J Neurol (2014) 261:640–642 DOI 10.1007/s00415-014-7277-z
JOURNAL CLUB
MOG-IgG in neuromyelitis optica Sebastian Luppe • Neil P. Robertson
Published online: 16 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Up to 90 % of patients with neuromyelitis optica (NMO) and many patients with NMO-like disorders, including isolated recurrent optic neuritis (ON) and longitudinal extensive myelitis, test positive for autoantibodies against aquaporin-4 (AQP4-IgG). Recent studies have shown that some patients with these clinical phenotypes who are seronegative for AQP4-IgG have antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), a protein exclusively expressed in the central nervous system (CNS) on the surface of oligodendrocytes. However, studies using MOG, expressed in Escherichia coli as a recombinant protein in a linear or refolded form, have led to contradictory results, with MOG antibodies being detected both in patients with multiple sclerosis (MS) but also in healthy controls. More recent studies have arguably used more specific cell-based assays (CBAs), expressing human MOG in its native conformation on the surface of live human embryonic kidney (HEK) cells. Using this methodology, MOG-IgG has been detected in the serum of children with demyelinating disorders, in particular acute disseminated encephalomyelitis (ADEM), as well as in paediatric and adult patients with AQP4-IgG seronegative NMO and NMO-like syndromes. Although it remains debatable whether MOG-IgG is truly pathogenic, it is currently unclear whether patients expressing this antibody have a similar disease course and similar requirements for immunosuppressive treatment as AQP4-IgG-positive patients. In this journal club we review three recent publications centred on patients with CNS demyelinating disorders and positive MOG-IgG serology. In addition we discuss S. Luppe N. P. Robertson (&) Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK e-mail: [email protected]
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whether antibodies against MOG could be employed as a useful biomarker for diagnosis and prognosis across the spectrum of NMO and NMO-like disorders.
Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica In this study serum samples from 106 children who had experienced an acute episode of a demyelinating CNS disease were tested for AQP4-IgG and MOG-IgG. This cohort included 29 cases with ADEM, 8 with NMO, 3 with acute cerebellitis, 32 with clinically isolated syndrome (CIS), 11 with MS, 14 with monophasic ON, 3 with recurrent ON, and 6 with myelitis. Sera from 20 children with unrelated neurological disorders were used as controls. CBAs with live HEK cells expressing the M1 and M23 isoforms of AQP4, or human MOG, were used to screen for the respective antibodies. Of the eight NMO cases (six females, age at onset 3–15 years), two tested positive for AQP4-IgG, and three tested positive for MOG-IgG. Three had neither MOG-IgG nor AQP4-IgG in their serum, and none had both antibodies. Seven of these eight had a relapsing disease course. Of the 29 children with ADEM, 13 (45 %) tested positive for MOG-IgG. In addition 2 of the 3 with recurrent ON, 2 of 14 (14 %) with monophasic ON, 1 of 11 (9 %) with MS, and 1 of 32 (3 %) with CIS also tested MOG-IgG-positive. Comments and discussion. The population surveyed in this study was diverse in phenotype but limited to children, and therefore, speaks to the relative frequency of paediatric MOG-IgG disease only, confirming that antibodies against MOG are present at relatively high frequency in children with CNS demyelinating diseases. More importantly, it has
J Neurol (2014) 261:640–642
also extended the spectrum of MOG-IgG seropositive CNS demyelinating diseases to include ADEM, as well as AQP4-IgG seronegative NMO and NMO-like disorder. In this context, the five cases of monophasic or recurrent ON with positive MOG-IgG serology reported in this study could be considered to be cases of MOG-IgG-positive NMOSD. The authors also conclude that children with MOG-IgG-positive disease have a better prognosis than those with AQP4-IgG-positive disease. However, few details on the severity of relapses, observed disease duration, or measured disability outcomes were provided to substantiate this observation, which could be only inferred from three selected case histories. Rosta´sy et al. (2013) Multiple Sclerosis 19(8): 1052–1059.
Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study Forty-six patients referred to an NMO specialist service were tested for AQP4-IgG and MOG-IgG. A CBA with HEK cells expressing human MOG, or the M23 isoform of AQP4, on their surface was used for analysis. Twenty patients tested positive for AQP4-IgG and were compared with 9 patients that tested positive for MOG-IgG; 17 patients were negative for both AQP4-IgG and MOG-IgG, and no patients were positive for both antibodies. Ninety per cent of the AQP4-IgG ? patients were female, but only four of nine (44 %) in the MOG-IgG ? patients. Patients with MOG-IgG disease were younger at onset (mean age at onset 32.3, SD 17.1) than those with AQP4 disease (mean age at onset 44.9, SD 14.8). None of the MOG-IgG-positive patients relapsed, although 40 % of the AQP4IgG ? patients had a relapsing course. All of the nine MOG-IgG ? patients had spinal cord involvement as part of their onset attack, and four presented with the classical Devic’s syndrome of simultaneous or sequential optic neuritis and myelitis, versus none of the AQP4-IgG positive patients. Overall, patients with MOG-IgG also had better disability outcomes as measured by the Extended Disability Status Scale (EDSS) than AQP4-IgG positive patients (median EDSS 0, range 0–2.5 vs median EDSS 4.0, range 0–8). Furthermore, evaluation of the spinal MRI studies demonstrated that MOG-IgG ? patients were more likely than AQP4-IgG ? patients to have suffered involvement of the conus (75 vs 0 %). In keeping with the generally improved outcome, the cord signal change demonstrated resolution on follow-up imaging in six out of seven patients in the MOG-IgG ? group, but in only one of four from the AQP4-IgG ? group.
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Comments and discussion. The patients selected for this study had been referred to a specialist NMO clinic, and the phenotype described may, therefore, represent NMO patients with positive MOG-IgG serology, rather than a broader MOG-IgG disease phenotype. However, there did appear to be clinical differences between the two groups; patients with MOG-IgG were more likely to be male, present with the classical Devic’s syndrome of simultaneous optic neuritis and myelitis, and to have conus involvement. Patients with MOG-IgG also appeared to have a consistently monophasic disease course with lower residual disability than patients with AQP4-IgG. The short follow-up (mean disease duration 18 months, range 2.2 – 38.5) might explain the observed monophasic disease course, although the recovery from the first attack may be a useful distinguishing feature. However, as the authors acknowledge, the number of observed cases was small, and clinical data were recorded with knowledge of the antibody status. Kitley et al. (2014) JAMA Neurology. doi:10.1001/ jamaneurol.2013.5857.
Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders In this multicentre study, sera from 215 paediatric and adult patients diagnosed with NMO/NMOSD were collected from two centres in Brazil and one centre in Japan. Once again CBAs with live HEK cells expressing the M23 isoform of AQP4, or human MOG, were used to test for the respective antibodies. Initial analysis was performed in Tokyo; positivity for MOG-IgG was then confirmed at a second centre, using a similar assay. Of the 215 patients, 139 (75 %) tested positive for AQP4-IgG, and 16 (7 %) for MOG-IgG. 60 (28 %) were seronegative, and none tested positive for both antibodies. Of the 76 AQP4-IgG negative NMO cases, 16 (21 %) tested positive for MOG-IgG. There was a strong female preponderance in the AQP4IgG ? group, whereas MOG-IgG ? patients were more likely to be male (F:M ratio 7.2:1 vs 0.6:1). Median age at onset was comparable in both groups (37 years, range 4–78 vs 37.5 years, range 3–70). Compared to patients with AQP4-IgG, patients with MOG-IgG more frequently had attacks involving the optic nerves than the spinal cord; however, only 1(6 %) patient with MOG-IgG experienced simultaneous optic neuritis and myelitis. In this study a relapsing disease course was observed in eight (50 %) patients with MOG-IgG (median 1.5, range 1–3). Of the patients with relapsing disease, those with MOG-IgG had a lower number of attacks (median 2, range 2–3) than those with AQP4-IgG (median 4, range 2–33). Patients with AQP4-IgG also had a higher number of myelitis attacks
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642
(median 2, range 0–30) than those with MOG-IgG (median 0, range 0–2). Lesions on MRI spine in MOG-IgG ? patients were more frequently distributed in the thoracolumbar region, whereas patients with AQP4-IgG more frequently had lesions in the cervicothoracic region. Disability outcomes were more favourable in the MOG-IgG group, with a median EDSS at last visit of 1.5 (range 0–8) in MOG-IgG ? patients versus 5.8 (range 1–8.5) AQP4IgG ? patients. Comments and discussion. In contrast to the previous study, 50 % of the patients with MOG-IgG-positive NMO had a relapsing disease course; whether this is an effect of modification of phenotype by ethnicity is unclear. Once again the period of clinical follow-up was short, with a median of 1 year (range 1–19) for MOG-IgG ? patients with monophasic disease versus 4.5 years (range 2–18) for those with recurrent disease, and might, therefore, explain the relatively low number of relapses observed. Furthermore, whilst studies of NMO-like disorders seem to have adopted the EDSS as an outcome measure, it may not be well suited to accurately reflect the amount of visual disability in a disease characterised by recurrent bouts of optic neuritis. More detailed analysis of the EDSS functional system scores or other measures of visual function may be needed in future analyses. Some consistency emerges from this cohort and includes the lack of a strong female predominance in MOG-IgG-associated disease compared with AQP4-IgG disease and also in the spatial distribution of MRI spinal lesions. The study design excluded patients with ADEM or MS, so it is important that this cohort of MOG-IgG patients not necessarily be taken as a reflection of the overall phenotype of the disease.
123
J Neurol (2014) 261:640–642
Sato et al. (2014) Neurology. doi:10.1212/WNL. 0000000000000101.
Conclusions All three studies found MOG-IgG in the serum of patients with AQP4-IgG-negative NMO and NMO-like disorders. Interestingly none of the patients reported were positive for both AQP4-IgG and MOG-IgG, which would seem to be evidence against the appearance of MOG-IgG as a bystander phenomenon, but rather suggests a primary pathogenic role. However, these studies do seem to suggest that MOG-IgG-associated disease has distinct clinical features compared to AQP4-IgG-positive patients including an equal sex distribution, better disability outcomes, and selective involvement of the conus in those patients with longitudinal myelitis. Studies with a longer follow-up and larger cohorts will clearly be needed to confirm these observations and also to clarify the use of relapsing disease as a distinguishing feature. Finally, the presence of a large number of cases seronegative for both antibodies in all three cohorts raises the possibility that other relevant autoantibodies may be identified in the future. Readers of this journal may also be interested to read a recent review article which provides further useful historical context of MOG IgG in demyelinating disorders: Reindl et al. (2013) The spectrum of MOG autoantibodyassociated demyelinating diseases. Nature reviews. Neurology 9(8): 455–461.
JOURNAL CLUB
MOG-IgG in neuromyelitis optica Sebastian Luppe • Neil P. Robertson
Published online: 16 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Up to 90 % of patients with neuromyelitis optica (NMO) and many patients with NMO-like disorders, including isolated recurrent optic neuritis (ON) and longitudinal extensive myelitis, test positive for autoantibodies against aquaporin-4 (AQP4-IgG). Recent studies have shown that some patients with these clinical phenotypes who are seronegative for AQP4-IgG have antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG), a protein exclusively expressed in the central nervous system (CNS) on the surface of oligodendrocytes. However, studies using MOG, expressed in Escherichia coli as a recombinant protein in a linear or refolded form, have led to contradictory results, with MOG antibodies being detected both in patients with multiple sclerosis (MS) but also in healthy controls. More recent studies have arguably used more specific cell-based assays (CBAs), expressing human MOG in its native conformation on the surface of live human embryonic kidney (HEK) cells. Using this methodology, MOG-IgG has been detected in the serum of children with demyelinating disorders, in particular acute disseminated encephalomyelitis (ADEM), as well as in paediatric and adult patients with AQP4-IgG seronegative NMO and NMO-like syndromes. Although it remains debatable whether MOG-IgG is truly pathogenic, it is currently unclear whether patients expressing this antibody have a similar disease course and similar requirements for immunosuppressive treatment as AQP4-IgG-positive patients. In this journal club we review three recent publications centred on patients with CNS demyelinating disorders and positive MOG-IgG serology. In addition we discuss S. Luppe N. P. Robertson (&) Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK e-mail: [email protected]
123
whether antibodies against MOG could be employed as a useful biomarker for diagnosis and prognosis across the spectrum of NMO and NMO-like disorders.
Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica In this study serum samples from 106 children who had experienced an acute episode of a demyelinating CNS disease were tested for AQP4-IgG and MOG-IgG. This cohort included 29 cases with ADEM, 8 with NMO, 3 with acute cerebellitis, 32 with clinically isolated syndrome (CIS), 11 with MS, 14 with monophasic ON, 3 with recurrent ON, and 6 with myelitis. Sera from 20 children with unrelated neurological disorders were used as controls. CBAs with live HEK cells expressing the M1 and M23 isoforms of AQP4, or human MOG, were used to screen for the respective antibodies. Of the eight NMO cases (six females, age at onset 3–15 years), two tested positive for AQP4-IgG, and three tested positive for MOG-IgG. Three had neither MOG-IgG nor AQP4-IgG in their serum, and none had both antibodies. Seven of these eight had a relapsing disease course. Of the 29 children with ADEM, 13 (45 %) tested positive for MOG-IgG. In addition 2 of the 3 with recurrent ON, 2 of 14 (14 %) with monophasic ON, 1 of 11 (9 %) with MS, and 1 of 32 (3 %) with CIS also tested MOG-IgG-positive. Comments and discussion. The population surveyed in this study was diverse in phenotype but limited to children, and therefore, speaks to the relative frequency of paediatric MOG-IgG disease only, confirming that antibodies against MOG are present at relatively high frequency in children with CNS demyelinating diseases. More importantly, it has
J Neurol (2014) 261:640–642
also extended the spectrum of MOG-IgG seropositive CNS demyelinating diseases to include ADEM, as well as AQP4-IgG seronegative NMO and NMO-like disorder. In this context, the five cases of monophasic or recurrent ON with positive MOG-IgG serology reported in this study could be considered to be cases of MOG-IgG-positive NMOSD. The authors also conclude that children with MOG-IgG-positive disease have a better prognosis than those with AQP4-IgG-positive disease. However, few details on the severity of relapses, observed disease duration, or measured disability outcomes were provided to substantiate this observation, which could be only inferred from three selected case histories. Rosta´sy et al. (2013) Multiple Sclerosis 19(8): 1052–1059.
Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study Forty-six patients referred to an NMO specialist service were tested for AQP4-IgG and MOG-IgG. A CBA with HEK cells expressing human MOG, or the M23 isoform of AQP4, on their surface was used for analysis. Twenty patients tested positive for AQP4-IgG and were compared with 9 patients that tested positive for MOG-IgG; 17 patients were negative for both AQP4-IgG and MOG-IgG, and no patients were positive for both antibodies. Ninety per cent of the AQP4-IgG ? patients were female, but only four of nine (44 %) in the MOG-IgG ? patients. Patients with MOG-IgG disease were younger at onset (mean age at onset 32.3, SD 17.1) than those with AQP4 disease (mean age at onset 44.9, SD 14.8). None of the MOG-IgG-positive patients relapsed, although 40 % of the AQP4IgG ? patients had a relapsing course. All of the nine MOG-IgG ? patients had spinal cord involvement as part of their onset attack, and four presented with the classical Devic’s syndrome of simultaneous or sequential optic neuritis and myelitis, versus none of the AQP4-IgG positive patients. Overall, patients with MOG-IgG also had better disability outcomes as measured by the Extended Disability Status Scale (EDSS) than AQP4-IgG positive patients (median EDSS 0, range 0–2.5 vs median EDSS 4.0, range 0–8). Furthermore, evaluation of the spinal MRI studies demonstrated that MOG-IgG ? patients were more likely than AQP4-IgG ? patients to have suffered involvement of the conus (75 vs 0 %). In keeping with the generally improved outcome, the cord signal change demonstrated resolution on follow-up imaging in six out of seven patients in the MOG-IgG ? group, but in only one of four from the AQP4-IgG ? group.
641
Comments and discussion. The patients selected for this study had been referred to a specialist NMO clinic, and the phenotype described may, therefore, represent NMO patients with positive MOG-IgG serology, rather than a broader MOG-IgG disease phenotype. However, there did appear to be clinical differences between the two groups; patients with MOG-IgG were more likely to be male, present with the classical Devic’s syndrome of simultaneous optic neuritis and myelitis, and to have conus involvement. Patients with MOG-IgG also appeared to have a consistently monophasic disease course with lower residual disability than patients with AQP4-IgG. The short follow-up (mean disease duration 18 months, range 2.2 – 38.5) might explain the observed monophasic disease course, although the recovery from the first attack may be a useful distinguishing feature. However, as the authors acknowledge, the number of observed cases was small, and clinical data were recorded with knowledge of the antibody status. Kitley et al. (2014) JAMA Neurology. doi:10.1001/ jamaneurol.2013.5857.
Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders In this multicentre study, sera from 215 paediatric and adult patients diagnosed with NMO/NMOSD were collected from two centres in Brazil and one centre in Japan. Once again CBAs with live HEK cells expressing the M23 isoform of AQP4, or human MOG, were used to test for the respective antibodies. Initial analysis was performed in Tokyo; positivity for MOG-IgG was then confirmed at a second centre, using a similar assay. Of the 215 patients, 139 (75 %) tested positive for AQP4-IgG, and 16 (7 %) for MOG-IgG. 60 (28 %) were seronegative, and none tested positive for both antibodies. Of the 76 AQP4-IgG negative NMO cases, 16 (21 %) tested positive for MOG-IgG. There was a strong female preponderance in the AQP4IgG ? group, whereas MOG-IgG ? patients were more likely to be male (F:M ratio 7.2:1 vs 0.6:1). Median age at onset was comparable in both groups (37 years, range 4–78 vs 37.5 years, range 3–70). Compared to patients with AQP4-IgG, patients with MOG-IgG more frequently had attacks involving the optic nerves than the spinal cord; however, only 1(6 %) patient with MOG-IgG experienced simultaneous optic neuritis and myelitis. In this study a relapsing disease course was observed in eight (50 %) patients with MOG-IgG (median 1.5, range 1–3). Of the patients with relapsing disease, those with MOG-IgG had a lower number of attacks (median 2, range 2–3) than those with AQP4-IgG (median 4, range 2–33). Patients with AQP4-IgG also had a higher number of myelitis attacks
123
642
(median 2, range 0–30) than those with MOG-IgG (median 0, range 0–2). Lesions on MRI spine in MOG-IgG ? patients were more frequently distributed in the thoracolumbar region, whereas patients with AQP4-IgG more frequently had lesions in the cervicothoracic region. Disability outcomes were more favourable in the MOG-IgG group, with a median EDSS at last visit of 1.5 (range 0–8) in MOG-IgG ? patients versus 5.8 (range 1–8.5) AQP4IgG ? patients. Comments and discussion. In contrast to the previous study, 50 % of the patients with MOG-IgG-positive NMO had a relapsing disease course; whether this is an effect of modification of phenotype by ethnicity is unclear. Once again the period of clinical follow-up was short, with a median of 1 year (range 1–19) for MOG-IgG ? patients with monophasic disease versus 4.5 years (range 2–18) for those with recurrent disease, and might, therefore, explain the relatively low number of relapses observed. Furthermore, whilst studies of NMO-like disorders seem to have adopted the EDSS as an outcome measure, it may not be well suited to accurately reflect the amount of visual disability in a disease characterised by recurrent bouts of optic neuritis. More detailed analysis of the EDSS functional system scores or other measures of visual function may be needed in future analyses. Some consistency emerges from this cohort and includes the lack of a strong female predominance in MOG-IgG-associated disease compared with AQP4-IgG disease and also in the spatial distribution of MRI spinal lesions. The study design excluded patients with ADEM or MS, so it is important that this cohort of MOG-IgG patients not necessarily be taken as a reflection of the overall phenotype of the disease.
123
J Neurol (2014) 261:640–642
Sato et al. (2014) Neurology. doi:10.1212/WNL. 0000000000000101.
Conclusions All three studies found MOG-IgG in the serum of patients with AQP4-IgG-negative NMO and NMO-like disorders. Interestingly none of the patients reported were positive for both AQP4-IgG and MOG-IgG, which would seem to be evidence against the appearance of MOG-IgG as a bystander phenomenon, but rather suggests a primary pathogenic role. However, these studies do seem to suggest that MOG-IgG-associated disease has distinct clinical features compared to AQP4-IgG-positive patients including an equal sex distribution, better disability outcomes, and selective involvement of the conus in those patients with longitudinal myelitis. Studies with a longer follow-up and larger cohorts will clearly be needed to confirm these observations and also to clarify the use of relapsing disease as a distinguishing feature. Finally, the presence of a large number of cases seronegative for both antibodies in all three cohorts raises the possibility that other relevant autoantibodies may be identified in the future. Readers of this journal may also be interested to read a recent review article which provides further useful historical context of MOG IgG in demyelinating disorders: Reindl et al. (2013) The spectrum of MOG autoantibodyassociated demyelinating diseases. Nature reviews. Neurology 9(8): 455–461.
