Pathophysiologie und Prognosefaktoren der Autoimmunenzephalitiden

Zusammenfassung

Die rasante Entdeckung immer neuer Autoimmunenzephalitiden umfasst vielgestaltige Krankheitsbilder von Epilepsien über Bewegungsstörungen bis zu Psychosen. Aufgrund des wachsenden Verständnisses der klinischen Symptomatik rücken zunehmend Fragen nach den pathophysiologischen Mechanismen und Prognosefaktoren in den Vordergrund. Wesentliche neue Erkenntnisse zur Ätiologie belegen die Triggerung von Autoimmunenzephalitiden durch verschiedene Tumoren, aber auch durch Infektionen des Nervensystems, wie die Herpes-Enzephalitis. Die Antikörper gegen neuronale Oberflächenstrukturen sind in aller Regel direkt pathogen und entfalten ihre Wirkung über die Internalisierung der Zielproteine, über Rezeptorblockade oder Komplementaktivierung. Für die Prognose maßgeblich sind Art und Titer des Antikörpers (z. B. gegen NMDA-, GABA-, AMPA-Rezeptoren oder spannungsgesteuerte Kaliumkanal-Komplexe), ein assoziierter Tumor, eine forcierte Immuntherapie sowie bildgebende und Liquor-Biomarker.

Abstract

More and more forms of autoimmune encephalitis are being identified with the clinical spectrum ranging from epilepsy over movement disorders to psychosis. The increasing appreciation of clinical symptoms raises questions about the underlying pathophysiological mechanisms and prognostic factors. Numerous novel findings on the aetiology demonstrate that diverse tumours, but also infections of the central nervous system such as Herpes encephalitis can trigger autoimmune encephalitis. Antibodies against neuronal surface epitopes are directly pathogenic in the majority of cases. They act via binding and internalization of target proteins, receptor blockage, or activation of complement. Most relevant for the patients’ prognosis are the type and titer of antibodies (e. g. against NMDA, GABA, AMPA receptors or voltage-gated potassium channel complexes), associated tumours, sufficiently aggressive immunotherapies, and imaging as well as cerebrospinal fluid biomarkers.

Schlüsselwörter

Enzephalitis - NMDA-Rezeptor - Autoantikörper - Pathogenese - Immuntherapie

Key words

encephalitis - NMDA receptor - autoantibodies - pathogenesis - immunotherapy

• Literatur

• 1 Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003; 349 (16) 1543-1554
• 2 Dalmau J, Tüzün E, Wu HY et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007; 61: 25-36
• 3 Prüss H, Dalmau J, Arolt V et al. Anti-NMDA-receptor encephalitis. An interdisciplinary clinical picture. Nervenarzt 2010; 81: 396-406
• 4 Varley J, Vincent A, Irani SR. Clinical and experimental studies of potentially pathogenic brain-directed autoantibodies: current knowledge and future directions. J Neurol 2015; 262: 1081-1095
• 5 Martinez-Hernandez E, Horvath J, Shiloh-Malawsky Y et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 2011; 77: 589-593
• 6 Bien CG, Vincent A, Barnett MH et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 2012; 135: 1622-1638
• 7 Prüss H, Dalmau J, Harms L et al. Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology 2010; 75: 1735-1739
• 8 Hughes EG, Peng X, Gleichman AJ et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010; 30: 5866-5875
• 9 Dalmau J, Gleichman AJ, Hughes EG et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7: 1091-1098
• 10 Gleichman AJ, Spruce LA, Dalmau J et al. Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain. J Neurosci 2012; 32: 11082-11094
• 11 Mikasova L, De Rossi P, Bouchet D et al. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain 2012; 135: 1606-1621
• 12 Planaguma J, Leypoldt F, Mannara F et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 2015; 138: 94-109
• 13 Moscato EH, Peng X, Jain A et al. Acute mechanisms underlying antibody effects in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol 2014; 76: 108-119
• 14 Manto M, Dalmau J, Didelot A et al. In vivo effects of antibodies from patients with anti-NMDA receptor encephalitis: further evidence of synaptic glutamatergic dysfunction. Orphanet J Rare Dis 2010; 5: 31
• 15 Lai M, Hughes EG, Peng X et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65: 424-434
• 16 Pettingill P, Kramer HB, Coebergh JA et al. Antibodies to GABAA receptor alpha1 and gamma2 subunits: Clinical and serologic characterization. Neurology 2015; 84: 1233-1241
• 17 Gleichman AJ, Panzer JA, Baumann BH et al. Antigenic and mechanistic characterization of anti-AMPA receptor encephalitis. Ann Clin Transl Neurol 2014; 1: 180-189
• 18 Manto MU, Laute MA, Aguera M et al. Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases. Ann Neurol 2007; 61: 544-551
• 19 Christgau S, Aanstoot HJ, Schierbeck H et al. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain. J Cell Biol 1992; 118: 309-320
• 20 Lalic T, Pettingill P, Vincent A et al. Human limbic encephalitis serum enhances hippocampal mossy fiber-CA3 pyramidal cell synaptic transmission. Epilepsia 2011; 52: 121-131
• 21 Ohkawa T, Fukata Y, Yamasaki M et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013; 33: 18161-18174
• 22 Quek AM, Britton JW, McKeon A et al. Autoimmune Epilepsy: Clinical Characteristics and Response to Immunotherapy. Arch Neurol 2012; 69: 582-593
• 23 Irani SR, Michell AW, Lang B et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol 2011; 69: 892-900
• 24 Irani SR, Stagg CJ, Schott JM et al. Faciobrachial dystonic seizures: the influence of immunotherapy on seizure control and prevention of cognitive impairment in a broadening phenotype. Brain 2013; 136: 3151-3162
• 25 Carvajal-Gonzalez A, Leite MI, Waters P et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain 2014; 137: 2178-2192
• 26 Lai M, Huijbers MG, Lancaster E et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol 2010; 9: 776-785
• 27 Belforte JE, Zsiros V, Sklar ER et al. Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes. Nat Neurosci 2010; 13: 76-83
• 28 Manahan-Vaughan D, von Haebler D, Winter C et al. A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats. Hippocampus 2008; 18: 125-134
• 29 Yu YE, Wen L, Silva J et al. Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability. Hum Mol Genet 2010; 19: 1702-1711
• 30 Nobile C, Michelucci R, Andreazza S et al. LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum Mutat 2009; 30: 530-536
• 31 Tabata E, Masuda M, Eriguchi M et al. Immunopathological significance of ovarian teratoma in patients with anti-N-methyl-d-aspartate receptor encephalitis. Eur Neurol 2014; 71: 42-48
• 32 Day GS, Laiq S, Tang-Wai DF et al. Abnormal neurons in teratomas in NMDAR encephalitis. JAMA Neurol 2014; 71: 717-724
• 33 Prüss H, Finke C, Höltje M et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Annals of Neurology 2012; 72: 902-911
• 34 Armangue T, Leypoldt F, Malaga I et al. Herpes Simplex Virus Encephalitis is a Trigger of Brain Autoimmunity. Ann Neurol 2014; 75: 317-323
• 35 Schäbitz WR, Rogalewski A, Hagemeister C et al. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology 2014; 83: 2309-2311
• 36 Fleischmann R, Prüss H, Rosche B et al. Severe Cognitive Impairment Associated With Intrathecal Antibodies to the NR1 Subunit of the N-Methyl-D-Aspartate Receptor in a Patient With Multiple Sclerosis. JAMA Neurol 2015; 72: 96-99
• 37 Titulaer MJ, Höftberger R, Iizuka T et al. Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis. Annals of Neurology 2014; 75: 411-428
• 38 Vittore D, Montojo T, Schartz A et al. Antibodies against NMDAR in a patient with glioblastoma multiforme: a case report. Barcelona: Lancet Neurology Autoimmune Conference; 2015
• 39 Rossi M, Mead S, Collinge J et al. Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2015; 86: 692-694
• 40 Mackay G, Ahmad K, Stone J et al. NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease. J Neurol 2012; 259: 1979-1981
• 41 Prüss H, Hoffmann C, Stenzel W et al. A case of inflammatory peripheral nerve destruction antedating anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm 2014; 1: e14
• 42 Pagadala P, Park CK, Bang S et al. Loss of NR1 subunit of NMDARs in primary sensory neurons leads to hyperexcitability and pain hypersensitivity: involvement of Ca(2+)-activated small conductance potassium channels. J Neurosci 2013; 33: 13425-13430
• 43 Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 1998; 4: 111-117
• 44 Adang LA, Lynch DR, Panzer JA. Pediatric anti-NMDA receptor encephalitis is seasonal. Ann Clin Transl Neurol 2014; 1: 921-925
• 45 Holtkamp M, Othman J, Buchheim K et al. Predictors and prognosis of refractory status epilepticus treated in a neurological intensive care unit. J Neurol Neurosurg Psychiatry 2005; 76: 534-539
• 46 Orange D, Frank M, Tian S et al. Cellular immune suppression in paraneoplastic neurologic syndromes targeting intracellular antigens. Arch Neurol 2012; 69: 1132-1140
• 47 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
• 48 Höftberger R, van Sonderen A, Leypoldt F et al. Encephalitis and AMPA receptor antibodies: Novel findings in a case series of 22 patients. Neurology 2015; 84: 2403-2412
• 49 Gresa-Arribas N, Titulaer MJ, Torrents A et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13: 167-177
• 50 Prüss H, Voltz R, Flath B et al. Anti-Ta-associated paraneoplastic encephalitis with occult testicular intratubular germ-cell neoplasia. J Neurol Neurosurg Psychiatry 2007; 78: 651-652
• 51 Mangler M, Trebesch de Perez I, Teegen B et al. Seroprevalence of anti-N-methyl-D-aspartate receptor antibodies in women with ovarian teratoma. J Neurol 2013; 260: 2831-2835
• 52 Irani SR, Alexander S, Waters P et al. 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 2010; 133: 2734-2748
• 53 Finke C, Kopp UA, Prüss H et al. Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry 2011; 83: 195-198
• 54 Shin YW, Lee ST, Shin JW et al. VGKC-complex/LGI1-antibody encephalitis: clinical manifestations and response to immunotherapy. J Neuroimmunol 2013; 265: 75-81
• 55 Dalmau J, Lancaster E, Martinez-Hernandez E et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011; 10: 63-74
• 56 Dale RC, Pillai S, Brilot F. Cerebrospinal fluid CD19(+) B-cell expansion in N-methyl-d-aspartate receptor encephalitis. Dev Med Child Neurol 2013; 55: 191-193
• 57 Leypoldt F, Hoftberger R, Titulaer MJ et al. Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response. JAMA Neurol 2015; 72: 180-186
• 58 Malter MP, Frisch C, Schoene-Bake JC et al. Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity. J Neurol 2014; 261: 1695-1705
• 59 Finke C, Kopp UA, Scheel M et al. Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol 2013; 74: 284-296
• 60 Finke C, Kopp UA, Pajkert A et al. Structural hippocampal damage following anti-NMDAR encephalitis. Biological Psychiatry 2015; DOI: 10.1016/j.biopsych.2015.02.024.
• 61 Heine J, Prüss H, Bartsch T et al. Imaging of autoimmune encephalitis – Relevance for clinical practice and hippocampal function. Neuroscience 2015; DOI: 10.1016/j.neuroscience.2015.05.037.