Main BETPSY results
Improvement of AE and PNS diagnosis and new biomarkers? (WP2)
Paraneoplastic neurologic syndromes (PNSs) are rare but now well-characterized immune-mediated neurologic diseases triggered by cancer and diagnosed by the presence of circulating autoantibodies. Among them, autoantibodies directed against intracellular neural antigens are strongly associated with the presence of an underlying cancer, and its detection is a cornerstone of PNS diagnosis. Autoimmune encephalitis constitute an emerging group of diseases for which the diagnosis and management may be challenging, and are usually associated with antibodies against neuroglial antigens used as biomarkers.
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Improvement of anti-GAD65 Abs diagnosis (WP2-WP3)
Neurological syndromes with antibodies against the glutamic acid decarboxylase 65 (GAD65-Ab) are a group of immune-mediated, usually non-paraneoplastic disorders including limbic encephalitis, cerebellar ataxia, and stiff person syndrome. No environmental factor has been strongly associated with these pathogeneses and the primary cause of neurological syndromes with antibodies against GAD 65 is unknown. However, genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases. A prompt diagnosis and treatment of patients with autoimmune disease with GAD65-Abs may lead to a better prognosis.
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Improvement of anti-LGI1 Abs diagnosis (WP2-WP3)
Patients with limbic encephalitis (LE) and antibodies against leucine-rich glioma-inactivated 1 (LGI1-Abs) are usually elderly men who develop severe anterograde amnesia, psychiatric symptoms, and seizures, along with medial temporal lobe abnormalities in brain MRI but, intriguingly, often without inflammatory signs in CSF routine analysis. Furthermore, contrary to other types of autoimmune encephalitis such as anti-NMDA receptor encephalitis, serum testing is more sensitive than CSF for the detection of LGI1-Abs in our experience, which has also been reported by others. The disease is also remarkably associated with the allele HLA-DRB1*07:01, which is found in nearly 90% of the patients. However, to date, whether patients without detectable LGI1-Abs in the CSF and those not carrying DRB1*07:01 show distinct particularities is still unclear. In addition, despite the response to immunotherapy in anti-LGI1 LE being satisfactory in most patients, the cognitive recovery is usually incomplete, and diverse prognostic factors have been reported. Nevertheless, the role of CSF positivity and human leukocyte antigen (HLA) on outcome has not been widely investigated.
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Improvement of anti-KELCH11 Abs diagnosis (WP2)
Antibodies targeting Kelch-like protein 11 (KLHL11-Abs) were initially identified in patients with a uniform clinical and oncological profile, namely young/middle-aged males with rhombencephalitis and testicular seminoma, potentially defining a new category of PNS. However, partially discordant findings suggesting that the clinical spectrum was more heterogeneous were recently reported, since half of the patients were female, some of them had co-occurring Abs targeting N-methyl-D-aspartate receptor and associated teratoma, and a few male patients had concomitant Ma2-Abs. Therefore, the exact clinical significance of KLHL11-Abs remains to be established clearly. Moreover, despite the detection of a T-cell-predominant infiltrate in brain samples and a KLHL11-specific T-cell response, the immunopathogenesis of this condition still remains elusive, in particular, the reason behind its frequent association with the otherwise rare spontaneously regressed (‘burned-out’) seminoma.
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Improvement of anti-AK5 Abs diagnosis (WP2)
Limbic encephalitis (LE) with antibodies against adenylate kinase 5 (AK5) is a rare non-paraneoplastic encephalitis, with only l6 patients reported to date. Its clinical picture is characterized by severe amnesia, mood disorders, and, intriguingly, a lack of seizures in most cases.This last feature contrasts with the most common non-paraneoplastic LE, antileucine-rich glioma-inactivated 1 (LGI1) and anti-contactin-associated protein-like 2 (CASPR2), which are typically associated with temporal lobe epilepsy. Besides clinical presentation, anti-AK5 LE differs from anti-LGI1 and anti-CASPR2 LE in the fact it is poorly responsive to immunotherapy. Furthermore, whereas antibodies against LGI1 and CASPR2 are thought to be pathogenic, based on the surface location of the antigens and in vitro and in vivo evidence, AK5 is a cytosolic antigen and AK5 antibodies are not believed to play a direct role in the disease pathogenesis. In addition, anti-LGI1 and anti-CASPR2 LE have both been recently found to have strong associations with specific human leukocyte antigen (HLA) class II haplotypes. In contrast, whether or not a particular HLA association exists in anti-AK5 LE is still unknown.
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Improvement of Ri-Abs syndromes diagnosis (WP2)
Ri-PNS is characterized by prominent cerebellar and brainstem involvement, followed by multisystem neurologic dysfunction, with a subacute or chronic/progressive course. This could mislead diagnosis toward a neurodegenerative or an inflammatory nonparaneoplastic condition, during which the presence of underlying tumor would not be investigated. Most patients are women with an associated breast tumor, whereas male patients have a wider cancer association. Neurologists should thus be aware of the more complex phenotype associated with Ri antibodies.
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Improvement of anti-NMDAR Abs diagnosis (WP2)
The discovery of autoantibodies (Abs) against neuroglial antigens has revolutionized the diagnosis and understanding of autoimmune neurologic diseases and has led to the clinical description of different subtypes of autoimmune encephalitis (AE), paraneoplastic neurologic syndromes (PNS), and inflammatory peripheral neuropathies.
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Detection of Anti-Ago Abs (WP2)
The discovery of autoantibodies (Abs) against neuroglial antigens has revolutionized the diagnosis and understanding of autoimmune neurologic diseases and has led to the clinical description of different subtypes of autoimmune encephalitis (AE), paraneoplastic neurologic syndromes (PNS), and inflammatory peripheral neuropathies.
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Improvement of CASPR2-Abs syndromes diagnosis (WP2)
Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) are found in patients with acquired neuromyotonia (NMT), limbic encephalitis (LE) and Morvan syndrome (MoS). Initial descriptions of MoS included both peripheral nerve hyperexcitability (PNH) and central nervous system (CNS) features but the co-occurrence of LE and NMT in some patients has raised doubts about whether these cases should be labelled as MoS. The recent description of a shared human leucocyte antigen (HLA) association (DRB1*11:01) has also supported the assumption of CASPR2-Abs disease as a single aetiopathogenic entity. Systematic studies of the distribution of neurological symptoms among CASPR2-Abs patients are therefore of major importance in order to establish a clear classification by describing the defining characteristics of each phenotype and the existence and range of overlap among them, which will provide better insight into their underlying mechanisms.
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Caracterization and Improvement of DNER-Abs diseases (WP2)
Ataxia with antibodies against Delta and Notch-like epidermal growth factor–related (DNER), or DNER ataxia, is a PCA associated with Hodgkin lymphoma.Anti-DNER antibodies correspond to a class of anti–Purkinje cell antibodies; they were known as anti-Tr antibodies until 2012, when DNER was identified as the antigenic target. DNER ataxia usually presents as a severe, subacute-onset ataxia and has a male predominance. It is important that there is no report on the long-term outcomes or whether such patients benefit from immunosuppressive treatments, although isolated cases of clinical improvement after treatment have been reported.
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Improvement of Yo PCD as well as others antibodies (GABABR, HU, Ri) associated with a cancer (WP4)
Paraneoplastic cerebellar degeneration (PCD) is a rare condition but is one of the commonest paraneoplastic neurologic disorders, mainly associated with breast and ovarian carcinomas. The main feature is a rapidly progressive cerebellar ataxia secondary to the specific destruction of Purkinje cells by cytotoxic T cells. About 50% of PCD cases are associated with anti-Yo autoantibodies (Yo-PCD), directed against Yo antigens CDR2 (cerebellar degeneration-related protein) and its paralogue CDR2L. The previous description of an uncommon and intense immune attack in Yo-PCD ovarian cancers highlighted that antitumor immunity has a lead role in paraneoplastic syndrome pathogenesis.
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Immune checkpoint inhibitors effects (WP2)
Immune checkpoint inhibitors (ICIs) are novel oncological treatments which show remarkable clinical efficacy in various malignant tumours, including melanoma and lung cancer. ICIs act by enhancing the patient’s immune system to fight cancer but it has been shown that ICIs can also induce paraneoplastic neurological syndromes (PNS).
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Epidemiology of PNS and AE (WP1-WP6)
Paraneoplastic neurological syndromes are rare and this rarity makes it difficult to collect large groups of patients in individual centers that would allow carrying out extensive epidemiological studies. Instead, most patients are referred to third-level neuroimmunology institutions, for antibody testing and experimental studies. Our study found an incidence of PNS that approximates 1/100,000 person-years and a prevalence of 4/100,000. Moreover, the incidence of PNS is increasing over time, probably due to increased awareness and improved detection techniques.
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HLA and Genetics (WP2-WP3)
Genetics is likely to play an important role in the pathogenesis of Ab-associated autoimmune neurological diseases. Indeed, it is not uncommon that patients or their relatives present with other systemic autoimmune diseases, suggesting a shared predisposition to self-tolerance loss. Human leukocyte antigen (HLA) is the main genetic factor related to autoimmune diseases, accounting for a half of known genetic predisposition. Although more than 200 associations between HLA and disease (immune-mediated or not) have been described, the underlying pathogenic mechanisms remain poorly defined.
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