprotein” OR MOG) AND (antibody OR antibodies OR IgG). All articles identified by this means were reviewed by a core group of physicians (S.J., B.W., F.P., K.R.) for clinical and paraclinical findings that have been frequently reported in association with MOG-IgG seropositivity in patients with CNS demyelination and which, therefore, may justify MOG-IgG testing, as well as for potential “red flags”, i.e., conditions that are typically found in inflammatory disorders of the CNS but have been reported to be absent or very rare in MOG-IgG-positive patients and thus may indicate diagnoses other than MOG-EM. Based on core group consensus, a first set of recommendations was formulated and then circulated to a broader panel of experts in the field from Australia, Denmark, France, Germany, Italy, Japan, South Korea, Spain, UK, and the USA for discussion and refinement. Panel members were invited by the core group based on eminence and previous contributions to the field. Based on several rounds of core group-led peer-to-peer discussions of the individual recommendations with all individual members of the panel, a final set of evidence- as well as eminence-based recommendations was drawn up to which all members gave their approval. All recommendations given here should be considered as expert consensus.
Recommendations on MOG-IgG testing
In Table 1, we propose indications for MOG-IgG testing based on clinical and paraclinical findings that are typical of MOG-EM and/or atypical for MS and were considered by the panel members to be associated with pre-test odds high enough to justify MOG-IgG testing or that demand MOG-IgG testing because of potentially significant therapeutic consequences of a positive test result according to expert consensus. These recommendations apply to all patients with suspected CNS demyelination of putative autoimmune etiology and an either monophasic or relapsing disease course. Given the very low pre-test probability , we recommend against general MOG-IgG testing in patients with a progressive disease course. In Table 2, we give a number of case vignettes of patients considered to be at high risk of MOG-EM to illustrate the broad spectrum of symptoms associated with that syndrome and the practical feasibility and relevance of the proposed criteria. In Table 3, we give a number of recommendations regarding assay selection, specimen sampling, and data interpretation. Finally, Table 4 lists conditions (“red flags”) that we believe are atypical for MOG-EM and should thus prompt physicians to challenge a positive MOG-IgG test result and seek a better explanation for the patients’ clinical and paraclinical findings.
In practice, many patients diagnosed with AQP4-IgG-negative NMOSD according to the IPND 2015 criteria  will meet also the criteria for MOG-IgG testing given in Table 1 and should thus be tested. However, MOG-IgG testing should not be restricted to patients with AQP4-IgG-negative NMOSD. While this approach seems to offer simplicity, it would be inappropriate for several reasons: (1) The IPND criteria for AQP4-IgG-negative NMOSD demand dissemination in space, which would prevent testing of many patients with syndromes compatible with MOG-EM (e.g., patients with isolated longitudinally extensive transverse myelitis [LETM], isolated bilateral ON, or isolated brainstem encephalitis). (2) They include magnetic resonance imaging (MRI) criteria that are based on lesion distribution patterns observed in AQP4-IgG-positive NMOSD, some of which reflect areas of high AQP4 expression; however, AQP4 is not the target antigen in MOG-EM. Accordingly, lesion distribution may differ between NMOSD and MOG-EM and some MOG-EM patients do not satisfy these criteria (e.g., patients with recurrent bilateral non-longitudinal ON without chiasm involvement plus non-NMOSD-typical brain lesions, those with severe and recurrent non-longitudinally extensive myelitis, and those with ADEM-like presentation with severe brain and brainstem involvement but no area postrema lesion). (3) Such a recommendation would imply testing of all patients for AQP4-IgG before they were tested for MOG-IgG, which might unnecessarily delay diagnosis and treatment. (4) The criteria for AQP4-IgG-negative NMOSD require exclusion of other diagnoses; this would constitute a logical repugnancy, since a negative test for MOG-IgG would be a prerequisite for MOG-IgG testing. (5) Finally, but less importantly, using NMOSD criteria for diagnosing MOG-EM would, in addition to resulting in a substantial loss in sensitivity and specificity, also be confusing to non-experts, given that AQP4-IgG-positive NMOSD and MOG-EM are distinct diseases with different target antigens (AQP4 vs. MOG), pathophysiology (astrocytopathy vs. primary demyelination), and clinical spectra.
Alternatively, should we restrict MOG-IgG testing to patients with AQP4-IgG-negative NMO according to Wingerchuk’s 2006 criteria ? This would again result in a substantial loss of patients at high risk of MOG-EM, since those criteria require a history of both ON and myelitis and would thus be inappropriate. Of note, MOG-IgG testing in patients with seronegative NMO according to the 2006 criteria is already covered by our recommendation to test all patients with LETM for MOG-IgG (see Table 1), since the 2006 criteria strictly require a history of LETM in patients negative for AQP4-IgG.
Instead, we propose to base the indication for MOG-IgG testing in patients with suspected CNS demyelination on the presence of specific clinical and paraclinical findings that are considered typical for MOG-EM and/or atypical for conventional MS (see Table 1).
During the consensus-finding process, concerns were raised regarding inclusion of the following treatment-related indications for MOG-IgG testing in Table 1:
Particularly good response to antibody-depleting therapies (plasma exchange [PEX], immunoadsorption [IA])
Particularly good response to B cell-depleting therapies (rituximab, ocrelizumab, ofatumumab) but relapse immediately after re-occurrence of B cells
It was argued by some members of the panel that good responses to PEX, IA, or B cell depletion have also been observed in conventional MS. However, consensus was achieved that if present in addition to any of the indications listed in Table 1, good response to antibody or B cell-depleting treatments or IVIG further increases the pre-test likelihood of MOG-EM and thus supports the decision to test for MOG-IgG.
Taking into account that MOG-IgG serum concentrations depend on disease activity (with higher concentrations during acute attacks) and treatment status (with lower concentrations while on immunosuppression) as well as on assay sensitivity, we recommend re-testing patients during acute attacks or during treatment-free intervals and/or in a second cell-based assay if MOG-IgG was negative at first examination but MOG-EM is still suspected based on the list of indications given in Table 1 .
Only sparse data are available on the usefulness of regular monitoring of antibody titers in individual patients known to be positive for MOG-IgG. Median MOG-IgG titers have indeed been shown to be significantly higher during relapse than during remission , making regular MOG-IgG testing a potentially promising method for predicting attacks and monitoring treatment efficacy. However, there are several limitations: While titers > 1:2560 were found only during acute attacks in a recent study using a live cell-based assay , some patients still had relatively low titers during acute attacks and others had relatively high titers during remission, suggesting that additional factors such as blood–CSF barrier damage, T cell activation, antibody affinity, or complement-activating activity may be involved, with no general cut-off value for relapse induction . In addition, treatment effects could play a role. Finally, intervals sufficient to detect imminent attacks in time have not yet been defined. Based on experience from studies on AQP4-IgG-positive NMOSD, in which serum antibody levels rise only very shortly before an attack , very close testing intervals may be required, which would make monitoring both expensive and challenging from a practical point of view. Accordingly, no general recommendation for regular monitoring of MOG-IgG titers for relapse prediction or treatment monitoring can currently be made.
Of note, some patients have been reported in whom MOG-IgG disappeared over time [2, 33,34,35]. Interestingly, many of these patients had monophasic disease. By contrast, MOG-IgG was detectable at the last follow-up in all patients (n = 18) with a relapsing disease course and available follow-up samples (mean interval 33 months since first testing; maximum follow-up period 10 years) in a recent study . Disappearance of MOG-IgG after the initial attack might thus have prognostic implications, and re-testing of MOG-IgG-positive patients 6–12 months after the first attack might therefore be useful. However, there are some limitations: Most of the reported monophasic patients were children or juveniles, and most had ADEM. Moreover, no long-term data were provided for most cases. This is important, since titers may fall below cut-off temporarily following treatment with steroids, plasma exchange, or immunosuppressants (or even spontaneously) and rise again at a later disease stage; accordingly, (transient) seroconversion has also been observed in a few patients with relapsing disease [2, 14, 33]. It would therefore be challenging to base long-term treatment decisions solely on whether MOG-IgG disappears or not after a first attack. If long-term treatment with immunosuppressants or oral steroids is abandoned by reason of conversion to seronegativity, close monitoring of the patient’s MOG-IgG serostatus is highly recommended to confirm seronegativity in the long-term course. Before making a diagnosis of “monophasic” MOG-EM and thus a decision against long-term treatment, one should also take into account that the interval between first and second attack in relapsing MOG-EM varies considerably among patients, with the second clinical attack occurring only after an interval of several years in some cases .
Diagnostic criteria for MOG-EM
There is an unmet need for diagnostic criteria for MOG-EM. However, no specific clinical or radiological findings (except for the general requirement of a demyelinating CNS lesion) have yet been identified that are present in all MOG-IgG-positive patients and which would thus represent a diagnostic sine qua non. A lack of Dawson’s finger lesions and ovoid/round lesions on brain MRI have been proposed to be typical for MOG-EM, but this awaits confirmation in independent and larger cohorts [36, 37]. We propose that for the time being MOG-EM should be diagnosed in all patients who meet all of the following criteria:
Monophasic or relapsing acute ON, myelitis, brainstem encephalitis, or encephalitis, or any combination of these syndromes
MRI or electrophysiological (visual evoked potentials in patients with isolated ON) findings compatible with CNS demyelination
Seropositivity for MOG-IgG as detected by means of a cell-based assay employing full-length human MOG as target antigen
In patients with conditions considered “red flags” as defined in Table 4 and in whom MOG-IgG has not yet been confirmed in a second (and third if necessary), methodologically different cell-based assay, a diagnosis of “possible MOG-EM” should be made, especially in the context of clinical studies and treatment trials.
Limitations and caveats
It is a limitation that all recommendations given here are necessarily based on expert consensus, owing to a lack of systematic and prospective studies. Moreover, as a general caveat, it should be stressed that before a diagnosis of MOG-EM is made, all available information, including clinical, radiological, electrophysiological, and laboratory data, need to be taken into account, and differential diagnoses, some of which are listed in Table 4, need to be excluded. Most of the information given in a previous consensus paper on differential diagnosis in MS  is also pertinent to MOG-EM. Finally, while the criteria proposed here can certainly help in identifying pediatric patients at high risk of being positive for MOG-IgG, they are primarily intended for use in adults and adolescents. Indications for MOG-IgG testing in children do not need to be as rigorous as in adults, since MOG-IgG is thought to be much more common in children with acquired demyelinating disease (up to 70% depending on age) than in their adult counterparts (≤ 1% in Western countries; probably ≤ 5% in Japan and other Asian countries because of lower MS prevalence). In consequence, the risk of an unfavorable ratio of FP to TP results outlined above is lower in children. While ADEM is the predominant clinical association in young children, in older children with MOG antibodies there is a shift towards presentation with ON, myelitis, and/or brainstem symptoms .
Here, we give for the first time indications for MOG-IgG testing and propose preliminary criteria for the diagnosis of MOG-EM. While we believe that our recommendations are highly timely considering the large numbers of patients currently being tested, we are well aware that they reflect current knowledge in an evolving field and may need to be adjusted when new clinical and paraclinical data emerge and novel and optimized assays become available.
Acute disseminated encephalomyelitis
ADEM with recurrent ON
Central nervous system
Chronic relapsing inflammatory optic neuropathy
Longitudinally extensive transverse myelitis
Myelin oligodendrocyte glycoprotein
Magnetic resonance imaging
Measles, rubella and zoster virus
NMO spectrum disorder
Oligoclonal IgG bands
Progressive multifocal leukoencephalopathy
Primary progressive MS
Posterior reversible encephalopathy syndrome
Secondary progressive MS
Visual evoked potentials
White cell count
Mader S, Gredler V, Schanda K, Rostasy K, Dujmovic I, Pfaller K, Lutterotti A, Jarius S, Di Pauli F, Kuenz B, et al. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J Neuroinflammation. 2011;8:184.
Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, Pache F, Stich O, Beume LA, Hummert MW, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin. J Neuroinflammation. 2016;13:279.
Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, Pache F, Stich O, Beume LA, Hummert MW, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation. 2016;13:280.
Jarius S, Kleiter I, Ruprecht K, Asgari N, Pitarokoili K, Borisow N, Hummert MW, Trebst C, Pache F, Winkelmann A, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: brainstem involvement - frequency, presentation and outcome. J Neuroinflammation. 2016;13:281.
Pache F, Zimmermann H, Mikolajczak J, Schumacher S, Lacheta A, Oertel FC, Bellmann-Strobl J, Jarius S, Wildemann B, Reindl M, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients. J Neuroinflammation. 2016;13:282.
Sepulveda M, Armangue T, Martinez-Hernandez E, Arrambide G, Sola-Valls N, Sabater L, Tellez N, Midaglia L, Arino H, Peschl P, et al. Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes. J Neurol. 2016;263:1349–60.
Kitley J, Waters P, Woodhall M, Leite MI, Murchison A, George J, Kuker W, Chandratre S, Vincent A, Palace J. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71:276–83.
Sato DK, Callegaro D, Lana-Peixoto MA, Waters PJ, de Haidar Jorge FM, Takahashi T, Nakashima I, Apostolos-Pereira SL, Talim N, Simm RF, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014;82:474–81.
Kitley J, Woodhall M, Waters P, Leite MI, Devenney E, Craig J, Palace J, Vincent A. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology. 2012;79:1273–7.
Ramanathan S, Dale RC, Brilot F. Anti-MOG antibody: the history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination. Autoimmun Rev. 2016;15:307–24.
Reindl M, Jarius S, Rostasy K, Berger T: Myelin oligodendrocyte glycoprotein antibodies: How clinically useful are they? Curr Opin Neurol. 2017;30:295–301.
Zamvil SS, Slavin AJ. Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder? Neurol Neuroimmunol Neuroinflamm. 2015;2:e62.
Hohlfeld R, Dornmair K, Meinl E, Wekerle H. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol. 2016;15:317–31.
Spadaro M, Gerdes LA, Krumbholz M, Ertl-Wagner B, Thaler FS, Schuh E, Metz I, Blaschek A, Dick A, Bruck W, et al. Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3:e257.
Miyazaki T, Nakajima H, Motomura M, Tanaka K, Maeda Y, Shiraishi H, Tsujino A. A case of recurrent optic neuritis associated with cerebral and spinal cord lesions and autoantibodies against myelin oligodendrocyte glycoprotein relapsed after fingolimod therapy. Rinsho Shinkeigaku. 2016;56:265–9.
Tsuburaya RS, Miki N, Tanaka K, Kageyama T, Irahara K, Mukaida S, Shiraishi K, Tanaka M. Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in a Japanese boy with recurrent optic neuritis. Brain and Development. 2015;37:145–8.
Wildemann B, Jarius S, Schwarz A, Diem R, Viehöver A, Hähnel S, Reindl M, Korporal-Kuhnke M. Failure of alemtuzumab therapy to control MOG encephalomyelitis. Neurology. 2017;89:207–9.
Chalmoukou K, Alexopoulos H, Akrivou S, Stathopoulos P, Reindl M, Dalakas MC. Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm. 2015;2:e131.
Mayer MC, Breithaupt C, Reindl M, Schanda K, Rostasy K, Berger T, Dale RC, Brilot F, Olsson T, Jenne D, et al. Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J Immunol. 2013;191:3594–604.
Ramanathan S, Reddel SW, Henderson A, Parratt JD, Barnett M, Gatt PN, Merheb V, Kumaran RY, Pathmanandavel K, Sinmaz N, et al. Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm. 2014;1:e40.
Matsuda R, Kezuka T, Umazume A, Okunuki Y, Goto H, Tanaka K. Clinical profile of anti-myelin oligodendrocyte glycoprotein antibody seropositive cases of optic neuritis. Neuroophthalmology. 2015;39:213–9.
Nishikawa Y, Oku H, Tonari K, Sugasawa J, Ikeda T. A case of CRION with high titer of MOG antibody. Neuro Ophthalmol Japan. 2016;33:27–31.
Oshiro A, Nakamura S, Tamashiro K, Fujihara K. Anti-MOG + neuromyelitis optica spectrum disorders treated with plasmapheresis. No To Hattatsu. 2016;48:199–203.
Spadaro M, Gerdes LA, Mayer MC, Ertl-Wagner B, Laurent S, Krumbholz M, Breithaupt C, Hogen T, Straube A, Giese A, et al. Histopathology and clinical course of MOG-antibody-associated encephalomyelitis. Ann Clin Transl Neurol. 2015;2:295–301.
Hacohen Y, Wong YY, Lechner C, Jurynczyk M, Wright S, Konuskan B, Kalser J, Poulat AL, Maurey H, Ganelin-Cohen E, et al. Disease Course and Treatment Responses in Children With Relapsing Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease. JAMA Neurol. 2018;epub ahead of print (https://doi.org/10.1001/jamaneurol.2017.4601).
Montcuquet A, Collongues N, Papeix C, Zephir H, Audoin B, Laplaud D, Bourre B, Brochet B, Camdessanche JP, Labauge P, et al. Effectiveness of mycophenolate mofetil as first-line therapy in AQP4-IgG, MOG-IgG, and seronegative neuromyelitis optica spectrum disorders. Mult Scler. 2017;23:1377–84.
Kister I, Paul F. Pushing the boundaries of neuromyelitis optica: does antibody make the disease? Neurology. 2015;85:118–9.
Jarius S, Wildemann B. Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical review of the literature. Brain Pathol. 2013;23:661–83.
Jarius S, Ruprecht K, Stellmann JP, Huss A, Ayzenberg I, Willing A, Trebst C, Pawlitzki M, Abdelhak A, Grüter T, et al: MOG-IgG in primary and secondary chronic progressive multiple sclerosis: a multicenter study of 200 patients and review of the literature. J Neuroinflammation 2018;15:88.
Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85:177–89.
Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66:1485–9.
Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, Lang W, Reindl M, Vincent A, Kristoferitsch W. Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain. 2008;131:3072–80.
Probstel AK, Dornmair K, Bittner R, Sperl P, Jenne D, Magalhaes S, Villalobos A, Breithaupt C, Weissert R, Jacob U, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology. 2011;77:580–8.
Di Pauli F, Mader S, Rostasy K, Schanda K, Bajer-Kornek B, Ehling R, Deisenhammer F, Reindl M, Berger T. Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases. Clin Immunol. 2011;138:247–54.
Hoftberger R, Sepulveda M, Armangue T, Blanco Y, Rostasy K, Cobo Calvo A, Olascoaga J, Ramio-Torrenta L, Reindl M, Benito-Leon J, et al. Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease. Mult Scler. 2015;21:866–74.
Jurynczyk M, Geraldes R, Probert F, Woodhall MR, Waters P, Tackley G, Deluca G, Chandratre S, Leite MI, Vincent A, Palace J: Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis. Brain. 2017;140:617–27.
Jurynczyk M, Tackley G, Kong Y, Geraldes R, Matthews L, Woodhall M, Waters P, Kuker W, Craner M, Weir A, et al. Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease. J Neurol Neurosurg Psychiatry. 2017;88:132–6.
Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, Galetta SL, Hutchinson M, Johnson RT, Kappos L, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008;14:1157–74.
Mariotto S, Ferrari S, Monaco S, Benedetti MD, Schanda K, Alberti D, Farinazzo A, Capra R, Mancinelli C, De Rossi N, et al: Clinical spectrum and IgG subclass analysis of anti-myelin oligodendrocyte glycoprotein antibody-associated syndromes: a multicenter study. J Neurol 2017, 264:2420-2430.
Jarius S, Ruprecht K, Wildemann B, Kuempfel T, Ringelstein M, Geis C, Kleiter I, Kleinschnitz C, Berthele A, Brettschneider J, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation. 2012;9:14.
Baumann M, Grams A, Djurdjevic T, Wendel EM, Lechner C, Behring B, Blaschek A, Diepold K, Eisenkolbl A, Fluss J, et al: MRI of the first event in pediatric acquired demyelinating syndromes with antibodies to myelin oligodendrocyte glycoprotein. J Neurol. 2018;265:845–55.
van Pelt ED, Wong YY, Ketelslegers IA, Hamann D, Hintzen RQ. Neuromyelitis optica spectrum disorders: comparison of clinical and magnetic resonance imaging characteristics of AQP4-IgG versus MOG-IgG seropositive cases in the Netherlands. Eur J Neurol. 2016;23:580–7.
Ramanathan S, Prelog K, Barnes EH, Tantsis EM, Reddel SW, Henderson AP, Vucic S, Gorman MP, Benson LA, Alper G, et al. Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis. Mult Scler. 2016;22:470–482.
Mealy MA, Whetstone A, Orman G, Izbudak I, Calabresi PA, Levy M. Longitudinally extensive optic neuritis as an MRI biomarker distinguishes neuromyelitis optica from multiple sclerosis. J Neurol Sci. 2015;355:59–63.
Akaishi T, Nakashima I, Takeshita T, Mugikura S, Sato DK, Takahashi T, Nishiyama S, Kurosawa K, Misu T, Nakazawa T, et al. Lesion length of optic neuritis impacts visual prognosis in neuromyelitis optica. J Neuroimmunol. 2016;293:28–33.
Storoni M, Davagnanam I, Radon M, Siddiqui A, Plant GT. Distinguishing optic neuritis in neuromyelitis optica spectrum disease from multiple sclerosis: a novel magnetic resonance imaging scoring system. J Neuroophthalmol. 2013;33:123–127.
Bouzar M, Daoudi S, Hattab S, Bouzar AA, Deiva K, Wildemann B, Reindl M, Jarius S. Neuromyelitis optica spectrum disorders with antibodies to myelin oligodendrocyte glycoprotein or aquaporin-4: Clinical and paraclinical characteristics in Algerian patients. J Neurol Sci. 2017;381:240–244.
Zhou L, Huang Y, Li H, Fan J, Zhangbao J, Yu H, Li Y, Lu J, Zhao C, Lu C, et al. MOG-antibody associated demyelinating disease of the CNS: a clinical and pathological study in Chinese Han patients. J Neuroimmunol. 2017;305:19–28.
Kim SM, Woodhall MR, Kim JS, Kim SJ, Park KS, Vincent A, Lee KW, Waters P. Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS. Neurol Neuroimmunol Neuroinflamm. 2015;2:e163.
Matthews L, Marasco R, Jenkinson M, Kuker W, Luppe S, Leite MI, Giorgio A, De Stefano N, Robertson N, Johansen-Berg H, et al. Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution. Neurology. 2013;80:1330–7.
Jarius S, Paul F, Franciotta D, Ruprecht K, Ringelstein M, Bergamaschi R, Rommer P, Kleiter I, Stich O, Reuss R, et al. Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures. J Neurol Sci. 2011;306:82–90.
Reiber H. Cerebrospinal fluid--physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases. Mult Scler. 1998;4:99–107.
Reiber H, Teut M, Pohl D, Rostasy KM, Hanefeld F. Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid. Mult Scler. 2009;15:1466–80.
Jurynczyk M, Messina S, Woodhall MR, Raza N, Everett R, Roca-Fernandez A, Tackley G, Hamid S, Sheard A, Reynolds G, et al. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain. 2017;140:3128–38.
Frau J, Villar LM, Sardu C, Secci MA, Schirru L, Ferraro D, Coghe G, Lorefice L, Fenu G, Bedin R, et al. Intrathecal oligoclonal bands synthesis in multiple sclerosis: is it always a prognostic factor? J Neurol. 2018;265:424–30.
Andersson M, Alvarez-Cermeno J, Bernardi G, Cogato I, Fredman P, Frederiksen J, Fredrikson S, Gallo P, Grimaldi LM, Gronning M, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry. 1994;57:897–902.
Jarius S, Metz I, Konig FB, Ruprecht K, Reindl M, Paul F, Bruck W, Wildemann B. Screening for MOG-IgG and 27 other anti-glial and anti-neuronal autoantibodies in 'pattern II multiple sclerosis' and brain biopsy findings in a MOG-IgG-positive case. Mult Scler. 2016;22:1541–9.
Konig FB, Wildemann B, Nessler S, Zhou D, Hemmer B, Metz I, Hartung HP, Kieseier BC, Bruck W. Persistence of immunopathological and radiological traits in multiple sclerosis. Arch Neurol. 2008;65:1527–32.
Cobo-Calvo Á, Ruiz A, D'Indy H, Poulat AL, Carneiro M, Philippe N, Durand-Dubief F, Deiva K, Vukusic S, Desportes V, Marignier R. MOG antibody-related disorders: common features and uncommon presentations. J Neurol. 2017;264:1945-55.
Titulaer MJ, Hoftberger R, Iizuka T, Leypoldt F, McCracken L, Cellucci T, Benson LA, Shu H, Irioka T, Hirano M, et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol. 2014;75:411–28.
Fan S, Xu Y, Ren H, Guan H, Feng F, Gao X, Ding D, Fang F, Shan G, Guan T, et al. Comparison of myelin oligodendrocyte glycoprotein (MOG)-antibody disease and AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) when they co-exist with anti-NMDA (N-methyl-D-aspartate) receptor encephalitis. Mult Scler Relat Disord. 2018;20:144–52.
Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: a systematic review of 122 cases reported. J Neurol. 2014;261:17–26.
Waters P, Woodhall M, O'Connor KC, Reindl M, Lang B, Sato DK, Jurynczyk M, Tackley G, Rocha J, Takahashi T, et al. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm. 2015;2:e89.
Peschl P, Schanda K, Zeka B, Given K, Bohm D, Ruprecht K, Saiz A, Lutterotti A, Rostasy K, Hoftberger R, et al. Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflammation. 2017;14:208.
Jarius S, Franciotta D, Bergamaschi R, Wildemann B, Wandinger KP: IgM antibodies to aquaporin-4 in neuromyelitis optica and related disorders. Clin Chem Lab Med 2010; in press.
Jarius S, Eichhorn P, Albert MH, Wagenpfeil S, Wick M, Belohradsky BH, Hohlfeld R, Jenne DE, Voltz R. Intravenous immunoglobulins contain naturally occurring antibodies that mimic antineutrophil cytoplasmic antibodies and activate neutrophils in a TNFalpha-dependent and fc-receptor-independent way. Blood. 2007;109:4376–82.
Arnold DM, Crowther MA, Meyer RM, Carruthers J, Ditomasso J, Heddle NM, McLeod A, Kelton JG. Misleading hepatitis B test results due to intravenous immunoglobulin administration: implications for a clinical trial of rituximab in immune thrombocytopenia. Transfusion. 2010;50:2577–81.
Garcia L, Huh YO, Fischer HE, Lichtiger B. Positive immunohematologic and serologic test results due to high-dose intravenous immune globulin administration. Transfusion. 1987;27:503.
Cortese A, Franciotta D, Alfonsi E, Visigalli N, Zardini E, Diamanti L, Prunetti P, Osera C, Gastaldi M, Berzero G, et al. Combined central and peripheral demyelination: clinical features, diagnostic findings, and treatment. J Neurol Sci. 2016;363:182–7.
Jarius S, Eichhorn P, Franciotta D, Petereit HF, Akman-Demir G, Wick M, Wildemann B. The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature. J Neurol. 2017;264:453–66.
Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler. 1998;4:111–7.
BW is grateful to the Dietmar Hopp Stiftung and to Merck Serono for funding research on MOG-IgG. AS is supported by La Marató de TV3 (20141830). We acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding programme Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls-Universität Heidelberg.
The work of BW was supported by the Dietmar Hopp Foundation; Merck Serono; German Federal Ministry of Education and Research (Competence Network Multiple Sclerosis); Deutsche Forschungsgemeinschaft (funding programme Open Access Publishing); Baden-Württemberg Ministry of Science, Research and the Arts; and Ruprecht-Karls-Universität Heidelberg. The funding sources had no role in study conception or design, data collection, analysis, or interpretation, or any other aspect pertinent to the article. None of the authors has been paid to write this article by a pharmaceutical company or other agency. The corresponding authors have final responsibility for the decision to submit for publication.
Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author upon reasonable request.
Ethics approval and consent to participate
OA has received grants by the German Research Foundation (DFG), the German Ministry for Education and Research (BMBF) (KKNMS; for NEMOS NationNMO FKZ 01GI1602), speaking fees and travel grants by Bayer, Biogen, Genzyme, Medimmune, Merck, Novartis, Roche, Sanofi, and Teva.
DF received one honorarium for a presentation from Biogen not related to the present paper.
KF serves on the advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Alexion Pharmaceuticals, and Medimmune; has received travel funding and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical; is on the editorial board for Clinical and Experimental Neuroimmunology; is an advisory board member for Sri Lanka Journal of Neurology; and received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, OnoPharmaceutical, Nihon Pharmaceutical, Genzyme Japan, Ministry of Education, Science and Technology of Japan, and Ministry of Health, Welfare and Labor of Japan.
AJ is supported by the NHS National Specialised Commissioning Group for NMO and has been a consultant for Shire, Alexion, Terumo-BCT and Chugai pharmaceuticals and has received research funding from Biogen and Alexion pharamaceuticals.
HJK has lectured, consulted, and received honoraria from Bayer Schering Pharma, Biogen, Genzyme, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Teva-Handok, and UCB; received a grant from the Ministry of Science, ICT & Future Planning; and accepted research funding from Genzyme, Kael-GemVax, Merck Serono, Teva-Handok, and UCB; serves on a steering committee for MedImmune; is a co-editor for the Multiple Sclerosis Journal – Experimental, Translational, and Clinical, and an associated editor for the Journal of Clinical Neurology.
IK has received honoraria for consultancy or lectures and travel reimbursement from Bayer Health Care, Biogen Idec, Chugai, Novartis, Shire and Roche and grant support from Biogen Idec, Novartis, Chugai and Diamed.
TK has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis, Sanofi Genzyme and Biogen-Idec as well as grant support from Chugai Pharma and Novartis.
ML receives support from Quest Diagnostics.
JP has received support for scientific meetings and honorariums for advisory work from Merck Serono, ABIDE, Biogen Idec, Novartis, Alexion, Medimmune, Teva, Chugai Pharma and Bayer Schering, and unrestricted grants from Merck Serono, Novartis, Biogen Idec and Bayer Schering. Grants from the MS society. GMSI, NIHR and Guthy- Jackson Foundation for research studies. She runs a nationally commissioned service for neuromyelitis optica and congenital myasthenia.
FP has received honoraria and research support from Alexion, Bayer, Biogen, Chugai, MerckSerono, Novartis, Genyzme, MedImmune, Shire, Teva, and serves on scientific advisory boards for Alexion, MedImmune and Novartis. He has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), German Federal Ministry for Education and Research (Competence Network Multiple Sclerosis), Guthy Jackson Charitable Foundation, EU Framework Program 7, National Multiple Sclerosis Society of the USA.
KR has received research support from the German Federal Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and Novartis as well as travel grants or speaking fees from the Guthy Jackson Charitable Foundation, Bayer Healthcare, Biogen Idec, Merck Serono, sanofi-aventis/Genzyme, Teva Pharmaceuticals, and Novartis.
AS is supported by La Marató de TV3 (20141830).
CT has received honoraria for consultation and expert testimony from Bayer Vital GmbH, Biogen Idec/GmbH, Genzyme GmbH and Novartis Pharmaceuticals. None of this interfered with the current report.
BGW receives royalties from RSR Ltd., Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for NMO and related disorders. He receives personal compensation for serving as a member of an adjudication committee for clinical trials in NMO being conducted by MedImmune and Alexion pharmaceutical companies. He is a consultant for Caladrius Biosciences regarding a clinical trial for NMO. He receives personal compensation for serving on a data safety monitoring board for Novartis for clinical trials in MS.
The work of BW was supported by research grants from the Dietmar Hopp Foundation, from Merck Serono and from the German Federal Ministry of Education and Research (Competence Network Multiple Sclerosis).
SJ, NA, RCD, and JDS declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
- Myelin oligodendrocyte glycoprotein (MOG) antibodies
- Consensus recommendations
- Antibody testing
- Multiple sclerosis (MS)
- Neuromyelitis optica spectrum disorders (NMOSD)
- Optic neuritis (ON), Myelitis