Anti-MOG associated encephalomyelitis

AntiMOG associated encephalomyelitis is an inflammatory demyelinating disease previously considered part of the multiple sclerosis spectrum, and currently considered an independent disease.[1]

Antibodies against the Myelin oligodendrocyte glycoprotein have received much of its laboratory attention in studies dealing with multiple sclerosis (MS). Several studies had pointed to a role for antibodies against MOG in the pathogenesis of MS, but most of them were written before the discovery of NMO-IgG and the NMO spectrum of diseases. MOG antibodies are currently considered mostly absent in multiple sclerosis.[2]

Though some patients present brain lesions they do not have the ovoid shape perpendicular to the ventricle typical of MS.[3]

Anti-MOG status is different depending whether it is measured by ELISA or by microarray (CBA). The proper way to identify it is by microarray, reacting patient serum with living cells, and detecting the binding IgG via a fluorescent-labeled secondary antibody.[4]

The presence of anti-MOG autoantibodies has been associated with the following conditions[5]

Some of them have been studied in detail:

Seronegative neuromyelitis optica

Anti-MOG autoimmunity has been found to be involved in the seronegative NMO[16][17] and also in optic neuritis and some fulminant forms of ADEM[9] MOG antibodies in NMOSD are variable depending on the seropositivity status[18]

Pediatric demyelination and ADEM

The anti-MOG spectrum in children is equally varied: out of a sample of 41 children with MOG-antibodies 29 had clinical NMOSD (17 relapsing), 8 had ADEM (4 relapsing with ADEM-ON), 3 had a single clinical event CIS, and 1 had a relapsing tumefactive disorder. Longitudinal myelitis was evident on MRI in 76[percent]. It has also been noted that percentage of children with anti-MOGantibodies respect a demyelinating sample is higher than for adults[19]

Double positive NMO

Some NMO patients present double positive for autoantibodies to AQP4 and MOG. These patients have MS-like brain lesions, multifocal spine lesions and retinal and optic nerves atrophy.[20] Other reports speak about the mutual exclusivity of MOG and AQP4 auto-antibodies.[21]

Clinical courses and Diagnosis

Two clinical courses have been documented:[22]

  • Relapsing
  • Monophasic

Currently three conditions are required to stablish a diagnosis[23]

  1. Monophasic or relapsing acute ON, myelitis, brainstem encephalitis, or encephalitis, or any combination of these syndromes
  2. MRI or electrophysiological (visual evoked potentials in patients with isolated ON) findings compatible with CNS demyelination
  3. Seropositivity for MOG-IgG as detected by means of a cell-based assay employing full-length human MOG as target antigen

MRI imaging can help to differenciate MS and MOG antibody disease. Adults and children with MOG antibody disease have brainstem lesions, often located in pons and fourth ventricle. Nevertheless, MOG antibody disease overlaps with AQP4 antibody disease.[24]

Histopathology

Demyelinating lesions of AntiMOG associated encephalomyelitis resemble MS pattern-II lesions.[25] The demyelinating lesion presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes and signs of complement system activation.

Some reports speak about the presence of oligoclonal bands and the possibility of a progressive course.[26]

Treatment

The anti-MOG spectrum has been found to be responsive to steroids,[27] and also to plasmapheresis, as any other pattern-II Inflammatory demyelinating diseases of the central nervous system.[28][29]

Anti-MOG positive patients should not be treated with interferons. It has been reported to make the disease worse.[4] There are also anecdotal reports against using Fingolimod.[30]

Causes

The causes why anti-MOG antibodies appear in the serum are still not known, but a connection to infectious mononucleosis has been proposed[31]

History

Reports about the involvement of anti-MOG antibodies in MS and other demyelinating diseases were appearing since the late 1980s, but evidence was always weak and inconsistent. The presence of MOG-IgG detected by enzyme-linked immunosorbent assay and Western blot was confusing until cell-based assay (CBA) appeared.[32]

The turning point, was in 2011, when Mader et al. developed a CBA assay using HEK 293 cells and observed that it had a higher specificity to detect anti-MOG in serum. These authors reported that some patients with NMOSD had high titers of anti-MOG antibodies similar to ADEM.[33]

Since that moment, anti-MOG seropositivity has been found consistently in ADEM, NMO, pediatric MS and atypical MS.[32]

Animal models

Animal models of MS, EAE, have shown that “MOG-specific EAE models (of different animal strains) display/mirror human multiple sclerosis" but basically explains the part involved in the optic neuritis[34] These models with anti-MOG antibodies have been investigated extensively and are considered the only antibodies with demyelinating capacity but again, EAE pathology is closer to NMO and ADEM than to the confluent demyelination observed in MS.

Anti-MOG mediated demyelination was shown to behave similar to NMO in animal models,[34] and currently it is considered even a biomarker against the MS diagnosis[35][36]

References

  1. ↑ Sudarshini Ramanathan, Russell C. Dale, Fabienne Brilot, Anti-MOG antibody: The history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination. Autoimmunity Reviews, Volume 15, Issue 4, April 2016, Pages 307–324, doi:10.1016/j.autrev.2015.12.004
  2. ↑ Ketelslegers, I. A.; Van Pelt, D. E.; Bryde, S.; Neuteboom, R. F.; Catsman-Berrevoets, C. E.; Hamann, D.; Hintzen, R. Q. (6 February 2015). "Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort". Multiple Sclerosis Journal. 21 (12): 1513–1520. doi:10.1177/1352458514566666. PMID 25662345.
  3. ↑ Kim, Sung-Min; et al. (2015). "Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS". Neurol Neuroimmunol Neuroinflamm. 2 (6): e163. doi:10.1212/NXI.0000000000000163.
  4. 1 2 Nakashima, Ichiro. "Anti-myelin oligodendrocyte glycoprotein antibody in demyelinating diseases". Clinical and Experimental Neuroimmunology. 6: 59–63. doi:10.1111/cen3.12262.
  5. 1 2 3 Reindl, M; Di Pauli, F; Rostásy, K; Berger, T (Aug 2013). "The spectrum of MOG autoantibody-associated demyelinating diseases". Nat Rev Neurol. 9 (8): 455–61. doi:10.1038/nrneurol.2013.118. PMID 23797245.
  6. ↑ Spadaro, Melania; et al. "Histopathology and clinical course of MOG-antibody-associated encephalomyelitis". Annals of Clinical and Translational Neurology. 2 (3): 295–301. doi:10.1002/acn3.164. PMC 4369279. PMID 25815356.
  7. ↑ Jae-Won Hyun el al. Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases, doi: https://dx.doi.org/10.1136/jnnp-2017-315998
  8. ↑ Baumann, M.; Hennes, E.M.; Schanda, K.; Karenfort, M.; Bajer-Kornek, B.; Diepold, K.; Fiedler, B.; Marquardt, I.; Strautmanis, J.; Vieker, S.; Reindl, M.; Rostásy, K. (2015). "Clinical characteristics and neuroradiological findings in children with multiphasic demyelinating encephalomyelitis and MOG antibodies". European Journal of Paediatric Neurology. 19 (Supplement 1): S21. doi:10.1016/S1090-3798(15)30066-0.
  9. 1 2 Di Pauli, Franziska; et al. (2015). "Fulminant demyelinating encephalomyelitis". Neurol Neuroimmunol Neuroinflamm. 2 (6): e175. doi:10.1212/NXI.0000000000000175. PMC 4635550. PMID 26587556.
  10. ↑ Jarius S, Metz I, König FB, Ruprecht K, Reindl M, Paul F, Brück 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 Feb;
  11. ↑ Franziska Di Pauli, Romana Höftberger, Markus Reindl, Ronny Beer, Paul Rhomberg, Kathrin Schanda, Douglas Sato, Kazuo Fujihara, Hans Lassmann, Erich Schmutzhard and Thomas Berger, Fulminant demyelinating encephalomyelitis. Insights from antibody studies and neuropathology. Neurol Neuroimmunol Neuroinflamm December 2015 vol. 2 no. 6 e175. doi=https://dx.doi.org/10.1212/NXI.0000000000000175
  12. ↑ Melania Spadaro et al., Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis, Neurol Neuroimmunol Neuroinflamm, October 2016 vol. 3 no. 5 e257, doi:10.1212/NXI.0000000000000257
  13. ↑ S. J. Pittock et al. Myelin oligodendrocyte glycoprotein antibodies in pathologically proven multiple sclerosis: frequency, stability and clinicopathologic correlations, Mult. Scle. Journal, 2007
  14. ↑ Chalmoukou, Konstantina; et al. (2015). "Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis". Neurol Neuroimmunol Neuroinflamm. 2 (4): e131. doi:10.1212/NXI.0000000000000131.
  15. ↑ Konstantina Chalmoukou et al. Recurrent Optic Neuritis (rON) is characterised by Anti-MOG Antibodies: A follow-up study" Neurology 2015; vol. 84 no. 14 Supplement P5.274
  16. ↑ Pröbstel, Anne-Katrin; et al. (2015). "Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype". Journal of Neuroinflammation. 12 (1): 46. doi:10.1186/s12974-015-0256-1. PMC 4359547. PMID 25889963.
  17. ↑ CYNTHIA MCKELVEY, Press Report, What’s the Role of Myelin Oligodendrocyte Glycoprotein in NMO?
  18. ↑ Berger, T.; Reindl, M. (2015). "Antibody biomarkers in CNS demyelinating diseases – a long and winding road,". European Journal of Neurology. 22 (8): 1162–1168. doi:10.1111/ene.12759. PMID 26010364.
  19. ↑ Silvia Tenembaum et al. Spectrum of MOG Autoantibody-Associated Inflammatory Diseases in Pediatric Patients, Neurology April 6, 2015 vol. 84 no. 14 Supplement I4-3A
  20. ↑ Ya, Yaping; et al. (2015). "Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD". Science China Life Sciences. doi:10.1007/s11427-015-4997-y.
  21. ↑ Martin S. Weber, Tobias Derfuss, Wolfgang Brück, Anti–Myelin Oligodendrocyte Glycoprotein Antibody–Associated Central Nervous System Demyelination—A Novel Disease Entity? August 2018, JAMA Neurol. 2018;75(8):909-910. doi:10.1001/jamaneurol.2018.1055
  22. ↑ Lekha Pandit et al., MOG-IgG-associated disease has a stereotypical clinical course, asymptomatic visual impairment and good treatment response, July 17, 2018, doi:10.1177/2055217318787829
  23. ↑ S. Jarius et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing, Journal of Neuroinflammation201815:134, https://doi.org/10.1186/s12974-018-1144-2
  24. ↑ Maciej Jurynczyk Ruth Geraldes Fay Probert Mark R. Woodhall Patrick Waters George Tackley Gabriele DeLuca Saleel Chandratre Maria I. Leite Angela Vincent, Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis, Brain, Volume 140, Issue 3, 1 March 2017, Pages 617–627, https://doi.org/10.1093/brain/aww350, 24 February 2017
  25. ↑ Spadaro Melania; et al. (2015). "Histopathology and clinical course of MOG-antibody-associated encephalomyelitis". Annals of Clinical and Translational Neurology. 2 (3): 295–301. doi:10.1002/acn3.164. PMC 4369279. PMID 25815356.
  26. ↑ Gil-Perotin, Sara et al. Progressive demyelination in the presence of serum (MOG)-IgG: a case report, Front. Neurol. | doi: 10.3389/fneur.2018.00340, 30 Apr 2018.
  27. ↑ Ichiro Nakashima, Anti-myelin oligodendrocyte glycoprotein antibody in demyelinating diseases, December 2015, doi:10.1111/cen3.12262
  28. ↑ Oshiro A, Nakamura S, Tamashiro K, Fujihara K. Anti-MOG + neuromyelitis optica spectrum disorders treated with plasmapheresis, No To Hattatsu. 2016 May;48(3):199-203
  29. ↑ Rocio Vazquez do Campo, Ramon Yarza, Sebastian Lopez Chiriboga and Kevin Barrett, Myelin Oligodendrocyte Glycoprotein (MOG) Autoimmunity. A Case Report, Neurology April 5, 2016 vol. 86 no. 16 Supplement P5.346
  30. ↑ 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 Apr 28;56(4):265-9. doi: 10.5692/clinicalneurol.cn-000756. Epub 2016 Mar 24. PMID 27010093
  31. ↑ Kakalacheva, Kristina; et al. (2016). "Infectious Mononucleosis Triggers Generation of IgG Auto-Antibodies against Native Myelin Oligodendrocyte Glycoprotein". Viruses. 8 (2): 51. doi:10.3390/v8020051.
  32. 1 2 Fujihara K, et al. (8 March 2018). "Myelin oligodendrocyte glycoprotein immunoglobulin G-associated disease: An overview". clin. and exp. neuroinmunology. doi:10.1111/cen3.12434.
  33. ↑ Mader, S; Gredler, V; Schanda, K; et al. (2011). "Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders". J Neuroinflammation. 8: 184. doi:10.1186/1742-2094-8-184.
  34. 1 2 Kezuka; et al. (2012). "Relationship Between NMO-Antibody and Anti–MOG Antibody in Optic Neuritis". Journal of Neuro-Ophthalmology. 32 (2): 107–110. doi:10.1097/WNO.0b013e31823c9b6c. PMID 22157536.
  35. ↑ Ketelslegers, Immy A; Van Pelt, Daniëlle E; Bryde, Susanne; Neuteboom, Rinze F; Catsman-Berrevoets, Coriene E; Hamann, Dörte; Hintzen, Rogier Q (2015). "Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort". Mult Scler. 21: 1513–1520. doi:10.1177/1352458514566666. PMID 25662345.
  36. ↑ Kitley, Joanna; et al. (2012). "Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype". Neurology. 79 (12): 1273–1277. doi:10.1212/WNL.0b013e31826aac4e. PMID 22914827.
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