Publications by authors named "Alberto Vogrig"

52 Publications

Characterization and management of neurological adverse events during immune-checkpoint inhibitors treatment: an Italian multicentric experience.

Neurol Sci 2021 Aug 23. Epub 2021 Aug 23.

"C. Mondino" National Neurological Institute, IRCCS Mondino Foundation, Via Mondino 2, 27100, Pavia, Italy.

Background: Neurological immune-related adverse events (nirAEs) are rare toxicities of immune-checkpoint inhibitors (ICI). With the increase of ICI oncological indications, their incidence is growing. Their recognition and management remain nevertheless challenging.

Methods: A national, web-based database was built to collect cases of neurological symptoms in patients receiving ICI and not attributable to other causes after an adequate workup.

Results: We identified 27 patients who developed nirAEs (20 males, median age 69 years). Patients received anti-PD1/PDL1 (78%), anti-CTLA4 (4%), or both (19%). Most common cancers were melanoma (30%) and non-small cell lung cancer (26%). Peripheral nervous system was mostly affected (78%). Median time to onset was 43.5 days and was shorter for peripheral versus central nervous system toxicities (36 versus 144.5 days, p = 0.045). Common manifestations were myositis (33%), inflammatory polyradiculoneuropathies (33%), and myasthenia gravis (19%), alone or in combination, but the spectrum of diagnoses was broad. Most patients received first-line glucocorticoids (85%) or IVIg (15%). Seven patients (26%) needed second-line treatments. At last follow-up, four (15%) patients were deceased (encephalitis, 1; myositis/myasthenia with concomitant myocarditis, 2; acute polyradiculoneuropathy, 1), while seven (26%) had a complete remission, eight (30%) partial improvement, and six (22%) stable/progressing symptoms. ICI treatment was discontinued in most patients (78%).

Conclusions: Neurological irAEs are rare but potentially fatal. They primarily affect neuromuscular structures but encompass a broad range of presentations. A prompt recognition is mandatory to timely withheld immunotherapy and administrate glucocorticoids. In corticoresistant or severely affected patients, second-line treatments with IVIg or plasmapheresis may result in additional benefit.
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http://dx.doi.org/10.1007/s10072-021-05561-zDOI Listing
August 2021

18F-FDG PET brain findings in disease-discordant monozygotic mosaic twins with Cri du Chat (5p-) syndrome.

Neurocase 2021 Jun 2;27(3):319-322. Epub 2021 Aug 2.

Nuclear Medicine Unit, ARNAS Ospedali Civico, Di Cristina E Benfratelli, Palermo, Italy.

We describe the first report on the genotype-phenotype patterns and [18F] fluoro-deoxygluycose (F-FDG) Positron Emission Tomography (PET) findings in two disease-discordant monozygotic twins with Cri du Chat syndrome (CdcS) presenting deletion of 5p, 46, XY, del(5)(p14)/46, XY. One twin showed a severe phenotype; significant F-FDG PET hypometabolism (p=0.001) was revealed in the left and right hemispheres, thalamus, cerebellum, and midbrain, whereas hypermetabolism was detected in the left premotor cortex. The other twin presented a mild phenotype; significant hypometabolism was detected only in the right side (parahippoccampal gyrus and cerebellum). Further studies should investigate the causes of phenotypic discordance in twins with CdcS.
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http://dx.doi.org/10.1080/13554794.2021.1957118DOI Listing
June 2021

Acute disseminated encephalomyelitis after SARS-CoV-2 vaccination.

Clin Neurol Neurosurg 2021 Sep 21;208:106839. Epub 2021 Jul 21.

Clinical Neurology, Azienda Ospedaliero Universitaria Friuli Centrale, Udine, Italy; Neurology Unit, Department of Medicine, University of Udine, Udine, Italy.

Several central and peripheral nervous system complications associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection have been recently described. An effective mass vaccination program is necessary to effectively reduce infection spread and, consequently, limit long-term sequelae, including those affecting the nervous system. Nevertheless, as more patients gain access to coronavirus disease 2019 (COVID-19) vaccines, it is important to report potential adverse events. Herein, we report a patient with previous history of post-infectious rhombencephalitis who developed an acute disseminated encephalomyelitis (ADEM) two weeks after being vaccinated for COVID-19.
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http://dx.doi.org/10.1016/j.clineuro.2021.106839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294707PMC
September 2021

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 2021 Jun 8. 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
June 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

SARS-CoV-2-related encephalitis with prominent parkinsonism: clinical and FDG-PET correlates in two patients.

J Neurol 2021 Apr 21. Epub 2021 Apr 21.

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

Considering the similarities with other pandemics due to respiratory virus infections and subsequent development of neurological disorders (e.g. encephalitis lethargica after the 1918 influenza), there is growing concern about a possible new wave of neurological complications following the worldwide spread of SARS-CoV-2. However, data on COVID-19-related encephalitis and movement disorders are still limited. Herein, we describe the clinical and neuroimaging (FDG-PET/CT, MRI and DaT-SPECT) findings of two patients with COVID-19-related encephalopathy who developed prominent parkinsonism. None of the patients had previous history of parkinsonian signs/symptoms, and none had prodromal features of Parkinson's disease (hyposmia or RBD). Both developed a rapidly progressive form of atypical parkinsonism along with distinctive features suggestive of encephalitis. A possible immune-mediated etiology was suggested in Patient 2 by the presence of CSF-restricted oligoclonal bands, but none of the patients responded favorably to immunotherapy. Interestingly, FDG-PET/CT findings were similar in both cases and reminiscent of those observed in post-encephalitic parkinsonism, with cortical hypo-metabolism associated with hyper-metabolism in the brainstem, mesial temporal lobes, and basal ganglia. Patient's FDG-PET/CT findings were validated by performing a Statistical Parametric Mapping analysis and comparing the results with a cohort of healthy controls (n = 48). Cerebrum cortical thickness map was obtained in Patient 1 from MRI examinations to evaluate the structural correlates of the metabolic alterations detected with FDG-PET/CT. Hypermetabolic areas correlated with brain regions showing increased cortical thickness, suggesting their involvement during the inflammatory process. Overall, these observations suggest that SARS-CoV-2 infection may trigger an encephalitis with prominent parkinsonism and distinctive brain metabolic alterations.
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http://dx.doi.org/10.1007/s00415-021-10560-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059684PMC
April 2021

Clinical and Prognostic Value of Immunogenetic Characteristics in Anti-LGI1 Encephalitis.

Neurol Neuroimmunol Neuroinflamm 2021 05 5;8(3). Epub 2021 Mar 5.

From the French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., L.T., A.V., A.-L.P., G.P., C.B., L.-D.D., B.J., V.R., J. Honnorat), Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; SynatAc Team (S.M.-C., L.T., A.V., A.-L.P., G.P., C.B., L.-D.D., B.J., V.R., J. Honnorat), Institut NeuroMyoGène, INSERM U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, France; Clinic Research and Epidemiology Department (J. Haesebaert), Hospices Civils de Lyon, Lyon, France, HESPER Team, EA 7425, Medicine School, Université Claude Bernard Lyon 1, France; Neurology Department 2-Mazarin (G.B., D.P., A. Alentorn), Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, APHP; Brain and Spinal Cord Institute (G.B., D.P., A. Alentorn), INSERM U1127/CNRS UMR 7255, Université Pierre-et-Marie-Curie, Universités Sorbonnes, Paris, France; HLA Laboratory (V.D.), French Blood Service, EFS Auvergne-Rhône-Alpes, Lyon, France; Stanford University Center for Sleep Sciences and Medicine (A. Ambati, E.M.), Palo Alto, CA; and Department of Psychiatry (R.T.), Hôpitaux Universitaires Henri Mondor, Créteil, France, Mondor Institute for Biomedical Research, INSERM U955, Université de Paris-Est-Créteil, France.

Objective: Antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) characterize a limbic encephalitis (LE) strongly associated with HLA-DRB1*07:01, although some patients lack LGI1-Abs in CSF or do not carry this allele. Whether they represent a different subtype of disease or have different prognoses is unclear.

Methods: Retrospective analysis of clinical features, IgG isotypes, and outcome according to LGI1-Ab CSF positivity and DRB1*07:01 in a cohort of anti-LGI1 LE patients.

Results: Patients with LGI1-Abs detected in both CSF and serum (105/134, 78%) were compared with those who were CSF negative (29/134, 22%). Both groups had similar clinical features and serum levels, but CSF-positive patients had shorter diagnostic delay, more frequently hyponatremia, inflammatory CSF, and abnormal MRI ( < 0.05). Human leukocyte antigen (HLA) genotyping was performed in 72/134 (54%) patients and 63/72 (88%) carried DRB1*07:01. Noncarriers (9/72, 12%) were younger, more commonly women, and had less frequently psychiatric and frontal symptoms ( < 0.05). No difference in IgG isotypes according to CSF positivity or HLA was found ( > 0.05). HLA and IgG isotypes were not associated with poor outcome (mRS >2 at last follow-up) in univariate analyses; CSF positivity was only identified as a poor outcome predictor in the multivariate analysis including the complete follow-up, whereas age and female sex also remained when just the first year was considered.

Conclusions: LE without CSF LGI1-Abs is clinically indistinguishable and likely reflects just a lesser LGI1-Ab production. HLA association is sex and age biased and presents clinical particularities, suggesting subtle differences in the immune response. Long-term outcome depends mostly on demographic characteristics and the intensity of the intrathecal synthesis.
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http://dx.doi.org/10.1212/NXI.0000000000000974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938443PMC
May 2021

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

Brain 2021 Apr 12. Epub 2021 Apr 12.

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

Limbic encephalitis (LE) with antibodies against adenylate kinase 5 (AK5) has been difficult to characterize because of its rarity. In this study, we identified 10 new cases and reviewed 16 previously reported patients, investigating clinical features, IgG subclasses, human leukocyte antigen (HLA), and CSF proteomic profiles. Patients with anti-AK5 LE were mostly men (20/26, 76.9%) of median age 66 years old (range 48-94). Predominant symptom was severe episodic amnesia in all patients, frequently associated with depression (17/25, 68.0%). Weight loss, asthenia, and anorexia were also highly characteristic, being present in 11/25 (44.0%) patients. Although epilepsy was always lacking at disease onset, seizures developed later in a subset of patients (4/25, 16.0%). All patients presented CSF abnormalities, such as pleocytosis (18/25, 72.0%), oligoclonal bands (18/25, 72.0%), and increased Tau (11/14, 78.6%). Temporal lobe hyper-intensities were almost always present at disease onset (23/26, 88.5%), evolving nearly invariably toward a severe atrophy in subsequent MRIs (17/19, 89.5%). This finding was in line with a poor response to immunotherapy, with only 5/25 (20.0%) patients responding. IgG1 was the predominant subclass, being the most frequently detected and the one with highest titres in nine CSF-serum paired samples. Temporal biopsy from one of our new cases showed massive lymphocytic infiltrates dominated by both CD4+ and CT8+ T-cells, intense granzyme B expression, and abundant macrophages/microglia. HLA analysis in 11 patients showed a striking association with HLA-B*08:01 (7/11, 63.6%; OR = 13.4, 95% CI [3.8-47.4]), C*07:01 (8/11, 72.7%; OR = 11.0, 95% CI [2.9-42.5]), DRB1*03:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]), DQB1*02:01 (8/11, 72.7%; OR = 13.5, 95% CI [3.5-52.0]), and DQA1*05:01 (8/11, 72.7%; OR = 14.4, 95% CI [3.7-55.7]) alleles, which formed the extended haplotype B8-C7-DR3-DQ2 in 6/11 (54.5%) patients (OR = 16.5, 95% CI [4.8-57.1]). Finally, we compared the CSF proteomic profile of five anti-AK5 patients with that of 40 controls and 10 cases with other more common non-paraneoplastic LE (five with antibodies against leucine-rich glioma inactivated 1 and five against contactin-associated protein-like 2), as well as 10 cases with paraneoplastic neurological syndromes (five with antibodies against Yo and five against Ma2). These comparisons revealed, respectively, 31 and seven significantly up-regulated proteins in anti-AK5 LE, mapping to apoptosis pathways and innate/adaptive immune responses. These findings suggest that the clinical manifestations of anti-AK5 LE result from a distinct T-cell mediated pathogenesis, with major cytotoxicity-induced apoptosis leading to a prompt and aggressive neuronal loss, likely explaining the poor prognosis and response to immunotherapy.
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http://dx.doi.org/10.1093/brain/awab153DOI Listing
April 2021

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

Brain 2021 06;144(5):e45

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083691PMC
June 2021

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

Neurology 2021 04 2;96(16):754-766. Epub 2021 Mar 2.

From the Clinical Neurology Unit (A.M., A.B., G.L.G., M.V., A.V.), Santa Maria Della Misericordia University Hospital; Department of Medicine (DAME) (A.M., G.L.G., M.V.), University of Udine Medical School, Italy; French Reference Center for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis (S.M.-C., J.H., A.V.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team (S.M.-C., J.H., A.V.), NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310; and University Claude Bernard Lyon 1 (S.M.-C., J.H., A.V.), Université de Lyon, France.

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

Methods: Systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 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 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 with the whole sample, myasthenic syndromes were significantly more Ab positive (33/56, 59%; < 0.001). Anti-programmed cell death protein 1/programmed cell death ligand 1 was more frequent in myasthenic syndromes (50/58, 86%; = 0.005) and less common in meningitis (2/13, 15%; < 0.001) and cranial neuropathies (13/31, 42%; = 0.005). Anti-cytotoxic T-lymphocyte antigen-4 ICIs were more frequent in meningitis (8/13, 62%; < 0.001) and less common in encephalitis (2/56, 4%; = 0.009) and myositis (12/136, 9%; = 0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; = 0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; = 0.003) and less common in encephalitis (19/56, 34%; = 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
April 2021

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

J Neurol 2021 Jul 5;268(7):2515-2522. 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
July 2021

Perampanel as add-on therapy in epilepsies with known etiology: A single center experience with long-term follow-up.

Epilepsy Behav Rep 2021 26;15:100393. Epub 2020 Oct 26.

Department of Medicine (DAME), University of Udine Medical School, Udine, Italy.

We report a retrospective monocentric study performed on 63 patients affected by epilepsy with known etiology, receiving perampanel as add-on therapy with at least 12-month follow-up. The purpose of our study was to evaluate efficacy and tolerability of perampanel in this group of epilepsies. Patients were classified into 2 groups based on the presence/absence of a single focal brain lesion on MRI, as epilepsy etiology: 48 subjects were affected by focal lesional epilepsy and 15 by non-focal lesional epilepsy. The retention rate was 76.2% and 53.9% at 12 and 24 months respectively. At 12 months, at least 40% of patients resulted responders, with a significant reduction in seizure frequency ( = 0.01), confirmed at 24 months. Considering epilepsy etiology, we found a better PER response in patients with focal lesional epilepsy. A significant correlation was observed between responder rates and EEG pattern. Only 30% of patients reported mild-moderate adverse events. Efficacy and tolerability of PER, in our study, are in line with the results reported in other real-world studies. Our data suggest the possibility of better PER response in patients with focal brain lesions, which indicates that this drug could be a therapeutic option in this population.
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http://dx.doi.org/10.1016/j.ebr.2020.100393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797501PMC
October 2020

Stroke in patients with COVID-19: Clinical and neuroimaging characteristics.

Neurosci Lett 2021 01 19;743:135564. Epub 2020 Dec 19.

Unit of Neuroradiology, Department of Diagnostic Imaging, Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy.

Acute cerebrovascular disease, particularly ischemic stroke, has emerged as a serious complication of infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the Coronavirus disease-2019 (COVID-19). Accumulating data on patients with COVID-19-associated stroke have shed light on specificities concerning clinical presentation, neuroimaging findings, and outcome. Such specificities include a propensity towards large vessel occlusion, multi-territory stroke, and involvement of otherwise uncommonly affected vessels. Conversely, small-vessel brain disease, cerebral venous thrombosis, and intracerebral hemorrhage appear to be less frequent. Atypical neurovascular presentations were also described, ranging from bilateral carotid artery dissection to posterior reversible encephalopathy syndrome (PRES), and vasculitis. Cases presenting with encephalopathy or encephalitis with seizures heralding stroke were particularly challenging. The pathogenesis and optimal management of ischemic stroke associated with COVID-19 still remain uncertain, but emerging evidence suggest that cytokine storm-triggered coagulopathy and endotheliopathy represent possible targetable mechanisms. Some specific management issues in this population include the difficulty in identifying clinical signs of stroke in critically ill patients in the intensive care unit, as well as the need for a protected pathway for brain imaging, intravenous thrombolysis, and mechanical thrombectomy, keeping in mind that "time is brain" also for COVID-19 patients. In this review, we discuss the novel developments and challenges for the diagnosis and treatment of stroke in patients with COVID-19, and delineate the principles for a rational approach toward precision medicine in this emerging field.
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http://dx.doi.org/10.1016/j.neulet.2020.135564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749733PMC
January 2021

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

HLA and immunological features of SARS-CoV-2-induced Guillain-Barré syndrome.

Neurol Sci 2020 Dec;41(12):3391-3394

Clinical Neurology Unit, Santa Maria della Misericordia University Hospital, Piazzale Santa Maria della Misericordia, 15, 33010, Udine, Italy.

We report the clinical and immunological features in a case of SARS-CoV-2-induced Guillain-Barré syndrome (Si-GBS), suggesting that (1) Si-GBS can develop even after paucisymptomatic COVID-19 infection; (2) a distinctive cytokine repertoire is associated with this autoimmune complication, with increased CSF concentration of IL-8, and moderately increased serum levels of IL-6, IL-8, and TNF-α; (3) a particular genetic predisposition can be relevant, since the patient carried several HLA alleles known to be associated with GBS, including distinctive class I (HLA-A33) and class II alleles (DRB1*03:01 and DQB1*05:01). To the best of our knowledge, this is the first case of GBS in which SARS-CoV-2 antibodies were detected in the CSF, further strengthening the role of the virus as a trigger. In conclusion, our study suggests that SARS-CoV-2 antibodies need to be searched in the serum and CSF in patients with GBS living in endemic areas, even in the absence of a clinically severe COVID-19 infection, and that IL-8 pathway can be relevant in Si-GBS pathogenesis. Further studies are needed to conclude on the relevance of the genetic findings, but it is likely that HLA plays a role in this setting as in other autoimmune neurological syndromes, including those triggered by infections.
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http://dx.doi.org/10.1007/s10072-020-04787-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530349PMC
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

Causality in COVID-19-associated stroke: a uniform case definition for use in clinical research.

J Neurol 2021 Mar 1;268(3):758-761. Epub 2020 Aug 1.

Unit of Neuroradiology, Department of Diagnostic Imaging, Istituto Ospedaliero Fondazione Poliambulanza, Brescia, Italy.

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http://dx.doi.org/10.1007/s00415-020-10103-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395574PMC
March 2021

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

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

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

Bilateral carotid artery dissection in a SARS-CoV-2 infected patient: causality or coincidence?

J Neurol 2020 Oct 12;267(10):2812-2814. Epub 2020 Jun 12.

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

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http://dx.doi.org/10.1007/s00415-020-09984-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292240PMC
October 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

Stroke in patients with SARS-CoV-2 infection: case series.

J Neurol 2020 Aug 20;267(8):2185-2192. Epub 2020 May 20.

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

Background: Italy is one of the most affected countries by the coronavirus disease 2019 (COVID-19). The responsible pathogen is named severe acute respiratory syndrome coronavirus (SARS-CoV-2). The clinical spectrum ranges from asymptomatic infection to severe pneumonia, leading to intensive care unit admission. Evidence of cerebrovascular complications associated with SARS-CoV-2 is limited. We herein report six patients who developed acute stroke during COVID-19 infection.

Methods: A retrospective case series of patients diagnosed with COVID-19 using reverse-transcriptase polymerase chain reaction (RT-PCR) on nasopharyngeal swabs, who developed clinical and neuroimaging evidence of acute stroke during SARS-CoV-2 infection.

Results: Six patients were identified (5 men); median age was 69 years (range 57-82). Stroke subtypes were ischemic (4, 67%) and hemorrhagic (2, 33%). All patients but one had pre-existing vascular risk factors. One patient developed encephalopathy prior to stroke, characterized by focal seizures and behavioral abnormalities. COVID-19-related pneumonia was severe (i.e., requiring critical care support) in 5/6 cases (83%). Liver enzyme alteration and lactate dehydrogenase (LDH) elevation were registered in all cases. Four patients (67%) manifested acute kidney failure prior to stroke. Four patients (67%) had abnormal coagulation tests. The outcome was poor in the majority of the patients: five died (83%) and the remaining one (17%) remained severely neurologically affected (mRS: 4).

Conclusions: Both ischemic and hemorrhagic stroke can complicate the course of COVI-19 infection. In our series, stroke developed mostly in patients with severe pneumonia and multiorgan failure, liver enzymes and LDH were markedly increased in all cases, and the outcome was poor.
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http://dx.doi.org/10.1007/s00415-020-09885-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238403PMC
August 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

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

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
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