Publications by authors named "Jérôme Honnorat"

256 Publications

Corrigendum: CSF HIV RNA Escape in Opsoclonus-Myoclonus-Ataxia Syndrome: Case Report and Review of the Literature.

Front Neurol 2021 17;12:665996. Epub 2021 Mar 17.

Unité des Ataxies Cérébelleuses, Service de Neurologie, Centre Hospitalier Universitaire (CHU)-Charleroi, Charleroi, Belgium.

[This corrects the article DOI: 10.3389/fneur.2020.585527.].
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http://dx.doi.org/10.3389/fneur.2021.665996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010907PMC
March 2021

Unclear association between COVID-19 and Guillain-Barré syndrome.

Brain 2021 Mar 23. Epub 2021 Mar 23.

Clinical Neurology Unit, Azienda Sanitaria Universitaria Friuli Centrale, Presidio Ospedaliero Santa Maria della Misericordia, Udine, Italy.

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http://dx.doi.org/10.1093/brain/awab068DOI Listing
March 2021

LTDpathies: a Novel Clinical Concept.

Cerebellum 2021 Mar 22. Epub 2021 Mar 22.

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

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http://dx.doi.org/10.1007/s12311-021-01259-2DOI Listing
March 2021

Neurologic Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review.

Neurology 2021 Mar 2. Epub 2021 Mar 2.

Clinical Neurology Unit, Santa Maria della Misericordia University Hospital, Udine, Italy

Objective: To define the clinical characteristics, management, and outcome of neurological immune-related adverse events (n-irAEs) of immune checkpoint inhibitors (ICIs).

Methods: Systematic review of the literature following the PRISMA guidelines.

Results: A total of 694 articles were identified. Two hundred fifty-six articles, with 428 individual patients, met the inclusion criteria. Reports regarding neuromuscular disorders (319/428, 75%) were more frequent than those on central nervous system (CNS) disorders (109/428, 25%). The most common n-irAEs reports were: myositis (136/428, 32%), Guillain-Barré syndrome and other peripheral neuropathies (94/428, 22%), myasthenic syndromes (58/428, 14%), encephalitis (56/428, 13%), cranial neuropathies (31/428, 7%), meningitis (13/428, 3%), CNS demyelinating diseases (8/428, 2%), and myelitis (7/428, 2%). Other CNS disorders were detected in 25/428 (6%) patients. Compared to the whole sample, myasthenic syndromes were significantly more Ab-positive (33/56, 59%; p<0.001). Anti-PD-1/PD-L1 were more frequent in myasthenic syndromes (50/58, 86%; p=0.005) and less common in meningitis (2/13, 15%; p<0.001) and cranial neuropathies (13/31, 42%; p=0.005).Anti-CTLA-4 ICIs were more frequent in meningitis (8/13, 62%; p<0.001) and less common in encephalitis (2/56, 4%; p=0.009) and myositis (12/136, 9%; p=0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; p=0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; p=0.003) and less common in encephalitis (19/56, 34%; p=0.001). The highest mortality rate was reached in myasthenic syndromes (28%).

Conclusion: Considering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.
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http://dx.doi.org/10.1212/WNL.0000000000011795DOI Listing
March 2021

Recurrent seizures of autoimmune origin: emerging phenotypes.

J Neurol 2021 Feb 27. Epub 2021 Feb 27.

Department of Neurology, University Hospital of Nancy, Nancy, France.

Objective: Recurrent seizures of autoimmune origin (AEp) are one of the most frequent causes of recurrent seizures or suspected epilepsy of unknown cause. The aim of this study was to identify specific phenotypes corresponding to AEp.

Methods: We retrospectively reviewed features of patients with recurrent seizures of unknown cause and investigated for suspected AEp (January 2015-May 2018). Patients were separated in: (1) AEpAb+: AEp with positive autoantibodies; (2) AEpAb-: suspected AEp (inflammatory central nervous system (CNS) profile) without autoantibodies; (3) NAEp: epilepsy without CNS inflammation.

Results: Eighty-nine epileptic patients underwent a CSF antibody detection. From the remaining 57 epileptic patients (32 excluded for a differential diagnosis), 61.4% were considered as AEp. 21% were AEpAb+ (4 NMDAR, 2 GABAbR, 3 GAD-Ab, 2 LGi1, 1 CASPR2), 40.4% AEpAb-, and 38.6% NAE. AE (AEpAb+ and AEpAb-) was significantly associated with antibody prevalence in epilepsy (APE) score ≥ 4 (80%), encephalitic phase (71.4%), psychiatric involvement (64.7%), cognitive impairment (50%), and status epilepticus (41.2%). Within the group of 29 patients without encephalitic phase and with chronic epilepsy (NEPp), 34.5% were defined as AEp. 10.4% were AEpAb+ (2 GAD, 1 CASPR2) and 24.1% were AEpAb-. NEP AEp was associated with non-cerebral autoimmune disorders, short epileptic disease duration, and cognitive impairment.

Conclusions: Autoimmune cause (AEp) should be assessed in patient suffering from recurrent seizures of unknown cause. Acute encephalitis is clearly the main AEp phenotype. AEp was also defined in more than one-third of chronic epilepsy patients (NEP) of unknown cause. Then, AEp may be combined with other autoimmune comorbidities, a shorter evolution of recurrent seizures, and cognitive impairment.
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http://dx.doi.org/10.1007/s00415-021-10457-1DOI Listing
February 2021

Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study.

J Neurol 2021 Feb 5. Epub 2021 Feb 5.

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

The common co-occurrence of autoimmune systemic diseases in patients with neurological disorders and antibodies against glutamic acid decarboxylase 65 (GAD65) suggests a shared genetic predisposition to these disorders. However, the nature and frequency of familial aggregation of autoimmune diseases, which might also support this hypothesis, have been poorly investigated. Herein, an exploratory, interview-based study was conducted with the aim of describing the autoimmune diseases displayed by the relatives of GAD65 neurological patients, their frequency, kinship, and potential patterns of inheritance. Patients were enrolled only if they had GAD65 antibodies in the cerebrospinal fluid and typical clinical phenotypes associated with such antibodies (stiff-person syndrome, cerebellar ataxia, limbic encephalitis, or temporal lobe epilepsy). A total of 65 patients were included in the study, and 44/65 (67.7%) reported family history of autoimmunity, including first-degree relatives in 36/65 (55.4%); the sibling recurrence risk (λ) was 5.5, reinforcing the hypothesis of an underlying strong genetic predisposition. Most pedigrees with familial autoimmunity (38/44, 86.4%) showed multiple autoimmune diseases, all but 2 of them with diabetes mellitus or autoimmune thyroid disease, therefore resembling autoimmune polyendocrine syndromes. Inheritance patterns were diverse, possibly autosomal dominant in 17/44 (38.6%) pedigrees or autosomal recessive in 5/44 (11.4%), and un-defined or complex in 24/44 (54.5%). However, a total of 21/65 (32.3%) patients had no identified family history of autoimmunity. In conclusion, these results suggest a variable and heterogeneous genetic predisposition to GAD65 neurological disorders, possibly involving multiple loci and modes of inheritance with different contribution in each family.
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http://dx.doi.org/10.1007/s00415-021-10424-wDOI Listing
February 2021

Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis.

Biol Psychiatry 2020 Nov 24. Epub 2020 Nov 24.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, King's College London, London, United Kingdom; South London and Maudsley NHS Foundation Trust, University College London, London, United Kingdom.

Background: When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear.

Methods: Sera from 387 patients with FEP (duration of psychosis <2 years, minimally or never treated with antipsychotics) undergoing initial treatment with amisulpride as part of the OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) trial (ClinicalTrials.gov number NCT01248195) were tested for NMDAR IgG antibodies using a live cell-based assay. Symptom severity was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale at baseline and again after 4 weeks of treatment with amisulpride.

Results: At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. The seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 vs. 4.0 months; p = .031). Eleven seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: after treatment, there was no between-groups difference in improvement in Positive and Negative Syndrome Scale scores or in the frequency of adverse medication effects.

Conclusions: These data suggest that in FEP, NMDAR antibody seropositivity alone is not an indication for using immunotherapy instead of antipsychotic medications. Further studies are required to establish what proportion of patients with FEP who are NMDAR antibody seropositive have coexisting cerebrospinal fluid inflammatory changes or other paraclinical evidence suggestive of a likely benefit from immunotherapy.
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http://dx.doi.org/10.1016/j.biopsych.2020.11.014DOI Listing
November 2020

CSF HIV RNA Escape in Opsoclonus-Myoclonus-Ataxia Syndrome: Case Report and Review of the Literature.

Front Neurol 2020 23;11:585527. Epub 2020 Nov 23.

Unité des Ataxies Cérébelleuses, Service de Neurologie, Centre Hospitalier Universitaire (CHU)-Charleroi, Charleroi, Belgium.

Human immunodeficiency viruses (HIV) infection is associated with a broad range of neurological manifestations, including opsoclonus-myoclonus ataxia syndrome (OMAS) occurring in primary infection, immune reconstitution syndrome or in case of opportunistic co-infection. We report the exceptional case of a 43-year-old female under HIV treatment for 10 years who presented initially with suspected epileptic seizure. Although the clinical picture slightly improved under anti-epileptic treatment, it was rapidly attributed to OMAS. The patient exhibited marked opsoclonus, mild dysarthria, upper limbs intermittent myoclonus, ataxia in 4 limbs, truncal ataxia, and a severe gait ataxia (SARA score: 34). The diagnostic work-up showed radiological and biological signs of central nervous system (CNS) inflammation and cerebral venous sinus thromboses. The HIV viral load was higher in cerebrospinal fluid (CSF) than in the blood (4,560 copies/ml vs. 76 copies/ml). She was treated for 5 days with pulsed corticotherapy. Dolutegravir and anticoagulation administration were initiated. Follow-ups at 2 and 4 months showed a dramatic improvement of clinical neurologic status (SARA score at 4 months: 1), reduction of CNS inflammation and revealed undetectable CSF and serum viral loads. This case underlines the importance of the evaluation of the CSF viral load in HIV patients developing OMAS and suggests CSF HIV RNA escape as a novel cause for OMAS.
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http://dx.doi.org/10.3389/fneur.2020.585527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719769PMC
November 2020

Cranial Nerve Disorders Associated With Immune Checkpoint Inhibitors.

Neurology 2021 02 14;96(6):e866-e875. Epub 2020 Dec 14.

From the French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (A.V., S.M.-C., B.J., G.P., V.R., V.D., D.P., F.D., J.H.) and Neuro-Cognition and Neuro-Ophthalmology Department (V.D., C.T.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H.), INSERM U1217/CNRS UMR5310; University Claude Bernard Lyon 1 (A.V., S.M.-C., B.J., G.P., V.R., V.D., F.D., J.H., C.T.), Université de Lyon, Lyon, France; Dermatology Department (F.S.), Centre Hospitalier de Valence; Neurology Department (M.E.), Centre Hospitalier de Libourne; Team ImpAct (C.T.), Lyon Neuroscience Research Center, INSERM U1028 CNRS UMR5292; and Neurology Department 2-Mazarin (D.P.), Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere Groupe, Hospitalier Pitie-Salpetriere et Universite Pierre et Marie Curie-Paris 6, AP-HP, France.

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.
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http://dx.doi.org/10.1212/WNL.0000000000011340DOI Listing
February 2021

Intellectual disability: dendritic anomalies and emerging genetic perspectives.

Acta Neuropathol 2021 02 23;141(2):139-158. Epub 2020 Nov 23.

Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH, 43210, USA.

Intellectual disability (ID) corresponds to several neurodevelopmental disorders of heterogeneous origin in which cognitive deficits are commonly associated with abnormalities of dendrites and dendritic spines. These histological changes in the brain serve as a proxy for underlying deficits in neuronal network connectivity, mostly a result of genetic factors. Historically, chromosomal abnormalities have been reported by conventional karyotyping, targeted fluorescence in situ hybridization (FISH), and chromosomal microarray analysis. More recently, cytogenomic mapping, whole-exome sequencing, and bioinformatic mining have led to the identification of novel candidate genes, including genes involved in neuritogenesis, dendrite maintenance, and synaptic plasticity. Greater understanding of the roles of these putative ID genes and their functional interactions might boost investigations into determining the plausible link between cellular and behavioral alterations as well as the mechanisms contributing to the cognitive impairment observed in ID. Genetic data combined with histological abnormalities, clinical presentation, and transgenic animal models provide support for the primacy of dysregulation in dendrite structure and function as the basis for the cognitive deficits observed in ID. In this review, we highlight the importance of dendrite pathophysiology in the etiologies of four prototypical ID syndromes, namely Down Syndrome (DS), Rett Syndrome (RTT), Digeorge Syndrome (DGS) and Fragile X Syndrome (FXS). Clinical characteristics of ID have also been reported in individuals with deletions in the long arm of chromosome 10 (the q26.2/q26.3), a region containing the gene for the collapsin response mediator protein 3 (CRMP3), also known as dihydropyrimidinase-related protein-4 (DRP-4, DPYSL4), which is involved in dendritogenesis. Following a discussion of clinical and genetic findings in these syndromes and their preclinical animal models, we lionize CRMP3/DPYSL4 as a novel candidate gene for ID that may be ripe for therapeutic intervention.
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http://dx.doi.org/10.1007/s00401-020-02244-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855540PMC
February 2021

Alterations of cerebral microcirculation in peritumoral edema: feasibility of in vivo sidestream dark-field imaging in intracranial meningiomas.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa108. Epub 2020 Aug 27.

Creatis Lab, CNRS UMR 5220, INSERM U1206, Lyon 1 University, INSA Lyon, Lyon, France.

Background: Intracranial meningiomas display a variable amount of peritumoral brain edema (PTBE), which can significantly impact perioperative morbidity. The role of microcirculatory disturbances in the pathogenesis of PTBE is still debated. The aim of this study was to microscopically demonstrate and intraoperatively quantify, for the first time, the alterations to microcirculation in PTBE using sidestream dark-field (SDF) imaging.

Methods: Adult patients with WHO grade I meningiomas were recruited over a 9-month period and divided into 2 groups depending on the absence (NE group) or the presence (E group) of PTBE. In vivo intraoperative microcirculation imaging was performed in the peritumoral area before and after microsurgical resection.

Results: Six patients were included in the NE group and 6 in the E group. At the baseline in the NE group, there was a minor decrease in microcirculatory parameters compared to normal reference values, which was probably due to the mass effect. In contrast, microcirculatory parameters in the E group were significantly altered, affecting both vessel density and blood flow values, with a drop of approximately 50% of normal values. Surgical resection resulted in a quasi-normalization of microcirculation parameters in the NE group, whereas in the E group, even if all parameters statistically significantly improved, post-resection values remained considerably inferior to those of the normal reference pattern.

Conclusion: Our study confirmed significant alterations of microcirculatory parameters in PTBE in meningiomas. Further in vivo SDF imaging studies may explore the possible correlation between the severity of these microcirculatory alterations and the postoperative neurological outcome.
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http://dx.doi.org/10.1093/noajnl/vdaa108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542984PMC
August 2020

Psychiatric symptoms in anti glutamic acid decarboxylase associated limbic encephalitis in adults: a systematic review.

Neurosci Biobehav Rev 2020 12 3;119:128-137. Epub 2020 Oct 3.

APHP- Behavioral Neuropsychiatric Unit, University Hospital La Pitié-Salpêtrière, Paris, France; APHP, Neurology Department 2-Mazarin, University Hospital La Pitié-Salpêtrière, Paris, France; APHP- Institute of Memory, Neurology Department, University Hospital La Pitié-Salpêtrière, Paris, France.

Autoimmune Limbic Encephalitis (LE) is a relatively new category of immune-mediated diseases with a wide range of neuropsychiatric symptoms. LE associated with Glutamic Acid Decarboxylase (GAD) antibodies is difficult to diagnose due to its possible atypical presentation with neuropsychiatric and behavioral features. We performed a systematic review of literature and retrieved 21 cases of anti GAD-associated LE with neuropsychiatric signs. Median age at onset was 27 years with a female predominance (81.0 %) and median diagnostic delay of 6 months. Clinical presentation included typical LE symptoms such as anterograde amnesia (95.2 %) and temporal lobe or tonico-clonic seizures (95.2 %). Psychiatric symptoms were described in 61.9 % of patients, presenting as anxiety, depressive symptoms, apathy and behavioral changes. Extra-limbic symptoms were present in 14.3 % of patients. No neoplasia associated was found. Some patients had poor epileptic, cognitive and psychiatric outcomes requiring prolonged immunosuppressive treatment. The description of the neuropsychiatric spectrum of anti-GAD LE and its specificities aims to improve our understanding of this entity, and may lead to earlier diagnosis as well as better outcome.
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http://dx.doi.org/10.1016/j.neubiorev.2020.08.015DOI Listing
December 2020

Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis.

Neurology 2020 12 14;95(22):e3012-e3025. Epub 2020 Sep 14.

From the Institut d'Investigacions Biomèdiques August Pi i Sunyer (M. Spatola, M.P.P., E.M., M.R.R., F.G., J.D.), Barcelona, Spain; Ragon Institute of MGH, MIT and Harvard Medical School (M. Spatola), Cambridge, MA; Interdisciplinary Institute for Neuroscience (M.P.P.), University of Bordeaux, France; Neurology Division (M. Simabukuro), University of São Paulo, School of Medicine, Brazil; Centre de Référence des Syndromes Neurologiques Paranéoplasiques et des Encéphalites Autoimmunes (S.M.-C., A.L.P., J.H.), Hospices Civils de Lyon, Université de Lyon, Université Claude Bernard Lyon1, INMG, Inserm U1217/CNRS UMR 5310, France; Institute of Clinical Chemistry and Department of Neurology (K.-P.W.), Department of Neuropediatrics (J.S.), and Department of Neuroradiology (P.S.), University Hospital Schleswig Holstein, Lübeck, Germany; Faculdade Israelita de Ciências da Saúde Albert Einstein and General Neurology Division (L.A.D.), Federal University of São Paulo, Brazil; Institute of Neurology, Fondazione Policlinico Universitario "A. Gemelli" IRCCS (R.I.), Rome, Italy; Department of Neurology (C.K.), University Hospital Bonn; Epilepsy Center Bethel (C.G.B.), Krankenhaus Mara, Bielefeld, Germany; Division of Neuropathology and Neurochemistry (R.H.), Department of Neurology, Medical University of Vienna, Austria; Neuroimmunology (F.L.), Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig Holstein, Kiel, Germany; Department of Neurology (M.J.T., P.S.S.), Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; University Hospital Clínic (F.G.), University of Barcelona; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain.

Objective: To clinically characterize patients with anti-metabotropic glutamate receptor (mGluR) 1 encephalitis, to identify prognostic factors, and to study the immunoglobulin G (IgG) subclasses and effects of antibodies on neuronal mGluR1 clusters.

Methods: Clinical information on new and previously reported patients was reviewed. Antibodies to mGluR1 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays, and their effects on mGluR1 clusters were studied on rat hippocampal neurons.

Results: Eleven new patients were identified (10 adults, 1 child);4 were female. In these and 19 previously reported cases (n = 30, median age 55 years), the main clinical manifestation was a subacute cerebellar syndrome that in 25 (86%) patients was associated with behavioral/cognitive changes or other neurologic symptoms. A tumor was found in 3 of 26 (11%). Brain MRI was abnormal in 7 of 19 (37%) at onset and showed cerebellar atrophy in 10 of 12 (83%) at follow-up. Twenty-five of 30 (83%) patients received immunotherapy. Follow-up was available for 25: 13 (52%) had clinical stabilization; 10 (40%) showed significant improvement; and 2 died. At the peak of the disease, patients with bad outcome at 2 years (modified Rankin Scale score > 2, n = 7) were more likely to have higher degree of initial disability, as reflected by a worse Scale for Assessment and Rating of Ataxia score, and more frequent need of assistance to walk. Antibodies to mGluR1 were mainly IgG1 and caused a significant decrease of mGluR1 clusters in cultured neurons.

Conclusions: Anti-mGluR1 encephalitis manifests as a severe cerebellar syndrome, often resulting in long-term disability and cerebellar atrophy. The antibodies are pathogenic and cause significant decrease of mGluR1 clusters in cultured neurons.
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http://dx.doi.org/10.1212/WNL.0000000000010854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734921PMC
December 2020

Epidemiology of paraneoplastic neurologic syndromes and autoimmune encephalitides in France.

Neurol Neuroimmunol Neuroinflamm 2020 11 26;7(6). Epub 2020 Aug 26.

From the Centre de Référence National pour les Syndromes Neurologiques Paranéoplasique (J. Hébert, A.V., S.M.-C., B.J., G.P., V.R., V.D., J. Honnorat), Hospices Civils de Lyon, Lyon, France; SynatAc Team (J. Hébert, A.V., S.M.-C., B.J., G.P., V.R., V.D., J. Honnorat), NeuroMyoGene Institute, INSERM U1217-CNRS UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France; Université de Lyon (J. Hébert, B.R., M.R.), Lyon, France; Université Lyon 1, Villeurbanne, France; CNRS UMR, Laboratoire de Biométrie et Biologie Évolutive, Équipe Biostatistique-Santé, Villeurbanne, France; Service de Biostatistique-Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France; Institut Pierre Louis d'Épidémiologie et de Santé Publique (J. Hébert), Faculté de Médecine, Sorbonne Université, Paris, France; AP-HP (D.P., G.B.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS, Paris, France; Inserm U 975 (D.P., G.B.), CNRS, UMR, Paris, France; and Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes (D.P., G.B.), Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Objective: To determine the observed and expected incidence rates of paraneoplastic neurologic syndromes (PNSs) and autoimmune encephalitides (AEs) diagnosed in France between 2016 and 2018, we conducted a population-based epidemiologic study.

Methods: Observed incidence rates were stratified by sex, age groups, region of care, year of diagnosis, and disease subgroups. National expected incidence rates were calculated based on rates obtained in the area directly adjacent to the Reference Center using a mixed Poisson model and compared with observed incidence rates.

Results: Six hundred thirty-two patients with definite PNS or AE met the inclusion criteria. The observed incidence rate of definite PNS and AE in France was 3.2 per million person-years (CI: 2.9-3.4) compared with an expected incidence rate of 7.1 per million person-years (CI: 3.9-11.4). The national observed incidence rate for the antibody-positive AE subgroup increased from 1.4 per million person-years (CI: 1.2-1.7) in 2016 to 2.1 per million person-years (CI: 1.7-2.4) in 2018, thus surpassing the incidence rate of classical PNS (1.2 per million person-years [CI: 1.0-1.5]) of 2018.

Conclusions: There was a significant widespread year-to-year increase in the incidence of diagnoses registered with the Reference Center for all subgroups of PNS and AE studied. The national observed incidence rate is likely underestimated due to underdiagnosis and underreporting.
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http://dx.doi.org/10.1212/NXI.0000000000000883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455315PMC
November 2020

Ketamine/xylazine and barbiturates modulate microglial morphology and motility differently in a mouse model.

PLoS One 2020 6;15(8):e0236594. Epub 2020 Aug 6.

Equipe Synaptopathies et Autoanticorps (SynatAc), Institut NeuroMyoGène, INSERM U1217/UMR CNRS 5310, Lyon, France.

Microglia, the resident immune cells of the brain, are highly ramified and motile and their morphology is strongly linked to their function. Microglia constantly monitor the brain parenchyma and are crucial for maintaining brain homeostasis and fine-tuning neuronal networks. Besides affecting neurons, anesthetics may have wide-ranging effects mediated by non-neuronal cells and in particular microglia. We thus examined the effect of two commonly used anesthetic agents, ketamine/xylazine and barbiturates, on microglial motility and morphology. A combination of two-photon in vivo imaging and electroencephalography (EEG) recordings in unanesthetized and anesthetized mice as well as automated analysis of ex vivo sections were used to assess morphology and dynamics of microglia. We found that administration of ketamine/xylazine and pentobarbital anesthesia resulted in quite distinct EEG profiles. Both anesthetics reduced microglial motility, but only ketamine/xylazine administration led to reduction of microglial complexity in vivo. The change of cellular dynamics in vivo was associated with a region-dependent reduction of several features of microglial cells ex vivo, such as the complexity index and the ramification length, whereas thiopental altered the size of the cytoplasm. Our results show that anesthetics have considerable effects on neuronal activity and microglial morphodynamics and that barbiturates may be a preferred anesthetic agent for the study of microglial morphology. These findings will undoubtedly raise compelling questions about the functional relevance of anesthetics on microglial cells in neuronal physiology and anesthesia-induced neurotoxicity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236594PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410236PMC
October 2020

Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias.

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

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

In the last years, different kinds of limbic encephalitis associated with autoantibodies against ion channels and synaptic receptors have been described. Many studies have demonstrated that such autoantibodies induce channel or receptor dysfunction. The same mechanism is discussed in immune-mediated cerebellar ataxias (IMCAs), but the pathogenesis has been less investigated. The aim of the present review is to evaluate what kind of cerebellar ion channels, their related proteins, and the synaptic machinery proteins that are preferably impaired by autoantibodies so as to develop cerebellar ataxias (CAs). The cerebellum predictively coordinates motor and cognitive functions through a continuous update of an internal model. These controls are relayed by cerebellum-specific functions such as precise neuronal discharges with potassium channels, synaptic plasticity through calcium signaling pathways coupled with voltage-gated calcium channels (VGCC) and metabotropic glutamate receptors 1 (mGluR1), a synaptic organization with glutamate receptor delta (GluRδ), and output signal formation through chained GABAergic neurons. Consistently, the association of CAs with anti-potassium channel-related proteins, anti-VGCC, anti-mGluR1, and GluRδ, and anti-glutamate decarboxylase 65 antibodies is observed in IMCAs. Despite ample distributions of AMPA and GABA receptors, however, CAs are rare in conditions with autoantibodies against these receptors. Notably, when the autoantibodies impair synaptic transmission, the autoimmune targets are commonly classified into three categories: release machinery proteins, synaptic adhesion molecules, and receptors. This physiopathological categorization impacts on both our understanding of the pathophysiology and clinical prognosis.
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http://dx.doi.org/10.3390/ijms21144936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404345PMC
July 2020

Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features.

J Neurol Neurosurg Psychiatry 2020 10 10;91(10):1076-1084. Epub 2020 Jul 10.

French National Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hôpital Neurologique, Hospices Civils de Lyon, Bron, France

Objective: Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.

Methods: A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.

Results: Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/-; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/-; 11/56, 19.6%). LE/- and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%).

Interpretation: Symptoms' distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.
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http://dx.doi.org/10.1136/jnnp-2020-323226DOI Listing
October 2020

Conventional MRI radiomics in patients with suspected early- or pseudo-progression.

Neurooncol Adv 2019 May-Dec;1(1):vdz019. Epub 2019 Sep 1.

Université Claude Bernard Lyon 1, Villeurbanne, France.

Background: After radiochemotherapy, 30% of patients with early worsening MRI experience pseudoprogression (Psp) which is not distinguishable from early progression (EP). We aimed to assess the diagnostic value of radiomics in patients with suspected EP or Psp.

Methods: Radiomics features (RF) of 76 patients (53 EP and 23 Psp) retrospectively identified were extracted from conventional MRI based on four volumes-of-interest. Subjects were randomly assigned into training and validation groups. Classification model (EP versus Psp) consisted of a random forest algorithm after univariate filtering. Overall (OS) and progression-free survivals (PFS) were predicted using a semi-supervised principal component analysis, and forecasts were evaluated using C-index and integrated Brier scores (IBS).

Results: Using 11 RFs, radiomics classified patients with 75.0% and 76.0% accuracy, 81.6% and 94.1% sensitivity, 50.0% and 37.5% specificity, respectively, in training and validation phases. Addition of promoter status improved accuracy to 83% and 79.2%, and specificity to 63.6% and 75%. OS model included 14 RFs and stratified low- and high-risk patients both in the training (hazard ratio [HR], 3.63; = .002) and the validation (HR, 3.76; = .001) phases. Similarly, PFS model stratified patients during training (HR, 2.58; = .005) and validation (HR, 3.58; = .004) phases using 5 RF. OS and PFS forecasts had C-index of 0.65 and 0.69, and IBS of 0.122 and 0.147, respectively.

Conclusions: Conventional MRI radiomics has promising diagnostic value, especially when combined with promoter status, but with moderate specificity. In addition, our results suggest a potential for predicting OS and PFS.
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http://dx.doi.org/10.1093/noajnl/vdz019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212855PMC
September 2019

Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors.

Ther Adv Neurol Disord 2020 24;13:1756286420932797. Epub 2020 Jun 24.

Centre de Référence National pour les Syndromes Neurologiques Paranéoplasiques, Hôpital Neurologique, 59 Boulevard Pinel, Bron Cedex, 69677, France.

Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinical data has demonstrated that the pathogenesis of PNSs is immune-mediated. Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated. Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications. In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions. Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis. Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens. Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer. Other triggering factors seem to be involved in AEs. Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system). In addition, in some AEs (e.g. LGI1-antibody encephalitis) an association with specific host-related factors [e.g., human leukocyte antigen (HLA)] was clearly demonstrated. We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis.
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http://dx.doi.org/10.1177/1756286420932797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318829PMC
June 2020

Microglia modulate gliotransmission through the regulation of VAMP2 proteins in astrocytes.

Glia 2021 Jan 7;69(1):61-72. Epub 2020 Jul 7.

INSERM U1217, CNRS UMR5310, Institut NeuroMyoGène, Lyon, France.

Vesicular release is one of the release mechanisms of various signaling molecules. In neurons, the molecular machinery involved in vesicular release has been designed through evolution to trigger fast and synchronous release of neurotransmitters. Similar machinery with a slower kinetic and a slightly different molecular assembly allows astrocytes to release various transmitters such as adenosine triphosphate (ATP), glutamate, and D-serine. Astrocytes are important modulators of neurotransmission through gliotransmitter release. We recently demonstrated that microglia, another type of glia, release ATP to modulate synaptic transmission using astrocytes as intermediate. We now report that microglia regulate astrocytic gliotransmission through the regulation of SNARE proteins in astrocytes. Indeed, we found that gliotransmission triggered by P2Y1 agonist is impaired in slices from transgenic mice devoid of microglia. Using total internal reflection fluorescence imaging, we found that the vesicular release of gliotransmitter by astrocytes was different in cultures lacking microglia compared to vesicular release in astrocytes cocultured with microglia. Quantification of the kinetic of vesicular release indicates that the overall release appears to be faster in pure astrocyte cultures with more vesicles close to the membrane when compared to astrocytes cocultured with microglia. Finally, biochemical investigation of SNARE protein expression indicates an upregulation of VAMP2 in absence of microglia. Altogether, these results indicate that microglia seems to be involved in the regulation of an astrocytic phenotype compatible with proper gliotransmission. The mechanisms described in this study could be of importance for central nervous system diseases where microglia are activated.
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http://dx.doi.org/10.1002/glia.23884DOI Listing
January 2021

Transient Neurological Symptoms Preceding Cerebellar Ataxia with Glutamic Acid Decarboxylase Antibodies.

Cerebellum 2020 Oct;19(5):715-721

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

A prompt diagnosis and treatment of patients with autoimmune cerebellar ataxia (CA) with antibodies against glutamic acid decarboxylase (GAD-Abs) may lead to a better prognosis. Herein, we report prodromal transient neurological symptoms that should raise clinical suspicion of CA with GAD-Abs. We initially identified a 70-year-old man who presented a first acute episode of vertigo, diplopia, and ataxia lasting 2 weeks. Two months later, he experienced a similar episode along with new-onset gaze-evoked nystagmus. After 4 months, downbeat nystagmus, left limb dysmetria, and gait ataxia progressively appeared, and an autoimmune CA was diagnosed based on the positivity of GAD-Abs in serum and cerebrospinal fluid (CSF). We searched retrospectively for similar presentations in a cohort of 31 patients diagnosed with CA and GAD-Abs. We found 11 (35.4%) patients (all women, median age 62 years; 8/11 [72.7%] with autoimmune comorbidities) with transient neurological symptoms antedating CA onset by a median of 3 months, including vertigo in 9 (81.8%; described as paroxysmal in 8) and fluctuating diplopia in 3 (27.3%) patients. The identification of transient neurological symptoms of unknown etiology, such as paroxysmal vertigo and fluctuating diplopia, should lead to GAD-Abs testing in serum and CSF, especially in patients with autoimmune comorbidities.
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http://dx.doi.org/10.1007/s12311-020-01159-xDOI Listing
October 2020

Initial surgical resection and long time to occurrence from initial diagnosis are independent prognostic factors in resected recurrent IDH wild-type glioblastoma.

Clin Neurol Neurosurg 2020 Sep 8;196:106006. Epub 2020 Jun 8.

Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, F-75013, Paris, France. Electronic address:

Objective: IDH wild-type glioblastoma is the most common and aggressive primary brain cancer in adults. At tumor recurrence, treatment decision-making is not standardized; several options include second surgery, reirradiation, and a second line of chemotherapy. In this retrospective monocentric study conducted at the era of WHO 2016 classification, we investigated IDH wild-type glioblastoma patients below the age of 70 to see (i) the clinical benefit of second surgery at recurrence and (ii) the prognostic factors in resected recurrent glioblastoma patients.

Methods: 229 newly diagnosed IDH wild-type glioblastoma patients below the age of 70 treated with the standard of care (SOC) were enrolled in the current study and stratified into two subgroups according to treatment at recurrence: re-resection and no re-resection.

Results: All experienced tumor recurrence with a median progression-free survival of 11 months. 25 % of patients were reoperated. Patients reoperated at recurrence had longer post-progression median overall survival compared to their non-reoperated counterparts (14 versus 9 months, p < .05). Initial surgical resection and a long time from the initial diagnosis to the first recurrence were independent prognostic factors for good outcomes in resected recurrent IDH-wild-type glioblastoma patients; however, tumor size before and after surgery did not impact post-surgical survival.

Conclusion: Our study supports surgical resection at recurrence as therapeutic in IDH wild-type glioblastoma patients aged below 70 and in good clinical condition regardless of preoperative tumor size, particularly in patients who experienced a longer time before first recurrence and surgery at initial diagnosis. Further prospective and larger studies are warranted to validate our findings.
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http://dx.doi.org/10.1016/j.clineuro.2020.106006DOI Listing
September 2020

Anti-Hu-associated paraneoplastic syndromes triggered by immune-checkpoint inhibitor treatment.

J Neurol 2020 Jul 25;267(7):2154-2156. Epub 2020 May 25.

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

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http://dx.doi.org/10.1007/s00415-020-09940-yDOI Listing
July 2020

Value of Onconeural Antibodies in Checkpoint Inhibitor-Related Toxicities.

Ann Neurol 2020 07 19;88(1):199-200. Epub 2020 May 19.

National Reference Center for Paraneoplastic Neurological Syndromes, Lyon Civil Hospices, Neurological Hospital, Lyon, France.

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http://dx.doi.org/10.1002/ana.25764DOI Listing
July 2020

Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome: An unusual presentation of anti-GFAP astrocytopathy.

Eur J Paediatr Neurol 2020 May 18;26:89-91. Epub 2020 Mar 18.

Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre, Pediatric Neurology Department, National Referral Center for Rare Inflammatory Brain and Spinal Diseases, France; Université Paris-Sud, UMR 1184-CEA-IDMIT, Center for Immunology of Viral Infections and Autoimmune Diseases, 94275, Le Kremlin Bicêtre, France. Electronic address:

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a rare recently defined antibody-mediated encephalitis. Meningo-encephalomyelitis presentation is frequent with lymphocytic pleiocytosis in the cerebro-spinal fluid and brain MRI classically demonstrates in 50% of cases, a linear perivascular enhancement extending radially from the ventricles. Here, we describe 2 cases of pediatric autoimmune GFAP astrocytopathy with limbic encephalitis presentation and peculiar MRI characteristics: one with normal MRI and the second suggestive of Mild Encephalitis/Encephalopathy with reversible splenial lesion syndrome (MERS). These two cases illustrate that anti-GFAP antibodies should be sought in children presenting limbic encephalitis with a normal and/or MERS suggestive MRI, as treatment strategies may differ.
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http://dx.doi.org/10.1016/j.ejpn.2020.03.002DOI Listing
May 2020

Diagnostic Criteria for Primary Autoimmune Cerebellar Ataxia-Guidelines from an International Task Force on Immune-Mediated Cerebellar Ataxias.

Cerebellum 2020 Aug;19(4):605-610

Tokyo Medical University, Tokyo, Japan.

Aside from well-characterized immune-mediated ataxias with a clear trigger and/or association with specific neuronal antibodies, a large number of idiopathic ataxias are suspected to be immune mediated but remain undiagnosed due to lack of diagnostic biomarkers. Primary autoimmune cerebellar ataxia (PACA) is the term used to describe this later group. An International Task Force comprising experts in the field of immune ataxias was commissioned by the Society for Research on the Cerebellum and Ataxias (SRCA) in order to devise diagnostic criteria aiming to improve the diagnosis of PACA. The proposed diagnostic criteria for PACA are based on clinical (mode of onset, pattern of cerebellar involvement, presence of other autoimmune diseases), imaging findings (MRI and if available MR spectroscopy showing preferential, but not exclusive involvement of vermis) and laboratory investigations (CSF pleocytosis and/or CSF-restricted IgG oligoclonal bands) parameters. The aim is to enable clinicians to consider PACA when encountering a patient with progressive ataxia and no other diagnosis given that such consideration might have important therapeutic implications.
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http://dx.doi.org/10.1007/s12311-020-01132-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351847PMC
August 2020

Central nervous system complications associated with immune checkpoint inhibitors.

J Neurol Neurosurg Psychiatry 2020 07 20;91(7):772-778. Epub 2020 Apr 20.

Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques, Hospices Civils de Lyon, Lyon, France

Objective: To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI).

Methods: Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI).

Results: We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053).

Conclusion: Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.
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http://dx.doi.org/10.1136/jnnp-2020-323055DOI Listing
July 2020

Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies.

J Neurol 2020 Jul 28;267(7):2083-2089. Epub 2020 Mar 28.

French Reference Center on Paraneoplastic Neurological Syndromes, Hospices Civils de Lyon, Hôpital Neurologique, 69677, Bron, France.

Objective: To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs).

Methods: We retrospectively analyzed the clinical records of 35 patients with temporal lobe epilepsy and CSF GAD65-Abs, collected from January 1993 to December 2016 and assessed cognitive impairment and seizure activity at last visit. Cognitive impairment was considered significant if impacting on daily life activities. Immunohistochemistry on rat brain slices and ELISA were used for antibody detection and titration.

Results: Median age was 30 years (range 2-63), 32/35 (91%) patients were female, and median follow-up was 68 months (range 7-232). At presentation, 20 patients had isolated temporal lobe epilepsy and 15 patients had other limbic symptoms, including anterograde amnesia (n = 10) and behavioral disturbances (n = 5). Progressive clinical deterioration over follow-up was reported in 28/35 patients (80%), including gradual increase of memory impairment (n = 25), and apparition of behavioral disturbances (n = 4) or mood disorders (n = 18). At last follow-up, 24/35 (69%) patients had cognitive disturbances with an impact on patient's daily life activities, and 28/35 (80%) still had active seizures.

Conclusion: Most patients with temporal lobe epilepsy and CSF GAD65-Abs develop a chronic disease with progressive cognitive impairment and refractory epilepsy regardless of the presence of additional limbic symptoms at onset.
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http://dx.doi.org/10.1007/s00415-020-09807-2DOI Listing
July 2020

Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes.

Neurol Neuroimmunol Neuroinflamm 2020 05 13;7(3). Epub 2020 Mar 13.

From the French Reference Center on Paraneoplastic Neurological Syndromes (B.D., S.M.-C., B.J., A.V., G.P., V.R., A.-L.P., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (B.D., S.M.-C., B.J., A.V., G.P., V.R., A.-L.P., V.D., J.H.), Institute NeuroMyoGène, INSERM U1217/CNRS UMR5310, Université Claude Bernard Lyon 1; and Department of Immunology (B.D., C.L., N.F.), Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Lyon, France.

Objective: To investigate the diagnostic yield of commercial immunodots to detect onconeural antibodies associated with paraneoplastic neurologic syndromes (PNSs), we analyzed the proportion of confirmed positive results using alternative techniques.

Methods: Sera (n = 5,300) of patients with suspected PNS were tested by PNS+2 blot (Ravo Diagnostika; January 2016-May 2017) or EUROLINE PNS 12 Ag (Euroimmun; July 2017-November 2018). Positive samples were further explored by in-house indirect immunofluorescence and a third in-house technique (Western blot or cell-based assay) using recombinant protein. Those found negative by these 2 techniques were considered as nonconfirmed. We analyzed the relationship between band intensity and final confirmation. Clinical data were collected for all confirmed results and nonconfirmed EUROLINE immunodots.

Results: PNS+2 blot was positive in 128/1,658 (7.7%) sera and confirmed in 47/128 (36.7%). EUROLINE was positive in 186/3,626 (5.1%) and confirmed in 56/186 (30.1%). Confirmation was highly variable among the antibodies tested, from 7.2% (PNS+2 blot) and 5.8% (EUROLINE) for anti-Yo to 88.2% (PNS+2 blot) and 65.0% (EUROLINE) for anti-Hu. None of the 27 weak positive sera by EUROLINE was confirmed. Band intensity in confirmed cases was variable among the antibodies from strong positive for all anti-Yo (n = 3) and anti-Hu (n = 11) to positive (n = 19) or strong positive (n = 9) for anti-SOX1. Among patients with a nonconfirmed EUROLINE result and available clinical information, all had an alternative diagnosis, and only 6.7% had cancer.

Conclusions: Immunodots may be useful for PNS screening, but a threshold should be established for each antibody, and clinical information and confirmation by other techniques are essential.

Classification Of Evidence: The study provides Class IV evidence that immunodot assays for onconeural antibodies accurately identify patients with paraneoplastic neurologic syndromes.
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http://dx.doi.org/10.1212/NXI.0000000000000701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136063PMC
May 2020

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies.

Neurol Neuroimmunol Neuroinflamm 2020 05 13;7(3). Epub 2020 Mar 13.

From the Centre de Référence National pour les Syndromes Neurologiques Paranéoplasique (C.S., A.V., B.J., S.M.-C., G.P., V.R., F.D., J.-C.A., V.D., J.H.), Hôpital Neurologique, Hospices Civils de Lyon; SynatAc Team (C.S., A.V., B.J., S.M.-C., G.P., V.R., F.D., V.D., J.H.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310; Université Claude Bernard Lyon 1 (C.S., A.V., B.J., S.M.-C., G.P., V.R., F.D., V.D., J.H.), Université de Lyon; AP-HP (G.B., D.P.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin et Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière (CRICM), UMRS 975; Inserm U 975 (G.B., D.P.), CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paranéoplasiques et Encéphalites Autoimmunes (G.B., D.P.), Groupe Hospitalier Pitié-Salpêtrière, Paris; and Service de Neurologie (J.-C.A.), CHU de Saint-Etienne, Saint-Etienne, France.

Objective: To describe the main syndrome and clinical course in a large cohort of patients with anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS).

Methods: Twenty-year retrospective nationwide study and systematic review of the literature.

Results: Thirty-six patients with complete clinical information were identified (median age 66 years, range: 47-87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1-64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54-0.85]), at 24 months 62% (95% CI [0.41-0.78]), and at 36 months 47% (95% CI [0.25-0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort.

Conclusions: Ri-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases.
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http://dx.doi.org/10.1212/NXI.0000000000000699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136048PMC
May 2020