Advertisement

Multiple Sklerose und andere autoimmune ZNS-Erkrankungen

  • Martin Stangel
  • Christoph Kleinschnitz
  • Mathias Mäurer
  • Peter Raab
  • Kurt-Wolfram Sühs
  • Corinna Trebst
Chapter

Zusammenfassung

Autoimmunerkrankungen des zentralen Nervensystems (ZNS) stellen eines der sich am schnellsten entwickelnden Gebiete in der Neurologie dar. Die Entdeckung neuer Autoantikörper hat zur Beschreibung neuer Krankheitsentitäten und zu einer Diversifizierung geführt, die einerseits eine gute differenzialdiagnostische Abgrenzung erfordert, ebenso wie es zu unterschiedlichen Therapieschemata führt. Aber auch klassische Erkrankungen wie die Multiple Sklerose haben mit der Abgrenzung der Neuromyelitis-Optica-Spektrumerkrankungen neue Impulse erhalten. Parallel dazu gab es eine beeindruckende Entwicklung bei den Immuntherapeutika, sodass für diese Erkrankungen unterschiedlichste Therapieoptionen bestehen.

Literatur

Literatur zu Abschn. 1.1

  1. Alusi SH, Worthington J, Glickman S, Bain PG (2001) A study of tremor in multiple sclerosis. Brain 124:720–730PubMedCrossRefPubMedCentralGoogle Scholar
  2. Ascherio A, Munger KL (2016) Epidemiology of multiple sclerosis: from risk factors to prevention – an update. Semin Neurol 36(2):103–114PubMedCrossRefPubMedCentralGoogle Scholar
  3. Bamer AM, Johnson KL, Amtmann D, Kraft GH (2008) Prevalence of sleep problems in individuals with multiple sclerosis. Mult Scler 14:1127–1130PubMedPubMedCentralCrossRefGoogle Scholar
  4. Capello E, Mancardi GL (2004) Marburg type and Balo’s concentric sclerosis: rare and acute variants of multiple sclerosis. Neurol Sci 25(Suppl 4):361–363CrossRefGoogle Scholar
  5. Chiaravalloti ND, DeLuca J (2008) Cognitive impairment in multiple sclerosis. Lancet Neurol 7:1139–1151PubMedCrossRefPubMedCentralGoogle Scholar
  6. Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, Nath A (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 9: 438–446PubMedCrossRefGoogle Scholar
  7. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, and Kappos L (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362: 402–415PubMedCrossRefGoogle Scholar
  8. Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359: 1786–1801Google Scholar
  9. Comi G, De SN, Freedman MS, Barkhof F, Polman CH, Uitdehaag BM et al (2012) Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 11 (1): 33–41PubMedCrossRefGoogle Scholar
  10. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, Elovaara I, Fazekas F, Hartung HP, Hillert J, King J, Komoly S, Lubetzki C, Montalban X, Myhr KM, Ravnborg M, Rieckmann P, Wynn D, Young C, and Filippi M (2009) Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 374: 1503–1511CrossRefGoogle Scholar
  11. Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj K, Sharrack B, and Filippi M (2008) Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet 371: 2085–2092CrossRefGoogle Scholar
  12. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T (1998) Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med 339:285–291PubMedCrossRefPubMedCentralGoogle Scholar
  13. Cree BA (2014) Multiple sclerosis genetics. Handb Clin Neurol 122:193–209PubMedCrossRefPubMedCentralGoogle Scholar
  14. Dippel FW, Mäurer M, Schinzel S, Müller-Bohn T, Larisch K (2015) Krankenversicherungsdaten bestätigen hohe Prävalenz der Multiplen Sklerose. Akt Neurol 42(4):191–196CrossRefGoogle Scholar
  15. Esposito S, Bonavita S, Sparaco M, Gallo A, Tedeschi G (2017) The role of diet in multiple sclerosis: a review. Nutr Neurosci 24:1–14Google Scholar
  16. Filippi M, Rocca MA, Ciccarelli O et al (2016) MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol 15:292–303PubMedPubMedCentralCrossRefGoogle Scholar
  17. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M et al (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367 (12): 1087–1097Google Scholar
  18. Frohman EM, Frohman TC, Zee DS, McColl R, Galetta S (2005) The neuro-ophthalmology of multiple sclerosis. Lancet Neurol 4:111–121PubMedCrossRefGoogle Scholar
  19. Garren H, Robinson WH, Krasulova E, Havrdova E, Nadj C, Selmaj K, Losy J, Nadj I, Radue EW, Kidd BA, Gianettoni J, Tersini K, Utz PJ, Valone F, Steinman L (2008) Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann Neurol 63: 611–620PubMedCrossRefGoogle Scholar
  20. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg SP, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ (2010) A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 362: 416–426PubMedCrossRefGoogle Scholar
  21. Gold R et al (2012) Diagnose und Therapie der Multiplen Sklerose. Leitlinie der Deutschen Gesellschaft für Neurologie, www.dgn.org
  22. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K et al (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367 (12): 1098–1107PubMedCrossRefGoogle Scholar
  23. Hartung HP, Aktas O, Menge T, Kieseier BC (2014) Immune regulation of multiple sclerosis. Handb Clin Neurol 122:3–14PubMedCrossRefGoogle Scholar
  24. Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, Krapf H, Zwingers T (2002) Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 360: 2018–2025CrossRefGoogle Scholar
  25. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B et al (2017) Ocrelizumab versus Interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 376 (3): 221–234PubMedCrossRefPubMedCentralGoogle Scholar
  26. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358: 676–688PubMedCrossRefPubMedCentralGoogle Scholar
  27. Hawker K, O'Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, Hauser SL, Waubant E, Vollmer T, Panitch H, Zhang J, Chin P, Smith CH (2009) Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 66: 460–471PubMedCrossRefPubMedCentralGoogle Scholar
  28. Henze T, Feneberg W, Flachenecker P, Seidel D, Albrecht H, Starck M, Meuth SG (2017) What is new in symptomatic MS treatment: Part 1-introduction and methodical approach, ataxia and tremor. Nervenarzt 88 (12): 1421–1427PubMedCrossRefGoogle Scholar
  29. Henze T, Feneberg W, Flachenecker P, Seidel D, Albrecht H, Starck M, Meuth SG (2017) What is new in symptomatic MS treatment: Part 2-gait disorder and spasticity. Nervenarzt 88 (12): 1428–1434PubMedCrossRefGoogle Scholar
  30. Henze T, Feneberg W, Flachenecker P, Seidel D, Albrecht H, Starck M, Meuth SG (2018) What is new in symptomatic MS treatment: Part 3-bladder dysfunction. Nervenarzt 89 (2): 184–192Google Scholar
  31. Henze T, Feneberg W, Flachenecker P, Seidel D, Albrecht H, Starck M, Meuth SG (2018) New aspects of symptomatic MS treatment: Part 4-sexual dysfunction and eye movement disorders. Nervenarzt 89 (2): 193–197Google Scholar
  32. Henze T, Feneberg W, Flachenecker P, Seidel D, Albrecht H, Starck M, Meuth SG (2017) New aspects of symptomatic MS treatment: Part 5 – fatigue. Nervenarzt.  https://10.1007/s00115-017-0442-8
  33. Henze T, Feneberg W, Flachenecker P, Seidel D, Albrecht H, Starck M, Meuth SG (2017) New aspects of symptomatic MS treatment: Part 6 – cognitive dysfunction and rehabilitation. Nervenarzt.  https://10.1007/s00115-017-0443-7
  34. Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, and Sandrock AW (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343: 898–904Google Scholar
  35. Jörg S, Grohme DA, Erzler M, Binsfeld M, Haghikia A, Müller DN, Linker RA, Kleinewietfeld M (2016) Environmental factors in autoimmune diseases and their role in multiple sclerosis. Cell Mol Life Sci 73(24):4611–4622PubMedPubMedCentralCrossRefGoogle Scholar
  36. Kapoor R, Furby J, Hayton T, Smith KJ, Altmann DR, Brenner R, Chataway J, Hughes RA, and Miller DH (2010) Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 9: 681–688PubMedCrossRefPubMedCentralGoogle Scholar
  37. Kappos L, Edan G, Freedman MS, Montalban X, Hartung HP, Hemmer B et al (2016) The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. Neurology 87 (10): 978–987PubMedPubMedCentralCrossRefGoogle Scholar
  38. Kappos L, Li D, Calabresi PA, O‘Connor P, Bar-Or A, Barkhof F et al (2011) Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378 (9805): 1779–1787CrossRefGoogle Scholar
  39. Kappos L, Radue EW, O‘Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, and Burtin P (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362: 387–401PubMedCrossRefPubMedCentralGoogle Scholar
  40. Kleinschnitz C, Meuth SG, Kieseier BC, Wiendl H (2007) Update on pathophysiologic and immunotherapeutic approaches for the treatment of multiple sclerosis. Nervenarzt 78:883–911PubMedCrossRefGoogle Scholar
  41. Klotz L, Berthele A, Brück W, Chan A, Flachenecker P, Gold R, Haghikia A, Hellwig K, Hemmer B, Hohlfeld R, Korn T, Kümpfel T, Lang M, Limmroth V, Linker RA, Meier U, Meuth SG, Paul F, Salmen A, Stangel M, Tackenberg B, Tumani H, Warnke C, Weber MS, Ziemssen T, Zipp F, Wiendl H (2016) Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action. Nervenarzt 87 (6): 645–659PubMedCrossRefGoogle Scholar
  42. Koch M, Uyttenboogaart M, Polman S, De Keyser J (2008) Seizures in multiple sclerosis. Epilepsia 49:948–953PubMedCrossRefGoogle Scholar
  43. Kolber P, Luessi F, Meuth SG, Klotz L, Korn T, Trebst C, Tackenberg B, Kieseier B, Kümpfel T, Fleischer V, Tumani H, Wildemann B, Lang M, Flachenecker P, Meier U, Brück W, Limmroth V, Haghikia A, Hartung HP, Stangel M, Hohlfeld R, Hemmer B, Gold R, Wiendl H, Zipp F (2015) [Current aspects of therapy conversion for multiple sclerosis]. Nervenarzt 86 (10): 1236–1247PubMedCrossRefPubMedCentralGoogle Scholar
  44. Leake JA, Albani S, Kao AS et al (2004) Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J 23:756–764PubMedCrossRefGoogle Scholar
  45. Lublin FD, Reingold SC, Cohen JA et al (2014) Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83:1–9CrossRefGoogle Scholar
  46. McGuigan C, Craner M, Guadagno J, Kapoor R, Mazibrada G, Molyneux P, Nicholas R, Palace J, Pearson OR, Rog D, Young CA (2016) Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry 87 (2): 117–125Google Scholar
  47. Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D, Clanet M, Comi G, Derfuss T, Fazekas F, Hartung HP, Havrdova E, Hemmer B, Kappos L, Liblau R, Lubetzki C, Marcus E, Miller DH, Olsson T, Pilling S, Selmaj K, Siva A, Sorensen PS, Sormani MP, Thalheim C, Wiendl H, Zipp F (2018) ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler 24 (2): 96–120PubMedCrossRefGoogle Scholar
  48. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G et al (2017) Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med 376 (3): 209–220PubMedCrossRefGoogle Scholar
  49. Moore P, Harding KE, Clarkson H, Pickersgill TP, Wardle M, Robertson NP (2013) Demographic and clinical factors associated with changes in employment in multiple sclerosis. Mult Scler 19(12):1647–1654PubMedCrossRefGoogle Scholar
  50. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. New Engl J Med 343:938–952PubMedCrossRefGoogle Scholar
  51. O’Connor P, Comi G, Freedman MS, Miller AE, Kappos L, Bouchard JP et al (2016) Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study. Neurology 86 (10): 920–930PubMedPubMedCentralCrossRefGoogle Scholar
  52. Pearce JM (2007) Balo’s encephalitis periaxialis concentrica. Eur Neurol 57:59–61PubMedCrossRefGoogle Scholar
  53. Pender MP, Burrows SR (2014) Epstein-Barr virus and multiple sclerosis: potential opportunities for immunotherapy. Clin Transl Immunology 3(10):e27PubMedPubMedCentralCrossRefGoogle Scholar
  54. Petersen G, Wittmann R, Arndt V, Göpffarth D (2014) Epidemiologie der Multiplen Sklerose in Deutschland. Nervenarzt 85:990–998PubMedCrossRefGoogle Scholar
  55. Pierrot-Deseilligny C, Souberbielle JC (2017) Vitamin D and multiple sclerosis: an update. Mult Scler Relat Disord 14:35–45PubMedCrossRefGoogle Scholar
  56. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, and Sandrock AW (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354: 899–910PubMedCrossRefGoogle Scholar
  57. Polman CH, Reingold SC, Banwell B et al. (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the „McDonald Criteria“ Ann Neurol 69:292–302PubMedPubMedCentralCrossRefGoogle Scholar
  58. Poser CM, Goutieres F, Carpentier MA, Aicardi J (1986) Schilder’s myelinoclastic diffuse sclerosis. Pediatrics 77:107–112PubMedGoogle Scholar
  59. Rao SM, Leo GJ, Bernardin L, Unverzagt F (1991) Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology 41:685–691PubMedCrossRefPubMedCentralGoogle Scholar
  60. Rolak LA, Fleming JO (2007) The differential diagnosis of multiple sclerosis. Neurologist 13:57–72PubMedCrossRefPubMedCentralGoogle Scholar
  61. Rovira A, Wattjes MP, Tintore M et al (2015) Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process. Nat Rev Neurol 11:471–482PubMedCrossRefPubMedCentralGoogle Scholar
  62. Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354:911–923PubMedCrossRefGoogle Scholar
  63. Scalfari A, Knappertz V, Cutter G, Goodin DS, Ashton R, Ebers GC (2013) Mortality in patients with multiple sclerosis. Neurology 81:184–192PubMedPubMedCentralCrossRefGoogle Scholar
  64. Selmaj K, Li DK, Hartung HP, Hemmer B, Kappos L, Freedman MS et al (2013) Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol 12 (8): 756–767PubMedCrossRefPubMedCentralGoogle Scholar
  65. Selter RC, Hemmer B (2013) Update on immunopathogenesis and immunotherapy in multiple sclerosis. Immunotargets Ther 2:21–30PubMedPubMedCentralGoogle Scholar
  66. Seze J de, Chapelotte M, Delalande S, Ferriby D, Stojkovic T, and Vermersch P (2004) Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. Mult Scler 10: 596–597PubMedCrossRefGoogle Scholar
  67. Spelman T, Kalincik T, Jokubaitis V, Zhang A, Pellegrini F, Wiendl H, Belachew S, Hyde R, Verheul F, Lugaresi A, Havrdová E, Horáková D, Grammond P, Duquette P, Prat A, Iuliano G, Terzi M, Izquierdo G, Hupperts RM, Boz C, Pucci E, Giuliani G, Sola P, Spitaleri DL, Lechner-Scott J, Bergamaschi R, Grand'Maison F, Granella F, Kappos L, Trojano M, Butzkueven H (2016) Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS. Neurol Clin Pract 6 (2): 102–115Google Scholar
  68. Spelman T, Kalincik T, Jokubaitis V, Zhang A, Pellegrini F, Wiendl H, Belachew S, Hyde R, Verheul F, Lugaresi A, Havrdová E, Horáková D, Grammond P, Duquette P, Prat A, Iuliano G, Terzi M, Izquierdo G, Hupperts RM, Boz C, Pucci E, Giuliani G, Sola P, Spitaleri DL, Lechner-Scott J, Bergamaschi R, Grand'Maison F, Granella F, Kappos L, Trojano M, Butzkueven H (2016) Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS. Neurol Clin Pract 6 (2): 102–115Google Scholar
  69. Seze J de, Chapelotte M, Delalande S, Ferriby D, Stojkovic T, and Vermersch P (2004) Intravenous corticosteroids in the postpartum period for reduction of acute exacerbations in multiple sclerosis. Mult Scler 10: 596–597PubMedCrossRefGoogle Scholar
  70. Stangel M, Penner IK, Kallmann BA, Lukas C, Kieseier BC (2015) Towards the implementation of ‚no evidence of disease activity‘ in multiple sclerosis treatment: the multiple sclerosis decision model. Ther Adv Neurol Disord 8 (1): 3–13CrossRefGoogle Scholar
  71. Swingler RJ, Compston DA (1992) The morbidity of multiple sclerosis. Q J Med 83:325–337PubMedPubMedCentralGoogle Scholar
  72. Tenembaum S, Chitnis T, Ness J, Hahn JS (2007) Acute disseminated encephalomyelitis. Neurology 68:23–36CrossRefGoogle Scholar
  73. Thompson AJ, Banwell BL, Barkhof F et al (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17:162–73Google Scholar
  74. The optic neuritis study group (2008) Multiple sclerosis risk after optic neuritis: final optic neuritis treatment trial follow-up. Arch Neurol 65:727–732PubMedCentralGoogle Scholar
  75. Tranchant C, Bhatia KP, Marsden CD (1995) Movement disorders in multiple sclerosis. Mov Disord 10:418–423PubMedCrossRefPubMedCentralGoogle Scholar
  76. Williamson EML, Berger JR (2017) Diagnosis and treatment of progressive multifocal leukoencephalopathy associated with multiple sclerosis therapies. Neurotherapeutics 14 (4): 961–973PubMedCrossRefPubMedCentralGoogle Scholar
  77. Xia L, Lin S, Wang ZC et al (2009) Tumefactive demyelinating lesions: nine cases and a review of the literature. Neurosurg Rev 32:171–179PubMedCrossRefPubMedCentralGoogle Scholar
  78. Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S (2015) Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol 28(3):206–219PubMedCrossRefPubMedCentralGoogle Scholar
  79. Zimmermann C, Hohlfeld R (1999) ‘Fatigue’ in multiple sclerosis. Nervenarzt 70:566–574Google Scholar

Literatur zu Abschn. 1.2

  1. Araki M, Matsuoka T, Miyamoto K, Kusunoki S, Okamoto T, Murata M et al (2014) Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 82(15):1302–1306PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ayzenberg I, Schollhammer J, Hoepner R, Hellwig K, Ringelstein M, Aktas O et al (2016) Efficacy of glatiramer acetate in neuromyelitis optica spectrum disorder: a multicenter retrospective study. J Neurol 263(3):575–582PubMedCrossRefPubMedCentralGoogle Scholar
  3. Bichuetti DB, Oliveira EM, Boulos FC, Gabbai AA (2012) Lack of response to pulse cyclophosphamide in neuromyelitis optica: evaluation of 7 patients. Arch Neurol 69(7):938–939PubMedCrossRefPubMedCentralGoogle Scholar
  4. Bizzoco E, Lolli F, Repice AM, Hakiki B, Falcini M, Barilaro A et al (2009) Prevalence of neuromyelitis optica spectrum disorder and phenotype distribution. J Neurol 256(11):1891–1898PubMedCrossRefPubMedCentralGoogle Scholar
  5. Chitnis T, Ness J, Krupp L, Waubant E, Hunt T, Olsen CS et al (2016) Clinical features of neuromyelitis optica in children: US Network of Pediatric MS Centers report. Neurology 86(3):245–252PubMedPubMedCentralCrossRefGoogle Scholar
  6. Elsone L, Kitley J, Luppe S, Lythgoe D, Mutch K, Jacob S et al (2014) Long-term efficacy, tolerability and retention rate of azathioprine in 103 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients: a multicentre retrospective observational study from the UK. Mult Scler 20(11):1533–1540PubMedCrossRefPubMedCentralGoogle Scholar
  7. Huh SY, Kim SH, Hyun JW, Joung AR, Park MS, Kim BJ et al (2014) Mycophenolate mofetil in the treatment of neuromyelitis optica spectrum disorder. JAMA Neurol 2014 71(11):1372–1378PubMedCrossRefPubMedCentralGoogle Scholar
  8. Jacob A, Matiello M, Weinshenker BG, Wingerchuk DM, Lucchinetti C, Shuster E et al (2009) Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol 66(9):1128–1133PubMedCrossRefPubMedCentralGoogle Scholar
  9. Jarius S, Ruprecht K, Wildemann B, Kuempfel T, Ringelstein M, Geis C et al (2012) Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 9:14PubMedPubMedCentralCrossRefGoogle Scholar
  10. Jeong IH, Park B, Kim SH, Hyun JW, Joo J, Kim HJ (2016) Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints. Mult Scler 22(3):329–339PubMedCrossRefPubMedCentralGoogle Scholar
  11. Kim SH, Kim W, Li XF, Jung IJ, Kim HJ (2011) Repeated treatment with rituximab based on the assessment of peripheral circulating memory B cells in patients with relapsing neuromyelitis optica over 2 years. Arch Neurol 68(11):1412–1420PubMedCrossRefGoogle Scholar
  12. Kim SH, Huh SY, Lee SJ, Joung A, Kim HJ (2013) A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol 70(9):1110–1117PubMedCrossRefPubMedCentralGoogle Scholar
  13. Kim SH, Jeong IH, Hyun JW, Joung A, Jo HJ, Hwang SH et al (2015) Treatment outcomes with rituximab in 100 patients with neuromyelitis optica: influence of FCGR3A polymorphisms on the therapeutic response to rituximab. JAMA Neurol 72(9):989–995PubMedCrossRefGoogle Scholar
  14. Kim SM, Woodhall MR, Kim JS, Kim SJ, Park KS, Vincent A et al (2015) Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS. Neurol Neuroimmunol Neuroinflamm 2(6):e163PubMedPubMedCentralCrossRefGoogle Scholar
  15. Kleiter I, Hellwig K, Berthele A, Kumpfel T, Linker RA, Hartung HP et al (2012) Failure of natalizumab to prevent relapses in neuromyelitis optica. Arch Neurol 69(2):239–245PubMedCrossRefGoogle Scholar
  16. Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Wegner B et al (2016) Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol 79(2):206–216PubMedCrossRefGoogle Scholar
  17. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K et al (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364(9451):2106–2112PubMedCrossRefPubMedCentralGoogle Scholar
  18. Lin J, Xue B, Chen Z, Huang X, Pang W, Quan W et al (2016) Effects of early using azathioprine in the acute phase in neuromyelitis optica spectrum disorder. Int J Neurosci 4:1–8Google Scholar
  19. Mealy MA, Wingerchuk DM, Palace J, Greenberg BM, Levy M (2014) Comparison of relapse and treatment failure rates among patients with neuromyelitis optica: multicenter study of treatment efficacy. JAMA Neurol 71(3):324–330PubMedCrossRefPubMedCentralGoogle Scholar
  20. Pellkofer HL, Krumbholz M, Berthele A, Hemmer B, Gerdes LA, Havla J et al (2011) Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab. Neurology 76(15):1310–1315PubMedCrossRefPubMedCentralGoogle Scholar
  21. Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF et al (2013) Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 12(6):554–562PubMedCrossRefPubMedCentralGoogle Scholar
  22. Qiu W, Kermode AG, Li R, Dai Y, Wang Y, Wang J et al (2015) Azathioprine plus corticosteroid treatment in Chinese patients with neuromyelitis optica. J Clin Neurosci 22(7):1178–1182PubMedCrossRefPubMedCentralGoogle Scholar
  23. Ringelstein M, Ayzenberg I, Harmel J, Lauenstein AS, Lensch E, Stogbauer F et al (2015) Long-term therapy with Interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurol 72(7):756–763PubMedCrossRefPubMedCentralGoogle Scholar
  24. Spadaro M, Gerdes LA, Krumbholz M, Ertl-Wagner B, Thaler FS, Schuh E et al (2016) Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 3(5):e257PubMedPubMedCentralCrossRefGoogle Scholar
  25. Tenembaum S, Chitnis T, Nakashima I, Collongues N, McKeon A, Levy M et al (2016) Neuromyelitis optica spectrum disorders in children and adolescents. Neurology 87(9 Suppl 2): 59–66PubMedCrossRefGoogle Scholar
  26. Trebst C, Berthele A, Jarius S, Kumpfel T, Schippling S, Wildemann B et al (2011a) Diagnosis and treatment of neuromyelitis optica : consensus recommendations of the neuromyelitis optica study group. Nervenarzt 82:768–777PubMedCrossRefGoogle Scholar
  27. Trebst C, Raab P, Voss EV, Rommer P, Abu-Mugheisib M, Zettl UK et al (2011b) Longitudinal extensive transverse myelitis – it’s not all neuromyelitis optica. Nat Rev Neurol 7(12):688–698PubMedCrossRefGoogle Scholar
  28. Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B et al (2014) Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 261(1):1–16PubMedCrossRefGoogle Scholar
  29. Wandinger KP, Stangel M, Witte T, Venables P, Charles P, Jarius S et al (2010) Autoantibodies against aquaporin-4 in patients with neuropsychiatric systemic lupus erythematosus and primary Sjogren’s syndrome. Arthritis Rheum 62(4):1198–2000PubMedCrossRefGoogle Scholar
  30. Weinshenker BG, O’Brien PC, Petterson TM, Noseworthy JH, Lucchinetti CF, Dodick DW et al (1999) A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease. Ann Neurol 46(6):878–886PubMedCrossRefGoogle Scholar
  31. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T et al (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85(2):177–189PubMedPubMedCentralCrossRefGoogle Scholar
  32. Wingerchuk DM (2007) Diagnosis and treatment of neuromyelitis optica. Neurologist 13(1):2–11PubMedCrossRefGoogle Scholar
  33. Wingerchuk DM, Weinshenker BG (2008) Neuromyelitis optica. Curr Treat Options Neurol 10(1):55–66PubMedCrossRefGoogle Scholar
  34. Yaguchi H, Sakushima K, Takahashi I, Nishimura H, Yashima-Yamada M, Nakamura M et al (2013) Efficacy of intravenous cyclophosphamide therapy for neuromyelitis optica spectrum disorder. Intern Med 52(9):969–972PubMedCrossRefGoogle Scholar

Literatur zu Abschn. 1.3

  1. Armangue T, Leypoldt F, Malaga I, Raspall-Chaure M, Marti I, Nichter C et al (2014) Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 75:317–323PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bauer J, Elger CE, Hans VH, Schramm J, Urbach H, Lassmann H, Bien CG (2007) Astrocytes are a specific immunological target in Rasmussen’s encephalitis. Ann Neurol 62(1):67–80PubMedCrossRefPubMedCentralGoogle Scholar
  3. Bien CG, Schulze-Bonhage A, Deckert M, Urbach H, Helmstaedter C, Grunwald T, Schaller C, Elger CE (2000) Limbic encephalitis not associated with neoplasm as a cause of temporal lobe epilepsy. Neurology 55(12):1823–1828PubMedCrossRefPubMedCentralGoogle Scholar
  4. Bien CG, Gleissner U, Sassen R, Widman G, Urbach H, Elger CE (2004) An open study of tacrolimus therapy in Rasmussen encephalitis. Neurology 62(11):2106–2109PubMedCrossRefGoogle Scholar
  5. Bien CG, Granata T, Antozzi C, Cross JH, Dulac O, Kurthen M, Lassmann H, Mantegazza R, Villemure JG, Spreafico R, Elger CE (2005) Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain 128(Pt 3):454–471PubMedCrossRefGoogle Scholar
  6. Brierley JB, Corsellis JAN, Hierons R, Nevin S (1960) Subacute encephalitis of later adult life mainly affecting the limbic areas. Brain 83:357–368CrossRefGoogle Scholar
  7. Buckley C, Oger J, Clover L, Tüzün E, Carpenter K, Jackson M, Vincent A (2001) Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 50(1):73–78PubMedCrossRefPubMedCentralGoogle Scholar
  8. Chinchilla D, Dulac O, Robain O, Plouin P, Ponsot G, Pinel JF, Graber D (1994) Reappraisal of Rasmussen’s syndrome with special emphasis on treatment with high doses of steroids. J Neurol Neurosurg Psychiatry 57(11):1325–1333PubMedPubMedCentralCrossRefGoogle Scholar
  9. Corsellis JA, Goldberg GJ, Norton AR (1968) „Limbic encephalitis“ and its association with carcinoma. Brain 91(3):481–496PubMedCrossRefGoogle Scholar
  10. Dalmau J (2008) Limbic encephalitis and variants related to neuronal cell membrane autoantigens. Rinsho Shinkeigaku 48(11):871–874PubMedCrossRefGoogle Scholar
  11. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7(12):1091–1098PubMedPubMedCentralCrossRefGoogle Scholar
  12. Dogan OM, Deuretzbacher D, Haensch CA, Hagedorn HJ, Halve S, Isenmann S et al (2015) Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series. J Neurol Neurosurg Psychiatry 86:965–972CrossRefGoogle Scholar
  13. Gold M, Pul R, Bach JP, Stangel M, Dodel R (2012) Pathogenic and physiological autoantibodies in the central nervous system. Immunol Rev 248:68–86PubMedCrossRefGoogle Scholar
  14. Granata T, Fusco L, Gobbi G, Freri E, Ragona F, Broggi G, Mantegazza R, Giordano L, Villani F, Capovilla G, Vigevano F, Bernardina BD, Spreafico R, Antozzi C (2003a) Experience with immunomodulatory treatments in Rasmussen’s encephalitis. Neurology 61(12):1807–1810PubMedCrossRefGoogle Scholar
  15. Granata T, Gobbi G, Spreafico R, Vigevano F, Capovilla G, Ragona F, Freri E, Chiapparini L, Bernasconi P, Giordano L, Bertani G, Casazza M, Dalla Bernardina B, Fusco L (2003b) Rasmussen’s encephalitis: early characteristics allow diagnosis. Neurology 60(3):422–425PubMedCrossRefGoogle Scholar
  16. Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D et al (2010) Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 10:835–844PubMedCrossRefGoogle Scholar
  17. Graus F, Saiz A, Lai M, Bruna J, López F, Sabater L, Blanco Y, Rey MJ, Ribalta T, Dalmau J (2008) Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology 71(12):930–936PubMedPubMedCentralCrossRefGoogle Scholar
  18. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T et al (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404PubMedPubMedCentralCrossRefGoogle Scholar
  19. Gultekin SH, Rosenfeld MR, Voltz R, Eichen J, Posner JB, Dalmau J (2000) Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain 123(Pt 7):1481–1494PubMedCrossRefGoogle Scholar
  20. Hart YM, Cortez M, Andermann F, Hwang P, Fish DR, Dulac O, Silver K, Fejerman N, Cross H, Sherwin A et al (1994) Medical treatment of Rasmussen’s syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients. Neurology 44(6):1030–1036PubMedCrossRefGoogle Scholar
  21. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A (2010) Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 133(9):2734–2748PubMedPubMedCentralCrossRefGoogle Scholar
  22. Jeffery OJ, Lennon VA, Pittock SJ, Gregory JK, Britton JW, McKeon A (2013) GABAB receptor autoantibody frequency in service serologic evaluation. Neurology 81:882–887PubMedPubMedCentralCrossRefGoogle Scholar
  23. Johnson N, Henry C, Fessler AJ, Dalmau J (2010) Anti-NMDA receptor encephalitis causing prolonged nonconvulsive status epilepticus. Neurology 75(16):1480–1482PubMedPubMedCentralCrossRefGoogle Scholar
  24. Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, Friedman D, Skeen MB, Grisold W, Kimura A, Ohta K, Iizuka T, Guzman M, Graus F, Moss SJ, Balice-Gordon R, Dalmau J (2010) Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol 9(1):67–76PubMedCrossRefGoogle Scholar
  25. Leypoldt F, Wandinger KP (2014) Paraneoplastic neurological syndromes. Clin Exp Immunol 175:336–348PubMedPubMedCentralCrossRefGoogle Scholar
  26. Leypoldt F, Armangue T, Dalmau J (2015) Autoimmune encephalopathies. Ann N Y Acad Sci 1338:94–114PubMedCrossRefGoogle Scholar
  27. Liguori R, Vincent A, Clover L, Avoni P, Plazzi G, Cortelli P, Baruzzi A, Carey T, Gambetti P, Lugaresi E, Montagna P (2001) Morvan’s syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124(Pt 12):2417–2426PubMedCrossRefGoogle Scholar
  28. Linke R, Schroeder M, Helmberger T, Voltz R (2004) Antibody-positive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis. Neurology 63(2):282–286PubMedCrossRefGoogle Scholar
  29. Malter MP, Helmstaedter C, Urbach H, Vincent A, Bien CG (2010) Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol 67(4):470–478PubMedCrossRefGoogle Scholar
  30. Mantegazza R, Bernasconi P, Baggi F, Spreafico R, Ragona F, Antozzi C, Bernardi G, Granata T (2002) Antibodies against GluR3 peptides are not specific for Rasmussen’s encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol 131(1–2):179–185PubMedCrossRefGoogle Scholar
  31. Martinez-Hernandez E, Arino H, McKeon A, Iizuka T, Titulaer MJ, Simabukuro MM et al (2016) Clinical and immunologic investigations in patients with Stiff-Person spectrum disorder. JAMA Neurol 73:714–720PubMedPubMedCentralCrossRefGoogle Scholar
  32. Matà S, Muscas GC, Naldi I, Rosati E, Paladini S, Cruciatti B, Bisulli F, Paganini M, Mazzi G, Sorbi S, Tinuper PJ (2008) Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies. Neuroimmunol 199(1–2):155–159CrossRefGoogle Scholar
  33. Mori M, Kuwabara S, Yoshiyama M, Kanesaka T, Ogata T, Hattori T (2002) Successful immune treatment for non-paraneoplastic limbic encephalitis. J Neurol Sci 201(1–2):85–88PubMedCrossRefGoogle Scholar
  34. Oguni H, Andermann F, Rasmussen TB (1992) The syndrome of chronic encephalitis and epilepsy. A study based on the MNI series of 48 cases. Adv Neurol 57:419–433PubMedGoogle Scholar
  35. Parpia AS, Li Y, Chen C, Dhar B, Crowcroft NS (2016) Encephalitis, Ontario, Canada, 2002–2013. Emerg Infect Dis 22PubMedPubMedCentralCrossRefGoogle Scholar
  36. Quartuccio N, Caobelli F, Evangelista L, Alongi P, Kirienko M, De BV et al (2015) The role of PET/CT in the evaluation of patients affected by limbic encephalitis: a systematic review of the literature. J Neuroimmunol 284:44–48PubMedCrossRefGoogle Scholar
  37. Sansing LH, Tüzün E, Ko MW, Baccon J, Lynch DR, Dalmau J (2007) A patient with encephalitis associated with NMDA receptor antibodies. Nat Clin Pract Neurol 3(5):291–296PubMedPubMedCentralCrossRefGoogle Scholar
  38. Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D (2012) Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 79:1094–1100PubMedPubMedCentralCrossRefGoogle Scholar
  39. Sonderen A van, Arino H, Petit-Pedrol M, Leypoldt F, Kortvelyessy P, Wandinger KP et al (2016) The clinical spectrum of Caspr2 antibody-associated disease. Neurology 87(5):521–528PubMedPubMedCentralCrossRefGoogle Scholar
  40. Tobias SM, Robitaille Y, Hickey WF, Rhodes CH, Nordgren R, Andermann F (2003) Bilateral Rasmussen encephalitis: postmortem documentation in a five-year-old. Epilepsia 44(1):127–130PubMedCrossRefGoogle Scholar
  41. Urbach H, Sassen R, Soeder BM, Flacke S, Becker A, Bien CG (2006a) Serial MRI in patients with aquired hippocampal sclerosis. Clin Neuroradiol 16:47–52CrossRefGoogle Scholar
  42. Urbach H, Soeder BM, Jeub M, Klockgether T, Meyer B, Bien CG (2006b) Serial MRI of limbic encephalitis. Neuroradiology 48(6):380–386PubMedCrossRefPubMedCentralGoogle Scholar
  43. Villani F, Pincherle A, Antozzi C, Chiapparini L, Granata T, Michelucci R, Rubboli G, Simone I, Bellomo R, Spreafico R (2006) Adult-onset Rasmussen’s encephalitis: anatomical-electrographic-clinical features of 7 Italian cases. Epilepsia 47(Suppl 5):41–46PubMedCrossRefGoogle Scholar
  44. Vincent A, Buckley C, Schott JM, Baker I, Dewar BK, Detert N, Clover L, Parkinson A, Bien CG, Omer S, Lang B, Rossor MN, Palace J (2004) Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127(Pt 3):701–712PubMedCrossRefPubMedCentralGoogle Scholar
  45. Watson R, Jiang Y, Bermudez I, Houlihan L, Clover L, McKnight K, Cross JH, Hart IK, Roubertie A, Valmier J, Hart Y, Palace J, Beeson D, Vincent A, Lang B (2004) Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis. Neurology 63(1):43–50PubMedCrossRefPubMedCentralGoogle Scholar
  46. Younes-Mhenni S, Janier MF, Cinotti L, Antoine JC, Tronc F, Cottin V, Ternamian PJ, Trouillas P, Honnorat J (2004) FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 127(Pt 10):2331–2338PubMedCrossRefPubMedCentralGoogle Scholar
  47. Zuliani L, Saiz A, Tavolato B, Giometto B, Vincent A, Graus F (2007) Paraneoplastic limbic encephalitis associated with potassium channel antibodies: value of anti-glial nuclear antibodies in identifying the tumour. J Neurol Neurosurg Psychiatry 78(2):204–205PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Deutschland, ein Teil von Springer Nature 2018

Authors and Affiliations

  • Martin Stangel
    • 1
  • Christoph Kleinschnitz
    • 2
  • Mathias Mäurer
    • 3
  • Peter Raab
    • 4
  • Kurt-Wolfram Sühs
    • 4
  • Corinna Trebst
    • 4
  1. 1.Klinik für NeurologieMedizinische Hochschule HannoverHannoverDeutschland
  2. 2.Neurologische KlinikUniversitätsklinikum WürzburgWürzburgDeutschland
  3. 3.Klinik für NeurologieStiftung JuliusspitalWürzburgDeutschland
  4. 4.Medizinische Hochschule HannoverNeuroradiologieHannoverDeutschland

Personalised recommendations