Publications by authors named "Jerome Honnorat"

291 Publications

Incidence and characteristics of pseudoprogression in IDH-mutant high-grade gliomas: a POLA network study.

Neuro Oncol 2022 Aug 12. Epub 2022 Aug 12.

Department of Neuro-Oncology, East Group Hospital, Hospices Civils de Lyon, Lyon, France.

Background: Incidence and characteristics of pseudoprogression in isocitrate dehydrogenase-mutant high-grade gliomas (IDHmt HGG) remain to be specifically described.

Methods: We analyzed pseudoprogression characteristics and explored the possibility of pseudoprogression misdiagnosis in IDHmt HGG patients, treated with radiotherapy (with or without chemotherapy), included in the French POLA network. Pseudoprogression was analyzed in patients with MRI available for review (reference cohort, n=200). Pseudoprogression misdiagnosis was estimated in this cohort and in an independent cohort (control cohort, n=543) based on progression free survival before and after first progression.

Results: In the reference cohort, 38 patients (19%) presented a pseudoprogression after a median time of 10.5 months after radiotherapy. Pseudoprogression characteristics were similar across IDHmt HGG subtypes. In most patients, it consisted in the appearance of one or several infracentimetric, asymptomatic, contrast-enhanced lesions occurring within 2 years after radiotherapy. The only factor associated with pseudoprogression occurrence was adjuvant PCV chemotherapy. Among patients considered as having a first true progression, 7 out of 41 (17%) in the reference cohort and 35 out of 203 (17%) in the control cohort were retrospectively suspected to have a misdiagnosed pseudoprogression. Patients with a misdiagnosed pseudoprogression were characterized by a time to event and an outcome similar to that of patients with a pseudoprogression but presented with larger and more symptomatic lesions.

Conclusion: In patients with an IDHmt HGG, pseudoprogression occurs later than in IDH-wildtype glioblastomas and seems not only frequent but also frequently misdiagnosed. Within the first 2 years after radiotherapy, the possibility of a pseudoprogression should be carefully considered.
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http://dx.doi.org/10.1093/neuonc/noac194DOI Listing
August 2022

Cerebellar Ataxia With Anti-DNER Antibodies: Outcomes and Immunologic Features.

Neurol Neuroimmunol Neuroinflamm 2022 Sep 8;9(5). Epub 2022 Aug 8.

From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (E.P., S.M.-C., A.V., A.-L.P., V.R., G.P., V.D.,J.H., B.J.), Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; Synaptopathies and Autoantibodies (SynatAc) Team (E.P., L.D.D., S.M.-C., A.V., V.W., N.C., V.D., J.H., B.J.), Institut NeuroMyoGène-MeLis, INSERM U1314/CNRS UMR 5284, Université de Lyon, France; Medical Imaging Sciences Program (S.H., W.Z.), Division of Health Professions, Faculty of Health Sciences, American University of Beirut, Lebanon; Center for Sleep Sciences and Medicine (J.-J.H., Aditya Ambati, E.M.), Stanford University, Palo Alto, CA; Service de Neurologie 2-Mazarin (Agusti Alentorn, D.P.), Hôpitaux Universitaires La Pitié-Salpêtrière-Charles Foix, APHP; Inserm U1127 CNRS UMR 7225 (Agusti Alentorn, D.P.), Institut du Cerveau et de la Moelle épinière, ICM, Université Pierre-et-Marie-Curie, Sorbonne Universités, Paris, France; INSERM Unité Mixte de Recherche (UMR) S1052 (A.T.-G.), Centre National de la Recherche UMR 5286, Centre de Recherche en Cancérologie de Lyon, France; Département de Pathologie (A.T.-G.), Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite Cedex, France; Service des Neurosciences (M.M.), UMons, Mons, Belgium; Service de Neurologie (M.M.), CHU-Charleroi, Charleroi, Belgium; Department of Radiology (F.C.), Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France; and Université Lyon 1 (F.C.), CREATIS-LRMN, CNRS/UMR/5220-INSERM U630, Villeurbanne, France.

Background And Objectives: There is no report on the long-term outcomes of ataxia with antibodies against Delta and Notch-like epidermal growth factor-related (DNER). We aimed to describe the clinical-immunologic features and long-term outcomes of patients with anti-DNER antibodies.

Methods: Patients tested positive for anti-DNER antibodies between 2000 and 2020 were identified retrospectively. In those with available samples, immunoglobulin G (IgG) subclass analysis, longitudinal cerebellum volumetry, human leukocyte antigen isotyping, and CSF proteomic analysis were performed. Rodent brain membrane fractionation and organotypic cerebellar slices were used to study DNER cell-surface expression and human IgG binding to the Purkinje cell surface.

Results: Twenty-eight patients were included (median age, 52 years, range 19-81): 23 of 28 (82.1%) were male and 23 of 28 (82.1%) had a hematologic malignancy. Most patients (27/28, 96.4%) had cerebellar ataxia; 16 of 28 (57.1%) had noncerebellar symptoms (cognitive impairment, neuropathy, and/or seizures), and 27 of 28 (96.4%) became moderately to severely disabled. Half of the patients (50%) improved, and 32.1% (9/28) had no or slight disability at the last visit (median, 26 months; range, 3-238). Good outcome significantly associated with younger age, milder clinical presentations, and less decrease of cerebellar gray matter volumes at follow-up. No human leukocyte antigen association was identified. Inflammation-related proteins were overexpressed in the patients' CSF. In the rodent brain, DNER was enriched in plasma membrane fractions. Patients' anti-DNER antibodies were predominantly IgG1/3 and bound live Purkinje cells in vitro.

Discussion: DNER ataxia is a treatable condition in which nearly a third of patients have a favorable outcome. DNER antibodies bind to the surface of Purkinje cells and are therefore potentially pathogenic, supporting the use of B-cell-targeting treatments.
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http://dx.doi.org/10.1212/NXI.0000000000200018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359625PMC
September 2022

Distinct movement disorders in contactin-associated-protein-like-2 antibody associated autoimmune encephalitis.

Brain 2022 Jul 25. Epub 2022 Jul 25.

Department of Neurology, Christian-Albrecht University of Kiel and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.

Autoimmune encephalitis (AE) can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory etiologies. In the elderly, anti-leucin-rich-glioma-inactivated-1 (LGI1) and contactin-associated-protein-like-2 (CASPR2) antibody-associated diseases compose a relevant fraction of AE. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures (FBDS) may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan`s syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2-autoantibody associated syndromes have caused substantial concern regarding necessity of autoantibody-testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centers in Europe. Patients with ataxia and/or movement disorders were analyzed in detail using questionnaires and video recordings. We recruited a comparator group with anti-leucin-rich-glioma-inactivated-1 (LGI1) encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2- and 15 (9.1%) both CASPR2- and LGI1-autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6% versus 3.8%; p < 0.001). This was evident in all subgroups: ataxia 22.6% versus 0.0%, myoclonus 14.6% versus 0.0%, tremor 11.0% versus 1.9%, or combinations thereof 9.8% versus 0.0% (all p < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, "mixed movement disorders", Morvan's syndrome and underlying tumors. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.
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http://dx.doi.org/10.1093/brain/awac276DOI Listing
July 2022

Immune and Genetic Signatures of Breast Carcinomas Triggering Anti-Yo-Associated Paraneoplastic Cerebellar Degeneration.

Neurol Neuroimmunol Neuroinflamm 2022 09 12;9(5). Epub 2022 Jul 12.

From the Synaptopathies and Autoantibodies (SynatAc) Team, Institut NeuroMyoGène-MeLiS, INSERM U1314/CNRS UMR 5284, Université de Lyon; French Reference Center on Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon; University of Lyon, Université Claude Bernard Lyon 1; Department of Biopathology, Centre Leon Berard; INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de Recherche en Cancérologie de Lyon; Cancer Genomics Platform, Department of Translational Research, Centre Leon Berard; Synergie Lyon Cancer- Bioinformatics Platform-Gilles Thomas, Centre de Recherche en Cancérologie de Lyon; and Laboratoire d'Immunothérapie des Cancers de Lyon (LICL), France.

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 , 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.
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http://dx.doi.org/10.1212/NXI.0000000000200015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278124PMC
September 2022

Childhood encephalitis in the Greater Mekong region (the SouthEast Asia Encephalitis Project): a multicentre prospective study.

Lancet Glob Health 2022 07;10(7):e989-e1002

National Institute of Hygiene and Epidemiology, Hanoi, Vietnam.

Background: Encephalitis is a worldwide public health issue, with a substantially high burden among children in southeast Asia. We aimed to determine the causes of encephalitis in children admitted to hospitals across the Greater Mekong region by implementing a comprehensive state-of-the-art diagnostic procedure harmonised across all centres, and identifying clinical characteristics related to patients' conditions.

Methods: In this multicentre, observational, prospective study of childhood encephalitis, four referral hospitals in Cambodia, Vietnam, Laos, and Myanmar recruited children (aged 28 days to 16 years) who presented with altered mental status lasting more than 24 h and two of the following minor criteria: fever (within the 72 h before or after presentation), one or more generalised or partial seizures (excluding febrile seizures), a new-onset focal neurological deficit, cerebrospinal fluid (CSF) white blood cell count of 5 per mL or higher, or brain imaging (CT or MRI) suggestive of lesions of encephalitis. Comprehensive diagnostic procedures were harmonised across all centres, with first-line testing was done on samples taken at inclusion and results delivered within 24 h of inclusion for main treatable causes of disease and second-line testing was done thereafter for mostly non-treatable causes. An independent expert medical panel reviewed the charts and attribution of causes of all the included children. Using multivariate analyses, we assessed risk factors associated with unfavourable outcomes (ie, severe neurological sequelae and death) at discharge using data from baseline and day 2 after inclusion. This study is registered with ClinicalTrials.gov, NCT04089436, and is now complete.

Findings: Between July 28, 2014, and Dec 31, 2017, 664 children with encephalitis were enrolled. Median age was 4·3 years (1·8-8·8), 295 (44%) children were female, and 369 (56%) were male. A confirmed or probable cause of encephalitis was identified in 425 (64%) patients: 216 (33%) of 664 cases were due to Japanese encephalitis virus, 27 (4%) were due to dengue virus, 26 (4%) were due to influenza virus, 24 (4%) were due to herpes simplex virus 1, 18 (3%) were due to Mycobacterium tuberculosis, 17 (3%) were due to Streptococcus pneumoniae, 17 (3%) were due to enterovirus A71, 74 (9%) were due to other pathogens, and six (1%) were due to autoimmune encephalitis. Diagnosis was made within 24 h of admission to hospital for 83 (13%) of 664 children. 119 (18%) children had treatable conditions and 276 (42%) had conditions that could have been preventable by vaccination. At time of discharge, 153 (23%) of 664 children had severe neurological sequelae and 83 (13%) had died. In multivariate analyses, risk factors for unfavourable outcome were diagnosis of M tuberculosis infection upon admission (odds ratio 3·23 [95% CI 1·04-10·03]), coma on day 2 (2·90 [1·78-4·72]), supplementary oxygen requirement (1·89 [1·25-2·86]), and more than 1 week duration between symptom onset and admission to hospital (3·03 [1·68-5·48]). At 1 year after inclusion, of 432 children who were discharged alive from hospital with follow-up data, 24 (5%) had died, 129 (30%) had neurological sequelae, and 279 (65%) had completely recovered.

Interpretation: In southeast Asia, most causes of childhood encephalitis are either preventable or treatable, with Japanese encephalitis virus being the most common cause. We provide crucial information that could guide public health policy to improve diagnostic, vaccination, and early therapeutic guidelines on childhood encephalitis in the Greater Mekong region.

Funding: Institut Pasteur, Institut Pasteur International Network, Fondation Merieux, Aviesan Sud, INSERM, Wellcome Trust, Institut de Recherche pour le Développement (IRD), and Fondation Total.
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http://dx.doi.org/10.1016/S2214-109X(22)00174-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9210261PMC
July 2022

Long-term evolution and prognostic factors of epilepsy in limbic encephalitis with LGI1 antibodies.

J Neurol 2022 Sep 20;269(9):5061-5069. Epub 2022 May 20.

Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and Lyon 1 University, Lyon, France.

Objective: To characterize the evolution of epilepsy in patients with leucine-rich glioma inactivated 1 antibody-associated (LGI1ab) limbic encephalitis, including factors associated with drug-resistant epilepsy (DRE).

Methods: Retrospective analysis of patients with LGI1 encephalitis managed at two tertiary epilepsy centers between 2005 and 2019 and whose samples were confirmed by the French Reference Center of Paraneoplastic Neurological Syndromes. Raw clinical, biological, EEG, and MRI data were reviewed. Two endpoints were defined: (i) Epilepsy remission: patients seizure free and in whom anti-seizure medications (ASM) have been stopped for at least 1 year at the last follow-up visit (ii) DRE: patients with persistent seizures at the last follow-up despite at least two ASM used at efficacious daily dose.

Results: 39 patients with LGI1 encephalitis were included with a median follow-up duration of 42 months (range 13-169). All of them reported seizures at the acute phase, with faciobrachial dystonic seizures (FBDS) in 23 (59%) and other focal seizures in 38 (97%), including 4 patients (10%) with de novo status epilepticus. At the last follow-up visit, 11 patients (28%) achieved epilepsy remission. Among the 28 patients with persistent epilepsy, eight (29%) fulfilled criteria of DRE. The only factor significantly associated with epilepsy remission was the time from clinical onset of the encephalitis to initiation of the first immunomodulatory treatment, with longer delay in patients with persistent epilepsy (7.5 ± 8.9 vs 2.4 ± 1.7 months, p = 0.006). Evolution to DRE was only driven by MRI evolution. Eight of the 15 patients (53%) who developed hippocampal atrophy (p = 0.007) also suffered from drug-resistant seizures at the last follow-up.

Significance: In patients with LGI1 encephalitis, rapid initiation of immunomodulatory treatment favors long-term epilepsy remission. Evolution to DRE might primarily reflect the anatomical lesion of limbic structures. Determining what modalities of immune treatment may alter these outcomes requires prospective studies with long-term follow-up.
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http://dx.doi.org/10.1007/s00415-022-11162-3DOI Listing
September 2022

Paraneoplastic encephalitis: clinically based approach on diagnosis and management.

Postgrad Med J 2022 May 19. Epub 2022 May 19.

Department of Neuro-oncology, Université Claude Bernard Lyon 1 Villeurbanne, Lyon, France

Paraneoplastic neurological syndromes (PNSs) comprise a subset of immune-mediated nervous system diseases triggered by an underlying malignancy. Each syndrome usually shows a distinct clinical presentation and outcome according to the associated neural antibodies. PNSs generally have a subacute onset with rapid progression and severe neurological disability. However, some patients may have hyperacute onset or even show chronic progression mimicking neurodegenerative diseases. Updated diagnostic criteria for PNS have been recently established in order to increase diagnostic specificity and to encourage standardisation of research initiatives related to PNS. Treatment for PNS includes oncological therapy and immunomodulation to halt neurological deterioration although current treatment options are seldom effective in reversing disability. Nevertheless, growing knowledge and better understanding of PNS pathogenesis promise better recognition, earlier diagnosis and novel treatment strategies. Considering that PNSs provide a model of effective anticancer immunity, the impact of these studies will extend far beyond the field of neurology.
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http://dx.doi.org/10.1136/postgradmedj-2022-141766DOI Listing
May 2022

Phase 3 Trial of Chemoradiotherapy With Temozolomide Plus Nivolumab or Placebo for Newly Diagnosed Glioblastoma With Methylated MGMT Promoter.

Neuro Oncol 2022 May 2. Epub 2022 May 2.

Yale University School of Medicine, New Haven, CT, USA.

Background: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase 3 randomized CheckMate 548 study was to evaluate RT+TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587).

Methods: Patients (N=716) were randomized 1:1 to NIVO [(240 mg every 2 weeks ×8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m 2 once daily during RT, then 150-200 mg/m 2 once daily days 1-5 of every 28-day cycle ×6)] or PBO+RT+TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients.

Results: As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO+RT+TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO+RT+TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO+RT+TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively.

Conclusions: NIVO added to RT+TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed.
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http://dx.doi.org/10.1093/neuonc/noac116DOI Listing
May 2022

Gyriform infiltration as imaging biomarker for molecular glioblastomas.

J Neurooncol 2022 May 1;157(3):511-521. Epub 2022 Apr 1.

Department of Neuro-Oncology, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France.

Background: Molecular glioblastomas (i.e. without the histological but with the molecular characteristics of IDH-wild-type glioblastoma) frequently lack contrast enhancement, which can wrongly lead to suspect a lower-grade glioma. Herein, we aimed to assess the diagnostic value of gyriform infiltration as an imaging marker for molecular glioblastomas.

Methods: Two independent investigators reviewed the MRI scans from patients with newly diagnosed gliomas for the presence of a gyriform infiltration defined as an elective cortical hypersignal on MRI FLAIR sequence. Diagnostic test performance of this sign for the diagnosis of molecular glioblastoma were calculated.

Results: A total of 426 patients were included, corresponding to 31 molecular glioblastoma, 294 IDH-wild-type glioblastoma, 50 IDH-mutant astrocytoma, and 51 IDH-mutant 1p19q-codeleted oligodendroglioma. A gyriform infiltration was observed in 16/31 (52%) molecular glioblastoma, 40/294 (14%) IDH-wild-type glioblastoma, and none of the IDH-mutant glioma. All the 56 gyriform-infiltration-positive tumors were IDH-wild-type and all but two had a TERT promoter mutation. The inter-rater agreement was good (κ = 0.69, p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the presence of a gyriform infiltration for the diagnosis of molecular glioblastoma were 52%, 90%, 29%, 96%, respectively. The median overall survival was better for gyriform-infiltration-negative patients compared to gyriform-infiltration-positive patients in the whole series and in patients with non-enhancing lesions (n = 95) (25.6 vs 16.9 months, p = 0.005 and 20.2 months vs not reached, p < 0.001).

Conclusion: Gyriform infiltration is a specific imaging marker of molecular glioblastomas that can help distinguishing these tumors from IDH-mutant lower-grade gliomas.
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http://dx.doi.org/10.1007/s11060-022-03995-9DOI Listing
May 2022

The Clinical Concept of LTDpathy: Is Dysregulated LTD Responsible for Prodromal Cerebellar Symptoms?

Brain Sci 2022 Feb 24;12(3). Epub 2022 Feb 24.

Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000 Charleroi, Belgium.

Long-term depression at parallel fibers-Purkinje cells (PF-PC LTD) is essential for cerebellar motor learning and motor control. Recent progress in ataxiology has identified dysregulation of PF-PC LTD in the pathophysiology of certain types of immune-mediated cerebellar ataxias (IMCAs). Auto-antibodies towards voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) induce dysfunction of PF-PC LTD, resulting in the development of cerebellar ataxias (CAs). These disorders show a good response to immunotherapies in non-paraneoplastic conditions but are sometimes followed by cell death in paraneoplastic conditions. On the other hand, in some types of spinocerebellar ataxia (SCA), dysfunction in PF-PC LTD, and impairments of PF-PC LTD-related adaptive behaviors (including vestibulo-ocular reflex (VOR) and prism adaptation) appear during the prodromal stage, well before the manifestations of obvious CAs and cerebellar atrophy. Based on these findings and taking into account the findings of animal studies, we re-assessed the clinical concept of LTDpathy. LTDpathy can be defined as a clinical spectrum comprising etiologies associated with a functional disturbance of PF-PC LTD with concomitant impairment of related adaptative behaviors, including VOR, blink reflex, and prism adaptation. In IMCAs or degenerative CAs characterized by persistent impairment of a wide range of molecular mechanisms, these disorders are initially functional and are followed subsequently by degenerative cell processes. In such cases, adaptive disorders associated with PF-PC LTD manifest clinically with subtle symptoms and can be prodromal. Our hypothesis underlines for the first time a potential role of LTD dysfunction in the pathogenesis of the prodromal symptoms of CAs. This hypothesis opens perspectives to block the course of CAs at a very early stage.
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http://dx.doi.org/10.3390/brainsci12030303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8946597PMC
February 2022

[Autoimmune encephalitis : an update].

Rev Prat 2022 Jan;72(1):85-90

Centre français de référence des syndromes neurologiques paranéoplasiques et des encéphalites auto-immunes, Hospices civils de Lyon ; Hôpital neurologique de Bron ; Hôpital neurologique de Lyon, France Équipe Synaptopathies et auto-anticorps (SynatAc), institut NeuroMyoGène, Inserm U1217/CNRS UMR 5310, université Claude-Bernard, Lyon, France.

Autoimmune encephalitis: an update. Autoimmune encephalitis (AE) are rare autoimmune disorders of the central nervous system associated with anti-neuron antibodies. Patients classically present with anterograde amnesia, temporal lobe seizures, and/or behavioral changes, along with a variety of possible other symptoms, depending on the autoantibody. AE with antibodies targeting intracellular proteins are usually paraneoplastic and carry a poor prognosis. AE with antibodies against neuron cell-surface proteins associate with cancer less frequently and usually have better outcomes. Diagnosis relies on the detection of associated anti-neuron antibodies, while management focuses on the treatment of underlying neoplasia along with immune-suppressive therapies.
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January 2022

Human Leukocyte Antigen Association Study Reveals DRB1*04:02 Effects Additional to DRB1*07:01 in Anti-LGI1 Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2022 03 3;9(2). Epub 2022 Feb 3.

From the Stanford University Center for Sleep Sciences (V.P.S., A.A., and E.M.), Stanford University School of Medicine, Palo Alto, CA; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., A.-L.P., V.R., and J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., A.-L.P., V.R., and J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1, Université de Lyon, France; Oxford Autoimmune Neurology Group (S.B. and S.I.), Nuffield Department of Clinical Neurosciences, University of Oxford; Department of Neurology (S.B. and S.I.), John Radcliffe Hospital, Oxford, United Kingdom; Department of Laboratory Medicine and Pathology (S.J.P. and D.D.), and Department of Neurology (S.J.P. and D.D.), Mayo Clinic, Rochester, MN; Department of Neurology (M.D.G., J.M.G., and S.D.), University of California, San Francisco; Department of Neurology (S.-T.L.), Seoul National University Hospital, South Korea; and Wellcome Centre for Human Genetics (J.K. and K.S.E.), Nuffield Department of Medicine, University of Oxford, United Kingdom.

Background And Objectives: To study human leukocyte antigen (HLA) allele associations in anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.

Methods: A multiethnic cohort of 269 patients with anti-LGI1 encephalitis and 1,359 controls was included. Four-digit HLA sequencing and genome wide association single-nucleotide polymorphism typing imputation (0.99 concordance) were used for HLA typing. Significance of primary and secondary associations was tested using χ, Fisher exact tests, or logistic regression with the control of population stratification covariates when applicable.

Results: DRB1*07:01 and DQA1*02:01, 2 alleles in strong linkage disequilibrium, were associated with the disease (90% vs 24%, OR = 27.8, < 10e) across ethnicity independent of variation at DRB3 and DQB1, 2 flanking HLA loci. DRB1*07:01 homozygosity was associated with a doubling of risk (OR = 2.1, = 0.010), suggesting causality. DRB1*07:01 negative subjects were younger ( = 0.003) and more frequently female ( = 0.015). Three patients with malignant thymomas did not carry DRB1*07:01, whereas patients with other tumors had high DRB1*07:01 frequency, suggesting that the presence of tumors other than thymomas may be coincidental and not causal. In both DRB1*07:01 heterozygous individuals and DRB1*07:01 negative subjects, DRB1*04:02 was associated with anti-LGI1 encephalitis, indicating an independent effect of this allele (OR = 6.85, = 4.57 × 10 and OR = 8.93, = 2.50 × 10, respectively). DRB1*04:02 was also independently associated with younger age at onset (β = -6.68, = 9.78 × 10). Major histocompatibility complex peptide-binding predictions using LGI1-derived peptides revealed divergent binding propensities for DRB1*04:02 and DRB1*07:01 alleles, suggesting independent pathogenic mechanisms.

Discussion: In addition to the established primary DRB1*07:01 association in anti-LGI1 encephalitis, we observe a secondary effect of DRB1*04:02 with lower age at onset. Our study provides evidence for secondary effects within HLA locus that correlate with clinical phenotypes in anti-LGI1 encephalitis.
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http://dx.doi.org/10.1212/NXI.0000000000001140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815287PMC
March 2022

Novelties in Autoimmune and Paraneoplastic Cerebellar Ataxias: Twenty Years of Progresses.

Cerebellum 2022 Aug 12;21(4):573-591. Epub 2022 Jan 12.

French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, 59 Boulevard Pinel, 69677, Bron Cedex, France.

Major advances in our knowledge concerning autoimmune and paraneoplastic cerebellar ataxias have occurred in the last 20 years. The discovery of several neural antibodies represents an undeniable contribution to this field, especially those serving as good biomarkers of paraneoplastic neurological syndromes and those showing direct pathogenic effects. Yet, many patients still lack detectable or known antibodies, and also many antibodies have only been reported in few patients, which makes it difficult to define in detail their clinical value. Nevertheless, a notable progress has additionally been made in the clinical characterization of patients with the main neural antibodies, which, although typically present with a subacute pancerebellar syndrome, may also show either hyperacute or chronic onsets that complicate the differential diagnoses. However, prodromal and transient features could be useful clues for an early recognition, and extracerebellar involvement may also be highly indicative of the associated antibody. Moreover, important advances in our understanding of the pathogenesis of cerebellar ataxias include the description of antibody effects, especially those targeting cell-surface antigens, and first attempts to isolate antigen-specific T-cells. Furthermore, genetic predisposition seems relevant, although differently involved according to cancer association, with particular HLA observed in non-paraneoplastic cases and genetic abnormalities in the tumor cells in paraneoplastic ones. Finally, immune checkpoint inhibitors used as cancer immunotherapy may rarely induce cerebellar ataxias, but even this undesirable effect may in turn serve to shed some light on their physiopathology. Herein, we review the principal novelties of the last 20 years regarding autoimmune and paraneoplastic cerebellar ataxias.
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http://dx.doi.org/10.1007/s12311-021-01363-3DOI Listing
August 2022

Cerebellar long-term depression and auto-immune target of auto-antibodies: the concept of LTDpathies.

Mol Biomed 2021 Jan 10;2(1). Epub 2021 Jan 10.

Unité des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000, Charleroi, Belgium.

There is general agreement that auto-antibodies against ion channels and synaptic machinery proteins can induce limbic encephalitis. In immune-mediated cerebellar ataxias (IMCAs), various synaptic proteins, such as GAD65, voltage-gated Ca channel (VGCC), metabotropic glutamate receptor type 1 (mGluR1), and glutamate receptor delta (GluR delta) are auto-immune targets. Among them, the pathophysiological mechanisms underlying anti-VGCC, anti-mGluR1, and anti-GluR delta antibodies remain unclear. Despite divergent auto-immune and clinical profiles, these subtypes show common clinical features of good prognosis with no or mild cerebellar atrophy in non-paraneoplastic syndrome. The favorable prognosis reflects functional cerebellar disorders without neuronal death. Interestingly, these autoantigens are all involved in molecular cascades for induction of long-term depression (LTD) of synaptic transmissions between parallel fibers (PFs) and Purkinje cells (PCs), a crucial mechanism of synaptic plasticity in the cerebellum. We suggest that anti-VGCC, anti-mGluR1, and anti-GluR delta Abs-associated cerebellar ataxias share one common pathophysiological mechanism: a deregulation in PF-PC LTD, which results in impairment of restoration or maintenance of the internal model and triggers cerebellar ataxias. The novel concept of LTDpathies could lead to improvements in clinical management and treatment of cerebellar patients who show these antibodies.
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http://dx.doi.org/10.1186/s43556-020-00024-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607360PMC
January 2021

Current Status of Biomarkers in Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

Int J Mol Sci 2021 Dec 4;22(23). Epub 2021 Dec 4.

Neuroimmunology and Neuroinflammation Group, Biomedical Research Institute of Málaga (IBIMA), 29007 Málaga, Spain.

The discovery of biomarkers in rare diseases is of paramount importance to allow a better diagnosis, improve predictions of outcomes, and prompt the development of new treatments. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder associated with the presence of antibodies targeting the GluN1 subunit of the NMDAR. Since it was discovered in 2007, large efforts have been made towards the identification of clinical, paraclinical, and molecular biomarkers to better understand the immune mechanisms that govern the course of the disease as well as to define predictors of treatment response and long-term outcomes. However, most of these biomarkers are still in an exploratory phase, with only a few candidates reaching the final phases of the always-complex process of biomarker development, mainly due to the low incidence of the disease and its recent description. Clinical and paraclinical markers are probably the most widely explored in anti-NMDAR encephalitis, five of them combined in a clinical score to predict 1 year outcome. On the contrary, soluble molecules, such as persistent antibody positivity, antibody titers, cytokines, and other inflammatory mediators, have been proposed as biomarkers of clinical activity, inflammation, prognosis, and treatment response, but further studies are required for their clinical validation including larger and more homogenous cohorts of patients. Similarly, genetic susceptibility biomarkers are still in the exploratory phase and, therefore, weak conclusions can for now only be achieved. Thus, further studies are warranted to define biomarkers and unravel the underlying mechanisms driving rare diseases such as anti-NMDAR encephalitis. Future international collaborative studies with prospective designs that enable the enrollment of large cohorts will allow for the identification and validation of novel biomarkers for clinical decision-making.
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http://dx.doi.org/10.3390/ijms222313127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658717PMC
December 2021

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

Neurology 2022 02 19;98(6):e653-e668. Epub 2021 Nov 19.

From Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (A.G.-D., R.M.), Service d'Imagerie Médicale (R.A.), and Centre de Référence des Syndromes Neurologiques Paranéoplasiques et Encéphalites Auto-immunes (V.R., B.J., S.M.-C., A.V., G.P., J.H.), Hôpital Neurologique Pierre Wertheimer, and Service de Neurologie Pédiatrique, Hôpital Femme Mère Enfant (C.F.), Hospices Civils de Lyon, Lyon/Bron; Institut NeuroMyoGène (V.R., B.J., S.M.-C., A.V., G.P., J.H.), INSERM 1217 et CNRS UMR5310; Université Claude Bernard Lyon 1 (V.R., B.J., S.M.-C., A.V., G.P., J.H.), Faculté de Médecine Lyon Est; Centre de Recherche en Neurosciences de Lyon (A.R., R.M.), INSERM 1028 et CNRS UMR5292, France; Stanford University Center for Sleep Sciences and Medicine (A.A.), Palo Alto, CA; Service de Neurologie Cognitive, Épilepsie, Sommeil et Mouvements Anormaux (M. Benaiteau) and Service de Neurologie Inflammatoire et Neuro-oncologie (F.R., J.C.), Hôpital Pierre-Paul Riquet, Hôpitaux de Toulouse; Service de Neuropédiatrie (K.D.), Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre; Service de Neurologie (T.d.B.), Hôpital Delafontaine, Centre Hospitalier de Saint-Denis; Service de Neurologie, Hôpital de Hautepierre (L.K.), Hôpitaux Universitaires de Strasbourg; Service de Neurologie (P.K.), Centre Hospitalier de Luxembourg; Service de Neurologie (F.S.) and Service de Médecine Interne (B.B.), Hôpitaux Civils de Colmar; Unité INSERM U-1118 (F.S.), Faculté de Médecine, Université de Strasbourg; Service de Médecine Interne (R.G.), Hôpital d'Instruction des Armées Legouest, Metz; Service de Neurologie (J.B.) and Service de Médecine Interne et Immunologie Clinique (A.B.), Centre Hospitalier Régional Universitaire de Tours; Service de Neurologie et Maladies Neuromusculaires (F.D.), Groupe Hospitalier Pellegrin, Hôpitaux de Bordeaux; Service de Médecine Intensive et Réanimation (N.I.), Hôpital Saint André, Bordeaux; Service de Neurologie (E.-C.R.), Hôpital Sainte Musse, Centre Hospitalier Intercommunal de Toulon; Service de Neurologie (M.G.), Hôpital Emile Muller, Mulhouse; Service de Neurologie (A.D.), Centre Hospitalier de Perpignan; Pôle Cardio-vasculaire et Métabolique (J.L.D.), Centre Hospitalier de Cayenne; Service de Neurologie (L.H.), Hôpital Central, CHRU Nancy; Service de Neurologie (A.-L.K.), CHU de Saint-Etienne, Saint-Priest-en-Jarez; Service de Neuropédiatrie (M.P.), Site Mère Enfant, CHU Martinique, Fort-de-France; Service de Neurologie (E.C.), CHU Gabriel-Montpied, CHU de Clermont-Ferrand; Service de Neurologie (A.L.), Hôpital d'Instruction des Armées Clermont-Tonnerre, Brest; Service de Neurologie (E.M.), Hôpital Fondation Adolphe de Rothschild, Paris; Service de Neurologie et Laboratoire de Neurosciences Fonctionnelles et Pathologies (D.A.), Centre Hospitalier Universitaire d'Amiens et Université de Picardie Jules Verne, Amiens; Service de Neurologie (P.D.), Hôpital Laënnec, Centre Hospitalier de Cornouaille, Quimper; Service de Neurologie (G.M.), Centre Hospitalier Universitaire de La Réunion, Saint Pierre; Service de Neurologie (C.D.), Hôpital Roger Salengro, Centre Hospitalier Universitaire de Lille; Service de Neurologie (V.B.), Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice; Service de Médecine Interne et Maladies Infectieuses (Q.B.), Centre Hospitalier d'Angoulême; Service de Neurologie (I.G.-C.) and Service de Réanimation (G.R.), Centre Hospitalier de Saint-Brieuc; Service de Médecine Polyvalente et de Médecine Interne (D.M.-T.), Centre Hospitalier Le Mans; Service de Neurologie (M. Bonnan), Centre Hospitalier de Pau; and Service de Neurologie/UNV (T.T.), Centre Hospitalier de Saintonge, Saintes, France.

Background And Objectives: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.

Methods: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.

Results: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.

Discussion: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.
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http://dx.doi.org/10.1212/WNL.0000000000013087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829963PMC
February 2022

Molecular profile to guide personalized medicine in adult patients with primary brain tumors: results from the ProfiLER trial.

Med Oncol 2021 Nov 5;39(1). Epub 2021 Nov 5.

Department of Medical Oncology, Leon Bérard Cancer Centre, 28, rue Laennec, 69373, Lyon, France.

Immunohistochemistry and recent molecular technologies progressively guided access to personalized anti-tumoral therapies. We explored the feasibility, efficacy, and the impact of molecular profiling in patients with advanced brain tumors. This multicentric prospective trial ProfiLER enrolled patients with primary brain tumors, who have been pre-treated with at least one line of anti-cancer treatment, and for whom molecular profiles had been achieved using next-generation sequencing and/or comparative genomic hybridization on fresh or archived samples from tumor, relapse, or biopsies. A molecular tumor board weekly analyzed results and proposed molecular-based recommended therapy (MBRT). From February 2013 to December 2015, we enrolled 141 patients with primary brain tumor and analyzed 105 patients for whom tumor genomic profiles had been achieved. Histology mainly identified glioblastoma (N = 46, 44%), low-grade glioma (N = 26, 25%), high-grade glioma (N = 12, 11%), and atypical and anaplastic meningioma (N = 8, 8%). Forty-three (41%) patients presented at least one actionable molecular alteration. Out of 61 alterations identified, the most frequent alterations occurred in CDKN2A (N = 18), EGFR (N = 12), PDGFRa (N = 8), PTEN (N = 8), CDK4 (N = 7), KIT (N = 6), PIK3CA (N = 5), and MDM2 (N = 3). Sixteen (15%) patients could not be proposed for a MBRT due to early death (N = 5), lack of available clinical trials (N = 9), or inappropriate results (N = 2). Only six (6%) of the 27 (26%) patients for whom a MBRT had been proposed finally initiated MBRT (everolimus (N = 3), erlotinib (N = 1), ruxolitinib (N = 1), and sorafenib (N = 1)), but discontinued treatment for toxicity (N = 4) or clinical progression (N = 2). High-throughput sequencing in patients with brain tumors may be routinely performed, especially when macroscopic surgery samples are available; nevertheless delays should be reduced. Criteria for clinical trial enrollment should be reconsidered in patients with brain tumors, and a panel of genes specifically dedicated to neurologic tumors should be developed to help decision-making in clinical practice.
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http://dx.doi.org/10.1007/s12032-021-01536-4DOI Listing
November 2021

How to diagnose and manage neurological toxicities of immune checkpoint inhibitors: an update.

J Neurol 2022 Mar 27;269(3):1701-1714. Epub 2021 Oct 27.

French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Lyon, France.

As the use of cancer immunotherapy with immune checkpoint inhibitors (ICIs) is expanding rapidly for the treatment of many tumor types, it is crucial that both neurologists and oncologists become familiar with the diagnosis and treatment of neurological immune-related adverse events (n-irAEs). These are rare complications, developing in their severe forms in only 1-3% of the patients, but are highly relevant due to their mortality and morbidity burden. The diagnosis of n-irAEs is-however-challenging, as many alternative diagnoses need to be considered in the complex scenario of a patient with advanced cancer developing neurological problems. A tailored diagnostic approach is advisable according to the presentation, clinical history, and known specificities of n-irAEs. Several patterns characterized by distinct clinical, immunological, and prognostic characteristics are beginning to emerge. For example, myasthenia gravis is more likely to develop after anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) treatment, while meningitis appears more frequently after anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) therapy. Also, peripheral neuropathy and Guillain-Barré syndrome seem to be more common in patients with an underlying melanoma. Central nervous system disorders (CNS) are less frequent and are more often associated with lung cancer, and some of them (especially those with limbic encephalitis and positive onconeural antibodies) have a poor prognosis. Herein, we provide an update of the recent advances in the diagnosis and treatment of neurological toxicities related to ICI use, focusing on the exclusion of alternative diagnoses, diagnostic specificities, and treatment of n-irAEs.
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http://dx.doi.org/10.1007/s00415-021-10870-6DOI Listing
March 2022

Role of LGI1 protein in synaptic transmission: From physiology to pathology.

Neurobiol Dis 2021 12 22;160:105537. Epub 2021 Oct 22.

Synaptopathies and Auto-antibodies (SynatAc) Team, Institut NeuroMyoGène, INSERM U1217/CNRS UMR 5310, Universités de Lyon, Université Claude Bernard Lyon 1, Lyon, France; Université Claude Bernard Lyon 1, Universités de Lyon, Lyon, France. Electronic address:

Leucine-Rich Glioma Inactivated protein 1 (LGI1) is a secreted neuronal protein highly expressed in the central nervous system and high amount are found in the hippocampus. An alteration of its function has been described in few families of patients with autosomal dominant temporal lobe epilepsy (ADLTE) or with autoimmune limbic encephalitis (LE), both characterized by epileptic seizures. Studies have shown that LGI1 plays an essential role during development, but also in neuronal excitability through an action on voltage-gated potassium Kv1.1 channels, and in synaptic transmission by regulating the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R). Over the last decade, a growing number of studies investigating LGI1 functions have been published. They aimed to improve the understanding of LGI1 function in the regulation of neuronal networks using different animal and cellular models. LGI1 appears to be a major actor of synaptic regulation by modulating trans-synaptically pre- and post-synaptic proteins. In this review, we will focus on LGI1 binding partners, "A Disintegrin And Metalloprotease (ADAM) 22 and 23", the complex they form at the synapse, and will discuss the effects of LGI1 on neuronal excitability and synaptic transmission in physiological and pathological conditions. Finally, we will highlight new insights regarding N-terminal Leucine-Rich Repeat (LRR) domain and C-terminal Epitempin repeat (EPTP) domain and their potentially distinct role in LGI1 function.
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http://dx.doi.org/10.1016/j.nbd.2021.105537DOI Listing
December 2021

Immune-Related Cerebellar Ataxia: A Rare Adverse Effect of Checkpoint Inhibitor Therapy.

J Neuroimmune Pharmacol 2021 Oct 22. Epub 2021 Oct 22.

Service d'Oncologie médicale, Institut de Cancérologie de Strasbourg, ICANS, Strasbourg, France.

Immune checkpoint inhibitors (ICIs) have led to a revolution in cancer management, mainly due to lasting long-term durable responses in a subset of patients with metastatic solid tumours (Gettinger et al. in JCO 36(17):1675-1684, 2018). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological immune-related adverse events (irAEs) has increased (2). Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs (Johnson et al. in J Immuno Cancer 7(1):134, 2019; Wang et al. in JAMA Oncol 4(12):1721, 2018). Small-cell lung cancer (SCLC) is common cause of neurologic paraneoplastic syndrome (Sebastian et al. in J Thorac Oncol 14(11):1878-1880, 2019). Nevertheless, the distinction between neurologic iRAEs and paraneoplastic neurological syndromes (PNSs) in patients with SCLC treated by ICIs remains challenging (Williams et al. JAMA Neurol 73(8):928, 2016). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological autoimmune adverse events has increased. Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs and have yet to be fully understood. We report a case of an immune induced cerebellar ataxia in a 47 year-old small-cell neuroendocrine carcinoma patient undergoing checkpoint blockade by atezolizumab, a programmed cell death-1 ligand (PDL-1) inhibitor. After 4 cycles of immunotherapy, the patient presented with kinetic and static cerebellar syndrome leading to the diagnosis of TRIM9-Abs ICI-related cerebellar irAE. Therapeutic management was discussed in multidisciplinary meetings in the lack of therapeutic guidelines. There was no clinical improvement. Because of high morbidity and no treatment evidence, neurologic symptoms developing under ICI require early diagnosis and may indicate the need for definitive treatment discontinuation.
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http://dx.doi.org/10.1007/s11481-021-10026-3DOI Listing
October 2021

Immunopathogenesis and proposed clinical score for identifying Kelch-like protein-11 encephalitis.

Brain Commun 2021 26;3(3):fcab185. Epub 2021 Aug 26.

French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, 69677 Bron, France.

In this study, we report the clinical features of Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome, design and validate a clinical score to facilitate the identification of patients that should be tested for Kelch-like protein 11 antibodies, and examine in detail the nature of the immune response in both the brain and the tumour samples for a better characterization of the immunopathogenesis of this condition. The presence of Kelch-like protein 11 antibodies was retrospectively assessed in patients referred to the French Reference Center for paraneoplastic neurological syndrome and autoimmune encephalitis with (i) antibody-negative paraneoplastic neurological syndrome [limbic encephalitis ( = 105), cerebellar degeneration ( = 33)] and (ii) antibody-positive paraneoplastic neurological syndrome [Ma2-Ab encephalitis ( = 34), antibodies targeting N-methyl-D-aspartate receptor encephalitis with teratoma ( = 49)]. Additionally, since 1 January 2020, patients were prospectively screened for Kelch-like protein 11 antibodies as new usual clinical practice. Overall, Kelch-like protein 11 antibodies were detected in 11 patients [11/11, 100% were male; their median (range) age was 44 (35-79) years], 9 of them from the antibody-negative paraneoplastic neurological syndrome cohort, 1 from the antibody-positive (Ma2-Ab) cohort and 1 additional prospectively detected patient. All patients manifested a cerebellar syndrome, either isolated (4/11, 36%) or part of a multi-system neurological disorder (7/11, 64%). Additional core syndromes were limbic encephalitis (5/11, 45%) and myelitis (2/11, 18%). Severe weight loss (7/11, 64%) and hearing loss/tinnitus (5/11, 45%) were common. Rarer neurologic manifestations included hypersomnia and seizures (2/11, 18%). Two patients presented phenotypes resembling primary neurodegenerative disorders (progressive supranuclear palsy and flail arm syndrome, respectively). An associated cancer was found in 9/11 (82%) patients; it was most commonly (7/9, 78%) a spontaneously regressed ('burned-out') testicular germ cell tumour. A newly designed clinical score (MATCH score: male, ataxia, testicular cancer, hearing alterations) with a cut-off ≥4 successfully identified patients with Kelch-like protein 11 antibodies (sensitivity 78%, specificity 99%). Pathological findings (three testicular tumours, three lymph node metastases of testicular tumours, one brain biopsy) showed the presence of a T-cell inflammation with resulting anti-tumour immunity in the testis and one chronic, exhausted immune response-demonstrated by immune checkpoint expression-in the metastases and the brain. In conclusion, these findings suggest that Kelch-like protein 11 antibody paraneoplastic neurological syndrome is a homogeneous clinical syndrome and its detection can be facilitated using the MATCH score. The pathogenesis is probably T-cell mediated, but the stages of inflammation are different in the testis, metastases and the brain.
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http://dx.doi.org/10.1093/braincomms/fcab185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453430PMC
August 2021

Paraneoplastic neurological syndromes: a practical approach to diagnosis and management.

Pract Neurol 2022 Feb 11;22(1):19-31. Epub 2021 Sep 11.

Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK

Paraneoplastic neurological syndromes (PNS) are the immune-mediated effects of a remote cancer and are characterised by an autoantibody response against antigens expressed by the tumour. Classically, well-characterised 'onconeuronal' antibodies target intracellular antigens and hence cannot access their antigens across intact cell membranes. The pathogenic mediators are likely to be neuronal-specific T cells. There is a variable response to immunotherapies and the clinical syndrome helps to direct the search for a specific set of tumours. By contrast, many newly emerging autoantibodies with oncological associations target cell surface epitopes and can exert direct pathogenic effects on both the central and peripheral nervous systems. Patients with these cell-surface directed autoantibodies often clearly respond to immunotherapies. Overall, the clinical, serological and oncological features in an individual patient help to determine the clinical relevance of the syndrome and hence guide its management. We summarise current knowledge and a practical approach to the investigation, diagnosis, treatment and outcomes of patients with suspected PNS.
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http://dx.doi.org/10.1136/practneurol-2021-003073DOI Listing
February 2022

Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases.

Neurol Neuroimmunol Neuroinflamm 2021 09 28;8(5). Epub 2021 Jul 28.

From French Reference Center on Paraneoplastic Neurological Syndrome (L.-D.D., S.M.-C., A.-L.P., V.R., A.V., B.J., J.-P.C., J.-C.A., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; Institute NeuroMyoGène (L.-D.D., C.P.M., S.M.-C., A.-L.P., Y.T., V.R., A.V., B.J., K.F., J.-P.C., J.-C.A., J.H.), INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, France; University Jean Monnet (C.P.M., Y.T., J.-P.C., J.-C.A.), Saint-Étienne, France; Department of Biochemistry (Y.T.), University Hospital of Saint-Etienne, France; University Grenoble Alpes (S.B., Y.C.), CEA, INSERM, IRIG, BGE, France; Cambridge Protein Arrays Ltd. (O.S., M.J.T.), Babraham Research Campus, United Kingdom; and Department of Neurology (K.F., J.-P.C., J.-C.A.), University Hospital of Saint-Etienne, France.

Objective: To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases.

Methods: Two distinct approaches (immunoprecipitation/mass spectrometry-based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples.

Results: Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments.

Conclusions: AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder.

Classification Of Evidence: This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls.
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http://dx.doi.org/10.1212/NXI.0000000000001032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362341PMC
September 2021

Core cerebrospinal fluid biomarker profile in anti-LGI1 encephalitis.

J Neurol 2022 Jan 8;269(1):377-388. Epub 2021 Jun 8.

Service de Neurocognition Et Neuro-Ophtalmologie, Hôpital Neurologique Pierre Wertheimer, Bron Cedex, France.

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.
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http://dx.doi.org/10.1007/s00415-021-10642-2DOI Listing
January 2022

Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab061. Epub 2021 Apr 19.

Cancer Initiation and Tumoral Cell Identity Department, Cancer Research Centre of Lyon (CRCL) INSERM 1052, CNRS 5286, Lyon, France.

Background: Diffuse hemispheric gliomas, H3 G34-mutant (DHG H3G34-mutant) constitute a distinct type of aggressive brain tumors. Although initially described in children, they can also affect adults. The aims of this study were to describe the characteristics of DHG H3G34-mutant in adults and to compare them to those of established types of adult WHO grade IV gliomas.

Methods: The characteristics of 17 adult DHG H3G34-mutant, 32 H3.3 K27M-mutant diffuse midline gliomas (DMG), 100 IDH-wildtype, and 36 IDH-mutant glioblastomas were retrospectively analyzed.

Results: Median age at diagnosis in adult DHG H3G34-mutant was 25 years (range: 19-33). All tumors were hemispheric. For 9 patients (56%), absent or faint contrast enhancement initially suggested another diagnosis than a high-grade glioma, and diffusion-weighted imaging seemed retrospectively more helpful to suspect an aggressive tumor than MR-spectroscopy and perfusion MRI. All cases were IDH-wildtype. Most cases were immunonegative for ATRX (93%) and Olig2 (100%) and exhibited promoter methylation (82%). The clinical and radiological presentations of adult DHG H3G34-mutant were different from those of established types of adult grade IV gliomas. Median overall survival of adult DHG H3G34-mutant was 12.4 months compared to 19.6 months ( = .56), 11.7 months ( = .45), and 50.5 months ( = .006) in H3.3 K27M-mutant DMG, IDH-wildtype, and IDH-mutant glioblastomas, respectively.

Conclusions: Adult DHG H3G34-mutant are associated with distinct characteristics compared to those of established types of adult WHO grade IV gliomas. This study supports considering these tumors as a new type of WHO grade IV glioma in future classifications.
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http://dx.doi.org/10.1093/noajnl/vdab061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156974PMC
April 2021

Intracranial non-myxoid angiomatoid fibrous histiocytoma with transcript fusion treated with doxorubicin: A case report.

Mol Clin Oncol 2021 Jul 9;15(1):131. Epub 2021 May 9.

Department of Neuro-Oncology, East Group Hospital, Hospices Civils de Lyon, 69677 Lyon, France.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that has only been reported in the central nervous system in case reports. After surgery, patients exhibit tumor recurrence. Pathological diagnosis of AHF remains difficult, especially in sites other than skin. AFH can harbor characteristic translocations implying that the Ewing sarcoma breakpoint region 1 gene () fuses with the transcription factor cyclic AMP response element binding () family genes. Doxorubicin is a chemotherapy that has previously been used successfully in two metastatic soft tissue AFH cases but never in intracranial AFH. The present report describes a case of an adult with a progressive classical intracranial non-myxoid AFH with transcript fusion 4 years after surgery. The patient was treated with doxorubicin as a single agent chemotherapy. This treatment resulted in a prolonged stable disease 15 months after treatment discontinuation. This is the first reported case of a treatment with doxorubicin in an adult with progressive intracranial AFH with transcript fusion which was sustained after treatment discontinuation.
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http://dx.doi.org/10.3892/mco.2021.2293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138849PMC
July 2021

Cerebrospinal Fluid IL-17A Could Predict Acute Disease Severity in Non-NMDA-Receptor Autoimmune Encephalitis.

Front Immunol 2021 13;12:673021. Epub 2021 May 13.

URRIS, Unité de Recherche Clinique Cote d'Azur-UR2CA, CRCSEP, Hôpital Pasteur 2, Centre Hospitalier Universitaire de Nice, Nice, France.

Introduction: Most of our knowledge into autoimmune encephalitis (AE) comes from N-Methyl-D-Aspartate Receptor (NMDAR) encephalitis. The concentrations of cytokines in cerebrospinal fluid (CSF) including IL-17A have been found to be increased and associated with poor outcome. However, data on the cytokine concentration in CSF and its correlation with outcome is lacking for other types of AE.

Objective: To report the concentrations of CSF sIL-2R, IL-6, IL-8, IL-10 and IL-17A and to correlate it with acute disease severity and the 1-year outcome in non-NMDAR AE.

Methods: We measured the CSF concentration of each cytokine in 20 AE patients, and compared IL-6 and IL-17A concentrations with 13 patients with CNS demyelinating diseases and 20 non-inflammatory controls. Patients were > 18yr and had at least 1-year clinical follow-up. Intracellular and NMDAR antibody (Ab) -mediated encephalitis were excluded. A mRS ≤ 2 was retained as a 1-year good outcome.

Results: The IL-17A concentration in CSF was higher in AE patients than in both control groups (<0.01). No difference was observed in CSF concentration of IL-6 between groups. At disease onset, a high CSF IL-17A concentration correlated with a high modified Rankin Scale (<0.05), a high Clinical Assessment Scale for Autoimmune Encephalitis score (<0.001) and ICU admission (<0.01). There was no correlation between the concentration of all CSF cytokines and the 1-year clinical outcome.

Conclusion: Our results show that CSF IL-17A could be interesting to assess initial severity in non-NMDAR AE. Thus, CSF IL-17A could be an interesting therapeutic target and be useful to assess early selective immunosuppressive therapy.
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http://dx.doi.org/10.3389/fimmu.2021.673021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158812PMC
October 2021

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.

Neurol Neuroimmunol Neuroinflamm 2021 07 18;8(4). Epub 2021 May 18.

From the Neuroimmunology Program (F.G., J.D.), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centre de Référence National pour les Syndromes Neurologiques Paranéoplasique (A.V., S.M.-C., J.-C.G.A., V.D., B.J., L.T., J.H.), Hôpital Neurologique, Hospices Civils de Lyon; SynatAc Team (A.V., S.M.-C., V.D., B.J., L.T., J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon; Université Claude Bernard Lyon 1 (A.V., S.M.-C., V.D., B.J., L.T., J.H.), Université de Lyon; Service de Neurologie (J.-C.G.A.), CHU de Saint-Etienne, France; Department of Neurology (D.D., A.M.), Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; Neurology Unit (B.G.), Trento Hospital, Azienda Provinciale per I Servizi Sanitari (APSS) di Trento, Italy; Oxford Autoimmune Neurology Group (S.R.I.), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, United Kingdom; Neuroimmunology Section (F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck; German Center for Neurodegenerative Diseases (DZNE) Berlin (H.P.), and Department of Neurology and Experimental Neurology (H.P.), Charité-Universitätsmedizin Berlin, Germany; Centre de Compétence des Syndromes Neurologiques Paranéoplasiques et Encéphalites Autoimmunes (D.P.), Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Department of Neurology 2 Mazarin (D.P.), and INSERM U 1127 (D.P.), CNRS UMR 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière Groupe, Hospitalier Pitié-Salpêtriêre et Université Pierre et Marie Curie-Paris 6, AP-HP, France; Department of Neurology (M.J.T.), Erasmus MC University Medical Center, Rotterdam, the Netherlands; Department of Clinical Medicine (C.A.V.), University of Bergen; Department of Neurology (C.A.V.), Haukeland University Hospital; Neuro-SysMed-Centre of Excellence for Experimental Therapy in Neurology (C.A.V.), Departments of Neurology and Clinical Medicine, Bergen, Norway; and Neurology Department (J.J.V.), Leiden University Medical Center, the Netherlands.

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.
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http://dx.doi.org/10.1212/NXI.0000000000001014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237398PMC
July 2021

Delayed Benefit From Aggressive Immunotherapy in Waxing and Waning Anti-IgLON5 Disease.

Neurol Neuroimmunol Neuroinflamm 2021 07 13;8(4). Epub 2021 May 13.

From the Department of Neurology (P.S., A.H., C.M., C.D., C.L., A.M.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Neurology (D.Z., J.S., F.P.), Versailles Hospital, Le Chesnay, France; Department of Neurology (D.Z.), CHU Yalgado Ouédraogo, Ouagadougou, Burkina Faso; Department of Neurophysiology (B.G.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Sorbonne University (C.L., I.A., A.M.), Paris, France; Sleep Disorder Unit (I.A., A.G.), Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Service de Neurologie 2-Mazarin (D.P.), Groupe Hospitalier Pitié-Salpêtrière et Université Pierre et Marie Curie-Paris 6, AP-HP, Centre de Compétence des Syndromes Neurologiques Paranéoplasiques et Encéphalites Autoimmunes, Paris, France; French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (J.H.), Hospices Civils de Lyon, Institut NeuroMyoGene, INSERM U1217/CNRS UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, France.

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http://dx.doi.org/10.1212/NXI.0000000000001009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192057PMC
July 2021

VEGF counteracts amyloid-β-induced synaptic dysfunction.

Cell Rep 2021 05;35(6):109121

Institut NeuroMyoGène (INMG), Synaptopathies and Autoantibodies, Institut National de la Santé et de la Recherche Médicale (INSERM), U1217, Centre National de la Recherche Scientifique (CNRS) UMR5310, 69000 Lyon, France; Université Claude Bernard Lyon 1, 69000 Lyon, France. Electronic address:

The vascular endothelial growth factor (VEGF) pathway regulates key processes in synapse function, which are disrupted in early stages of Alzheimer's disease (AD) by toxic-soluble amyloid-beta oligomers (Aβo). Here, we show that VEGF accumulates in and around Aβ plaques in postmortem brains of patients with AD and in APP/PS1 mice, an AD mouse model. We uncover specific binding domains involved in direct interaction between Aβo and VEGF and reveal that this interaction jeopardizes VEGFR2 activation in neurons. Notably, we demonstrate that VEGF gain of function rescues basal synaptic transmission, long-term potentiation (LTP), and dendritic spine alterations, and blocks long-term depression (LTD) facilitation triggered by Aβo. We further decipher underlying mechanisms and find that VEGF inhibits the caspase-3-calcineurin pathway responsible for postsynaptic glutamate receptor loss due to Aβo. These findings provide evidence for alterations of the VEGF pathway in AD models and suggest that restoring VEGF action on neurons may rescue synaptic dysfunction in AD.
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http://dx.doi.org/10.1016/j.celrep.2021.109121DOI Listing
May 2021
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