title: Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis.
abstract: Magnetic resonance imaging has linked chronic voltage-gated potassium channel (VGKC) complex antibody-mediated limbic encephalitis with generalized hippocampal atrophy. However, autoantibodies bind to specific rodent hippocampal subfields. Here, human hippocampal subfield (subiculum, cornu ammonis 1-3, and dentate gyrus) targets of immunomodulation-treated LGI1 VGKC-complex antibody-mediated limbic encephalitis were investigated using in vivo ultra-high resolution (0.39 × 0.39 × 1.0 mm3) 7.0 T magnetic resonance imaging [n = 18 patients, 17 patients (94%) positive for LGI1 antibody and one patient negative for LGI1/CASPR2 but positive for VGKC-complex antibodies, mean age: 64.0 ± 2.55 years, median 4 years post-limbic encephalitis onset; n = 18 controls]. First, hippocampal subfield quantitative morphometry indicated significant volume loss confined to bilateral CA3 [F(1,34) = 16.87, P < 0.0001], despite hyperintense signal evident in 5 of 18 patients on presentation. Second, early and later intervention (<3 versus >3 months from symptom onset) were associated with CA3 atrophy. Third, whole-brain voxel-by-voxel morphometry revealed no significant grey matter loss. Fourth, CA3 subfield atrophy was associated with severe episodic but not semantic amnesia for postmorbid autobiographical events that was predicted by variability in CA3 volume. The results raise important questions about the links with histopathology, the impact of the observed focal atrophy on other CA3-mediated reconstructive and episodic mechanisms, and the role of potential antibody-mediated pathogenicity as part of the pathophysiology cascade in humans.
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.|National Hospital for Neurology and Neurosurgery, London, London, UK.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Miller
authors.affiliation: Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Trevor T-J
authors.initials: TT
authors.lastname: Chong
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.|Australian National University, Research School of Psychology, Canberra, ACT, AUS.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Aimola Davies
authors.affiliation: Centre for Anaesthesia, Critical Care and Pain Medicine, University College London Hospital, London UK.
authors.forename: Tammy W C
authors.initials: TWC
authors.lastname: Ng
authors.affiliation: Division of Brain Sciences, Charing Cross Campus, Imperial College London, London UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Sarosh R
authors.initials: SR
authors.lastname: Irani
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Vincent
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.|Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: Masud
authors.initials: M
authors.lastname: Husain
authors.affiliation: Neurology Department, Queen Elizabeth Neuroscience Centre, University Hospitals of Birmingham, Birmingham, UK.
authors.forename: Saiju
authors.initials: S
authors.lastname: Jacob
authors.affiliation: Neurology Department, Queen's Medical Centre, Nottingham, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Maddison
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kennard
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Penny A
authors.initials: PA
authors.lastname: Gowland
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: Clive R
authors.initials: CR
authors.lastname: Rosenthal
mesh_terms: D000328:Adult; D000368:Aged; D000647:Amnesia / Q000150:complications / Q000473:pathology; D001284:Atrophy / Q000150:complications / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D056654:CA3 Region, Hippocampal / Q000473:pathology*; D016022:Case-Control Studies; D005260:Female; D066128:Gray Matter / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020363:Limbic Encephalitis / Q000150:complications / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D024642:Potassium Channels, Voltage-Gated / Q000276:immunology*; D011506:Proteins / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011506:Proteins
keywords: amnesia; hippocampal subfields; hippocampus; limbic encephalitis; ultra-high resolution 7.0 T MRI