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EUROIMMUN
Differentialdiagnostik autoimmuner
ZNS-Erkrankungen
Teil 2 – Enzephalitiden
Dr. rer. nat. Jasmin Aldag
EUROIMMUN AG
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EUROIMMUN
Stiff-Person-
Syndrom
Autoimmun-
Neuropathie
Myasthenie-
Syndrom
Autoimmun-
Enzephalitis
Zerebelläre
Syndrome
Erkrankungen mit
Demyelinisierung
Antikörper-assoziierte
Syndrome
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EUROIMMUN
Stiff-Person-
Syndrom
Autoimmun-
Neuropathie
Myasthenie-
Syndrom
Autoimmun-
Enzephalitis
Zerebelläre
Syndrome
Erkrankungen mit
Demyelinisierung
Erkrankungen des
ZNS
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EUROIMMUN Abbildung modifiziert nach Lancaster and Dalmau, Nat Review Neurol 2012
Intrazelluläre Antigene
Hu, Yo, Ri, CV2, Ma, SOX1,
Zic4, ANNA-3, PCA-2, GAD
Zelloberflächen-/Synapsenantigene
NMDAR, AMPAR, GABABR, VGKC,
LGI1, CASPR2, mGluR1, mGluR5,
GlyR, DPPX, D2R, AQP4, Tr, AChR
Autoantikörper in der Neurologie
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EUROIMMUN
Entzündung des limbischen
Systems können eine Vielzahl
von Symptomen verursachen:
Limbische Enzephalitis
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EUROIMMUN
• Gedächnisstörungen
• Psychiatrische Symptome
• Epilepsie
Entzündung des limbischen
Systems können eine Vielzahl
von Symptomen verursachen:
Limbische Enzephalitis
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EUROIMMUN
Diagnostik:
Virale Enzephalitis (HSV)
Limbische Enzephalitis
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EUROIMMUN
Diagnostik:
Virale Enzephalitis (HSV)
Antikörper gerichtet gegen
• intrazelluläre/klassische paraneoplastische Antigene:
Hu, Ma2, CV2, Amphiphysin
• Zellmembran Antigene:
Glutamatrezeptoren (Typen NMDA und AMPA), VGKC (LGI1,
CASPR2), GABAB-Rezeptoren, „Antikörper gegen Neuropil“
Limbische Enzephalitis
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EUROIMMUN
Antikörper gegen intrazelluläre vs
Oberflächenantigene (Hippocampus)
Lancaster E, Dalmau J et al. Neurology 2011
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EUROIMMUN
Antikörper
gegen
Klinisches Syndrom Paraneoplastische
Fälle
Assoziierte
Tumore
NMDAR NMDAR-Enzephalitis 9%-55% (Abhängig von Alter,
Geschlecht, Ethnizität)
Ovarialteratom
(seltener andere)
AMPAR Limbische Enzephalitis,
atypische Psychose
70% Lunge, Thymom,
Mammakarzinom
GABARB
Limbische Enzephalitis 60% SCLC
LGI1 Limbische Enzephalitis <20% SCLC, Thymom
CASPR2 Neuromyotonie,
Morvan-Syndrom,
Limbische Enzephalitis
<20% Thymom
Antikörper gegen neuronale Oberflächenantigene
Lancaster E, Dalmau J et al. Neurology 2011
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EUROIMMUN
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EUROIMMUN Dalmau et al., Lancet Neurology 2011
Anti-NMDA-Rezeptor Enzephalitis
Prodromale
Phase
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EUROIMMUN Dalmau et al., Lancet Neurology 2011
Anti-NMDA-Rezeptor Enzephalitis
Prodromale
Phase
Unruhe, Halluzinationen,
Psychosen, Gedächnis-
störung, Sprachreduzierung,
mit /ohne Krampfanfälle
Bewegungsstörungen,
Koma, Hypoventilation, mit
/ohne autonome Instabilität
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EUROIMMUN Dalmau et al., Lancet Neurology 2011
Anti-NMDA-Rezeptor Enzephalitis
Prodromale
Phase
Unruhe, Halluzinationen,
Psychosen, Gedächnis-
störung, Sprachreduzierung,
mit /ohne Krampfanfälle
Bewegungsstörungen,
Koma, Hypoventilation, mit
/ohne autonome Instabilität
Klinische Verschlechterung
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EUROIMMUN Dalmau et al., Lancet Neurology 2011
Anti-NMDA-Rezeptor Enzephalitis
Prodromale
Phase
Unruhe, Halluzinationen,
Psychosen, Gedächnis-
störung, Sprachreduzierung,
mit /ohne Krampfanfälle
Bewegungsstörungen,
Koma, Hypoventilation, mit
/ohne autonome Instabilität
Klinische Verschlechterung
Klinische Verbesserung
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EUROIMMUN
One day, I woke up in a strange hospital
room, strapped to my bed, under guard,
and unable to move or speak.
Only weeks earlier I had been a healthy
twenty-four year old, beginning a career
as a cub reporter at the New York Post.
As weeks ticked by and I moved
inexplicably from violence to catatonia,
$1 million worth of blood tests and brain
scans revealed nothing. The exhausted
doctors were ready to commit me to the
psychiatric ward, in effect condemning me
to a lifetime of institutions, or death,
until Dr. Souhel Najjar joined my team.
www.susannahcahalan.com
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EUROIMMUN Titulaer et al., Lancet Neurology 2013
Anti-NMDA-Rezeptor Enzephalitis
Patientenalter bei Erkrankungsbeginn
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EUROIMMUN Titulaer et al., Lancet Neurology 2013
Anti-NMDA Rezeptor Enzephalitis
Erste Symptome der Patienten
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EUROIMMUN Titulaer et al., American Academy of Neurology´s annual meeting 2012, abstract
Anti-NMDA Rezeptor Enzephalitis
Klinische Merkmale, Behandlung u. Prognose von 500 Patienten
~75% der Patienten zeigen eine vollständige /weitgehende Verbesserung
Genesungsprozess kann > 24 Monate dauern
Outcome ist abhängig von
- Verzögerung bei der Behandlung
- Schwere der Erkrankung
Wenn 1st line Immuntherapie (Steroide, IVIg u/o Plasmapherese) fehlschlägt,
ist eine 2nd line Behandlung (Rituximab o Cyclophosphamid) meist effektiv.
Rückfälle in 14%, 73% davon bei Patienten ohne Tumor
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EUROIMMUN
Referenzmethode: Radioimmun-Assay (RIA)
Dendrotoxin bindet an Kv1.1, Kv1.2 und Kv1.6
Kv-assoziierte Proteine: LGI1, CASPR2, weitere...
Antikörper gegen Spannungsabhängige
Kaliumkanäle (VGKC)
Diagnostisch wegweisend bei:
• Limbischer Enzephalitis
• Neuromyotonie
• Morvan‘s Syndrom
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EUROIMMUN
Die Mehrheit der VGKC Antikörper richtet sich
gegen komplexierte Proteine
80 %
17 %
3 %
„VGKC-Komplex
Antikörper“
o LGI1
o CASPR2
o unbekannte Antigene
o Kv1.1, Kv1.2, Kv1.6
Irani et al., Brain 2010
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EUROIMMUN
Laboratoriumsdiagnostik
von Antikörpern gegen Oberflächenantigene
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EUROIMMUN
Cerebellum
Charakteristische Muster, jedoch nicht spezifisch!
→ monospezifische Assays notwendig
Immunhistochemie (IHC)
Hippocampus
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EUROIMMUN
Wandinger et al., J Lab Med 2011
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EUROIMMUN
Wandinger et al., J Lab Med 2011
Cyclophosphamide
Rituximab
Plasmapheresis
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EUROIMMUN
Verlaufsuntersuchungen sinnvoll ?
• Antikörpertiter im Liquor, nicht Serum, korrelieren mit Aktivität
• Antikörpersistenz im Serum
Frechette et al., Neurology 2011
Hansen et al., Arch. Neurol. 2012
• Persistenz der intrathekalen NMDAR-Antikörper Synthese
Alexopoulos et al., J. Neurol. 2011
Akute NMDAR Enzephalitis:
Remission:
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EUROIMMUN
Verlaufsuntersuchungen sinnvoll ?
• Antikörpertiter im Liquor, nicht Serum, korrelieren mit Aktivität
• Antikörpersistenz im Serum
Frechette et al., Neurology 2011
Hansen et al., Arch. Neurol. 2012
• Persistenz der intrathekalen NMDAR-Antikörper Synthese
Alexopoulos et al., J. Neurol. 2011
Klinik entscheidend!
Akute NMDAR Enzephalitis:
Remission:
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EUROIMMUN Hansen H-C et al., JAMA Neurol 2013;70:117-9.
Nachweis von NMDAR Antikörpern 16 Jahre
nach Präsentation der Symtome
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EUROIMMUN
Serum:
Hu, Yo, Ri, Ma, CV2, Amphiphysin, Recoverin, SOX1,
Zic4, Tr, PCA-2, ANNA-3 Intrazelluläre-Antigene
Laboranforderung: Serum oder Liquor?
AQP4 Oberflächen-Antigen
Liquor und Serum:
NMDAR, GABABR, AMPAR, LGI1, CASPR2, GAD
Oberflächen-Antigene
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EUROIMMUN
Zusammenfassung
o Diagnostikstrategie:
Antikörper gegen Oberflächenantigene
IIFT (Gewebe und/oder RC-IIFT)
o Untersuchungsmaterial:
Liquor und Serum (ANSA, GAD)
o ANSA sind häufiger als klassische PNS Ak - Differentialdiagnose
neurologischer, psychatrischer und pädiatrischer Krankheitsbilder
o Multiparametrische Testung ist klinisch notwendig
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EUROIMMUN
NMDAR + CASPR2
0,9%
NMDAR + GABAB
0,9%
Neuropil / classical
(NMDAR + Hu)
1,9% classical / classical
(Hu + CV2) 2,8%
Neuropil / Neuropil Anti-Hu
5,6% Anti-Yo
8,2%
Anti-Ri
9,3%
Anti-Ma
1,9%
Anti-CV2
3,7%
Anti-Amphiphysin
0,9%
Anti-PCA2 0,9%
Anti-NMDAR
38%
Anti-AMPAR
0%
Anti-GABAB 2,8%
Anti-LGI1
11,1%
Anti-CASPR2
11,1%
Häufigkeit von Autoantikörpern
n=108 Patienten
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EUROIMMUN
NMDAR + CASPR2
0,9%
NMDAR + GABAB
0,9%
Neuropil / classical
(NMDAR + Hu)
1,9% classical / classical
(Hu + CV2) 2,8%
Neuropil / Neuropil Anti-Hu
5,6% Anti-Yo
8,2%
Anti-Ri
9,3%
Anti-Ma
1,9%
Anti-CV2
3,7%
Anti-Amphiphysin
0,9%
Anti-PCA2 0,9%
Anti-NMDAR
38%
Anti-AMPAR
0%
Anti-GABAB 2,8%
Anti-LGI1
11,1%
Anti-CASPR2
11,1%
Häufigkeit von Autoantikörpern
31% der Ergebnisse weichen ab von der Anforderung!
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EUROIMMUN
Weitere spezifische Antikörper…
Antikörper gegen Klinisches Syndrom Paraneoplastische Fälle
GlyR Stiff-Person Syndrom, PERM +/- Hodgkin-Lymphom
mGluR1 Cerebellitis +/- Hodgkin-Lymphom
mGluR5 Ophelia-Syndrom Hodgkin-Lymphom
Dopamin(D2)R Basalganglien-Enzephalitis, Chorea
Sydenham -
DPPX (Kv4.2) Enzephalitis, prodromale Diarrhoe -
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EUROIMMUN
Danke für Ihre Aufmerksamkeit