Sergio Muñiz-Castrillo

Bio: Sergio Muñiz-Castrillo is an academic researcher from Claude Bernard University Lyon 1. The author has contributed to research in topics: Medicine & Limbic encephalitis. The author has an hindex of 10, co-authored 27 publications receiving 279 citations. Previous affiliations of Sergio Muñiz-Castrillo include French Institute of Health and Medical Research & Pierre-and-Marie-Curie University.

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

Abstract: 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 The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic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 The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.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.

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

Abstract: 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.

Central nervous system complications associated with immune checkpoint inhibitors

Abstract: 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 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.

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

Abstract: 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-Barre 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%; p < 0.001). Anti-programmed cell death protein 1/programmed cell death ligand 1 was more frequent in myasthenic syndromes (50/58, 86%; p = 0.005) and less common in meningitis (2/13, 15%; p < 0.001) and cranial neuropathies (13/31, 42%; p = 0.005). Anti-cytotoxic T-lymphocyte antigen-4 ICIs were more frequent in meningitis (8/13, 62%; p < 0.001) and less common in encephalitis (2/56, 4%; p = 0.009) and myositis (12/136, 9%; p = 0.01). Combination of different ICIs was more frequent in cranial neuropathies (12/31, 39%; p = 0.005). Melanoma was more frequent in patients with peripheral neuropathies (64/94, 68%; p = 0.003) and less common in encephalitis (19/56, 34%; p = 0.001). The highest mortality rate was reached in myasthenic syndromes (28%). CONCLUSION Considering the increasing use of ICI therapy in the forthcoming future, this information can be valuable in assisting neurologists and oncologists in early n-irAEs diagnosis and treatment.

Epidemiology of paraneoplastic neurologic syndromes and autoimmune encephalitides in France

Abstract: 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 (CI95%: 2.9–3.4) compared with an expected incidence rate of 7.1 per million person-years (CI95%: 3.9–11.4). The national observed incidence rate for the antibody-positive AE subgroup increased from 1.4 per million person-years (CI95%: 1.2–1.7) in 2016 to 2.1 per million person-years (CI95%: 1.7–2.4) in 2018, thus surpassing the incidence rate of classical PNS (1.2 per million person-years [CI95%: 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.

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes

Abstract: 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.

Society for immunotherapy of cancer (sitc) clinical practice guideline on immune checkpoint inhibitor-related adverse events

Abstract: Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.

The Clinical Spectrum of Caspr2-Antibody Associated Disease (S12.008)

Abstract: Objective: We describe a large cohort of contactin-associated protein 2 (Caspr2) patients with this disorder and provide a framework for patient recognition. Background: Caspr2 is a membrane protein closely related to the voltage-gated potassium channel (VGKC). The clinical spectrum of Caspr2 antibodies is diverse and poorly known. Recognition of this disorder is important because it is treatable. Methods: Clinical information and patients’ serum and CSF samples were assessed at two neuroimmunology centers in Barcelona or Rotterdam. Antibody studies were investigated using previously reported brain immunohistochemistry and cell-based assays. Clinical information was obtained by the authors or provided by treating physicians after patients’informed consent.Results: Thirty-eight patients were included, 89[percnt] were male. The median age at symptom onset was 66 years. The nadir of the disease was reached at a median of 4 months, but in 30[percnt] of the patients was reached after 1 year. The most frequent syndromes included Morvan’s syndrome (29[percnt]), limbic encephalitis (LE) with additional symptoms (26[percnt]) or LE (16[percnt]). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy, cerebellar symptoms, peripheral nervous hyperexcitability, autonomic dysfunction, insomnia, neuropathic pain and weight loss. The presence of an underlying tumor (usually thymoma) occurred in 19[percnt] of the patients. IgG4 subclass antibodies were present in 94[percnt] of the patients. Full or partial response to treatment occurred in 93[percnt] of the patients; overall, 73[percnt] had a favorable outcome. Relapses occurred in 25[percnt] of the patients. Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients, but usually includes a set of well-established symptoms. The recognition of this spectrum of symptoms and the consideration of a protracted clinical course are essential for the early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement. Disclosure: Dr. Sonderen has nothing to disclose. Dr. Arino has nothing to disclose. Dr. Petit-Pedrol has nothing to disclose. Dr. Leypoldt has received personal compensation for activities with Grifols as a speaker. Dr. Kortvelyessy has nothing to disclose. Dr. Lancaster has nothing to disclose. Dr. Wirtz has nothing to disclose. Dr. Schreurs has nothing to disclose. Dr. Sillevis Smitt has nothing to disclose. Dr. Graus has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity from the board of Up-To-Date. Dr. Dalmau has received royalty payments from Memorial Sloan-Kettering Cancer Center. Dr. Dalmau has received research support from Euroimmun. Dr. Titulaer has nothing to disclose.

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum.

Abstract: Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.

Autoantibodies in neurological disease

Abstract: The realization that autoantibodies can contribute to dysfunction of the brain has brought about a paradigm shift in neurological diseases over the past decade, offering up important novel diagnostic and therapeutic opportunities. Detection of specific autoantibodies to neuronal or glial targets has resulted in a better understanding of central nervous system autoimmunity and in the reclassification of some diseases previously thought to result from infectious, 'idiopathic' or psychogenic causes. The most prominent examples, such as aquaporin 4 autoantibodies in neuromyelitis optica or NMDAR autoantibodies in encephalitis, have stimulated an entire field of clinical and experimental studies on disease mechanisms and immunological abnormalities. Also, these findings inspired the search for additional autoantibodies, which has been very successful to date and has not yet reached its peak. This Review summarizes this rapid development at a point in time where preclinical studies have started delivering fundamental new data for mechanistic understanding, where new technologies are being introduced into this field, and - most importantly - where the first specifically tailored immunotherapeutic approaches are emerging.