Neurocognition team

Neuro-cognition and neuro-ophthalmology department

The service brings together the expertise relating to two specialties: the management of neurocognitive disorders and vision disorders of neurological origin.


Research team: Melis, Synatac


As a neurologist, within the neuro-cognition and neuro-ophthalmology department and within the Memory Resource Research Center of the Hospices Civils de Lyon, Professor Virginie DESESTRET takes care of patients suffering from neurocognitive pathologies, mainly of neurodegenerative, autoimmune and iatrogenic. She is developing an axis of clinical and translational research on the cognitive impact of anti-cancer therapies (in particular immunotherapies and targeted therapies).

As a histologist, within the MeLiS team, she carries out mechanistic research activity on the pathophysiology of paraneoplastic neurological syndromes, based on histomolecular, tumor and brain analysis. The objective is to understand the mechanisms of breakdown of immune tolerance at the origin of the autoimmune disease and its impact on brain and particularly cognitive functioning.

Research axis

  • Immunopathology of paraneoplastic neurological syndromes
  • Neurodegeneration
  • Neurocognitive impacts of anti-cancer therapies
  • Clinico-pathological confrontations


  • CISTAR “Cancer Immune Surveillance and Therapeutic tARgeting” team, Lyon Cancer Research Center, INSERM U 1052/CNRS UMR 5286. B. Dubois, C. Caux
  • Department of Clinical Medicine, Medical Faculty, University of Bergen, Bergen, Norway. Pr C. Vedeler
  • Experimental Neuro-oncology Team, Brain and Marrow Institute (ICM), UMR 7225 –Inserm U 1127. A. Alentorn, M. Sanson
  • Gilles Thomas Bioinformatics Platform, Lyon Cancer Research Center, INSERM U 1052/CNRS UMR 5286. Alain VIARI, Laurie Tonon
  • Department of Anatomical Pathology at the Pôle Est Biology Center. Pr D. Meyronet
  • Biopathology Department and Translational Molecular Biology Platform of the Center Léon Bérard, I. Treilleux, D. Pissaloux, V. Attignon
  • “Immune regulation at muco-cutaneous surfaces” team, Institute of Molecular and Cellular Pharmacology (IPMC) – Valbonne. F. Anjuere
  • Onco-pharmacology team, Lyon Cancer Research Center. Professor Michael Duruisseaux
  • INSERM Unit U1296 “Radiations: Defense, Health, Environment”. Social Psychology Center (PôPS). M Pannard
  • BIORAN team Lyon Neurosciences Research Center. G. Becker, I. Quadrio


  1. Advances in treatments of patients with classical and emergent neurological toxicities of anticancer agents.

Bompaire F, Birzu C, Bihan K, Desestret V, Fargeot G, Farina A, Joubert B, Leclercq D, Nichelli L, Picca A, Tafani C, Weiss N, Psimaras D, Ricard D. 

Rev Neurol (Paris). 2023 Jun;179(5):405-416. doi: 10.1016/j.neurol.2023.03.015. Epub 2023 Apr 12. PMID: 37059646.


2. Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo-Associated Paraneoplastic Cerebellar Degeneration
Peter E, Treilleux I, Wucher V, Jougla E, Vogrig A, Pissaloux D, Paindavoine S, Berthet J, Picard G, Rogemond V, Villard M, Vincent C, Tonon L, Viari A, Honnorat J, Dubois B, Desestret V

Neurol Neuroimmunol Neuroinflamm (2022) — Abstract


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Background and objectives: Paraneoplastic cerebellar degeneration (PCD) with anti-Yo antibodies is a cancer-related autoimmune disease directed against neural antigens expressed by tumor cells. A putative trigger of the immune tolerance breakdown is genetic alteration of Yo antigens. We aimed to identify the tumors’ genetic and immune specificities involved in Yo-PCD pathogenesis. Methods: Using clinicopathologic data, immunofluorescence (IF) imaging, and whole-transcriptome analysis, 22 breast cancers (BCs) associated with Yo-PCD were characterized in terms of oncologic characteristics, genetic alteration of Yo antigens, differential gene expression profiles, and morphofunctional specificities of their in situ antitumor immunity by comparing them with matched control BCs. Results: Yo-PCD BCs were invasive carcinoma of no special type, which early metastasized to lymph nodes. They overexpressed human epidermal growth factor receptor 2 (HER2) but were hormone receptor negative. All Yo-PCD BCs carried at least 1 genetic alteration (variation or gain in copy number) on CDR2L, encoding the main Yo antigen that was found aberrantly overexpressed in Yo-PCD BCs. Analysis of the differentially expressed genes found 615 upregulated and 54 downregulated genes in Yo-PCD BCs compared with HER2-driven control BCs without PCD. Ontology enrichment analysis found significantly upregulated adaptive immune response pathways in Yo-PCD BCs. IF imaging confirmed an intense immune infiltration with an overwhelming predominance of immunoglobulin G-plasma cells. Discussion: These data confirm the role of genetic alterations of Yo antigens in triggering the immune tolerance breakdown but also outline a specific biomolecular profile in Yo-PCD BCs, suggesting a cancer-specific pathogenesis.

3. Tissue-resident CD8+T cells drive compartmentalized and chronic autoimmune damage against CNS neurons
Frieser D, Pignata A, Khajavi L, Shlesinger D, Gonzalez-Fierro C, Nguyen XH, Yermanos A, Merkler D, Höftberger R, Desestret V, Mair KM, Bauer J, Masson F, Liblau RS

Sci Transl Med (2022) — Abstract


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The mechanisms underlying the chronicity of autoimmune diseases of the central nervous system (CNS) are largely unknown. In particular, it is unclear whether tissue-resident memory T cells (TRM) contribute to lesion pathogenesis during chronic CNS autoimmunity. Here, we observed that a high frequency of brain-infiltrating CD8+ T cells exhibit a TRM-like phenotype in human autoimmune encephalitis. Using mouse models of neuronal autoimmunity and a combination of T single-cell transcriptomics, high-dimensional flow cytometry, and histopathology, we found that pathogenic CD8+ T cells behind the blood-brain barrier adopt a characteristic TRM differentiation program, and we revealed their phenotypic and functional heterogeneity. In the diseased CNS, autoreactive tissue-resident CD8+ T cells sustained focal neuroinflammation and progressive loss of neurons, independently of recirculating CD8+ T cells. Consistently, a large fraction of autoreactive tissue-resident CD8+ T cells exhibited proliferative potential as well as proinflammatory and cytotoxic properties. Persistence of tissue-resident CD8+ T cells in the CNS and their functional output, but not their initial differentiation, were crucially dependent on CD4+ T cells. Collectively, our results point to tissue-resident CD8+ T cells as essential drivers of chronic CNS autoimmunity and suggest that therapies targeting this compartmentalized autoreactive T cell subset might be effective for treating CNS autoimmune diseases.

4. Core cerebrospinal fluid biomarker profile in anti-LGI1 encephalitis
Lardeux P, Fourier A, Peter E, Dorey A, Muñiz-Castrillo S, Vogrig A, Picard G, Rogemond V, Verdurand M, Formaglio M, Joubert B, Froment Tilikete C, Honnorat J, Quadrio I, Desestret V

J Neurol (2022) — Abstract


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Objective: To compare CSF biomarkers’ levels in patients suffering from anti-Leucine-rich Glioma-Inactivated 1 (LGI1) encephalitis to neurodegenerative [Alzheimer’s disease (AD), Creutzfeldt-Jakob’s disease (CJD)] and primary psychiatric (PSY) disorders. Methods: Patients with LGI1 encephalitis were retrospectively selected from the French Reference Centre database between 2010 and 2019 and enrolled if CSF was available for biomarkers analysis including total tau (T-tau), phosphorylated tau (P-tau), amyloid-beta Aβ1-42, and neurofilaments light chains (Nf L). Samples sent for biomarker determination as part of routine practice, and formally diagnosed as AD, CJD, and PSY, were used as comparators. Results: Twenty-four patients with LGI1 encephalitis were compared to 39 AD, 20 CJD and 20 PSY. No significant difference was observed in T-tau, P-tau, and Aβ1-42 levels between LGI1 encephalitis and PSY patients. T-Tau and P-Tau levels were significantly lower in LGI1 encephalitis (231 and 43 ng/L) than in AD (621 and 90 ng/L, p < 0.001) and CJD patients (4327 and 55 ng/L, p < 0.001 and p < 0.01). Nf L concentrations of LGI1 encephalitis (2039 ng/L) were similar to AD (2,765 ng/L) and significantly higher compared to PSY (1223 ng/L, p < 0.005), but significantly lower than those of CJD (13,457 ng/L, p < 0.001). Higher levels of Nf L were observed in LGI1 encephalitis presenting with epilepsy (3855 ng/L) compared to LGI1 without epilepsy (1490 ng/L, p = 0.02). No correlation between CSF biomarkers’ levels and clinical outcome could be drawn. Conclusion: LGI encephalitis patients showed higher Nf L levels than PSY, comparable to AD, and even higher when presenting epilepsy suggesting axonal or synaptic damage linked to epileptic seizures.

5. Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes
Graus F, Vogrig A, Muñiz-Castrillo S, Antoine JG, Desestret V, Dubey D, Giometto B, Irani SR, Joubert B, Leypoldt F, McKeon A, Prüss H, Psimaras D, Thomas L, Titulaer MJ, Vedeler CA, Verschuuren JJ, Dalmau J, Honnorat J

Neurol Neuroimmunol Neuroinflamm (2021) — Abstract


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Objective: The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS. Methods: A panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project. Results: The panel proposed to substitute classical syndromes with the term high-risk phenotypes for cancer and introduce the concept of intermediate-risk phenotypes. The term onconeural antibody was replaced by high risk (>70% associated with cancer) and intermediate risk (30%-70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided. Conclusions: The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

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

Brain (2021) — Abstract


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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.

7. Cranial Nerve Disorders Associated With Immune Checkpoint Inhibitors. Neurology
Vogrig A, Muñiz-Castrillo S, Joubert B, Picard G, Rogemond V, Skowron F, Egri M, Desestret V, Tilikete C, Psimaras D, Ducray F, Honnorat J

Neurology (2021) — Abstract


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Objective: To describe the spectrum, treatment, and outcome of cranial nerve disorders associated with immune checkpoint inhibitor (Cn-ICI). Methods: This nationwide retrospective cohort study on Cn-ICI (2015-2019) was conducted using the database of the French Refence Center. In addition, a systematic review of the literature (MEDLINE, Scopus, and Web of Science) for records published between 2010 and 2019 was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the search terms cranial nerve or neuropathy or palsy and immune checkpoint inhibitors. Results: Among 67 cases with ICI-related neurologic toxicities diagnosed in our reference center, 9 patients with Cn-ICI were identified (7 men, 78%, median age 62 years [range 26-82 years]). Patients were receiving a combination of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death 1 (PD-1)/PD-1 ligand (n = 5, 56%) or anti-PD-1 antibodies alone (n = 4, 44%). Cn-ICI involved optic (n = 3), vestibulocochlear (n = 3), abducens (n = 2), facial (n = 2), and oculomotor (n = 1) nerves. Two patients had involvement of 2 different cranial nerves. Treatment comprised corticosteroids (n = 8, 89%), ICI permanent discontinuation (n = 7, 78%), plasma exchange (n = 2, 22%), and IV immunoglobulin (n = 1, 11%). Median follow-up was 11 months (range 1-41 months). In 3 cases (33%), neurologic deficit persisted/worsened despite treatment: 2 optic and 1 vestibulocochlear. Among cases from the literature and the present series combined (n = 39), the most commonly affected cranial nerves were facial (n = 13, 33%), vestibulocochlear (n = 8, 21%), optic (n = 7, 18%), and abducens (n = 4, 10%). Trigeminal, oculomotor, and glossopharyngeal nerves were less frequently affected (total n = 7). Conclusion: Cranial nerve disorders can complicate treatment with ICIs. Approximately one-third of the patients had persisting deficits, most frequently involving hearing and vision loss.

8. Immunopathological characterization of ovarian teratomas associated with anti-N-methyl-D-aspartate receptor encephalitis
Chefdeville A, Treilleux I, Mayeur ME, Couillault C, Picard G, Bost C, Mokhtari K, Vasiljevic A, Meyronet D, Rogemond V, Psimaras D, Dubois B, Honnorat J, Desestret V

Acta Neuropathol Commun (2019) — Abstract


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Encephalitis with anti-NMDAR antibodies (NMDAR-E) is a severe autoimmune neurological disorder, defined by a clinical presentation of encephalitis and the presence of IgG targeting the GluN1 subunit of NMDA receptors in the CSF. An underlying ovarian teratoma is commonly associated with this autoimmune disease suggesting a role of the tumor in immunopathogenesis. In this study, we characterized the salient histopathological features of 27 ovarian teratomas associated with NMDAR-E (3 immature and 24 mature teratomas) and 40 controls without associated encephalitis. All but one NMDAR-E-associated teratomas contained a nervous tissue component, while less than 40% of control teratomas did (p < 0.001). GluN1 expression by teratomatous nervous tissue seemed to be more often glial in NMDAR-E teratomas than in control teratomas (73% vs. 29%, p < 0.05). Strikingly, 3 out of 24 NMDAR-E-associated mature teratomas contained neuroglial tissue exhibiting histopathological features of central nervous system neuroglial tumor, while such glioma-like features are exceptionally described in the literature on ovarian teratomas. Moreover, NMDAR-E associated teratomas differed from sporadic ovarian teratomas by consistent and prominent infiltration of the nervous tissue component by immune cells, comprised of T- and B-cells and mature dendritic cells organized in tertiary lymphoid structures, with IgG and IgA deposits and plasma cells in close contact to the neuroglial tissue.These data demonstrate an association between massive infiltration of NMDAR-E-associated teratomas by immune cells and particular glial features of its neuroglial component, suggesting that this glial tissue might be involved in triggering or sustaining the anti-tumor response associated with the auto-immune neurological disease.

9. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration
Small M, Treilleux I, Couillault C, Pissaloux D, Picard G, Paindavoine S, Attignon V, Wang Q, Rogemond V, Lay S, Ray-Coquard I, Pfisterer J, Joly F, Du Bois A, Psimaras D, Bendriss-Vermare N, Caux C, Dubois B, Honnorat J, Desestret V

Acta Neuropathol (2018) — Abstract


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Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.

10. Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies
Vialatte de Pémille C, Berzero G, Small M, Psimaras D, Giry M, Daniau M, Sanson M, Delattre JY, Honnorat J, Desestret V, Alentorn A

Br J Cancer (2018) — Abstract


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Background: Paraneoplastic neurological syndromes are rare conditions where an autoimmune reaction against the nervous system appears in patients suffering from a tumour, but not linked to the spreading of the tumour. A break in the immune tolerance is thought to be the trigger. Methods: The transcriptomic profile of 12 ovarian tumours (OT) from patients suffering from paraneoplastic cerebellar degeneration (PCD) linked to anti-Yo antibodies (anti-Yo PCD OT) was compared with 733 ovarian tumours (OT control) from different public databases using linear model analysis. Results: A prominent significant transcriptomic over-representation of CD8+ and Treg cells was found in anti-Yo PCD OT, as compared to the OT control. However, the overall degree of immune cell infiltration was similar, according to the ESTIMATE immune score. We also found an under-representation of M2 macrophages in anti-Yo PCD OT. Furthermore, the differentially expressed genes were enriched for AIRE-related genes, a well-known transcription factor associated with a broad range of autoimmune diseases. Finally, we found that the differentially expressed genes were correlated to the transcriptomic profiling of the cerebellar structures. Conclusions: Our data pinpointed the enrichment of acquired immune response, particularly high density of CD8+ lymphocytes, and high-level expression of CDR-related antigens in anti-Yo PCD OT.