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Muñiz-Castrillo S, Hedou JJ, Ambati A, et al. Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis. Brain. 2021;144(9):2709-2721doi: 10.1093/brain/awab153.
Muñiz-Castrillo, S., Hedou, J. J., Ambati, A., Jones, D., Vogrig, A., Pinto, A. L., Benaiteau, M., de Broucker, T., Fechtenbaum, L., Labauge, P., Murnane, M., Nocon, C., Taifas, I., Vialatte de Pémille, C., Psimaras, D., Joubert, B., Dubois, V., Wucher, V., Desestret, V., Mignot, E., & Honnorat, J. (2021). Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis. Brain : a journal of neurology, 144(9), 2709-2721. https://doi.org/10.1093/brain/awab153
Muñiz-Castrillo, Sergio, et al. "Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis." Brain : a journal of neurology vol. 144,9 (2021): 2709-2721. doi: https://doi.org/10.1093/brain/awab153
Muñiz-Castrillo S, Hedou JJ, Ambati A, Jones D, Vogrig A, Pinto AL, Benaiteau M, de Broucker T, Fechtenbaum L, Labauge P, Murnane M, Nocon C, Taifas I, Vialatte de Pémille C, Psimaras D, Joubert B, Dubois V, Wucher V, Desestret V, Mignot E, Honnorat J. Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis. Brain. 2021 Oct 22;144(9):2709-2721. doi: 10.1093/brain/awab153. PMID: 33843981; PMCID: PMC8557339.
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Brain. 2021 Oct 22;144(9):2709-2721. doi: 10.1093/brain/awab153.

Distinctive clinical presentation and pathogenic specificities of anti-AK5 encephalitis.

Brain : a journal of neurology

Sergio Muñiz-Castrillo, Julien Jacques Hedou, Aditya Ambati, David Jones, Alberto Vogrig, Anne-Laurie Pinto, Marie Benaiteau, Thomas de Broucker, Laura Fechtenbaum, Pierre Labauge, Matthew Murnane, Claire Nocon, Irina Taifas, Clément Vialatte de Pémille, Dimitri Psimaras, Bastien Joubert, Valérie Dubois, Valentin Wucher, Virginie Desestret, Emmanuel Mignot, Jérôme Honnorat

Affiliations

  1. French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Bron 69677, France.
  2. SynatAc Team, Institute NeuroMyoGène, INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, Lyon 69372, France.
  3. Stanford University Center for Narcolepsy, Palo Alto, CA 94304, USA.
  4. Pathology and Laboratory Medicine, Albany Medical Center Hospital, Albany, NY 12208, USA.
  5. Neurology Department, Hôpital Pierre-Paul Riquet, Toulouse 31300, France.
  6. Neurology Department, Hôpital Pierre Delafontaine, Centre Hospitalier de Saint-Denis, Saint-Denis 93200, France.
  7. Neurology Department, Centre Hospitalier Henri Mondor, Paris 94000, France.
  8. Neurology Department, Centre Hospitalier Universitaire de Montpellier, Montpellier 34295, France.
  9. Neurology Department, Albany Medical Center Hospital, Albany, NY 12208, USA.
  10. Neurology Department, Centre Hospitalier de Dax, Dax 40100, France.
  11. Neurology Department, Hôpital d'Instruction des Armées Percy, Clamart 92140, France.
  12. Neurology Department, Groupe Hospitalier Paris Saint Joseph, Paris 75014, France.
  13. Neurology Department 2-Mazarin, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, APHP, Paris 75013, France.
  14. Brain and Spinal Cord Institute, INSERM U1127/CNRS UMR 7255, Université Pierre-et-Marie-Curie, Universités Sorbonnes, Paris 75013, France.
  15. HLA Laboratory, French Blood Service, EFS Auvergne-Rhône-Alpes, Lyon 69150, France.

PMID: 33843981 PMCID: PMC8557339 DOI: 10.1093/brain/awab153

Abstract

Limbic encephalitis with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leucocyte antigen and CSF proteomic profiles. Patients with anti-AK5 limbic encephalitis were mostly male (20/26, 76.9%) with a median age of 66 years (range 48-94). The predominant symptom was severe episodic amnesia in all patients, and this was frequently associated with depression (17/25, 68.0%). Weight loss, asthenia and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%) and increased Tau (11/14, 78.6%). Temporal lobe hyperintensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably towards severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with the highest titres in nine CSF-serum paired samples. A temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T cells, intense granzyme B expression and abundant macrophages/microglia. Human leucocyte antigen (HLA) analysis in 11 patients showed a striking association with HLA-B*08:01 [7/11, 63.6%; odds ratio (OR) = 13.4, 95% confidence interval (CI): 3.8-47.4], C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI: 2.9-42.5), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI: 3.5-52.0) and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI: 3.7-55.7) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI: 4.8-57.1). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 control subjects and 10 cases with other more common non-paraneoplastic limbic encephalitis (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed 31 and seven significantly upregulated proteins in anti-AK5 limbic encephalitis, respectively mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 limbic encephalitis result from a distinct T cell-mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: [email protected].

Keywords: adenylate kinase 5; human leucocyte antigen; limbic encephalitis; proteomics

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