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

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 (p = 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

Web-based telemonitoring and delivery of caregiver support for patients with Parkinson disease after deep brain stimulation: protocol

The increasing number of patients, the high costs of management, and the chronic progress of the disease that prevents patients from performing even simple daily activities make Parkinson disease (PD) a complex pathology with a high impact on society. In particular, patients implanted with deep brain stimulation (DBS) electrodes face a highly fragile stabilization period, requiring specific support at home. However, DBS patients are followed usually by untrained personnel (caregivers or family), without specific care pathways and supporting systems

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

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

Anti-Hu Antibodies in Patients With Neurologic Side Effects of Immune Checkpoint Inhibitors

Background and ObjectivesTo clinically characterize post-immune checkpoint inhibitor (ICI) Hu antibody (Ab) neurologic disorders, we analyzed Hu-Ab-positive patients with neurologic immune-related adverse events (n-irAEs) and compared them with patients with other n-irAEs, ICI-naive patients with Hu-Ab paraneoplastic neurologic syndromes (PNSs) identified in the same study center, and those with Hu-Ab n-irAEs reported elsewhere.MethodsPatients whose samples were sent to the French reference center for a suspicion of n-irAE (2015-2021) were identified; those with a final diagnosis of n-irAE and Hu-Ab were included. Control groups included patients with a final diagnosis of n-irAE occurring during the same period as the patients included (2018-2021) but without Hu-Ab, and ICI-naive patients with Hu-Ab PNS diagnosed during the same period; a systematic review was performed to identify previous reports.ResultsEleven patients with Hu-Ab and n-irAEs were included (median age, 66 years, range 44-76 years; 73% men). Ten patients had small cell lung cancer, and 1 had lung adenocarcinoma. The median follow-up from onset was 3 months (range 0.5-18 months). Compared with those with other n-irAEs (n = 63), Hu-Ab-positive patients had more frequently co-occurring involvement of both central and peripheral nervous systems (36% vs 8%, p = 0.02) and limbic (54% vs 14%, p 3) at diagnosis was higher among Hu-Ab n-irAEs (91% vs 52%, p = 0.02). Patients with Hu-Ab had also poorer outcome (100% vs 28%, p < 0.01) and higher mortality (91% vs 46%, p < 0.01). There was no significant difference in terms of clinical features between Hu-Ab n-irAEs and ICI-naive Hu-Ab PNS (n = 92), but there was a poorer outcome (56/78, 71%, p < 0.01) and higher mortality (26%, p < 0.01) among the former. No significant difference was found between the patients reported herein and those in the literature.DiscussionThe presence of Hu-Ab identifies a subgroup of n-irAEs that consistently reproduce the phenotypes of Hu-Ab-related PNS, supporting the hypothesis of ICI triggering or unmasking PNS. As these patients show high disability and mortality, further studies are required to investigate the underlying immunopathogenic mechanisms and to improve the outcome of Hu-Ab n-irAEs

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

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.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.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.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.Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

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

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

Facteurs déclenchant et pathogenèse des syndromes neurologiques paranéoplasiques

Les syndromes neurologiques paranéoplasiques (SNP) sont des affections rares à médiation immunitaire déclenchées par la présence d'un cancer et associées à des anticorps neuronaux spécifiques. Les SNP sont le produit d’une réaction du système immunitaire contre une tumeur entrainant une destruction de neurones du système nerveux. Ces mécanismes sont probablement liés à une combinaison de caractéristiques de l'hôte, du cancer associé et de facteurs environnementaux. Il est intéressant de noter que les patients atteints de SNP semblent avoir un meilleur pronostic tumoral que ceux qui ont un cancer histologiquement identique non associé à un SNP, ce qui indique que l'étude des troubles paranéoplasiques peut fournir des informations importantes pour la compréhension de l'immunité anti-cancéreuse. De plus, ils offrent une perspective unique pour comprendre les mécanismes sous-jacents à l'attaque des neurones dans le cadre des maladies autoimmunes. Malgré de nombreuses avancées dans la caractérisation clinique et biologique de ces syndromes, la pathogenèse du SNP reste encore largement obscure. L'hypothèse principale est qu'une réponse immunitaire aberrante est dirigée vers des antigènes neuronaux qui sont physiologiquement exprimés par le système nerveux et anormalement par les cellules cancéreuses. Cependant les mécanismes exacts de cette réaction immunitaire croisée sont totalement inconnus. A cet égard, l'analyse du déclenchement et des facteurs prédisposant aux SNP peuvent fournir des indices importants sur l'immunopathogenèse de ces troubles neurologiques. Il a été récemment démontré dans des contextes expérimentaux et cliniques que l'immunothérapie du cancer à l'aide d'inhibiteurs de points de contrôle immunitaires (ICI) peut déclencher des troubles neurologiques similaires au SNP. Cependant, le spectre clinique des troubles neurologiques déclenchés par l'immunothérapie reste incomplètement compris, principalement en raison de la rareté de ces événements indésirables. Il a également été montré récemment que certaines tumeurs de patients atteints de SNP avaient des caractéristiques moléculaires distinctes qui pourraient expliquer la rupture de tolérance immune, mais aucune étude n'a examiné jusqu'à présent ces spécificités dans le cancer le plus fréquemment associée au SNP, qui est le cancer du poumon à petites cellules (CPPC). Notre projet de thèse visait à examiner les spécificités tumorales des SNP et le rôle de l'immunothérapie du cancer en tant que déclencheurs de SNP, afin d'améliorer nos connaissances cliniques et biologiques de ces syndromes et comprendre la physiopathologie de ces affections. Dans la première partie de ce projet de doctorat, qui comprend 4 études différentes et successives, nous décrivons le spectre clinique, les associations d'anticorps et la nature des troubles neurologiques déclenchés par les ICI. Dans la deuxième partie de ce travail de thèse, qui comprend 2 études, nous nous sommes intéressés aux mécanismes de la rupture de tolérance immunitaire dans les SNP. En conclusion, le présent projet de doctorat soutient le point de vue selon lequel l'association entre le cancer et le SNP est causale, et pas seulement temporelle, comme le soulignent les critères de diagnostic mis à jour. Des signatures génétiques spécifiques du cancer sont probablement responsables du déclenchement de la réponse immunitaire, qui peut à son tour entraîner une attaque immunitaire efficace contre la tumeur. De plus, le traitement par ICI peut induire des syndromes cliniquement et biologiquement similaires au SNP.Paraneoplastic neurological syndromes (PNS) are rare immune-mediated conditions triggered by the presence of cancer and associated with specific neuronal antibodies. PNS occur at the intersection between immune system, tumor, and nervous system, where a combination of host characteristics, cancer-related specificities, and environmental factors may play a role. Interestingly, patients with PNS have a better prognosis than those with histologically identical cancers not associated to PNS, which indicates that the study of paraneoplastic disorders can provide important insights for the comprehension of anti-cancer immunity. In addition, they provide a unique perspective into the mechanisms underlying the attack of neurons in antibody-mediated neurological disorders. Despite many recent advances in the clinical and antibody characterization, the pathogenesis of PNS still remains largely obscure. The main hypothesis is that an aberrant immune response is directed towards neuronal antigens that are physiologically expressed by the nervous system and ectopically by cancer cells, however the exact mechanisms of this cross-immune reaction are totally unknown. In this regard, the analysis of triggering and predisposing factors of PNS can provide important clues into the immunopathogenesis of these neurological conditions. Firstly, it was recently demonstrated in both experimental and clinical settings that cancer immunotherapy using immune checkpoint inhibitors (ICI) can trigger neurological disorders similar to PNS. However, the clinical spectrum of these neurological disorders triggered by ICI remains incompletely understood, mostly due to the rarity of these adverse events. Secondly, it was speculated that the tumors of patients with PNS may have distinct molecular characteristics which might explain the immune tolerance breakdown, but no study has examined so far these specificities in the malignancy most frequently associated with PNS, which is small-cell lung cancer (SCLC). Thirdly, the immune mechanism of PNS which results in tumor regression still need to be elucidated. The present PhD project aimed at examining tumor specificities in PNS and cancer immunotherapy as relevant triggers of PNS, in order to improve our clinical and biological knowledge of these syndromes and the understanding on the pathophysiology of these conditions as well as to provide some answers to the three major points discussed above. In the first part of this PhD project, which includes 4 studies, we describe clinical spectrum, antibody associations, and outcome of neurological disorders triggered by ICI. In the second part of this PhD project, which includes 2 studies, we investigated the mechanisms through which the rupture of immune tolerance occurs in paraneoplastic disorders, leading to an immune attack against both the tumor and the nervous system. In conclusion, the present PhD project supports the view that the association between cancer and PNS is causal, and not merely temporal, as highlighted in the updated diagnostic criteria. Specific genetic signatures of cancer are likely responsible for triggering the immune response, which can in turn results in an efficient immune attack against the tumour. In addition, ICI treatment can induce syndromes clinically and biologically similar to PNS

Facteurs déclenchant et pathogenèse des syndromes neurologiques paranéoplasiques

Paraneoplastic neurological syndromes (PNS) are rare immune-mediated conditions triggered by the presence of cancer and associated with specific neuronal antibodies. PNS occur at the intersection between immune system, tumor, and nervous system, where a combination of host characteristics, cancer-related specificities, and environmental factors may play a role. Interestingly, patients with PNS have a better prognosis than those with histologically identical cancers not associated to PNS, which indicates that the study of paraneoplastic disorders can provide important insights for the comprehension of anti-cancer immunity. In addition, they provide a unique perspective into the mechanisms underlying the attack of neurons in antibody-mediated neurological disorders. Despite many recent advances in the clinical and antibody characterization, the pathogenesis of PNS still remains largely obscure. The main hypothesis is that an aberrant immune response is directed towards neuronal antigens that are physiologically expressed by the nervous system and ectopically by cancer cells, however the exact mechanisms of this cross-immune reaction are totally unknown. In this regard, the analysis of triggering and predisposing factors of PNS can provide important clues into the immunopathogenesis of these neurological conditions. Firstly, it was recently demonstrated in both experimental and clinical settings that cancer immunotherapy using immune checkpoint inhibitors (ICI) can trigger neurological disorders similar to PNS. However, the clinical spectrum of these neurological disorders triggered by ICI remains incompletely understood, mostly due to the rarity of these adverse events. Secondly, it was speculated that the tumors of patients with PNS may have distinct molecular characteristics which might explain the immune tolerance breakdown, but no study has examined so far these specificities in the malignancy most frequently associated with PNS, which is small-cell lung cancer (SCLC). Thirdly, the immune mechanism of PNS which results in tumor regression still need to be elucidated. The present PhD project aimed at examining tumor specificities in PNS and cancer immunotherapy as relevant triggers of PNS, in order to improve our clinical and biological knowledge of these syndromes and the understanding on the pathophysiology of these conditions as well as to provide some answers to the three major points discussed above. In the first part of this PhD project, which includes 4 studies, we describe clinical spectrum, antibody associations, and outcome of neurological disorders triggered by ICI. In the second part of this PhD project, which includes 2 studies, we investigated the mechanisms through which the rupture of immune tolerance occurs in paraneoplastic disorders, leading to an immune attack against both the tumor and the nervous system. In conclusion, the present PhD project supports the view that the association between cancer and PNS is causal, and not merely temporal, as highlighted in the updated diagnostic criteria. Specific genetic signatures of cancer are likely responsible for triggering the immune response, which can in turn results in an efficient immune attack against the tumour. In addition, ICI treatment can induce syndromes clinically and biologically similar to PNS.Les syndromes neurologiques paranéoplasiques (SNP) sont des affections rares à médiation immunitaire déclenchées par la présence d'un cancer et associées à des anticorps neuronaux spécifiques. Les SNP sont le produit d’une réaction du système immunitaire contre une tumeur entrainant une destruction de neurones du système nerveux. Ces mécanismes sont probablement liés à une combinaison de caractéristiques de l'hôte, du cancer associé et de facteurs environnementaux. Il est intéressant de noter que les patients atteints de SNP semblent avoir un meilleur pronostic tumoral que ceux qui ont un cancer histologiquement identique non associé à un SNP, ce qui indique que l'étude des troubles paranéoplasiques peut fournir des informations importantes pour la compréhension de l'immunité anti-cancéreuse. De plus, ils offrent une perspective unique pour comprendre les mécanismes sous-jacents à l'attaque des neurones dans le cadre des maladies autoimmunes. Malgré de nombreuses avancées dans la caractérisation clinique et biologique de ces syndromes, la pathogenèse du SNP reste encore largement obscure. L'hypothèse principale est qu'une réponse immunitaire aberrante est dirigée vers des antigènes neuronaux qui sont physiologiquement exprimés par le système nerveux et anormalement par les cellules cancéreuses. Cependant les mécanismes exacts de cette réaction immunitaire croisée sont totalement inconnus. A cet égard, l'analyse du déclenchement et des facteurs prédisposant aux SNP peuvent fournir des indices importants sur l'immunopathogenèse de ces troubles neurologiques. Il a été récemment démontré dans des contextes expérimentaux et cliniques que l'immunothérapie du cancer à l'aide d'inhibiteurs de points de contrôle immunitaires (ICI) peut déclencher des troubles neurologiques similaires au SNP. Cependant, le spectre clinique des troubles neurologiques déclenchés par l'immunothérapie reste incomplètement compris, principalement en raison de la rareté de ces événements indésirables. Il a également été montré récemment que certaines tumeurs de patients atteints de SNP avaient des caractéristiques moléculaires distinctes qui pourraient expliquer la rupture de tolérance immune, mais aucune étude n'a examiné jusqu'à présent ces spécificités dans le cancer le plus fréquemment associée au SNP, qui est le cancer du poumon à petites cellules (CPPC). Notre projet de thèse visait à examiner les spécificités tumorales des SNP et le rôle de l'immunothérapie du cancer en tant que déclencheurs de SNP, afin d'améliorer nos connaissances cliniques et biologiques de ces syndromes et comprendre la physiopathologie de ces affections. Dans la première partie de ce projet de doctorat, qui comprend 4 études différentes et successives, nous décrivons le spectre clinique, les associations d'anticorps et la nature des troubles neurologiques déclenchés par les ICI. Dans la deuxième partie de ce travail de thèse, qui comprend 2 études, nous nous sommes intéressés aux mécanismes de la rupture de tolérance immunitaire dans les SNP. En conclusion, le présent projet de doctorat soutient le point de vue selon lequel l'association entre le cancer et le SNP est causale, et pas seulement temporelle, comme le soulignent les critères de diagnostic mis à jour. Des signatures génétiques spécifiques du cancer sont probablement responsables du déclenchement de la réponse immunitaire, qui peut à son tour entraîner une attaque immunitaire efficace contre la tumeur. De plus, le traitement par ICI peut induire des syndromes cliniquement et biologiquement similaires au SNP