EDITORIAL
The two faces of neuromyelitis optica
Brian G. Weinshenker, MD, FRCP(C) Dean M. Wingerchuk, MD, FRCP(C)
Correspondence to Dr. Weinshenker: [email protected] Neurology® 2014;82:466–467
Over the past 15 years, it had seemed as if neuromyelitis optica (NMO) might be a distinct and homogeneous subtype of CNS demyelinating disease distinguishable from the heterogeneous assortment of patients captured by the umbrella diagnosis of “multiple sclerosis (MS).” NMO had distinctive clinical, radiologic, and pathologic characteristics, and, in most cases, a highly specific biomarker, aquaporin-4 (AQP4) autoantibodies, was detectable.1 However, recent observations might be interpreted as dashing hopes of NMO being a single disorder with uniform pathogenesis. The clinical presentation of NMO is increasingly recognized as heterogeneous. A variety of cerebral, diencephalic, and brainstem presentations1,2 may occur as presenting features or over the course of the disease, which may have been previously considered inconsistent with the diagnosis. However, most of the manifestations of NMO seem to be explained by the distribution and level of expression of AQP4, so the heterogeneity of clinical manifestations does not seriously challenge the hypothesis of uniform pathogenesis.3,4 A more vexing issue has been the 10%–30% of persons who are seronegative for the AQP4 autoantibody despite evaluation with the most sensitive cell-based assays available. Do they represent a distinct entity? In this issue of Neurology®, Sato et al.5 report results from a large Japanese and Brazilian patient sample evaluated for presence of serum antibodies targeting AQP4 or myelin oligodendrocyte glycoprotein (MOG). They find that 3 serologically defined groups (anti-AQP41, anti-MOG1, and neither) have overlapping characteristics but some distinguishing group features, suggesting that they could represent distinct disorders. Importantly, no patient was both anti-AQP41 and anti-MOG1. Compared to anti-AQP41 patients (n 5 139), the much smaller group of anti-MOG1 patients (n 5 16) included more men, more with optic neuritis rather than myelitis, and more with bilateral simultaneous optic neuritis, single attacks, caudal myelitis, and better recovery from attacks. MOG antibodies are associated with acute disseminated encephalomyelitis (ADEM) rather than relapsing demyelinating disease.
These observations suggest that there may be 2 forms of NMO, corresponding to the 2 forms we described in 1999: monophasic (selectively anti-MOG1) and relapsing (typically anti-AQP41).6 Previous work has hinted that MOG antibodies may be detected in anti-AQP4-seronegative patients with an NMO phenotype. Kitley et al.7 reported 4 such patients (3 male) who, as in the Sato et al. study, had a favorable outcome after their sentinel attack and did not relapse during 12 months of follow-up. These congruent results by 2 investigative groups might be viewed as supporting each other’s tentative conclusions that anti-AQP41 and anti-MOG1 NMO may be separate disorders. This conclusion is consistent with phenotypic differences between monophasic and relapsing cases described by us in 19996 and later by others.8 Individuals with the monophasic form did not have the striking female preponderance as did the relapsing patients; they were also younger, more commonly had bilateral simultaneous optic neuritis and myelitis, and were less likely to have systemic autoimmune disease and detectable anti-AQP4.6,8 However, before accepting this attractive and simple schema of an NMO dichotomy (autoimmune relapsing anti-AQP41 vs ADEM-like monophasic anti-MOG1), one should be mindful of several caveats and complexities that may bear on the interpretation of these results. MOG antibodies have a somewhat checkered history. Claims that MOG antibodies, detected by Western blot, were associated with increased risk of future relapse in patients with clinically isolated demyelinating syndromes suggestive of MS were ultimately disproven,9 although persistence of MOG antibodies subsequently has been associated with risk of relapse.10 MOG antibodies occur in a variety of clinical syndromes of demyelinating disease, including NMO. These antibodies are relatively more common in pediatric demyelinating syndromes relative to adults, especially in children with ADEM, during which it is transiently present except in those who later developed MS.10 The patterns of anti-MOG can be classified according to the specific extracellular loops recognized by patient sera,
See page 474 From the Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; and the Department of Neurology (D.M.W.), Mayo Clinic, Scottsdale, AZ. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 466
© 2014 American Academy of Neurology
whether a single or multiple antigens are recognized, and whether they cross-react with mouse MOG; these categories of autoantibody response are distributed differently among subtypes of patients with CNS demyelinating disease.11 Unlike anti-AQP4, which appears to be pathogenic, the import of MOG antibodies remains unclear and passive transfer of disease has not been successfully accomplished. Furthermore, the observation by Sato et al. that no patient is both anti-AQP41 and anti-MOG1 is contradicted by 2 different publications that report dual seropositivity in a total of 7 patients, in one of whom anti-MOG was detected by a transfected cell-binding assay12 and in 6 by ELISA.13 These patients had a severe clinical course or poor outcome despite treatment. Differences in methodology of detection (ELISA vs cell-binding assay) may contribute to the discrepancies about whether anti-AQP4 and anti-MOG coexist. Serologic observations with AQP4 autoantibodies have led to dramatic enhancement in understanding of the distribution of CNS lesions in NMO and understanding of clinical syndromes. Whether the recent observations with anti-MOG will prove as important for clinical diagnosis and pathogenic understanding of NMO as anti-AQP4 will require further careful prospective longitudinal studies with adequate sample size, relevant controls, and consistent assay methodology. Perhaps 2 autoantibodies will be sufficient to account for most of the monophasic and relapsing course subtypes of what we currently diagnose as NMO. However, as Albert Einstein cautioned: Everything should be made as simple as possible, but no simpler. AUTHOR CONTRIBUTIONS Brian G. Weinshenker: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision. Dean Wingerchuk: drafting/revising the manuscript.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock S, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805–815. 2. Kim W, Park M-S, Lee S-H, et al. Characteristic brain magnetic resonance imaging abnormalities in central nervous system aquaporin-4 autoimmunity. Mult Scler 2010; 16:1229–1236. 3. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63:964–968. 4. Matiello M, Schaefer-Klein J, Sun D, Weinshenker BG. Aquaporin 4 expression and tissue susceptibility to neuromyelitis optica. JAMA Neurol 2013;70:1118–1125. 5. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibodypositive NMO spectrum disorders. Neurology 2014;82: 474–481. 6. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999;53:1107–1114. 7. Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012;79:1273–1277. 8. Jarius S, Ruprecht K, Wildemann B, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 2012;9:14. 9. Lim ET, Berger T, Reindl M, et al. Anti-myelin antibodies do not allow earlier diagnosis of multiple sclerosis. Mult Scler 2005;11:492–494. 10. Probstel AK, Dornmair K, Bittner R, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology 2011;77:580–588. 11. Mayer MC, Breithaupt C, Reindl M, 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;191:3594–3604. 12. Woodhall M, Çoban A, Waters P, et al. Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica. J Neurol Sci 2013;335:221–223. 13. Kezuka T, Usui Y, Yamakawa N, et al. Relationship between NMO-antibody and anti–MOG antibody in optic neuritis. J Neuro-ophthalmology 2012;32: 107–110.
Neurology 82
February 11, 2014
467
The two faces of neuromyelitis optica Brian G. Weinshenker and Dean M. Wingerchuk Neurology 2014;82;466-467 Published Online before print January 10, 2014 DOI 10.1212/WNL.0000000000000114 This information is current as of January 10, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/6/466.full.html
References
This article cites 13 articles, 7 of which you can access for free at: http://www.neurology.org/content/82/6/466.full.html##ref-list-1
Citations
This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/82/6/466.full.html##otherarticles
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Acute disseminated encephalomyelitis http://www.neurology.org//cgi/collection/acute_disseminated_encephal omyelitis All Demyelinating disease (CNS) http://www.neurology.org//cgi/collection/all_demyelinating_disease_cn s Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis Optic neuritis; see Neuro-ophthalmology/Optic Nerve http://www.neurology.org//cgi/collection/optic_neuritis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
The two faces of neuromyelitis optica
Brian G. Weinshenker, MD, FRCP(C) Dean M. Wingerchuk, MD, FRCP(C)
Correspondence to Dr. Weinshenker: [email protected] Neurology® 2014;82:466–467
Over the past 15 years, it had seemed as if neuromyelitis optica (NMO) might be a distinct and homogeneous subtype of CNS demyelinating disease distinguishable from the heterogeneous assortment of patients captured by the umbrella diagnosis of “multiple sclerosis (MS).” NMO had distinctive clinical, radiologic, and pathologic characteristics, and, in most cases, a highly specific biomarker, aquaporin-4 (AQP4) autoantibodies, was detectable.1 However, recent observations might be interpreted as dashing hopes of NMO being a single disorder with uniform pathogenesis. The clinical presentation of NMO is increasingly recognized as heterogeneous. A variety of cerebral, diencephalic, and brainstem presentations1,2 may occur as presenting features or over the course of the disease, which may have been previously considered inconsistent with the diagnosis. However, most of the manifestations of NMO seem to be explained by the distribution and level of expression of AQP4, so the heterogeneity of clinical manifestations does not seriously challenge the hypothesis of uniform pathogenesis.3,4 A more vexing issue has been the 10%–30% of persons who are seronegative for the AQP4 autoantibody despite evaluation with the most sensitive cell-based assays available. Do they represent a distinct entity? In this issue of Neurology®, Sato et al.5 report results from a large Japanese and Brazilian patient sample evaluated for presence of serum antibodies targeting AQP4 or myelin oligodendrocyte glycoprotein (MOG). They find that 3 serologically defined groups (anti-AQP41, anti-MOG1, and neither) have overlapping characteristics but some distinguishing group features, suggesting that they could represent distinct disorders. Importantly, no patient was both anti-AQP41 and anti-MOG1. Compared to anti-AQP41 patients (n 5 139), the much smaller group of anti-MOG1 patients (n 5 16) included more men, more with optic neuritis rather than myelitis, and more with bilateral simultaneous optic neuritis, single attacks, caudal myelitis, and better recovery from attacks. MOG antibodies are associated with acute disseminated encephalomyelitis (ADEM) rather than relapsing demyelinating disease.
These observations suggest that there may be 2 forms of NMO, corresponding to the 2 forms we described in 1999: monophasic (selectively anti-MOG1) and relapsing (typically anti-AQP41).6 Previous work has hinted that MOG antibodies may be detected in anti-AQP4-seronegative patients with an NMO phenotype. Kitley et al.7 reported 4 such patients (3 male) who, as in the Sato et al. study, had a favorable outcome after their sentinel attack and did not relapse during 12 months of follow-up. These congruent results by 2 investigative groups might be viewed as supporting each other’s tentative conclusions that anti-AQP41 and anti-MOG1 NMO may be separate disorders. This conclusion is consistent with phenotypic differences between monophasic and relapsing cases described by us in 19996 and later by others.8 Individuals with the monophasic form did not have the striking female preponderance as did the relapsing patients; they were also younger, more commonly had bilateral simultaneous optic neuritis and myelitis, and were less likely to have systemic autoimmune disease and detectable anti-AQP4.6,8 However, before accepting this attractive and simple schema of an NMO dichotomy (autoimmune relapsing anti-AQP41 vs ADEM-like monophasic anti-MOG1), one should be mindful of several caveats and complexities that may bear on the interpretation of these results. MOG antibodies have a somewhat checkered history. Claims that MOG antibodies, detected by Western blot, were associated with increased risk of future relapse in patients with clinically isolated demyelinating syndromes suggestive of MS were ultimately disproven,9 although persistence of MOG antibodies subsequently has been associated with risk of relapse.10 MOG antibodies occur in a variety of clinical syndromes of demyelinating disease, including NMO. These antibodies are relatively more common in pediatric demyelinating syndromes relative to adults, especially in children with ADEM, during which it is transiently present except in those who later developed MS.10 The patterns of anti-MOG can be classified according to the specific extracellular loops recognized by patient sera,
See page 474 From the Department of Neurology (B.G.W.), Mayo Clinic, Rochester, MN; and the Department of Neurology (D.M.W.), Mayo Clinic, Scottsdale, AZ. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 466
© 2014 American Academy of Neurology
whether a single or multiple antigens are recognized, and whether they cross-react with mouse MOG; these categories of autoantibody response are distributed differently among subtypes of patients with CNS demyelinating disease.11 Unlike anti-AQP4, which appears to be pathogenic, the import of MOG antibodies remains unclear and passive transfer of disease has not been successfully accomplished. Furthermore, the observation by Sato et al. that no patient is both anti-AQP41 and anti-MOG1 is contradicted by 2 different publications that report dual seropositivity in a total of 7 patients, in one of whom anti-MOG was detected by a transfected cell-binding assay12 and in 6 by ELISA.13 These patients had a severe clinical course or poor outcome despite treatment. Differences in methodology of detection (ELISA vs cell-binding assay) may contribute to the discrepancies about whether anti-AQP4 and anti-MOG coexist. Serologic observations with AQP4 autoantibodies have led to dramatic enhancement in understanding of the distribution of CNS lesions in NMO and understanding of clinical syndromes. Whether the recent observations with anti-MOG will prove as important for clinical diagnosis and pathogenic understanding of NMO as anti-AQP4 will require further careful prospective longitudinal studies with adequate sample size, relevant controls, and consistent assay methodology. Perhaps 2 autoantibodies will be sufficient to account for most of the monophasic and relapsing course subtypes of what we currently diagnose as NMO. However, as Albert Einstein cautioned: Everything should be made as simple as possible, but no simpler. AUTHOR CONTRIBUTIONS Brian G. Weinshenker: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision. Dean Wingerchuk: drafting/revising the manuscript.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock S, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805–815. 2. Kim W, Park M-S, Lee S-H, et al. Characteristic brain magnetic resonance imaging abnormalities in central nervous system aquaporin-4 autoimmunity. Mult Scler 2010; 16:1229–1236. 3. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol 2006;63:964–968. 4. Matiello M, Schaefer-Klein J, Sun D, Weinshenker BG. Aquaporin 4 expression and tissue susceptibility to neuromyelitis optica. JAMA Neurol 2013;70:1118–1125. 5. Sato DK, Callegaro D, Lana-Peixoto MA, et al. Distinction between MOG antibody-positive and AQP4 antibodypositive NMO spectrum disorders. Neurology 2014;82: 474–481. 6. Wingerchuk DM, Hogancamp WF, O’Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology 1999;53:1107–1114. 7. Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 2012;79:1273–1277. 8. Jarius S, Ruprecht K, Wildemann B, et al. Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 2012;9:14. 9. Lim ET, Berger T, Reindl M, et al. Anti-myelin antibodies do not allow earlier diagnosis of multiple sclerosis. Mult Scler 2005;11:492–494. 10. Probstel AK, Dornmair K, Bittner R, et al. Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis. Neurology 2011;77:580–588. 11. Mayer MC, Breithaupt C, Reindl M, 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;191:3594–3604. 12. Woodhall M, Çoban A, Waters P, et al. Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica. J Neurol Sci 2013;335:221–223. 13. Kezuka T, Usui Y, Yamakawa N, et al. Relationship between NMO-antibody and anti–MOG antibody in optic neuritis. J Neuro-ophthalmology 2012;32: 107–110.
Neurology 82
February 11, 2014
467
The two faces of neuromyelitis optica Brian G. Weinshenker and Dean M. Wingerchuk Neurology 2014;82;466-467 Published Online before print January 10, 2014 DOI 10.1212/WNL.0000000000000114 This information is current as of January 10, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/6/466.full.html
References
This article cites 13 articles, 7 of which you can access for free at: http://www.neurology.org/content/82/6/466.full.html##ref-list-1
Citations
This article has been cited by 1 HighWire-hosted articles: http://www.neurology.org/content/82/6/466.full.html##otherarticles
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Acute disseminated encephalomyelitis http://www.neurology.org//cgi/collection/acute_disseminated_encephal omyelitis All Demyelinating disease (CNS) http://www.neurology.org//cgi/collection/all_demyelinating_disease_cn s Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis Optic neuritis; see Neuro-ophthalmology/Optic Nerve http://www.neurology.org//cgi/collection/optic_neuritis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
