Publications by authors named "Geraldine Picard"

25 Publications

  • Page 1 of 1

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

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

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

J Neurol Neurosurg Psychiatry 2020 Oct 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

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

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

Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies.

J Neurol 2020 Jul 9;267(7):1906-1911. Epub 2020 Mar 9.

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

The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01-DQB1*02:01-DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p = 0.03, OR 3.96, 95% CI [1.54-10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p = 0.05, OR 3.54, 95% CI [1.40-8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p = 0.05, OR 0.15, 95% CI [0.02-0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers (p > 0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.
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http://dx.doi.org/10.1007/s00415-020-09782-8DOI Listing
July 2020

Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors.

Neurol Neuroimmunol Neuroinflamm 2019 11 7;6(6). Epub 2019 Aug 7.

From the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (A.V., M.F., B.J., G.P., V.R., A.-L.P., S.M.-C., F.D., V.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique; Synatac Team, NeuroMyoGene Institute, INSERM U1217/CNRS UMR5310, Lyon, France; University Claude Bernard Lyon 1, Université de Lyon; Service de Pneumologie-Oncologie Thoracique-Soins Intensifs Respiratoires (M.R.), Centre Hospitalier Universitaire de Rouen; Service d'Oncologie Médicale (J.R.), Institut de Cancérologie de l'Ouest René Gauducheau, St. Herblain; Service de Pneumologie (C.D.), Centre Hospitalier de Saint-Quentin; Service de Neurologie et Unité Neuro-Vasculaire-Hôpital de La Cavale Blanche (L.G.), Brest; Service de Neurologie et Unité Neurovasculaire (M.P.-G.), Centre Hospitalier Régional d'Orléans; Service de Neurologie-Pathologies Inflammatoires (J.L.), Centre Hospitalier Universitaire de Lille; and AP-HP (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, CNRS, UMR 7225; Centre de Compétence des Syndromes Neurologiques Paraneoplasiques et Encéphalites Autoimmunes, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

Objective: To report the induction of anti-Ma2 antibody-associated paraneoplastic neurologic syndrome (Ma2-PNS) in 6 patients after treatment with immune checkpoint inhibitors (ICIs). We also analyzed (1) patient clinical features compared with a cohort of 44 patients who developed Ma2-PNS without receiving ICI treatment and (2) the frequency of neuronal antibody detection before and after ICI implementation.

Methods: Retrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.

Results: Our series of patients included 5 men and 1 woman (median age, 63 years). The patients were receiving nivolumab (n = 3), pembrolizumab (n = 2), or a combination of nivolumab and ipilimumab (n = 1) for treatment of neoplasms that included lung (n = 4) and kidney (n = 1) cancers and pleural mesothelioma (n = 1). Clinical syndromes comprised a combination of limbic encephalitis and diencephalitis (n = 3), isolated limbic encephalitis (n = 2), and a syndrome characterized by ophthalmoplegia and head drop (n = 1). No significant clinical difference was observed between our 6 patients and the overall cohort of Ma2-PNS cases. Post-ICI Ma2-PNS accounted for 35% of the total 17 Ma2-PNS diagnosed in our center over the 2017-2018 biennium. Eight cases had been detected in the preceding biennium 2015-2016, corresponding to a 112% increase of Ma2-PNS frequency since the implementation of ICIs in France. Despite ICI withdrawal and immunotherapy, 4/6 patients died, and the remaining 2 showed a moderate to severe disability.

Conclusions: We show a clear association between ICI use and increased diagnosis of Ma2-PNS. Physicians need to be aware that ICIs can trigger Ma2-PNS because clinical presentation can be challenging.
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http://dx.doi.org/10.1212/NXI.0000000000000604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705619PMC
November 2019

Immunopathological characterization of ovarian teratomas associated with anti-N-methyl-D-aspartate receptor encephalitis.

Acta Neuropathol Commun 2019 03 11;7(1):38. Epub 2019 Mar 11.

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

Encephalitis with anti-NMDAR antibodies (NMDAR-E) is a severe autoimmune neurological disorder, defined by a clinical presentation of encephalitis and the presence of IgG targeting the GluN1 subunit of NMDA receptors in the CSF. An underlying ovarian teratoma is commonly associated with this autoimmune disease suggesting a role of the tumor in immunopathogenesis. In this study, we characterized the salient histopathological features of 27 ovarian teratomas associated with NMDAR-E (3 immature and 24 mature teratomas) and 40 controls without associated encephalitis. All but one NMDAR-E-associated teratomas contained a nervous tissue component, while less than 40% of control teratomas did (p < 0.001). GluN1 expression by teratomatous nervous tissue seemed to be more often glial in NMDAR-E teratomas than in control teratomas (73% vs. 29%, p < 0.05). Strikingly, 3 out of 24 NMDAR-E-associated mature teratomas contained neuroglial tissue exhibiting histopathological features of central nervous system neuroglial tumor, while such glioma-like features are exceptionally described in the literature on ovarian teratomas. Moreover, NMDAR-E associated teratomas differed from sporadic ovarian teratomas by consistent and prominent infiltration of the nervous tissue component by immune cells, comprised of T- and B-cells and mature dendritic cells organized in tertiary lymphoid structures, with IgG and IgA deposits and plasma cells in close contact to the neuroglial tissue.These data demonstrate an association between massive infiltration of NMDAR-E-associated teratomas by immune cells and particular glial features of its neuroglial component, suggesting that this glial tissue might be involved in triggering or sustaining the anti-tumor response associated with the auto-immune neurological disease.
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http://dx.doi.org/10.1186/s40478-019-0693-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410529PMC
March 2019

Isolated seizures are a common early feature of paraneoplastic anti-GABA receptor encephalitis.

J Neurol 2019 Jan 20;266(1):195-206. Epub 2018 Nov 20.

French Reference Center on Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon, Neuro-Oncologie, Hôpital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, 69677, Bron Cedex, France.

Objective: To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABA receptor antibodies (GABAR-Abs).

Methods: Retrospective clinical study of CSF-confirmed cases of GABAR-Abs encephalitis.

Results: We identified 22 patients (4 female) with GABAR-Abs, with a median age of 64 years (range 55-85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10 days (range 1-30), the recurrent seizures' phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26 days (range 6-65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2 years).

Conclusion: Paraneoplastic GABAR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.
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http://dx.doi.org/10.1007/s00415-018-9132-0DOI Listing
January 2019

Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibodies.

J Neurol 2018 Oct 12;265(10):2190-2200. Epub 2018 Jul 12.

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

Objective: The aim of this study was to describe specificities of patients with NMDA receptor antibody (NMDAR-Ab) encephalitis associated with a malignant tumor.

Methods: Retrospective observational study of 252 patients with NMDAR-Ab encephalitis of the French Paraneoplastic Neurological Syndrome Reference Center. Patients were classified in three groups: (1) non-malignant ovarian teratomas, (2) malignant ovarian teratomas (immature), and (3) other malignant tumors.

Results: Sixty patients (23.8%) had an associated tumor and 15 (6%) were malignant. No particular neurological symptom was observed in these patients. Ovarian teratomas were the most frequent (51 cases) with 6 of them immature (11.8% of teratomas). Nine patients (3.6%) developed other malignant tumors (3 small cell lung carcinomas, 1 uterine adenocarcinoma, 1 prostate adenocarcinoma, 1 Hodgkin lymphoma, 1 pineal dysgerminoma, 1 neuroblastoma and 1 pancreatic neuroendocrine tumor). Among patients with a cancer other than teratoma, 6/9 were elderly patients (median age 65 years, representing 30% of elderly patients with such encephalitis) compared to a median age of 26 years in adult patients included herein. The clinical course was similar in the three groups, other than a higher death rate among patients with malignant tumors (86 versus 2%; p < 0.001) mainly due to tumor progression (5/7 deaths).

Conclusion: Immature ovarian teratomas represent 11.8% of all teratomas in patients with NDMAR-Ab encephalitis. The other malignant tumors are mainly observed in elderly patients. The presence of a malignant tumor does not impact the neurological presentation but is directly associated with a higher risk of death.
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http://dx.doi.org/10.1007/s00415-018-8970-0DOI Listing
October 2018

Initial clinical presentation of young children with N-methyl-d-aspartate receptor encephalitis.

Eur J Paediatr Neurol 2018 May 28;22(3):404-411. Epub 2017 Dec 28.

Centre Français de Référence des Syndromes Neurologiques Paranéoplasiques, Hospices Civils de Lyon, Hôpital Neurologique, F-69677 Bron, France; Université Claude Bernard Lyon 1, CNRS UMR-5310, INSERM U-1217, Institut NeuroMyoGène, F-69003 Lyon, France. Electronic address:

Autoimmune encephalitis with anti-N-methyl-d-aspartate receptor autoantibodies (NMDA-R-Abs) is a recently described disease affecting adult and pediatric patients. Symptoms of the disease are now perfectly described in the adult population but the clinical presentation is less known in young children. The aim of the present study was to describe the clinical presentation and the specificities of symptoms presented by young children with NMDA-R-Abs encephalitis to improve diagnosis of this disease, and to compare these to a series of previously published female adult patients. Fifty cases of children younger than twelve years of age diagnosed with NMDA-R-Abs encephalitis between January 1, 2007 and December 31, 2016 (27 females and 23 males) were retrospectively studied. The first neurological symptoms observed in young children with NMDA-R-Abs encephalitis were characterized by seizure (72%), especially focal seizure (42%), within a median of 15 days before other encephalitis symptoms; other patients mostly had behavioral disorders (26%). The seizures were frequently difficult to diagnose because of the transient unilateral dystonic or tonic posturing presentation or sudden unilateral pain in the absence of clonic movements. A post-ictal motor deficit was also frequently observed. This clinical presentation is different from that observed in adult females with NMDA-R-Abs encephalitis who initially present mainly psychiatric disorders (67%) or cognitive impairment (19%), and less frequently seizures (14%). The diagnosis of NMDA-R-Abs encephalitis should be systematically considered in young children of both sexes who present neurological symptoms suggesting recent seizures (focal or generalized) without obvious other etiology.
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http://dx.doi.org/10.1016/j.ejpn.2017.12.014DOI Listing
May 2018

Complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies.

J Neuroimmunol 2018 02 18;315:28-32. Epub 2017 Dec 18.

Center for Sleep Sciences and Medicine, Stanford University, 3165 Porter Drive, Palo Alto, CA 94304, USA. Electronic address:

Anti-Yo paraneoplastic cerebellar degeneration (PCD) is a devastating autoimmune complication of gynecological cancers. We hypothesized that as for other autoimmune diseases, specific HLA haplotypes are associated. We conducted high resolution HLA typing of Class I/Class II in 40 cases versus ethnically matched controls. Three cases with anti-Yo antibodies and peripheral neuropathy were also included. We detected protective effects of DPA1*01:03~DPB1*04:01 (OR=0, p=0.0008), DRB1*04:01~DQA1*03:03(OR=0, p=0.0016) and DPA1*01:03~DPB1*04:01 (OR=0.35, p=0.0047) overall. Increased DRB1*13:01~DQA1*01:03~DQB1*06:03 was also found in PCD ovarian cases (OR=5.4, p=0.0016). These results suggest differential genetic susceptibility to anti-Yo per cancer and with a primary HLA Class II involvement.
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http://dx.doi.org/10.1016/j.jneuroim.2017.12.012DOI Listing
February 2018

Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration.

Acta Neuropathol 2018 04 3;135(4):569-579. Epub 2018 Jan 3.

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

Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.
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http://dx.doi.org/10.1007/s00401-017-1802-yDOI Listing
April 2018

Autoimmune episodic ataxia in patients with anti-CASPR2 antibody-associated encephalitis.

Neurol Neuroimmunol Neuroinflamm 2017 Jul 14;4(4):e371. Epub 2017 Jun 14.

Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques (B.J., L.T., V.D., V.R., G.P., F.D., D.P., J.-C.A., J.-Y.D., J.H.), Service de Neuro-Réanimation (F.G.), Hôpital Neurologique, Hospices Civils de Lyon, Bron; Institut NeuroMyoGene INSERM U1217/CNRS UMR 5310 (B.J., F.G., L.T., M.S.-M., V.D., V.R., G.P., F.D., J.H.), University of Lyon-Université Claude Bernard Lyon 1; Service de Neurologie (P.C., J.-C.A.), Hôpital Bellevue, Centre Hospitalier Universitaire de Saint-Étienne; and Département de Neurologie (D.P., J.-Y.D.), Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, France.

Objective: To report paroxysmal episodes of cerebellar ataxia in a patient with anti-contactin-associated protein-like 2 (CASPR2) antibody-related autoimmune encephalitis and to search for similar paroxysmal ataxia in a cohort of patients with anti-CASPR2 antibody-associated autoimmune encephalitis.

Methods: We report a patient with paroxysmal episodes of cerebellar ataxia observed during autoimmune encephalitis with anti-CASPR2 antibodies. In addition, clinical analysis was performed in a retrospective cohort of 37 patients with anti-CASPR2 antibodies to search for transient episodes of ataxia. Paroxysmal symptoms were further specified from the referral physicians, the patients, or their relatives.

Results: A 61-year-old man with limbic encephalitis and anti-CASPR2 antibodies developed stereotyped paroxysmal episodes of cerebellar ataxia, including gait imbalance, dysarthria, and dysmetria, 1 month after the onset of the encephalitis. The ataxic episodes were specifically triggered by orthostatism and emotions. Both limbic symptoms and transient ataxic episodes resolved after treatment with steroids and IV cyclophosphamide. Among 37 other patients with anti-CASPR2 antibodies, we identified 5 additional cases with similar paroxysmal ataxic episodes that included gait imbalance (5 cases), slurred speech (3 cases), limb dysmetria (3 cases), and nystagmus (1 case). All had concomitant limbic encephalitis. Paroxysmal ataxia was not observed in patients with neuromyotonia or Morvan syndrome. Triggering factors (orthostatism or anger) were reported in 4 patients. Episodes resolved with immunomodulatory treatments in 4 patients and spontaneously in 1 case.

Conclusions: Paroxysmal cerebellar ataxia must be added to the spectrum of the anti-CASPR2 antibody syndrome.
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http://dx.doi.org/10.1212/NXI.0000000000000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471489PMC
July 2017

Neuroleptic intolerance in patients with anti-NMDAR encephalitis.

Neurol Neuroimmunol Neuroinflamm 2016 Oct 29;3(5):e280. Epub 2016 Aug 29.

Université Paris-Est (F.L., M.L.), INSERM U955, Laboratoire Psychiatrie Translationnelle, et AP-HP, DHU Pe-PSY, Pole de Psychiatrie et d'Addictologie des Hôpitaux Universitaires Henri Mondor, et Fondation FondaMental, Créteil; French Reference Center on Paraneoplastic Neurological Syndrome (L.T., G.P., V.D., F.D., V.R., D.P., J.-C.A., J.-Y.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Bron; Institut NeuroMyoGene (INMG) INSERM U1217/CNRS UMR 5310 (L.T., V.D., F.D., V.R., J.-C.A., J.H.), Lyon; Université de Lyon-Université Claude Bernard Lyon 1 (L.T., V.D., F.D., J.H.); AP-HP (D.P., J.-Y.D.), Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris; Service de Neurologie (J.-C.A.), CHU de Saint-Etienne et Université de Lyon, Saint-Etienne; Inserm (J.-Y.D.), U 1127, CNRS, UMR 7225, ICM, Sorbonne Universités, UPMC Univ Paris 06, UM 75 Paris; and Université de Bordeaux (L.G.), Interdisciplinary Institute for Neuroscience, UMR 5297, France.

Objective: To precisely describe the initial psychiatric presentation of patients with anti-NMDA receptor (NMDAR) antibodies encephalitis (anti-NMDAR encephalitis) to identify potential clues enhancing its early diagnosis.

Methods: We retrospectively studied the French Reference Centre medical records of every adult patient with anti-NMDAR encephalitis to specify the patients' initial psychiatric symptoms leading to hospitalization in a psychiatric department and the reasons underlying the diagnosis of anti-NMDAR encephalitis.

Results: The medical records of 111 adult patients were reviewed. Psychiatric features were the initial presentation in 65 patients (59%). Among them, several psychiatric manifestations were observed, including visual and auditory hallucinations (n = 26, 40%), depression (n = 15, 23%), mania (n = 5, 8%), acute schizoaffective episode (n = 15, 23%), and eating disorder or addiction (n = 4; 6%). Forty-five patients (40% of total cohort) were first hospitalized in a psychiatric institution (91% women), with a median duration of stay of 9 days (range 0.25-239 days). Among them, 24 patients (53%) had associated discreet neurologic signs at the first evaluation, while 17 additional patients (38%) developed neurologic signs within a few days. Twenty-one patients (47%) were transferred to a medical unit for a suspicion of antipsychotic intolerance characterized by high temperature, muscle rigidity, mutism or coma, and biological results suggesting rhabdomyolysis.

Conclusions: Several psychiatric presentations were observed in patients with anti-NMDAR encephalitis, although none was specific; however, patients, mostly women, also had discreet neurologic signs that should be carefully assessed as well as signs of antipsychotic intolerance that should raise suspicion for anti-NMDAR encephalitis.
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http://dx.doi.org/10.1212/NXI.0000000000000280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004531PMC
October 2016

Anti-N-Methyl-d-Aspartate Receptor Encephalitis in Adult Patients Requiring Intensive Care.

Am J Respir Crit Care Med 2017 02;195(4):491-499

16 Medical and Infectious Diseases Intensive Care Unit, Hôpital Bichat-Claude-Bernard, and.

Rationale: Encephalitis caused by anti-N-methyl-d-aspartate receptor (NMDAR) antibodies is the leading cause of immune-mediated encephalitis. There are limited data on intensive care unit (ICU) management of these patients.

Objectives: To identify prognostic factors of good neurologic outcome in patients admitted to an ICU with anti-NMDAR encephalitis.

Methods: This was an observational multicenter study of all consecutive adult patients diagnosed with anti-NMDAR encephalitis at the French National Reference Centre, admitted to an ICU between 2008 and 2014. The primary outcome was a good neurologic outcome at 6 months after ICU admission, defined by a modified Rankin Scale score of 0-2.

Measurements And Main Results: Seventy-seven patients were included from 52 ICUs. First-line immunotherapy consisted of steroids (n = 61/74; 82%), intravenous immunoglobulins (n = 71/74; 96%), and plasmapheresis (n = 17/74; 23%). Forty-five (61%) patients received second-line immunotherapy (cyclophosphamide, rituximab, or both). At 6 months, 57% of patients had a good neurologic outcome. Independent factors of good neurologic outcome were early (≤8 d after ICU admission) immunotherapy (odds ratio, 16.16; 95% confidence interval, 3.32-78.64; for combined first-line immunotherapy with steroids and intravenous immunoglobulins vs. late immunotherapy), and a low white blood cell count on the first cerebrospinal examination (odds ratio, 9.83 for <5 vs. >50 cells/mm; 95% confidence interval, 1.07-90.65). Presence of nonneurologic organ failures at ICU admission and occurrence of status epilepticus during ICU stay were not associated with neurologic outcome.

Conclusions: The prognosis of adult patients with anti-NMDAR encephalitis requiring intensive care is good, especially when immunotherapy is initiated early, advocating for prompt diagnosis and early aggressive treatment.
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http://dx.doi.org/10.1164/rccm.201603-0507OCDOI Listing
February 2017

Characterization of a Subtype of Autoimmune Encephalitis With Anti-Contactin-Associated Protein-like 2 Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and Seizures.

JAMA Neurol 2016 09;73(9):1115-24

Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques, Hôpital Neurologique, Hospices Civils de Lyon, Lyon, France.2Institut NeuroMyoGene, INSERM 1217/CNRS 5310, Université de Lyon, Lyon, France.3Université Claude-Bernard Lyon 1, Université de Lyon, Lyon, France.

Importance: Autoantibodies against contactin-associated protein-like 2 (CASPR2) are observed in several neurological syndromes, including neuromyotonia (NMT), Morvan syndrome (MoS), and limbic encephalitis.

Objective: To characterize the clinical and biological presentations of patients with anti-CASPR2 antibodies in the cerebrospinal fluid (CSF).

Design, Setting, And Participants: We conducted a retrospective cohort analysis of 18 patients who had anti-CASPR2 antibodies in their CSF between March 2009 and November 2015 at the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques in Lyon, France. Additionally, we analyzed 15 patients who were diagnosed as having NMT or MoS as a comparative group.

Main Outcomes And Measures: Clinical presentations, anti-CASPR2 antibodies specificities, brain magnetic resonance imaging, and CSF analyses, cancer prevalence, and evolution.

Results: In this cohort of 18 patients with anti-CASPR2 antibodies in their CSF, 17 (94.4%) were male and had a median (range) age of 64.5 (53-75) years; in the second group, 9 of 15 patients (60.0%) with NMT or MoS were male and had a median (range) age of 51 years (1 month to 75 years). Only 3 patients (16.7%) in this cohort had a previous or concomitant history of cancer (prostate, hematological, or thyroid), whereas 9 patients (60.0%) in the second group had a malignant thymoma. Symptoms of limbic encephalitis were observed in all patients, including temporal lobe seizures in 16 patients (88.9%) and memory disorders in 17 patients (94.4%) from the cohort. Extralimbic signs were also evident in 12 of 18 patients (66.7%), including cerebellar ataxia in 6 patients (33.3%). Only 2 patients (11.1%) from the cohort were diagnosed as having NMT. Brain magnetic resonance imaging displayed T2-weighted temporolimbic abnormalities in 14 of 15 patients (93.3%) in the second group. Cerebrospinal fluid analysis was abnormal in 9 of 12 patients (75.0%). For 16 of 18 patients (88.9%), follow-up was performed for at least a 6-month period (median [range], 34 [11-114] months). Of these, 15 (93.8%) improved and 6 (37.5%) relapsed. In all patients in this cohort, IgG4 autoantibodies were detected in the CSF. Anti-CASPR2 antibodies in the CSF targeted the laminin G1 and discoidin domains of CASPR2 in all patients. Importantly, anti-CASPR2 antibodies were detected in the serum but not in the CSF of all patients with NMT or MoS.

Conclusions And Relevance: In this cohort study, anti-CASPR2 antibodies in the CSF are associated with a subtype of autoimmune encephalitis with prominent limbic involvement and seizures that is rarely associated with cancer. Conversely, patients with NMT and MoS have anti-CASPR2 antibodies only in the serum but not in the CSF and frequently present with a malignant thymoma. The anti-CASPR2 antibodies found in these patients targeted the discoidin and laminin G1 domains of CASPR2 and always included IgG4 autoantibodies.
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http://dx.doi.org/10.1001/jamaneurol.2016.1585DOI Listing
September 2016

CSF IgA NMDAR antibodies are potential biomarkers for teratomas in anti-NMDAR encephalitis.

Neurol Neuroimmunol Neuroinflamm 2015 Dec 29;2(6):e166. Epub 2015 Oct 29.

Lyon Neuroscience Research Center (V.D., A.C., C. Bost, F.D., V.R., C. Blanc, O.P., J.-C.A., J.H.), INSERM U1028/CNRS UMR 5292; Université de Lyon-Université Claude Bernard Lyon 1 (V.D., A.C., C. Bost, F.D., V.R., C. Bardel, O.P., J.H.); the Department of Neurology D (V.D.) and French Reference Center on Paraneoplastic Neurological Syndrome (A.V., C. Bost, F.D., G.P., V.R., M.-O.C., C. Blanc, J.-C.A., J.-Y.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Bron; Service de Biostatistique (C. Bardel), Hospices Civils de Lyon, CNRS UMR 5558; Laboratoire de Biométrie et Biologie Evolutive (C. Bardel), Equipe Biostatistique-Santé, Villeurbanne; the Department of Biopathology (I.T.), Centre de Recherche en Cancérologie de Lyon; Service de Neurologie (J.-C.A.), CHU de Saint-Etienne et Université de Lyon, Saint-Etienne; and Service de Neurologie Mazarin (J.-Y.D.), Groupe Hospitalier Pitié-Salpêtrière, APHP, Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, UMR S975, CNRS, UMR 7225, Paris, France.

Objective: To evaluate the presence of immunoglobulin A (IgA) subtype of anti-NMDA receptor (NMDAR) antibodies (IgA-NMDAR-Abs) in the CSF of patients with immunoglobulin G (IgG)-NMDAR-Ab encephalitis and to describe the potential association with a specific clinical pattern.

Methods: The retrospective analysis for the presence of IgA-NMDAR-Abs in 94 CSF samples from patients with anti-NMDAR encephalitis diagnosed between October 2007 and February 2014 was conducted at the French Reference Centre on Paraneoplastic Neurological Syndrome. This observational study compared 39 patients with both IgA- and IgG-NMDAR-Abs to 55 patients with only IgG-NMDAR-Abs.

Results: In the retrospective cohort, 41% of the patients with NMDAR-Ab encephalitis had both CSF IgG- and IgA-NMDAR-Abs. Approximately half of the IgA-NMDAR-Ab-positive patients (18/38, 49%) definitively possessed associated tumors, primarily ovarian teratomas (17/18, 94%), compared with only 5% (3/55) of the patients in the IgA-NMDAR-Ab-negative group (p < 0.001). In the adult female population at risk for ovarian teratoma, the detection of CSF IgA-NMDAR-Ab positivity showed 85% sensitivity, 70% specificity, a 57% positive predictive value, and a 90% negative predictive value for the diagnosis of ovarian teratoma. No other specific clinical features or clinical outcome were associated with CSF IgA-NMDAR-Ab positivity.

Conclusion: These results suggest that in patients with IgG-NMDAR-Ab encephalitis, CSF IgA-NMDAR-Abs could be used as a biological marker for the presence of an ovarian teratoma.
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http://dx.doi.org/10.1212/NXI.0000000000000166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630685PMC
December 2015

Treatment and outcome of children and adolescents with N-methyl-D-aspartate receptor encephalitis.

J Neurol 2015 Aug 19;262(8):1859-66. Epub 2015 May 19.

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

The objective of this study is to describe the treatment and outcome of children and adolescents with N-methyl-D-aspartate receptor (NMDA-R) encephalitis. A retrospective study of children and adolescents with NMDA-R encephalitis was performed by the French Paraneoplastic Neurological Syndrome Reference Center between January 1, 2007 and December 31, 2012. The modified Rankin scale (mRS) was used to assess outcome. Thirty-six children and adolescents with NMDA-R encephalitis were studied. All of the patients received first-line immunotherapy (corticosteroids, intravenous immunoglobulins or plasma exchange), and 81% received second-line immunotherapy (rituximab or cyclophosphamide). Median time between first-line and second-line treatment was 26 days. During the first 24 months, 30 of 36 patients (83%) achieved a good outcome (mRS ≤ 2) and 20 of 36 patients (56%) achieved complete recovery (mRS = 0). Median time to good outcome and to complete recovery was 6 and 24 months, respectively. Three patients (8%) relapsed, one patient died. In multivariate analysis, age >12 years was a predictor of good outcome and initial mRS ≤ 3 was a predictor of complete recovery. Despite a higher rate of patients who received second-line immunotherapy, the outcome of the patients in the present series was very similar to the outcome reported in previous series. The present study highlights the need for clinical trials to determine the optimal treatment of NMDA-R encephalitis.
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http://dx.doi.org/10.1007/s00415-015-7781-9DOI Listing
August 2015

Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis.

Neurology 2014 Feb 17;82(7):556-63. Epub 2014 Jan 17.

From the French Reference Center on Paraneoplastic Neurological Syndrome (A.V, V.D., F.D., G.P., G.C., V.R., J.-C.A., J.-Y.D., J.H.), Hospices Civils de Lyon, Hôpital Neurologique, Neuro-Oncology, Bron; Lyon Neuroscience Research Center (A.V., V.D., F.D., J.-C.A., J.H.), INSERM U1028/CNRS UMR 5292, Lyon; Université de Lyon-Université Claude Bernard Lyon 1 (A.V., V.D., F.D., J.H.), Lyon; Service de Neurologie (J.-C.A.), CHU de Saint-Etienne, Saint-Etienne; and Service de Neurologie Mazarin (J.-Y.D.), Groupe Hospitalier Pitié-Salpêtrière, APHP, Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR S975, CNRS, UMR 7225, Paris, France.

Objective: The aim of this study was to describe the clinical features and specificities of adult male patients with NMDA receptor antibodies (NMDAr-Abs) encephalitis.

Methods: Observational study of 13 adult male patients who were diagnosed with NMDAr-Abs encephalitis at the French Paraneoplastic Neurological Syndrome Reference Center.

Results: Adult male patients frequently presented initially with a seizure (8/13, 61.5%). Seizures were partial in 5/8 patients and were followed only a few days later (median 12 days; range 2-17 days) by psychiatric or cognitive symptoms. Conversely, adult female patients rarely presented with a seizure initially (8/58, 14%, p < 0.001), and most of their seizures were generalized and were rapidly followed (median 2 days; range 1-7 days) by behavioral and psychiatric features. Additionally, in male patients the disease was rarely associated with a tumor (1/13 or 8%, a perineal schwannoma); in contrast, 41% of female patients had an associated tumor (95% of which were ovarian teratomas; p = 0.02 male vs female association with tumor). The incidences of abnormalities in ancillary tests, treatment modalities, clinical evolution, and outcome were equal for both subgroups.

Conclusion: Adult male patients who have partial seizures, normal MRI results, and no clear etiology should be tested for NMDAr-Abs to avoid any delays in treatment initiation. Adult female patients who had a seizure as the first symptom are infrequent when NMDAr-Abs encephalitis is diagnosed; additionally, their clinical pattern is different from male patients, with more generalized seizures and rapid development of behavioral and psychiatric symptoms. The differences in hormonal influence could contribute to this difference in clinical pattern.
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http://dx.doi.org/10.1212/WNL.0000000000000126DOI Listing
February 2014

Human epidermal growth factor receptor 2 overexpression in breast cancer of patients with anti-Yo--associated paraneoplastic cerebellar degeneration.

Neuro Oncol 2012 Apr 20;14(4):506-10. Epub 2012 Feb 20.

Service of Neurology and Pathology, Hospital Juan Ramón Jiménez, Huelva, Spain.

Isolated case reports suggest that breast tumors from patients with paraneoplastic cerebellar degeneration (PCD) and Yo antibodies overexpress human epidermal growth factor receptor 2 (HER2). HER2 overexpression is present in 15%-25% of breast cancers and is associated with poor prognosis. We retrospectively analyzed the status of HER2 in breast tumors of 27 patients with anti-Yo-associated PCD to evaluate whether HER2 overexpression in this group of patients is higher than expected. In addition, we analyzed HER2 status of 19 breast tumors from patients with paraneoplastic neurological syndromes and Ri antibodies to see whether HER2 was specifically related to anti-Yo-associated PCD. We also assessed cdr2 expression (the onconeural antigen recognized by Yo antibodies) in 21 HER2-positive breast tumors from patients without paraneoplastic neurological syndromes. HER2 was overexpressed in 26 patients (96.3%) with anti-Yo-associated PCD but only in 2 patients (10.5%) with paraneoplastic neurological syndromes associated with Ri antibodies (P< .0001). Only 5 (23.8%) of the 21 HER2-positive breast tumors showed cdr2 immunoreactivity. This study shows a very high frequency of HER2 overexpression in breast cancers in patients with anti-Yo-associated PCD but not in those from patients with Ri antibodies. Although the expression of cdr2 onconeural antigen is not high in HER2-positive breast cancers, HER2 overexpression seems to be an important requirement to develop an anti-Yo-associated PCD.
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http://dx.doi.org/10.1093/neuonc/nos006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309857PMC
April 2012