title: Neuropathological criteria of anti-IgLON5-related tauopathy.
abstract: We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define "definite", "probable" and "possible" diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A "definite" diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a "probable" diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A "possible" diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.
authors.affiliation: Neurological Tissue Bank of the Biobanc-Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Ellen
authors.identifier: 0000-0003-2948-4187
authors.initials: E
authors.lastname: Gelpi
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.|Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.affiliation: Neurology Department, Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain.|Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Graus
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, UCL-Institute of Neurology, University College London, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Ling
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, UCL-Institute of Neurology, University College London, London, UK.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: Neuropathology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Dawson
authors.affiliation: Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Mara
authors.initials: M
authors.lastname: Popovic
authors.affiliation: Department for Vascular Neurology and Intensive Neurological Therapy, University Medical Centre Ljubljana, Ljubljana, Slovenia.
authors.forename: Janja
authors.initials: J
authors.lastname: Pretnar-Oblak
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Högl
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Erich
authors.initials: E
authors.lastname: Schmutzhard
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerda
authors.initials: G
authors.lastname: Ricken
authors.affiliation: Neurology Department, Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Santamaria
authors.affiliation: Neuroimmunology Program, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Dalmau
authors.affiliation: Institute of Neuropathology, University Hospital Zurich, Zürich, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.affiliation: Queen Square Brain Bank for Neurological Disorders, UCL-Institute of Neurology, University College London, London, UK. t.revesz@ucl.ac.uk.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.affiliation: Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
mesh_terms: D000368:Aged; D001921:Brain / Q000276:immunology* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000276:immunology / Q000473:pathology; D024801:Tauopathies / Q000175:diagnosis* / Q000276:immunology* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C000591569:IgLON5 protein, human; D016875:tau Proteins
keywords: Brainstem; IgLON5; NREM; Parasomnia; Tauopathy