Neuroimmunological Registries in Germany

Abstract

Several neuroimmunological registries have been established in Germany during the last 10 years. The common aim is to investigate the course of different diseases, mainly under various therapeutic conditions, to identify predictive factors as well as the side effects of immunomodulating therapies. Six nationwide neuroimmunological registries will be presented in this article. The German Network for Research on Autoimmune Encephalitis (GENERATE) with more than 40 participating clinical centers and 570 documented patients (September 2016) collects data and biomaterials of autoimmune encephalitis with known and unknown antibodies. The registry coordinates and mediates between scientists and clinicians and acts as a platform for the development of guidelines and procedures. The neuromyelitis optica study group (NEMOS) has established a national registry for patients with neuromyelitis optica and neuromyelitis optica spectrum disorders. In addition to 22 academic hospitals, 17 regional hospitals and several practices are participating. Currently, 250 patients are enrolled. Moreover, NEMOS is now establishing a prospective patient cohort (NationNMO) within the competence network multiple sclerosis. Current research focuses on treatment strategies for relapses and interval therapy of neuromyelitis optica. The competence network multiple sclerosis has initiated a multi-center, prospective cohort study of patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (MS) (NationMS), with the aim of long-term follow-up and clinical and paraclinical characterization of the patients. Between August 2010 and December 2014, 1,212 patients in 22 university und non-university centers were enrolled in the NationMS cohort. Standardized clinical data as well as biomaterial and MRI images were collected and stored. The German MS Society (DMSG, Bundesverband e.V.) established in 2001 a long-term project to obtain a consistent and reliable overview of MS patients in Germany. Since 2014 the registry has been revised comprehensively, with the main purpose of establishing a permanent data repository for healthcare research while ensuring the collection, storage and provision of data over decades and enabling the description of long-term outcomes. Currently, more than 170 German centers are participating and over 48,000 patients are enrolled in the registry. Since 2013, the competence network multiple sclerosis has established the immunotherapy registry REGIMS with the objective to obtain information on incidence, type and characteristics of adverse events of new immunomodulating therapies for patients with multiple sclerosis or clinical isolated syndrome. As of January 2017 more than 700 patients have been recruited from 36 active centers. The German Multiple Sclerosis and Pregnancy Registry aims to obtain safety information of disease modifying drug exposure during pregnancy. In addition to safety aspects, disease course during pregnancy and postpartum and the identification of predictors of disease activity are investigated. During the last ten years 1,500 pregnant MS patients were prospectively enrolled in the registry and at least 250 new pregnancies are followed every year. These six registries make an important epidemiological and scientific contribution. Numerous colleagues from clinics and practice support these registries. The objective is the closer understanding of the disease course, the influence of therapeutic decisions and thus the improvement of counseling and care.

Key words

neuroimmunological registries - autoimmune encephalitis - neuromyelitis optica spectrum disorders - multiple sclerosis

• References

• 1 Vora NM, Holman RC, Mehal JM. et al. Burden of encephalitis-associated hospitalizations in the United States, 1998-2010. Neurology 2014; 82: 443-451
• 2 Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci 2015; 1338: 94-114
• 3 Lewerenz J, Jarius S, Wildemann B. et al. Autoantikörper-assoziierte autoimmune Enzephalitiden und Zerebellitiden. Nervenarzt 2016; 87: 1293-1299
• 4 Titulaer MJ, McCracken L, Gabilondo I. et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study. Lancet Neurol 2013; 12: 157-165
• 5 Lucchinetti CF, Mandler RN, McGavern D. et al. A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain 2002; 125: 1450-1461
• 6 Lennon VA, Wingerchuk DM, Kryzer TJ. et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet 2004; 364: 2106-2112
• 7 Lennon VA, Kryzer TJ, Pittock SJ. et al. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005; 202: 473-477
• 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 Jarius S, Probst C, Borowski K. et al. Standardized method for the detection of antibodies to aquaporin-4 based on a highly sensitive immunofluorescence assay employing recombinant target antigen. J Neurol Sci 2010; 291: 52-56
• 10 Harmel J, Ringelstein M, Ingwersen J. et al. Interferon-beta-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab. BMC Neurol 2014; 14: 247
• 11 Trebst C, Berthele A, Jarius S. et al. [Diagnosis and treatment of neuromyelitis optica. Consensus recommendations of the Neuromyelitis Optica Study Group]. Nervenarzt 2011; 82: 768-777
• 12 Wingerchuk DM, Lennon VA, Pittock SJ. et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66: 1485-1489
• 13 Trebst C, Jarius S, Berthele A. et al. Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 2014; 261: 1-16
• 14 Aktas O. Natalizumab in clinical practice: Managing the risks, enjoying the benefits. J Neurol Neurosurg Psychiatry 2014; 85: 1181
• 15 Kleiter I, Hellwig K, Berthele A. et al. Failure of natalizumab to prevent relapses in neuromyelitis optica. Arch Neurol 2012; 69: 239-245
• 16 Kleiter I, Hellwig K, Berthele A. et al. Is it too early to predict the failure of natalizumab in NMO?-Reply. Arch Neurol 2012; 69: 1085-1086
• 17 Ringelstein M, Metz I, Ruprecht K. et al. Contribution of spinal cord biopsy to diagnosis of aquaporin-4 antibody positive neuromyelitis optica spectrum disorder. Mult Scler 2014; 20: 882-888
• 18 Krumbholz M, Hofstadt-van Oy U, Angstwurm K. et al. Very late-onset neuromyelitis optica spectrum disorder beyond the age of 75. J Neurol 2015; 262: 1379-1384
• 19 Borisow N, Kleiter I, Gahlen A. et al. Influence of female sex and fertile age on neuromyelitis optica spectrum disorders. Mult Scler 2016; 23: 1092-1103
• 20 Kleiter I, Gahlen A, Borisow N. et al. Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol 2016; 79: 206-216
• 21 Jarius S, Ruprecht K, Kleiter I. et al. MOG-IgG in NMO and related disorders: A multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin. J Neuroinflammation 2016; 13: 279
• 22 Jarius S, Ruprecht K, Kleiter I. et al. MOG-IgG in NMO and related disorders: A multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation 2016; 13: 280
• 23 Jarius S, Kleiter I, Ruprecht K. et al. MOG-IgG in NMO and related disorders: A multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome. J Neuroinflammation 2016; 13: 281
• 24 Pandit L, Asgari N, Apiwattanakul M. et al Demographic and clinical features of neuromyelitis optica: A review. Mult Scler 2015; 21: 845-853
• 25 Petersen G, Wittmann R, Arndt V. et al. [Epidemiology of multiple sclerosis in Germany: Regional differences and drug prescription in the claims data of the statutory health insurance]. Nervenarzt 2014; 85: 990-998
• 26 Pugliatti M, Rosati G, Carton H. et al. The epidemiology of multiple sclerosis in Europe. Eur J Neurol 2006; 13: 700-722
• 27 Kingwell E, Marriott JJ, Jette N. et al. Incidence and prevalence of multiple sclerosis in Europe: A systematic review. BMC Neurol 2013; 13: 128
• 28 Barkhof F, Filippi M, Miller DH. et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120: 2059-2069
• 29 Polman CH, Reingold SC, Banwell B. et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69: 292-302
• 30 Polman CH, Reingold SC, Edan G. et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005; 58: 840-846
• 31 Simon JW, Paslack R, Robienski J. et al. Biomaterialbanken–Rechtliche Rahmenbedingungen.. Schriftenreihe der Telematikplattform für Medizinische Forschungsnetze (TMF), Bd 2. Berlin: Medizinisch Wissenschaftliche Verlagsgesellschaft; 2006
• 32 Dankowski T, Buck D, Andlauer TF. et al. Successful replication of GWAS hits for multiple sclerosis in 10,000 Germans using the exome array. Genet Epidemiol 2015; 39: 601-608
• 33 Andlauer TF, Buck D, Antony G. et al. Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation. Sci Adv 2016; 2: e1501678
• 34 Kolber P, Luessi F, Meuth SG. et al. [Current aspects of therapy conversion for multiple sclerosis]. Nervenarzt 2015; 86: 1236-1247
• 35 Klotz L, Berthele A, Bruck W. et al. [Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action]. Nervenarzt 2016; 87: 645-659
• 36 Flachenecker P, Zettl U, Götze U. et al. MS-Register in Deutschland - abschließende Ergebnisse der Pilotphase. Neurol Rehab 2007; 13: 193-200
• 37 Flachenecker P, Stuke K, Elias W. et al. Multiple-Sklerose-Register in Deutschland. Dtsch Ärztebl 2008; 105: 113-119
• 38 Stuke K, Flachenecker P, Zettl UK. et al. Symptomatology of MS: results from the German MS Registry. J Neurol 2009; 256: 1932-1935
• 39 Khil L, Flachenecker P, Zettl UK et al. Patientenversorgung bei Multipler Sklerose: Vergleich der Basisdaten verschiedener Versorgungsstrukturen im Deutschen MS-Register. 82 Kongresses der Deutschen Gesellschaft für Neurologie mit Fortbildungsakademie. 2009;
• 40 Khil L, Flachenecker P, Zettl UK et al. Update on the German MS Register: Immunotherapy and drug discontinuation. 25th Congress of the european committee for treatment and research in multiple sclerosis; 2009;
• 41 Rommer PS, Buckow K, Ellenberger D. et al. Patients characteristics influencing the longitudinal utilization of steroids in multiple sclerosis–an observational study. Eur J Clin Invest 2015; 45: 587-593
• 42 Skierlo S, Rommer PS, Zettl UK. Symptomatic treatment in multiple sclerosis-interim analysis of a nationwide registry. Acta Neurol Scand 2017; 135: 394-399
• 43 Stahmann A, Meyer C, Lee M. et al. PRO-Dokumentation von Lebensqualitätsdaten im MS-Register der Deutschen Multiplen Sklerose Gesellschaft (DMSG). Bundesverband e.V. Forum der Medizin_Dokumentation und Medizin_Informatik - mdi. März 2015; 17: 18-19
• 44 Stahmann A, Buckow K, Ellenberger D et al. Das MS-Register der DMSG als Plattform für die MS-Forschung. 88. Kongress der Deutschen Gesellschaft für Neurologie mit Fortbildungsakademie; 2015;
• 45 Flachenecker P, Stuke K. National MS registries. J Neurol 2008; 255 (Suppl. 06) 102-108
• 46 Petersen G, Wittmann R, Arndt V. et al. Epidemiology of multiple sclerosis in Germany. Nervenarzt 2014; 85: 990-998
• 47 Stahmann A, Buckow K, Ellenberger D. et al. The German MS Register: update on immunotherapy. ECTRIMS Online Library 2016; P1138
• 48 Garg N, Smith TW. An update on immunopathogenesis, diagnosis, and treatment of multiple sclerosis. Brain Behav 2015; 5: e00362
• 49 Michel L, Larochelle C, Prat A. Update on treatments in multiple sclerosis. Presse Med. 2015; 44: e137-e151
• 50 Butzkueven H, Chapman J, Cristiano E. et al. MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis. Mult Scler 2006; 12: 769-774
• 51 Hillert J, Stawiarz L. The Swedish MS registry - clinical support tool and scientific resource. Acta Neurol Scand 2015; 132: 11-19
• 52 Romero RS, Lunzmann C, Bugge JP. Pregnancy outcomes in patients exposed to interferon beta-1b. J Neurol Neurosurg Psychiatry 2015; 86: 587-589
• 53 Neudorfer O, Sandberg-Wollheim M, Coyle PK. et al. The Glatiramer acetate pregnancy database. ECTRIMS Online Library 2015; 116357: P1507
• 54 Friend S, Richman S, Bloomgren G. et al. Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study. BMC Neuro 2016; 16: 150
• 55 Geissbühler Y, Vile J, Koren G et al. Cumulative data on pregnancy outcomes after exposure to fingolimod and in coparison with the general population. 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); September 14-17, 2016; London, UK2016
• 56 Vukusic S, Hutchinson M, Hours M. et al. Pregnancy and multiple sclerosis (the PRIMS study): Clinical predictors of post-partum relapse. Brain 2004; 127: 1353-1360
• 57 Salemi G, Callari G, Gammino M. et al. The relapse rate of multiple sclerosis changes during pregnancy: A cohort study. Acta Neurol Scand 2004; 110: 23-26
• 58 Hughes SE, Spelman T, Gray OM. et al. Predictors and dynamics of postpartum relapses in women with multiple sclerosis. Mult Scler 2014; 20: 739-746
• 59 Rigau V, Mania A, Befort P. et al. Lethal multiple sclerosis relapse after natalizumab withdrawal. Neurology 2012; 79: 2214-2216
• 60 Hellwig K, Gold R. Immune reconstitution inflammatory syndrome after withdrawal of natalizumab?. Neurology 2011; 76: 1362-1363 author reply 3
• 61 Hellwig K, Haghikia A, Gold R. Pregnancy and natalizumab: results of an observational study in 35 accidental pregnancies during natalizumab treatment. Mult Scler 2011; 17: 958-963
• 62 Hellwig K, Haghikia A, Rockhoff M. et al. Multiple sclerosis and pregnancy: Experience from a nationwide database in Germany. Ther Adv Neurol Disord 2012; 5: 247-253
• 63 Paavilainen T, Kurki T, Parkkola R. et al. Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis. Eur J Neurol 2007; 14: 1216-1221
• 64 Fragoso YD, Boggild M, Macias-Islas MA. et al. The effects of long-term exposure to disease-modifying drugs during pregnancy in multiple sclerosis. Clin Neurol Neurosurg 2013; 115: 154-159
• 65 Herbstritt S, Langer-Gould A, Rockhoff M. et al. Glatiramer acetate during early pregnancy: A prospective cohort study. Mult Scler 2016; 22: 810-816
• 66 Thiel S, Langer-Gould A, Rockhoff M. et al. Interferon-beta exposure during first trimester is safe in women with multiple sclerosis-A prospective cohort study from the German Multiple Sclerosis and Pregnancy Registry. Mult Scler 2016; 22: 801-809
• 67 Ebrahimi N, Herbstritt S, Gold R. et al. Pregnancy and fetal outcomes following natalizumab exposure in pregnancy. A prospective, controlled observational study. Mult Scler 2015; 21: 198-205
• 68 Haghikia A, Langer-Gould A, Rellensmann G. et al. Natalizumab use during the third trimester of pregnancy. JAMA Neurol 2014; 71: 891-895
• 69 Spicher C, Thiel S, Klaaßen-Mielke R et al. Reversal of relapse pattern during pregnancy in women treated with natalizumab up to pregnancy (P2.096). Neurology 2016; 86 (16 Supplement):
• 70 Hellwig K, Rockhoff M, Herbstritt S. et al. Exclusive breastfeeding and the effect on postpartum multiple sclerosis relapses. JAMA Neurol 2015; 72: 1132-1138
• 71 Park-Wyllie L, Mazzotta P, Pastuszak A. et al. Birth defects after maternal exposure to corticosteroids: Prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000; 62: 385-392