Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease
Authors: Grüter Thomas , Möllers Franziska E , Tietz Anja , Dargvainiene Justina , Melzer Nico , Heidbreder Anna , Strippel Christine , Kraft Andrea , Höftberger Romana , Schöberl Florian , Thaler Franziska S , Wickel Jonathan , Chung Ha-Yeun , Seifert Frank , Tschernatsch Marlene , Nagel Michael , Lewerenz Jan , Jarius Sven , Wildemann Brigitte C , de Azevedo Lucie , Heidenreich Fedor , Heusgen Raphaela , Hofstadt-van Oy Ulrich , Linsa Andreas , Maaß Jannis Justus , Menge Til , Ringelstein Marius , Pedrosa David J , Schill Josef , Seifert-Held Thomas , Seitz Caspar , Tonner Silke , Urbanek Christian , Zittel Simone , Markewitz Robert , Korporal-Kuhnke Mirjam , Schmitter Thomas , Finke Carsten , Brüggemann Norbert , Bien Corinna I , Kleiter Ingo , Gold Ralf , Wandinger Klaus-Peter , Kuhlenbäumer Gregor , Leypoldt Frank , Ayzenberg Ilya ,   for the German Network for Research on Autoimmune Encephalitis (GENERATE), Leypoldt Frank , Melzer Nico , Melzer Kristin Stefanie , Geis Christian , Ayzenberg Ilya , van Baalen Andreas , Baumgartner Annette , Berger Robert , Blaes Franz , Blaschek Astrid , Doppler Kathrin , Ebinger Friedrich , Endres Dominique , Faiss Jürgen Hartmut , Finke Alexander , Finke Carsten , Dik Andre , Friedemann Paul , Friese Manuel , Gorsler Anna , Groß Catharina , Handreka Robert , Häusler Martin , Held Valentin , Hoffmann Frank , Hofstadt-van Oy Ulrich , Kellinghaus Christoph , Kraft Andrea , Krämer Markus , Krogias Christos , Körtvélyessy Peter , Kümpfel Tanja , Lewerenz Jan , Linsa Andeas , Menge Til , Heide Wolfgang , Havla Joachim , Malter Michael , Meuth Sven , Mönig Constanze , Mono Marie-Luise , Nagel Michael , Obrocki Jost , von Poderwils Felix , Priller Josef , Reimann Gernot , Ringelstein Marius , Rostasy Kevin , Seidel Günter , Stammel Oliver , Stoppe Muriel , Sommer Claudia , Sühs Kurt-Wolfram , Kaufmann Max , Schaumberg Jens , Schmidt Jens , Schreiber Stephan , Stolze Henning , Tauber Simone , Thaler Franziska , Bergh Florian Then , Trebst Corinna , Urbanek Christian , Wandinger Klaus-Peter , Weissert Robert , Wiendl Heinz , Wildemann Brigitte , Mues Sigrid , Bien Christian , Prüß Harald , Balint Bettina , Trendelenburg George , Grau Armin , Hellwig Kerstin , Lehrich Christoph , Gallus Marco , Ehrlich Sven , Bauer Sebastian , Siebenbrodt Kai , Rosenow Felix , Wickel Jonathan , Ha-Yeun Chung , Adelmann Michael , Benesch Sonka , Strippel Christine , Wagner Judith , Türedi Methab , Jansen Martina , Schmütz Ina-Isabelle , Berning Sascha , Binder Andreas , Gebhard Marcel , Bien Corinna , Bernsen Sarah , Penner Loana , Dargvainiene Justina , Ismail Fatme Seval , Syrbe Steffen , Schröder Ina , Wunderlich Benjamin , Hillebrand Philip , Eisenhut Katharina , Appeltshauser Luise , Entscheva Marina , Baatz Sebastian , Bittner Stefan , Witt Karsten , Pfefferkorn Thomas , Piepgras Johannes , Zieger Lara , Reinecke Raphael , Fitzner Dirk , Bittner Daniel , Rüegg Stephan , Pröbstel Anne-Katrin , Räuber Saskia Jania , von Mering Matthias , Rohner Hendrik , Philipsen Alexandra , Hansen Niels , Flotats-Bastardas Marina , Edelhoff Lena , Trollmann Regina , Knake Susanne , Rau Johanna Maria Helena , Meyer zu Hörste Gerd , Grauer Oliver , Kovac Stjepana , Baade-Büttner Carolin , Gül Halime , Fazeli Walid , Lünemann Jan , Schuster Simon , Schreyer Gesa , Senel Makbule , van's Gravesande Karin Storm , Dreesmann Mona , Tumani Hayrettin , Karenfort Michael , Hoffmann Anna , Sturm Dietrich , Haghikia Aiden , Pfeffer Lena Kristina , Decker Julia Maren , Fousse Mathias , Meister Monika , Schimmel Mareike , Falk Kim Kristin , Juranek Aleksandra , Huppke Peter , Rüber Theodor , Vogel Niklas , Harms Antonia , Reichen Ina 
Published: March 2022

Abstract
Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome.
Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined.
We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome.
In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.