We summarize the recent discoveries on genetic predisposition to autoimmune encephalitis and paraneoplastic neurological syndromes (PNS), emphasizing clinical and pathophysiological implications.
The ...human leukocyte antigen (HLA) is the most studied genetic factor in autoimmune encephalitis and PNS. The HLA haplotype 8.1, which is widely known to be related to systemic autoimmunity, has been only weakly associated with a few types of autoimmune encephalitis and PNS. However, the strongest and most specific associations have been reported in a subgroup of autoimmune encephalitis that comprises antileucine-rich glioma-inactivated 1 (LGI1) limbic encephalitis, associated with DRB1∗07 : 01 , anticontactin-associated protein-like 2 (CASPR2) limbic encephalitis, associated with DRB1∗11 : 01 , and anti-IgLON5 disease, associated with DRB1∗10 : 01∼DQA1∗01∼DQB1∗05 . Non-HLA genes have been poorly investigated so far in autoimmune encephalitis, mainly in those lacking HLA associations such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, with only a few genome-wide association studies (GWAS) reporting equivocal results principally limited by small sample size.
Genetic predisposition seems to be driven mostly by HLA in a group of autoimmune encephalitis characterized by being nonparaneoplastic and having predominantly IgG4 autoantibodies. The contribution of non-HLA genes, especially in those diseases lacking known or strong HLA associations, will require large cohorts enabling GWAS to be powerful enough to render meaningful results.
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 The 2004 PNS criteria are ...partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic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 The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project.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.
ObjectiveSmall‐cell lung cancer (SCLC) is the malignancy most frequently associated with paraneoplastic neurological syndromes (PNS) and can trigger different antibody responses against intracellular ...(Hu) or neuronal surface (GABABR) antigens. Our aim was to clarify whether the genomic and transcriptomic features of SCLC are different in patients with anti‐GABABR or anti‐Hu PNS compared with SCLC without PNS.MethodsA total of 76 SCLC tumor samples were collected: 34 anti‐Hu, 14 anti‐GABABR, and 28 SCLC without PNS. The study consisted of 4 steps: (1) pathological confirmation; (2) next generation sequencing using a panel of 98 genes, including those encoding the autoantibodies targets ELAVL1‐4, GABBR1‐2, and KCTD16; (3) genome‐wide copy number variation (CNV); and (4) whole‐transcriptome RNA sequencing.ResultsCNV analysis revealed that patients with anti‐GABABR PNS commonly have a gain in chromosome 5q, which contains KCTD16, whereas anti‐Hu and control patients often harbor a loss. No significantly different number of mutations regarding any onconeural genes was observed. Conversely, the transcriptomic profile of SCLC was different, and the differentially expressed genes allowed effective clustering of the samples into 3 groups, reflecting the antibody‐based classification, with an overexpression of KCTD16 specific to anti‐GABABR PNS. Pathway analysis revealed that tumors of patients with anti‐GABABR encephalitis were enriched in B‐cell signatures, as opposed to those of patients with anti‐Hu, in which T‐cell‐ and interferon‐γ‐related signatures were overexpressed.InterpretationSCLC genetic and transcriptomic features differentiate anti‐GABABR, anti‐Hu, and non‐PNS tumors. The role of KCTD16 appears to be pivotal in the tumor immune tolerance breakdown of anti‐GABABR PNS. ANN NEUROL 2023;94:1102–1115
Leucine-Rich Glioma Inactivated protein 1 (LGI1) is a secreted neuronal protein highly expressed in the central nervous system and high amount are found in the hippocampus. An alteration of its ...function has been described in few families of patients with autosomal dominant temporal lobe epilepsy (ADLTE) or with autoimmune limbic encephalitis (LE), both characterized by epileptic seizures. Studies have shown that LGI1 plays an essential role during development, but also in neuronal excitability through an action on voltage-gated potassium Kv1.1 channels, and in synaptic transmission by regulating the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R). Over the last decade, a growing number of studies investigating LGI1 functions have been published. They aimed to improve the understanding of LGI1 function in the regulation of neuronal networks using different animal and cellular models. LGI1 appears to be a major actor of synaptic regulation by modulating trans-synaptically pre- and post-synaptic proteins. In this review, we will focus on LGI1 binding partners, “A Disintegrin And Metalloprotease (ADAM) 22 and 23”, the complex they form at the synapse, and will discuss the effects of LGI1 on neuronal excitability and synaptic transmission in physiological and pathological conditions. Finally, we will highlight new insights regarding N-terminal Leucine-Rich Repeat (LRR) domain and C-terminal Epitempin repeat (EPTP) domain and their potentially distinct role in LGI1 function.
Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these ...biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known.
We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive.
Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases.
TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.
The post-acute evolution of the cognitive and psychiatric features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been poorly investigated so far. In recent work published in Lancet ...Neurology, Guasp et al. report that the neuropsychiatric symptoms of the post-acute phase mirror those observed in schizophrenia, although only patients with anti-NMDAR encephalitis showed improvements of their symptoms.
OBJECTIVETo 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.
METHODSRetrospective nationwide study of all patients with Ma2-PNS developed during ICI treatment between 2017 and 2018.
RESULTSOur 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.
CONCLUSIONSWe 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.
Recently, several autoimmune neurological diseases have been defined by the presence of autoantibodies against different antigens of the nervous system. These autoantibodies have been demonstrated to ...be specific and useful biomarkers, and most of them are also pathogenic. These aspects have increased the value of autoantibodies in neurological practice, as they enable to establish more accurate diagnosis and to better understand the underlying mechanisms of the autoimmune neurological diseases when they are compared to those lacking them. Nevertheless, the exact mechanisms leading to the autoimmune response are still obscure. Genetic predisposition is likely to play a role in autoimmunity, HLA being the most reported genetic factor. Herein, we review the current knowledge about associations between HLA and autoimmune neurological diseases with autoantibodies. We report the main alleles and haplotypes, and discuss the clinical and pathogenic implications of these findings.
Paraneoplastic neurological syndromes (PNSs) are rare complications of systemic cancers that can affect all parts of the central and/or peripheral nervous system. A body of experimental and clinical ...data has demonstrated that the pathogenesis of PNSs is immune-mediated. Nevertheless, the mechanisms leading to immune tolerance breakdown in these conditions remain to be elucidated. Despite their rarity, PNSs offer a unique perspective to understand the complex interplay between cancer immunity, effect of immune checkpoint inhibitors (ICIs), and mechanisms underlying the attack of neurons in antibody-mediated neurological disorders, with potentially relevant therapeutic implications. In particular, it is reported that ICI treatment can unleash PNSs and that the immunopathological features of PNS-related tumors are distinctive, showing prominent tumor-infiltrating lymphocytes and germinal center reactions. Intriguingly, similar pathological substrates have gained further attention as potential biomarkers of ICI-sensitivity and oncological prognosis. Moreover, the genetic analysis of PNS-associated tumors has revealed specific molecular signatures and mutations in genes encoding onconeural proteins, leading to the production of highly immunogenic neoantigens. Other than PNSs, autoimmune encephalitides (AEs) comprise a recently described group of disorders characterized by prominent neuropsychiatric symptoms, diverse antibody spectrum, and less tight association with cancer. Other triggering factors seem to be involved in AEs. Recent data have shed light on the importance of preceding infections (in particular, herpes simplex virus encephalitis) in inducing neurological autoimmune disorders in susceptible individuals (those with a selective deficiency in the innate immune system). In addition, in some AEs (e.g. LGI1-antibody encephalitis) an association with specific host-related factors e.g., human leukocyte antigen (HLA) was clearly demonstrated. We provide herein a comprehensive review of the most recent findings in the field of PNSs and AEs, with particular focus on their triggering factors and immunopathogenesis.
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