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August 09, 2011; 77 (6) Articles

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis

A.K. Pröbstel, K. Dornmair, R. Bittner, P. Sperl, D. Jenne, S. Magalhaes, A. Villalobos, C. Breithaupt, R. Weissert, U. Jacob, M. Krumbholz, T. Kuempfel, A. Blaschek, W. Stark, J. Gärtner, D. Pohl, K. Rostasy, F. Weber, I. Forne, M. Khademi, T. Olsson, F. Brilot, E. Tantsis, R.C. Dale, H. Wekerle, R. Hohlfeld, B. Banwell, A. Bar-Or, E. Meinl, T. Derfuss
First published July 27, 2011, DOI: https://doi.org/10.1212/WNL.0b013e318228c0b1
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Abstract

Objective: To study the longitudinal dynamics of anti–myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases.

Methods: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry.

Results: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels.

Conclusions: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

GLOSSARY

ADEM=
acute disseminated encephalomyelitis;
CIS=
clinically isolated syndrome;
HD=
healthy donor;
Ig=
immunoglobulin;
IgG=
immunoglobulin G;
IgM=
immunoglobulin M;
mAb=
monoclonal antibody;
MCF=
mean channel fluorescence;
MOG=
myelin oligodendrocyte glycoprotein;
MS=
multiple sclerosis;
NTL=
nontransgenic littermate;
OND=
other neurologic disease;
ONND=
other non-neurologic disease;
PE=
phycoerythrin

Antibodies to myelin oligodendrocyte glycoprotein (MOG) have long been known to induce or contribute to demyelination in various animal models.1,2 MOG is exclusively expressed at the outermost lamellae of the myelin sheath in the CNS.3,4 These characteristics make it a perfect candidate target for autoantibodies in multiple sclerosis (MS).

While the potential relevance of anti-MOG immunoglobulins (Ig) in animal models is undisputed, the presence, abundance, or predictive value of anti-MOG Ig in the sera of patients with MS is highly controversial.5,6 This may be partially based on the usage of different assays: ELISA and Western blots with recombinant MOG detect linear rather than conformational epitopes.5,–,10 These antibodies are found in patients and healthy controls. Animal experiments, however, have suggested that flow cytometry with MOG-transfected cells is able to demonstrate conformational epitope specificity, and that recognition of cell-bound MOG is linked to pathogenic activity.11 While the literature about anti-MOG in adult MS is still contradictory even when transfected cells are used,12,–,15 there is a consensus emerging that antibodies against native MOG are found in a proportion of children with acute demyelination.15,–,18

The aim of this study was to analyze whether the persistence of anti-MOG Ig distinguishes those children with a monophasic demyelinating illness from childhood MS. To this end, we examined serial samples enrolled in the prospective Canadian Pediatric Demyelinating Disease Study.

METHODS

Patients and control donors.

For the cross-sectional study, sera from 251 participants (161 children, 90 adults) were analyzed (figure 1, table 1, table e-1 on the Neurology® Web site at www.neurology.org). These included 54 children with acute disseminated encephalomyelitis (ADEM) (one with multiphasic ADEM), 65 children with MS, 7 children with clinically isolated syndrome (CIS), 21 children with other neurologic diseases (OND, such as epilepsy, seizures, cerebral palsy, ataxia), 14 children with other non-neurologic diseases (ONND, such as asthma, fractures, bronchitis, hemophilia), 62 patients with adult-onset MS, and 28 adult healthy donors (HD). Of the total 126 children with demyelination, baseline sera were collected within an average of 14 days (1–75 days) of acute demyelination in 103 children. In 23 children, baseline sera were not available but samples were collected at the second clinical MS-confirming attack (n =8) or at serial visits (n =15) (table e-1). The mean period of observation was 44 months (12–75 months) for children diagnosed with ADEM, 48 months (5–107 months) for children diagnosed with MS, and 58 months (41–74 months) for the patients with CIS (table e-1). The patients were categorized for race according to the NIH guidelines. Ethnicity was not collected.

Figure 1
Figure 1 Overview of patient cohort in the cell-based assay
View this table:
Table 1

Patient demographics

For the longitudinal study, serial samples from 77 children presenting with an acquired demyelinating syndrome were collected as part of the prospective Canadian Pediatric Demyelinating Disease Study, and were analyzed blinded as to MS outcome. Children with acute demyelination were categorized as ADEM or CIS according to international criteria19,20 and all were reviewed clinically at 3, 6, and 12 months and annually as well as at the time of a further clinical attack. The diagnosis of MS required clinical or MRI evidence of disease dissemination in time.19,21 As of the last assessment, 40 of the 77 children in the longitudinal cohort were classified as having MS (including 4 children with an initial ADEM-like attack followed by a second non-ADEM attack or by MRI evidence of clinically silent new lesions, but for whom 2 non-ADEM attacks had not yet occurred,19 as these children were considered highly likely to have MS); 36 were diagnosed with monophasic ADEM and one child had a monophasic CIS event.

Baseline samples for children in the longitudinal cohort were obtained within an average of 15 days (1–51 days) from the onset of symptoms (table e-1). An average of 4 samples (2–7 samples) were tested per patient over the mean time period of 30 months (3–62 months) at intervals of about 0, 3, 6, and 12 months, followed by yearly intervals.

The pediatric and adult patient cohorts on the whole were not consecutively collected since different centers were involved. This may introduce a potential bias which warrants further prospective cohort studies. However, the patient samples provided by the Canadian Pediatric Demyelinating Disease Study reflect a prospective longitudinal consecutive cohort.

MOG-transfected cell lines and FACS measurements.

The full length sequence (247 amino acids) of human MOG cDNA was obtained from human brain, cloned into the expression plasmid pRSVneo, and transfected into the human rhabdomyosarcoma cell line TE 671 (ATCC). Stably transfected clones were obtained by selection with 1.5 mg/mL G418 (Sigma, Seelze, Germany).

Surface expression was detected by flow cytometry using the anti-MOG mouse monoclonal 8.18C522 at a concentration of 0.5 μg/mL and detected with goat antimouse Ig-phycoerythrin (PE) 1:150 (Dako, Hamburg, Germany). For detection of serum antibodies, 100,000 MOG-transfected cells or the same amount of untransfected cells were suspended in 1% fetal calf serum in phosphate-buffered saline. The cells were incubated with a 1:50 serum dilution in FACS buffer for 1 hour and washed 3 times. Surface-bound antibodies were detected with antihuman immunoglobulin G (IgG)-PE 1:50 (Jackson ImmunoResearch) and antihuman immunoglobulin M (IgM)–PE 1:5 (BD Biosciences, Heidelberg, Germany). To determine the IgG isotypes antihuman IgG 1 and 4-PE 1:1,000 and antihuman IgG 2 and 3-PE 1:500 (Southern Biotech, Eching, Germany) were used. As a positive control we used 8.18C5 staining as described above.

For each patient, we calculated the ratio of the geometric mean channel fluorescence of the transfected cell line divided by the untransfected cell line. The cutoff was set to 4 standard deviations above the mean of pediatric controls. Therefore in our study the geometric mean channel fluorescence (MCF) ratio of 1.45 represents the cutoff. Measurements of MOG-positive patients and patients or controls close to the cutoff (geometric mean channel fluorescence between 1.15 and 1.65) were repeated up to 4 times.

Competition assay.

MOG transfectants were incubated with 2.5 μg/mL 8–18C5, 1:50 serum of relapsing-remitting mice developing spontaneously anti-MOG Ig,23 1:50 serum of nontransgenic littermates (NTL) or buffer, respectively, for 45 minutes. The cells were incubated with 10, 2.5, 0.625 μg/mL 8–18C5 antibody for one patient serum. Anti-MOG human positive sera were used at 2 different dilutions (between 1:50 and 1:30,000) depending on the baseline antibody reactivity and incubated with the differently pretreated MOG transfectants for 45 minutes. The staining procedure was as described above. PE-labeled antihuman IgG preabsorbed with NTL mouse serum was used as secondary antibody.

Standard protocol approvals, registrations, and patient consents.

The study was approved by the local ethical committees and all patients gave their informed consent for the study.

Statistical analysis.

The one-way analysis of variance on ranks (Kruskal-Wallis test) was used to compare antibody titers between patients and controls. The Spearman rank correlation test was applied to correlate anti-MOG response and age. The χ2 test with Yates correction was used to correlate anti-MOG response and gender. SigmaStat (SPSS Inc.) was used for all calculations.

RESULTS

Anti-MOG antibodies are present in a subset of children with acute demyelination but only rarely and at low levels in adult MS and not in controls.

In order to investigate the reactivity against conformationally preserved MOG, we examined whether antibodies present in the sera of patients bind to MOG-transfected cells by flow cytometry (figure 2A). The MOG transfectants were bound by sera from 31 of 126 pediatric demyelination patients (figure 2E). Thirty-five percent of pediatric patients with ADEM, 29% of pediatric patients with CIS, and 15% of pediatric patients with MS, but none of the pediatric controls, recognized conformationally preserved MOG (Kruskal-Wallis test: p < 0.05) (figure 2E). Anti-MOG reactivity could be measured down to a dilution of 1:12,150 in a patient with high anti-MOG reactivity (figure 2B). Interestingly, we noted that within the 31 anti-MOG-positive children, 9 of the 10 highest reactivities were seen in patients with monophasic ADEM (figure 2E). Anti-MOG reactivities with a geometric MCF ratio at baseline above 20 were seen in 7 of 19 MOG antibody–positive patients with ADEM, but in only one of the 10 MOG antibody–positive pediatric patients with MS (figure 3).

Figure 2
Figure 2 Features of the autoantibody response against native conformational myelin oligodendrocyte glycoprotein (MOG)
Figure 3
Figure 3 Differences in the anti–myelin oligodendrocyte glycoprotein (MOG) reactivity between pediatric patients with acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS)

MOG antibodies were most frequent in children between age 3 and 8 years (Spearman correlation coefficient: rs=−0.4098, p < 0.0001) (figure e-1). Of the children who were MOG positive, 65% were between age 3 and 8 years. Of the children with demyelination aged between 3 and 8 years, 43% had antibodies to MOG. MOG reactivity was not seen in very young patients below age of 1.5 years (n =2). There was no correlation between antibodies to MOG and gender (χ2 test: p =0.527): 61% (19/31) of the MOG-positive patients and 53% (50/95) of the MOG-negative patients were female.

There were no differences noted in acuity at onset, exposure to corticosteroids, or relapse activity (patients with MS) between the 31 MOG-positive pediatric patients with ADEM, MS, or CIS and the MOG antibody–negative patients.

There was a striking difference between childhood demyelination and adult MS. While 25% (31/126) of childhood demyelination patients recognized MOG, only 6% (4/62) of the adult patients with MS recognized MOG and only with very low antibody levels. There was no obvious influence of treatment on the serum findings; of the MOG-positive patients, 2 adult patients with MS were receiving interferon-β at the time of sampling, while 2 were treatment-naive. The average geometric MCF in MOG antibody–positive adult patients with relapsing-remitting MS was 1.65, whereas the average geometric MCF of MOG antibody–positive pediatric patients with MS was 8.70. None of the 28 adult controls recognized the MOG transfectants.

MOG-specific antibodies are IgG 1 and their binding is largely blocked by the monoclonal antibody 8–18C5 and pathogenic MOG-specific antibodies arising in a spontaneous encephalitis model.

Having seen that only antibodies to native conformational MOG differed between patients and controls (figure 2E), we were interested in the immunologic features of this autoimmune response. Therefore, we investigated the isotype of these antibodies by FACS in 8 pediatric patients who were definitely positive for antibodies against native MOG with an average geometric mean channel fluorescence ratio of 6.02. In 8/8 patients the anti-MOG antibodies were of the complement activating isotype IgG 1. None of the patients were positive for IgM or IgG 2, IgG 3, or IgG 4 (figure 2C).

We analyzed whether anti-MOG antibodies from these children were directed against the pathogenic 8–18C5 epitope or other pathogenic epitopes recognized in a model of spontaneous encephalitis (RR mouse).23 To this end, we performed a competition with the monoclonal antibody (mAb) 8–18C5 or serum from diseased mice in the cell-bound assay. Anti-MOG reactivity could be reduced in sera from 7 out of 8 MOG-positive pediatric patients by pretreatment of the transfectants with pathogenic mouse serum or the 8–18C5 antibody, while in none of the patients was the anti-MOG reactivity reduced by pretreating the cells with buffer or serum of control mice. Figure 2D shows an example of one patient.

Longitudinal analysis of anti-MOG reactivity in ADEM and childhood MS.

We asked whether anti-MOG antibodies persist over time and whether this may relate to different disease courses. Serial analysis of 25 pediatric patients positive for anti-MOG antibodies at disease onset (ADEM n =16, MS n =8, CIS n =1) showed that antibodies to cell-bound MOG declined in monophasic ADEM (n =16) and fell below detection in 10 of these 16 patients within 14 months (figure 4A). In the remaining 6 patients with ADEM, 3 had only one follow-up sample available and while antibody levels declined, values remained above detection level (at 3 months in 2 patients and at 12.5 months in one patient); in one patient antibody levels went below detection limit after 36 months, and in the remaining 2 patients with ADEM with very high reactivities at disease onset, antibody levels declined but stayed above detection limit at 12 and 14 months (figures 3 and 4A). In the one patient with CIS with positive anti-MOG detected at the time of acute demyelination, antibody levels declined below detection within 12 months (data not shown). In none of these 17 patients did anti-MOG antibody titers increase above the level detected at onset at any of the serial timepoints.

Figure 4
Figure 4 Longitudinal analysis of anti–myelin oligodendrocyte glycoprotein (MOG) reactivity in pediatric patients with acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS)

In contrast, in 6 out of 8 patients with positive anti-MOG antibodies at acute demyelination and who were eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during the observation period of up to 61 months (figures 3 and 4B). In the other 2 patients, levels of antibodies to MOG continuously declined through the course of disease: in one of them the anti-MOG antibodies were still detectable in the observation period of 49 months, while in the other patient levels went below detection limit after 3 years. In 3 out of 8 patients the antibodies decreased below detection in at least one serial sample, but antibody titers then increased subsequently.

Censoring the data for patients followed for a minimum of 12 months, the antibody levels declined in 13/13 patients with ADEM without increasing again over time, while levels persisted with fluctuations showing a recurrent increase of antibody levels in 5/7 patients with MS (figures 3 and 4).

In one patient with ADEM with no MOG antibodies at disease onset, low level (geometric MCF ratio =2.66) antibodies were detected in serum collected 2 years after the acute ADEM event but titers then decreased in subsequent samples. None of the other MOG-negative patients at baseline (n =51) developed anti-MOG over the time of follow-up at any timepoint.

The level of anti-MOG Ig at disease onset did not correlate with disease severity as measured by the Expanded Disability Status Scale score24 (data not shown). The anti-MOG titers at onset also were not predictive of antibody persistence, as patients with the highest level of anti-MOG Ig were almost exclusively children with ADEM for whom antibody reactivity decreased with time (figures 3 and 4A).

DISCUSSION

The presence of anti-MOG antibodies at acute demyelination identifies a subset of children with ADEM, rare pediatric patients with CIS, and a proportion of children manifesting with the first attack of MS. This finding is in line with reports from other groups that could also detect MOG antibodies with different assays in a subgroup of children with acute CNS demyelination.15,–,18,25 So far, only a correlation of MOG antibodies with age has been established, pointing to an increased prevalence of these antibodies in patients below the age of 10 years.15,17 Our study, which comprised a total number of 31 children with anti-MOG and 95 children without antibodies to MOG, did not show an obvious difference in clinical presentation, disease severity, or treatment responses in MOG antibody–positive and negative patients. The presence of MOG antibodies at disease onset can also not distinguish between monophasic and chronic disease, since MOG antibodies were found in both disease entities. However, we noted that the time course of MOG antibodies was different in ADEM compared to childhood MS. We report that in all prospectively analyzed children with ADEM the anti-MOG antibodies continuously declined and 63% of those patients lost their antibodies to MOG within 1 year. In contrast, in children diagnosed with MS, anti-MOG antibodies tended to persist.

The rapid disappearance of autoantibodies to MOG in ADEM, but their persistence in some children with MS, suggests a fundamental difference in immune response to myelin proteins in transient as compared to chronic CNS demyelination. ADEM is a monophasic disease and often appears to follow an infection.20,26 Thus it is tempting to speculate that the generation of MOG antibodies in the context of ADEM occurs through immune recognition of pathogenic antigens that bear similarity to MOG. Resolution of infection then removes the inciting antigens with a subsequent decline and eventually loss of antibodies. This mechanism of a cross-reacting immune response is also discussed for Guillain-Barré syndrome.27,28 In contrast, the persistence of anti-MOG antibodies in a proportion of childhood MS is similar to the persistence of autoantibodies typically seen in chronic autoimmune diseases such as neuromyelitis optica or myasthenia gravis. The low frequency of anti-MOG antibodies indicates a complex heterogeneity of autoimmune responses in demyelinating diseases.

Are these antibodies to MOG pathogenic or do they “only” form a potentially valuable prognostic biomarker? While the formal pathogenicity remains to be shown in transfer experiments (which is difficult due to the small amount of pediatric serum available), the following lines of evidence suggest potential pathogenicity: 1) MOG antibodies in these children recognize the conformationally intact MOG, which was found to be a prerequisite for pathogenicity of MOG antibodies in an animal model11; 2) antibodies against conformationally intact MOG are of the complement activating IgG 1 isotype, as has been noted in another recent report,15 and complement activation is a major pathogenic mechanism of anti-MOG antibodies in animals29; 3) there are also hints that these MOG antibodies can induce cell-mediated cytotoxicity8; 4) the epitopes recognized by MOG antibodies in children highly overlap with the epitopes recognized by pathogenic anti-MOG Ig in animals, specifically the pathogenic mAb 8–18C5 largely competes with the binding of the patient sera (this study and reference 15) and sera of mice developing spontaneously pathogenic anti-MOG Ig23 efficiently block binding of patient antibodies to MOG transfectants.

In parallel to the pediatric samples, we analyzed adult patients with MS and found that antibodies to conformationally intact MOG are of low frequency and intensity in these adult patients. Our observation of a decline of anti-MOG Ig in a few children with MS might partially explain the low frequency of anti-MOG Ig in adult MS vs childhood MS. Further longitudinal analyses of children with persisting MOG antibodies (observation period now up to 5 years) until they reach adulthood will give more insight into the temporal profile of the anti-MOG antibody response. It is also possible that the capacity for anti-MOG generation is simply greater in the pediatric context. It will also be interesting to see if MOG antibody–positive patients with MS show a different disease course or treatment response compared to MOG antibody–negative patients with MS.

We show that antibodies to cell-bound MOG are transient in ADEM, but persist in some children with MS. This supports the view that ADEM and childhood MS have distinct immunologic profiles.

AUTHOR CONTRIBUTIONS

A.K. Pröbstel: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis, study supervision, obtaining funding. Prof. Dornmair: analysis or interpretation of data, contribution of vital reagents/tools/patients, acquisition of data, study supervision. R. Bittner: analysis or interpretation of data, acquisition of data. P. Sperl: analysis or interpretation of data, acquisition of data. Dr. Jenne: analysis or interpretation of data, contribution of vital reagents/tools/patients. S. Magalhaes: study concept or design, acquisition of data. A. Villalobos: drafting/revising the manuscript, coordination of shipment of samples to be tested. Dr. Breithaupt: study concept or design. Prof. Weissert: drafting/revising the manuscript, contribution of vital reagents/tools/patients. Prof. Jacob: drafting/revising the manuscript, study concept or design. Dr. Krumbholz: analysis or interpretation of data, contribution of vital reagents/tools/patients. Dr. Kümpfel: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, contribution of vital reagents/tools/patients. Dr. Blaschek: drafting/revising the manuscript, contribution of vital reagents/tools/patients. Dr. Stark: drafting/revising the manuscript, analysis or interpretation of data, acquisition of data. Prof. Gärtner: analysis or interpretation of data, acquisition of data. Prof. Pohl: drafting/revising the manuscript, acquisition of data. Dr. Rostasy: drafting/revising the manuscript, acquisition of data. Prof. Weber: drafting/revising the manuscript, contribution of vital reagents/tools/patients, acquisition of data. Dr. Forne: analysis or interpretation of data, acquisition of data. Dr. Khademi: analysis or interpretation of data, contributed with part of the samples from adult MS/controls and provided with related clinical and paraclinical data. Prof. Olsson: drafting/revising the manuscript, analysis or interpretation of data, contribution of vital reagents/tools/patients. Dr. Brilot: study concept or design, analysis or interpretation of data, contribution of vital reagents/tools/patients. Dr. Tantsis: study concept or design, acquisition of data. Dr. Dale: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, contribution of vital reagents/tools/patients, patient samples provision. Dr. Wekerle: drafting/revising the manuscript, study concept or design, obtaining funding. Prof. Hohlfeld: drafting/revising the manuscript, study concept or design. Dr. Banwell: drafting/revising the manuscript, study concept or design, acquisition of data, obtaining funding. Dr. Bar-Or: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, contribution of vital reagents/tools/patients, statistical analysis, study supervision, obtaining funding. Dr. Meinl: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision, obtaining funding. Dr. Derfuss: drafting/revising the manuscript, study concept or design, analysis or interpretation of data, study supervision.

ACKNOWLEDGMENT

The authors thank Drs. Hannah Pellkofer and Joachim Havla for comments on the manuscript; Guru Krishnamoorthy and Kerstin Berer for providing serum of the RR mouse; Martina Soelch, Uwe Fandrich, and Florian Augstein for technical assistance; and Dr. I. Sinicina for aid.

DISCLOSURE

A.K. Pröbstel, Prof. Dornmair, R. Bittner, and P. Sperl report no disclosures. Dr. Jenne receives research support from the German Research Council. S. Magalhaes, A. Villalobos, and Dr. Breithaupt report no disclosures. Prof. Weissert was formerly employed by Merck Serono S.A. Geneva, Switzerland. Prof. Jacob serves on a scientific advisory board for SuppreMol GmbH. Dr. Krumbholz reports no disclosures. Dr. Kümpfel has received funding for travel and speaker honoraria from Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., Merck Serono, Novartis, and Biogen Idec; and has received research support from Bayer Schering Pharma. Dr. Blaschek has received funding for travel from Bayer Schering Pharma and receives research support from Merck Serono. Dr. Stark reports no disclosures. Prof. Gärtner has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries Ltd.; has served as Editor of Neuropediatrics and on the editorial boards of Klinische Pädiatrie, Monatsschrift Kinderheilkunde, and Neuropädiatrie; and receives research support from Novartis, BMBF, and DFG. Prof. Pohl serves on scientific advisory boards for Biogen Idec and Merck Serono; and has received funding for travel and/or speaker honoraria from Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, ENS, Merck Serono, University of Wisconsin, CMSC, LACTRIMS, and NMSS. Dr. Rostasy reports no disclosures. Prof. Weber has received speaker honoraria from Bayer Schering Pharma, Biogen Idec, Orion Corporation, honoraria for consultancy from Pfizer Inc., Orion Corporation and Merck-Serono; is author on patents Methods for predicting the response of multiple sclerosis patients to interferon therapy and diagnosing multiple sclerosis and Methods for predicting an antibody response to interferon therapy in multiple sclerosis patients; and receives research support from Bayer Schering Pharma, Teva Pharmaceutical Industries Ltd., and BMBF (Krankheitsbezogenes Kompetenznetz Multiple Sklerose). Dr. Forne and Dr. Khademi report no disclosures. Prof. Olsson serves/has served on scientific advisory boards for Merck Serono, Biogen Idec, sanofi-aventis, and Novartis; has received speaker honoraria from Novartis, Biogen Idec, sanofi-aventis, and Merck Serono; and receives research support from Merck Serono, Biogen Idec, sanofi-aventis, Bayer Schering Pharma, Novartis, the Swedish Research Council, the EU FP6, the Söderbergs Foundation, the Bibbi and Nils Jensens Foundation, the Montel Williams Foundation, and the Swedish Brain foundation. Dr. Brilot receives research support from the Tourette Syndrome Association, USA, the Brain Foundation Australia, and the Trish Multiple Sclerosis Foundation Australia. Dr. Tantsis reports no disclosures. Dr. Dale serves on a scientific advisory board for the Brisbane Children’s Hospital; receives publishing royalties for Autoimmune and Inflammatory Disorders of the Nervous System in Children (Mac Keith Press, 2009); received a speaker honorarium from Biogen Idec; and has received research support from the American Tourette Syndrome Association and the Brain Foundation. Dr. Wekerle reports no disclosures. Prof. Hohlfeld serves on scientific advisory boards for Novartis, Biogen Idec, Bayer Schering Pharma, Merck Serono, sanofi-aventis, Teva Pharmaceutical Industries Ltd., and CSL Behring; has received funding for travel from Novartis, Biogen Idec, Bayer Schering Pharma, Merck Serono, sanofi-aventis, and Teva Pharmaceutical Industries Ltd.; serves on the editorial boards of Neurology®, Deutsche Medizinische Wochenschrift, Expert Opinion on Biological Therapy, International MS Journal, Journal of Neuroimmunology, Multiple Sclerosis, Nervenarzt, Practical Neurology, Seminars in Immunopathology, and Therapeutic Advances in Neurological Disorders; has served as a consultant for Novartis, Biogen Idec, Bayer Schering Pharma, Merck Serono, sanofi-aventis, and Teva Pharmaceutical Industries Ltd.; and has received research support from Novartis, Biogen Idec, Bayer Schering Pharma, and Teva Pharmaceutical Industries Ltd. Dr. Banwell serves on a scientific advisory board for Biogen Idec; has received funding for travel and/or speaker honoraria from Biogen Idec, Merck Serono, Teva Pharmaceutical Industries Ltd., and Bayer Schering Pharma; serves on the editorial boards of Neurology®, Multiple Sclerosis, and Multiple Sclerosis and Related Disorders; has served as a consultant for Bayer Schering Pharma and Biogen Idec; and receives research support from the Multiple Sclerosis Society of Canada, the Multiple Sclerosis Scientific Research Foundation, and the Canadian Institutes of Health Research. Dr. Bar-Or serves on scientific advisory boards for BioMS Medical, DioGenix, Inc., Ono Pharmaceutical Co. Ltd., GlaxoSmithKline, and Roche; serves on the editorial boards of Neurology® and Clinical and Experimental Neuroimmunology; has received speaker honoraria from Biogen Idec, Bayhill Therapeutics, Bayer Schering Pharma (Berlex), Eli Lilly and Company, Genentech, Inc., GlaxoSmithKline, Merck Serono, Novartis, Wyeth, and Teva Pharmaceutical Industries Ltd.; and receives research support from Biogen Idec, Genentech, Inc., and Teva Pharmaceutical Industries Ltd. Dr. Meinl has received a speaker honorarium from Teva Pharmaceutical Industries Ltd.; serves on the editorial boards of the Journal of Pathology and Clinical Experimental Immunology; and receives research support from the Novartis Foundation. Dr. Derfuss serves on scientific advisory boards for Novartis, Merck Serono, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Novartis, Merck Serono, and Bayer Schering Pharma; and receives research support from Novartis, Merck Serono, the German Research Foundation, and the Swiss MS Society.

Footnotes

  • Study funding: Supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 571), the BMBF (Krankheitsbezogenes Kompetenznetz Multiple Sklerose), Excellence Initiative of the Ludwig-Maximilians-University Munich, the FoeFoLe of the Ludwig-Maximilians-University, the Gemeinnützige Hertie Stiftung, and the Research Foundation of the MS Society of Canada to the Canadian Pediatric Demyelinating Disease Study Group.

  • Supplemental data at www.neurology.org

  • Received November 24, 2010.
  • Accepted April 6, 2011.

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