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Paraneoplastische neurologische Syndrome und Autoimmunenzephalitiden

Paraneoplastic neurological syndromes and autoimmune encephalitis

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Zusammenfassung

Als paraneoplastische neurologische Syndrome (PNS) werden seltene neurologische Erkrankungen bezeichnet, die in zeitlicher Nähe zu einer Tumordiagnose auftreten, jedoch nicht direkt Folge des Tumors, seiner Metastasen oder bedingt durch die Tumorbehandlung sind. Ursächlich ist am ehesten eine fehlgeleitete Immunreaktion. Neben den klassischen PNS, die in Assoziation mit Antikörpern gegen intrazelluläre Antigene auftreten und nur begrenzt auf eine Behandlung ansprechen, wurden in den letzten Jahren neue Entitäten von Autoimmunenzephalitiden fakultativ-paraneoplastischer Genese beschrieben. Letztere sind mit Antikörpern gegen neuronale Oberflächenantigene assoziiert und weisen eine höhere Prävalenz als die klassischen PNS auf. Beide Krankheitsgruppen unterscheiden sich insbesondere hinsichtlich der Prognose und des Ansprechens auf eine Immunbehandlung. Darüber hinaus sind die Antikörper gegen neuronale Oberflächenantigene im Sinne einer „synaptischen Autoimmunität“ wahrscheinlich direkt an der Pathogenese dieser Syndrome beteiligt.

Summary

Paraneoplastic neurological syndromes (PNS) are defined as remote effects on the central and peripheral nervous system that are not caused directly by the tumor, its metastases and treatment, or metabolic disorders. The most probable cause is a falsely initiated immune reaction. Well-defined classical PNSs are associated with distinct tumors and occur with onconeural antibodies directed against intracellular neuronal antigens. However, response to therapy is limited. Recently, new antibodies directed against neuronal surface antigens were described in encephalitic syndromes of autoimmune origin. These probably antibody-mediated disorders are more frequent than classical PNS, occur with or without tumor association and often show a good response to immunosuppressive treatment.

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Abb. 1

Abbreviations

AGNA:

antigliale nukleäre Antikörper

AMPA-R:

α-Amino-3-Hydroxy-5-Methyl-4-Isoxazol-Propion-Säure-Rezeptor

ANNA-3:

antineuronaler Antikörper 3

APCA-2:

Anti-Purkinje-Zell-Antikörper 2

ARHGAP26:

rho GTPase activating protein 26

CASPR2:

contactin-associated protein-like 2

CV2/CRMP5:

collapsin response mediator protein 5

DNER:

delta/notch-like epidermal growth factor-related receptor

D2R:

Dopamin-2-Rezeptor

FBDS:

faziobrachiale dystone Anfälle

FDG-PET:

Fluordesoxyglucose-Positronenemissionstomographie

GABAB-R:

γ-Amino-Buttersäure-Rezeptor

GAD:

Glutamat-Decarboxylase

GluR:

Glutamatrezeptor

GlyR:

Glycin-Rezeptor

LE:

limbische Enzephalitis

LEMS:

Lambert-Eaton-Myasthenie-Syndrom

LGI1:

leucine-rich glioma inactivated 1

mGluR5:

metabotroper Glutamatrezeptor 5

nACh R:

nikontinerger ganglionärer Acetylcholin-Rezeptor

NMDA-R:

N-Methyl-D-Aspartat-Rezeptor

OCT:

optische Kohärenztomographie

OMS:

Opsoklonus-Myoklonus-Syndrom

PEM:

paraneoplastische Enzephalomyelitis

PERM:

progressive Enzephalomyelitis mit Rigidität und Myoklonus

PKD:

paraneoplastische Kleinhirndegeneration

PNS:

paraneoplastische neurologische Syndrome

SCLC:

small cell lung cancer (kleinzelliges Lungenkarzinom)

SOX1:

sry-like high mobility group box 1

SSN:

subakute sensorische Neuropathie

VGCC:

voltage-gated calcium channel

VGKC:

voltage gated potassium channel

Zic4:

zinc-finger of the cerebellum protein 4

Literatur

  1. Denny-Brown D (1948) Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiatry 11:73–87

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Graus F, Cordon-Cardo C, Posner JB (1985) Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 35:538–543

    Article  PubMed  CAS  Google Scholar 

  3. Graus F, Delattre JY, Antoine JC et al (2004) Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75:1135–1140

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. Graus F, Saiz A, Dalmau J (2010) Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 257:509–517

    Article  PubMed  CAS  Google Scholar 

  5. Rosenfeld MR, Titulaer MJ, Dalmau J (2012) Paraneoplastic syndromes and autoimmune encephalitis: five new things. Neurol Clin Pract 2:215–223

    Article  PubMed Central  PubMed  Google Scholar 

  6. Granerod J, Ambrose HE, Davies NW et al (2010) Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. Lancet Infect Dis 10:835–844

    Article  PubMed  Google Scholar 

  7. Bien CG, Vincent A, Barnett MH et al (2012) Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135:1622–1638

    Article  PubMed  Google Scholar 

  8. Graaff E de, Maat P, Hulsenboom E et al (2012) Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. Ann Neurol 71:815–824

    Article  PubMed  CAS  Google Scholar 

  9. Graus F, Dalmau J (2012) Paraneoplastic neurological syndromes. Curr Opin Neurol 25:795–801

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Tschernatsch M, Singh P, Gross O et al (2010) Anti-SOX1 antibodies in patients with paraneoplastic and non-paraneoplastic neuropathy. J Neuroimmunol 226:177–180

    Article  PubMed  CAS  Google Scholar 

  11. Vincent A, Bien CG, Irani SR et al (2011) Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 10:759–772

    Article  PubMed  CAS  Google Scholar 

  12. Monstad SE, Drivsholm L, Storstein A et al (2004) Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer. J Clin Oncol 22:795–800

    Article  PubMed  CAS  Google Scholar 

  13. Stich O, Graus F, Rasiah C et al (2003) Qualitative evidence of anti-Yo-specific intrathecal antibody synthesis in patients with paraneoplastic cerebellar degeneration. J Neuroimmunol 141:165–169

    Article  PubMed  CAS  Google Scholar 

  14. Stich O, Jarius S, Kleer B et al (2007) Specific antibody index in cerebrospinal fluid from patients with central and peripheral paraneoplastic neurological syndromes. J Neuroimmunol 183:220–224

    Article  PubMed  CAS  Google Scholar 

  15. Geis C, Weishaupt A, Hallermann S et al (2010) Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 133:3166–3180

    Article  PubMed  Google Scholar 

  16. Lancaster E, Dalmau J (2012) Neuronal autoantigens – pathogenesis, associated disorders and antibody testing. Nat Rev Neurol 8:380–390

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Albert ML, Darnell JC, Bender A et al (1998) Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 4:1321–1324

    Article  PubMed  CAS  Google Scholar 

  18. Pellkofer H, Schubart AS, Höftberger R et al (2004) Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain 127:1822–1830

    Article  PubMed  Google Scholar 

  19. Poepel A, Jarius S, Heukamp LC et al (2007) Neurological course of long-term surviving patients with SCLC and anti-Hu syndrome. J Neurol Sci 263:145–148

    Article  PubMed  CAS  Google Scholar 

  20. Titulaer MJ, Soffietti R, Dalmau J et al (2011) Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 18:19-e3

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Dalmau J, Rosenfeld MR (2008) Paraneoplastic syndromes of the CNS. Lancet Neurol 7:327–340

    Article  PubMed Central  PubMed  Google Scholar 

  22. Dalmau J, Rosenfeld MR (2010) Update on paraneoplastic neurologic disorders. Community Oncol 7:219–224

    Article  PubMed Central  PubMed  Google Scholar 

  23. Leypoldt F, Wandinger KP, Voltz R (2012) Neues bei paraneoplastischen Syndromen in der Neurologie. Akt Neurol 39:60–73

    Article  Google Scholar 

  24. Doss S, Nümann A, Ziegler A et al (2014) Anti-Ca/anti-ARHGAP26 antibodies associated with cerebellar atrophy and cognitive decline. J Neuroimmunol 267:102–104

    Article  PubMed  CAS  Google Scholar 

  25. Gresa-Arribas N, Titulaer MJ, Torrents A et al (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 13:167–177

    Article  PubMed  CAS  Google Scholar 

  26. Ohkawa T, Fukata Y, Yamasaki M et al (2013) Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 33:18161–18174

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  27. Hughes EG, Peng X, Gleichman AJ et al (2010) Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 30:5866–5875

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  28. Lai M, Hughes EG, Peng X et al (2009) AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 65:424–434

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  29. Prüss H, Finke C, Höltje M et al (2012) N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 72:902–911

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Armangue T, Leypoldt F, Málaga I et al (2013) Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol (Epub ahead of print)

  31. Lancaster E, Martinez-Hernandez E, Dalmau J (2011) Encephalitis and antibodies to synaptic and neuronal cell surface proteins. Neurology 77:179–189

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Titulaer MJ, McCracken L, Gabilondo I et al (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12:157–165

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Giometto B, Grisold W, Vitaliani R et al (2010) Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol 67:330–335

    Article  PubMed  Google Scholar 

  34. Pittock SJ, Kryzer TJ, Lennon VA (2004) Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 56:715–719

    Article  PubMed  CAS  Google Scholar 

  35. Baumgartner A, Rauer S, Mader I et al (2013) Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. J Neurol 260:2744–2753

    Article  PubMed  Google Scholar 

  36. Psimaras D, Carpentier AF, Rossi C et al (2010) Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 81:42–45

    Article  PubMed  CAS  Google Scholar 

  37. Hadjivassiliou M, Alder SJ, Van Beek EJ et al (2009) PET scan in clinically suspected paraneoplastic neurological syndromes: a 6-year prospective study in a regional neuroscience unit. Acta Neurol Scand 119:186–193

    Article  PubMed  CAS  Google Scholar 

  38. Titulaer MJ, Wirtz PW, Willems LN et al (2008) Screening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J Clin Oncol 26:4276–4281

    Article  PubMed  Google Scholar 

  39. Dimachkie MM, Barohn RJ (2012) Idiopathic inflammatory myopathies. Semin Neurol 32:227–236

    Article  PubMed Central  PubMed  Google Scholar 

  40. Flanagan EP, McKeon A, Lennon VA et al (2011) Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues. Neurology 76:2089–2095

    Article  PubMed  CAS  Google Scholar 

  41. Camdessanché JP, Jousserand G, Ferraud K et al (2009) The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 132:1723–1733

    Article  PubMed Central  PubMed  Google Scholar 

  42. Vernino S, Low PA, Fealey RD et al (2000) Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 343:847–855

    Article  PubMed  CAS  Google Scholar 

  43. Pittock SJ, Lennon VA (2008) Aquaporin-4 autoantibodies in a paraneoplastic context. Arch Neurol 65:629–632

    PubMed  Google Scholar 

  44. Titulaer MJ, Klooster R, Potman M et al (2009) SOX antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J Clin Oncol 27:4260–4267

    Article  PubMed  CAS  Google Scholar 

  45. Kramme C, Bien CG (2013) Immune-mediated epilepsy and encephalopathy. Nervenarzt 84:442–449

    Article  PubMed  CAS  Google Scholar 

  46. Irani SR, Alexander S, Waters P et al (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 133:2734–2748

    Article  PubMed Central  PubMed  Google Scholar 

  47. Jarius S, Hoffmann L, Clover L et al (2008) CSF findings in patients with voltage gated potassium channel antibody associated limbic encephalitis. J Neurol Sci 268:74–77

    Article  PubMed  CAS  Google Scholar 

  48. Petit-Pedrol M, Armangue T, Peng X et al (2014) Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol (Epub ahead of print)

  49. Boronat A, Sabater L, Saiz A et al (2011) GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology 76:795–800

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Lancaster E, Martinez-Hernandez E, Titulaer MJ et al (2011) Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 77:1698–1701

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  51. Vitaliani R, Mason W, Ances B et al (2005) Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 58:594–604

    Article  PubMed Central  PubMed  Google Scholar 

  52. Schmitt SE, Pargeon K, Frechette ES et al (2012) Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis. Neurology 79:1094–1100

    Article  PubMed Central  PubMed  Google Scholar 

  53. Leypoldt F, Buchert R, Kleiter I et al (2012) Fluorodeoxyglucose positron emission tomography in anti-N-methyl-D-aspartate receptor encephalitis: distinct pattern of disease. J Neurol Neurosurg Psychiatry 83:681–686

    Article  PubMed Central  PubMed  Google Scholar 

  54. Mas N, Saiz A, Leite MI et al (2011) Antiglycine-receptor encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 82:1399–1401

    Article  PubMed  Google Scholar 

  55. Dale RC, Merheb V, Pillai S et al (2012) Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain 135:3453–3468

    Article  PubMed  Google Scholar 

  56. McKeon A (2013) Paraneoplastic and other autoimmune disorders of the central nervous system. Neurohospitalist 3:53–64

    Article  PubMed Central  PubMed  Google Scholar 

  57. Keime-Guibert F, Graus F, Fleury A et al (2000) Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 68:479–482

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  58. Borisow N, Prüss H, Paul F (2013) Therapeutic options for autoimmune encephalomyelitis. Nervenarzt 84:461–465

    Article  PubMed  CAS  Google Scholar 

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Einhaltung ethischer Richtlinien

Interessenkonflikt. S. Rauer ist Mitinhaber der Firma ravo-Diagnostika GmbH, Freiburg. Diese Firma entwickelt, produziert und vertreibt serologische Testkits zur Bestimmung paraneoplastischer antineuronaler Autoantikörper. O. Stich und S. Rauer haben Vortragshonorare von folgenden Firmen erhalten: Bayer, Baxter, Biogen, Merck-Serono, Novartis, RG, Sanofi Aventis, Genzyme, Teva. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

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  1. Abteilung für Neurologie und Neurophysiologie, Neurozentrum, Universitätsklinik Freiburg, Breisacher Str. 64, 79106, Freiburg, Deutschland

    O. Stich & S. Rauer

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  1. O. Stich
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  2. S. Rauer
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Correspondence to O. Stich.

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Stich, O., Rauer, S. Paraneoplastische neurologische Syndrome und Autoimmunenzephalitiden. Nervenarzt 85, 485–501 (2014). https://doi.org/10.1007/s00115-014-4030-x

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