Characterisation of TRIM46 autoantibody-associated paraneoplastic neurological syndrome

2021 ◽  
pp. jnnp-2021-326656
Author(s):  
Cristina Valencia-Sanchez ◽  
Andrew M Knight ◽  
M Bakri Hammami ◽  
Yong Guo ◽  
John R Mills ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Limbic Encephalitis ◽  
Staining Pattern ◽  
Clinical Information ◽  
Paraneoplastic Neurological Syndrome ◽  
Immunofluorescence Assay ◽  
Cerebellar Syndrome ◽  
Specific Staining ◽  
Transfected Cos7 Cell ◽  
Neuroendocrine Carcinomas

ObjectivesTo report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients.MethodsArchived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen.ResultsIgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25–87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration.ConclusionsThis study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.

scholarly journals Paraneoplastic neurological syndromes: clinical presentations and management

2021 ◽  
Vol 14 ◽  
pp. 175628642098532
Author(s):  
Michelle F. Devine ◽  
Naga Kothapalli ◽  
Mahmoud Elkhooly ◽  
Divyanshu Dubey
Keyword(s):  
Patient Outcomes ◽  
Neurological Disorders ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Management Strategies ◽  
Paraneoplastic Neurological Syndrome ◽  
Paraneoplastic Neurological Syndromes ◽  
Onconeural Antibodies ◽  
Clinical Presentations ◽  
Paraneoplastic Neurological Disorders

We provide an overview of the varied presentations of paraneoplastic neurological syndromes. We also review the onconeural antibodies and their particular oncological and neurological associations. Recognition of these syndromes and their oncological associations is crucial, as early diagnosis and management has been associated with better patient outcomes. Specific management strategies and prognosis vary widely depending on the underlying etiology. An understanding of the relevant clinical details, imaging findings, and other diagnostic information can help tailor treatment approaches. We provide an outline of the diagnostic evaluation and treatment of various paraneoplastic neurological disorders, presenting with central and/or peripheral nervous system involvement. We briefly discuss neurologic immune checkpoint inhibitor-related adverse events, which can occasionally present with paraneoplastic neurological syndrome phenotypes.

scholarly journals Novel Molecular Determinants of Response or Resistance to Immune Checkpoint Inhibitor Therapies in Melanoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Wenjing Zhang ◽  
Yujia Kong ◽  
Yuting Li ◽  
Fuyan Shi ◽  
Juncheng Lyu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Alkylating Agents ◽  
Clinical Information ◽  
Immune Checkpoints ◽  
Mutational Signatures ◽  
Driver Genes ◽  
Immune Resistance ◽  
Melanoma Patients

BackgroundImmune checkpoint inhibitor (ICI) therapy dramatically prolongs melanoma survival. Currently, the identified ICI markers are sometimes ineffective. The objective of this study was to identify novel determinants of ICI efficacy.MethodsWe comprehensively curated pretreatment somatic mutational profiles and clinical information from 631 melanoma patients who received blockade therapy of immune checkpoints (i.e., CTLA-4, PD-1/PD-L1, or a combination). Significantly mutated genes (SMGs), mutational signatures, and potential molecular subtypes were determined. Their association with ICI responses was assessed simultaneously.ResultsWe identified 27 SMGs, including four novel SMGs (COL3A1, NRAS, NARS2, and DCC) that are associated with ICI efficacy and well-known driver genes. COL3A1 mutations were associated with improved ICI overall survival (hazard ratio (HR): 0.64, 95% CI: 0.45–0.91, p = 0.012), whereas immune resistance was observed in patients with NRAS mutations (HR: 1.42, 95% CI: 1.10–1.82, p = 0.006). The presence of the tobacco smoking-related signature was significantly correlated with inferior prognoses (HR: 1.42, 95% CI: 1.11–1.82, p = 0.005). In addition, the signature resembling that of alkylating agents and a newly discovered signature both exhibited extended prognoses (both HR < 1, p < 0.05). Based on the activities of the extracted 6 mutational signatures, we identified one immune subtype that was significantly associated with better ICI outcomes (HR: 0.44, 95% CI: 0.23–0.87, p = 0.017).ConclusionWe uncovered several novel SMGs and re-annotated mutational signatures that are linked to immunotherapy response or resistance. In addition, an immune subtype was found to exhibit favorable prognoses. Further studies are required to validate these findings.

scholarly journals Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies

2020 ◽  
Vol 7 (3) ◽  
pp. e699 ◽  
Author(s):  
Claire Simard ◽  
Alberto Vogrig ◽  
Bastien Joubert ◽  
Sergio Muñiz-Castrillo ◽  
Géraldine Picard ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Information ◽  
Review Of The Literature ◽  
Cerebellar Syndrome ◽  
Neurologic Disorder ◽  
Paraneoplastic Neurologic Syndrome ◽  
Clinical Difference ◽  
Oculomotor Disturbances ◽  
Diagnostic Pitfalls ◽  
French Cohort

ObjectiveTo describe the main syndrome and clinical course in a large cohort of patients with anti–Ri-associated paraneoplastic neurologic syndrome (Ri-PNS).MethodsTwenty-year retrospective nationwide study and systematic review of the literature.ResultsThirty-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.ConclusionsRi-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.

scholarly journals Prevalence of anti-nuclear autoantibodies (ANA) in the general Polish population - analysis of the influence of sex and age on the variability of ANA.

2021 ◽  
Author(s):  
Paweł Krzemień ◽  
Sławomir Kasperczyk ◽  
Maciej Banach ◽  
Aleksandra Kasperczyk ◽  
Michał Dobrakowski ◽  
...  
Keyword(s):  
Staining Pattern ◽  
Population Analysis ◽  
Adult Population ◽  
Developed Countries ◽  
Immunofluorescence Assay ◽  
Polish Population ◽  
Serum Samples ◽  
Antinuclear Autoantibodies ◽  
Positive Results ◽  
Positive Population

Abstract Objectives: Diagnosis of Systemic Autoimmune Rheumatic Diseases using antinuclear autoantibodies (ANA) is dependent on many factors and varies between populations, such that the screening dilution used for indirect immunofluorescence assay (IIFA) should be defined locally for each population. The aim of the study was firstly, to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cut-off threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA staining patterns.Methods: The tested material included serum samples from 1731 participants (1043 women and 688 men) that were tested with the commercially available IIFA using two cut-off thresholds 1:100 and 1:160.Results: We found ANA in 260 participants (15.0%), but the percentage of positive results strongly depended on the cut-off level. For a cut-off threshold 1:100, the positive population was 19.5% and for the 1:160 cut-off threshold, it was 11.7%. The most prevalent ANA staining pattern was AC-2 Dense Fine speckled (50%), followed by AC-21 Reticular/AMA (14.38%) ANA were more common in women (72%); 64% of ANA positive patients were over 50 years of age.Conclusion: ANA prevalence in the Polish population is at a level observed in other highly developed countries. ANA were more prevalent in women and elderly individuals. In order to reduce the number of positive results released, we suggest that Polish laboratories should set 1:160 as the cut-off threshold.

scholarly journals GABAA receptor autoimmunity

2019 ◽  
Vol 6 (3) ◽  
pp. e552 ◽  
Author(s):  
Kevin O'Connor ◽  
Patrick Waters ◽  
Lars Komorowski ◽  
Anastasia Zekeridou ◽  
Chu-Yueh Guo ◽  
...  
Keyword(s):  
Validation Study ◽  
Clinical Course ◽  
Clinical Information ◽  
Laboratory Diagnosis ◽  
Immunofluorescence Assay ◽  
University Of Oxford ◽  
Antibody Staining ◽  
Neurologic Sequelae ◽  
Refractory Seizures ◽  
The University

ObjectiveWe sought to validate methods for detection and confirmation of GABAA receptor (R)-IgG and clinically characterize seropositive cases.MethodsArchived serum and CSF specimens (185 total) suspected to harbor GABAAR-IgG were evaluated by indirect immunofluorescence assay (IFA). Twenty-six specimens from 19 patients appeared suspicious for GABAAR–IgG positivity by IFA, based on prior reports and comparison with commercial GABAAR antibody staining. Aliquots of those specimens were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAAR-IgG by cell-based assays (CBAs) using HEK293-indicator cells transfected with plasmids encoding different GABAAR subunits.ResultsEight specimens (of 26 tested; 4 serums, 4 CSFs) from 5 patients were confirmed by CBA to be GABAAR-IgG positive. Patient IgGs were always reactive with α1β3 GABAAR subunits. One more patient was identified clinically after this validation study. Median age for the 6 patients at serologic diagnosis was 44 years (range, 1–71 years), and 4 of them were male. Among the 4 for whom clinical information was available (2 treated by the authors), all had encephalitis and antiepileptic drug refractory seizures. Three out of 4 patients treated with a combination of immunotherapies had good outcomes. The fourth, recognized to have an autoimmune cause late in the clinical course, had severe permanent neurologic sequelae and brain atrophy.ConclusionsThough not as common as NMDA-R encephalitis, GABAAR encephalitis generally has a characteristic clinical-radiologic presentation and is treatable, making accurate laboratory diagnosis critical.

scholarly journals Natalizumab may control immune checkpoint inhibitor–induced limbic encephalitis

2018 ◽  
Vol 5 (2) ◽  
pp. e439 ◽  
Author(s):  
Andreas F. Hottinger ◽  
Rita de Micheli ◽  
Vanessa Guido ◽  
Alexandra Karampera ◽  
Patric Hagmann ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Limbic Encephalitis ◽  
Checkpoint Inhibitor

scholarly journals Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG

Neurology ◽  
2019 ◽  
Vol 93 (10) ◽  
pp. e954-e963 ◽  
Author(s):  
Josephe A. Honorat ◽  
A. Sebastian Lopez-Chiriboga ◽  
Thomas J. Kryzer ◽  
Lars Komorowski ◽  
Madeleine Scharf ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Western Blot ◽  
Adaptor Protein ◽  
Sensory Neuropathy ◽  
Clinical Information ◽  
Sympathetic Ganglia ◽  
Immunofluorescence Assay ◽  
Mass Spectrometry Analysis ◽  
Antigen Specificity ◽  
Spectrometry Analysis

ObjectiveTo describe phenotypes, treatment response, and outcomes of autoimmunity targeting a synaptic vesicle coat protein, the neuronal (B2) form of adaptor protein–3 (AP3).MethodsArchived serum and CSF specimens (from 616,025 screened) harboring unclassified synaptic antibodies mimicking amphiphysin–immunoglobulin G (IgG) on tissue-based indirect immunofluorescence assay (IFA) were re-evaluated for novel IgG staining patterns. Autoantigens were identified by western blot and mass spectrometry. Recombinant western blot and cell-binding assay (CBA) were used to confirm antigen specificity. Clinical data were obtained retrospectively.ResultsSerum (10) and CSF (6) specimens of 10 patients produced identical IFA staining patterns throughout mouse nervous system tissues, most prominently in cerebellum (Purkinje neuronal perikarya, granular layer synapses, and dentate regions), spinal cord gray matter, dorsal root ganglia, and sympathetic ganglia. The antigen revealed by mass spectrometry analysis and confirmed by recombinant assays (western blot and CBA) was AP3B2 in all. Of 10 seropositive patients, 6 were women; median symptom onset age was 42 years (range 24–58). Clinical information was available for 9 patients, all with subacute onset and rapidly progressive gait ataxia. Neurologic manifestations were myeloneuropathy (3), peripheral sensory neuropathy (2), cerebellar ataxia (2), and spinocerebellar ataxia (2). Five patients received immunotherapy; none improved, but they did not worsen over the follow-up period (median 36 months; range 3–94). Two patients (both with cancer) died. One of 50 control sera was positive by western blot only (but not by IFA or CBA).ConclusionAP3B2 (previously named β-neuronal adaptin-like protein) autoimmunity appears rare, is accompanied by ataxia (sensory or cerebellar), and is potentially treatable.

scholarly journals IgLON5 antibody

2017 ◽  
Vol 4 (5) ◽  
pp. e385 ◽  
Author(s):  
Josephe A. Honorat ◽  
Lars Komorowski ◽  
Keith A. Josephs ◽  
Kai Fechner ◽  
Erik K. St Louis ◽  
...  
Keyword(s):  
Psychiatric Symptoms ◽  
Brain Mri ◽  
Disease Onset ◽  
Clinical Information ◽  
Immunofluorescence Assay ◽  
Bladder Function ◽  
Mri Findings ◽  
Respiratory Dysfunction ◽  
Insidious Onset ◽  
Mouse Tissues

Objective:To describe the phenotypes, treatment response, and outcome of IgLON5 autoimmunity.Methods:Archived serum and CSF specimens from 367 patients known to harbor unclassified antibodies which stained neural synapses diffusely (mimicking amphiphysin-IgG) were reevaluated by indirect immunofluorescence assay (IFA) using a composite of mouse tissues and recombinant IgLON5-transfected cell-based assay (CBA, Euroimmun).Results:Available specimens (serum, 25; CSF, 9) from 26/367 patients (7%) had identical IFA appearance and robust IgLON5 CBA positivity. Clinical information was available for 20/26 patients; 13 were women. Median disease-onset age was 62 years (range, 46–75 years). Most patients had insidious onset and progression of neurological symptoms affecting movement and sleep predominantly. Sleep disorders were sleep-disordered breathing (11) and parasomnias (3). Brainstem disorders were gait instability (14), dysphagia (10), abnormal eye movements (7), respiratory dysfunction (6), ataxia (5), craniocervical dystonia (3), and dysarthria (3). Findings compatible with hyperexcitability included myoclonus (3), cramps (3), fasciculations (2), and exaggerated startle (2). Neuropsychiatric disorders included cognitive dysfunction (6), psychiatric symptoms (5), and seizures (1). Dysautonomia, in 9, affected bladder function (7), gastrointestinal motility (3), thermoregulation (3), and orthostatic tolerance (1). Just 2 patients had coexisting autoimmune disease. Brain MRI findings were nonspecific and CSF was noninflammatory in all tested. Seven of 9 immunotherapy-treated patients improved: 6 of those 7 were stable at last follow-up. Three untreated patients died. Each IgLON5-IgG subclass (1–4) was readily detectable in ≥80% of specimens using CBA.Conclusions:IgLON5-IgG is diagnostic of a potentially treatable neurological disorder, where autoimmune clues are otherwise lacking.

scholarly journals Immune Checkpoint Inhibitor-Induced Limbic Encephalitis during Treatment with Atezolizumab in a Patient with Small-Cell Lung Cancer: A Case Report and Review of the Literature

2022 ◽  
Vol 2022 ◽  
pp. 1-5
Author(s):  
Koki Nakashima ◽  
Yoshiki Demura ◽  
Kosuke Kurokawa ◽  
Toshihiro Takeda ◽  
Norihiro Jikuya ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Limbic Encephalitis ◽  
Checkpoint Inhibitors ◽  
Brain Magnetic Resonance Imaging ◽  
Paraneoplastic Neurological Syndrome ◽  
Small Cell ◽  
Small Cell Lung

Paraneoplastic neurological syndrome (PNS) is associated with malignancies, including small-cell lung cancer. Recently, PNS cases among patients with small-cell lung cancer (SCLC) induced by immune checkpoint inhibitors have increased. We herein report a 66-year-old man with SCLC who developed disorientation, dysphagia, and gait disturbance after three courses of treatment with atezolizumab. Brain magnetic resonance imaging revealed a high-intensity area in the bilateral temporal lobes. Blood test results were positive for anti-Hu and anti-Zic4 antibodies, which led to the diagnosis of limbic encephalitis as PNS. Some symptoms improved with intravenous administration of steroids and immunoglobulins.

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