Specific clinical and radiological characteristics of anti-NMDA receptor autoimmune encephalitis following herpes encephalitis.

BACKGROUND: Herpes simplex virus encephalitis (HSE) frequently triggers secondary anti-N-methyl-D-aspartate receptor encephalitis (NMDARE), but markers predicting the occurrence of this entity (HSE-NMDARE) are lacking. METHODS: We conducted a retrospective description of patients with HSE-NMDARE diagnosed between July 2014 and August 2022 and compared them to both patients with regular forms of HSE and NMDARE. RESULTS: Among the 375 patients with NMDARE, 13 HSE-NMDARE were included. The median age was 19 years (0.5-73), 4/13 (31%) were children < 4 years old, and 7/13 (54%) were male. The median time between HSE and NMDARE onset was 30 days (21-46). During NMDARE, symptoms differed from HSE, including increased behavioral changes (92% vs 23%, p = 0.008), movements disorders (62% vs 0%, p = 0.013), and dysautonomia (54% vs 0%, p = 0.041). Compared to 21 patients with regular HSE, patients with HSE-NMDARE more often achieved severity-associated criteria on initial MRIs, with extensive lesions (11/11, 100% vs 10/21, 48%, p = 0.005) and bilateral diffusion-weighted imaging sequence abnormalities (9/10, 90% vs 6/21, 29%, p = 0.002). Compared to 198 patients with regular NMDARE, patients with HSE-NMDARE were more frequently males (7/13, 54% vs 43/198, 22%; p = 0.015) and children < 4 (4/13, 31% vs 14/198, 7%; p = 0.016), with a worse 12-month mRS (2[1-6] vs 1[0-6], p = 0.023). CONCLUSIONS: Herein, patients with HSE-NMDARE have a poorer long-term prognosis than patients with regular NMDARE. We report a greater rate of severity-associated criteria on initial MRIs for HSE-NMDARE compared to regular HSE, which may help identify patients with higher risk of HSE-NMDARE.

Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Anti-AGO1 Antibodies Identify a Subset of Autoimmune Sensory Neuronopathy.

BACKGROUND AND OBJECTIVES: Autoantibodies (Abs) improve diagnosis and treatment decisions of idiopathic neurologic disorders. Recently, we identified Abs against Argonaute (AGO) proteins as potential autoimmunity biomarkers in neurologic disorders. In this study, we aim to reveal (1) the frequency of AGO1 Abs in sensory neuronopathy (SNN), (2) titers and IgG subclasses, and (3) their clinical pattern including response to treatment. METHODS: This retrospective multicentric case/control study screened 132 patients with SNN, 301 with non-SNN neuropathies, 274 with autoimmune diseases (AIDs), and 116 healthy controls (HCs) for AGO1 Abs through ELISA. Seropositive cases were also tested for IgG subclasses, titers, and conformation specificity. RESULTS: AGO1 Abs occurred in 44 patients, comprising significantly more of those with SNN (17/132 [12.9%]) than those with non-SNN neuropathies (11/301 [3.7%]; p = 0.001), those with AIDs (16/274 [5.8%]; p = 0.02), or HCs (0/116; p < 0.0001). Ab titers ranged from 1:100 to 1:100,000. IgG subclass was mainly IgG1, and 11/17 AGO1 Ab-positive SNN (65%) had a conformational epitope. AGO1 Ab-positive SNN was more severe than AGO1 Ab-negative SNN (e.g., SNN score: 12.2 vs 11.0, p = 0.004), and they more frequently and more efficiently responded to immunomodulatory treatments than AGO1 Ab-negative SNN (7/13 [54%] vs 6/37 [16%], p = 0.02). Regarding the type of treatments more precisely, this significant difference was confirmed for the use of IV immunoglobulins (IVIg) but not for steroids or second-line treatments. Multivariate logistic regression adjusted for potential confounders showed that AGO1 Ab positivity was the only predictor of response to treatment (OR 4.93, 1.10-22.24 95% CI, p = 0.03). DISCUSSION: Although AGO Abs are not specific for SNN, based on our retrospective data, they may identify a subset of cases with SNN with more severe features and a possibly better response to IVIg. The significance of AGO1 Abs in clinical practice needs to be explored on a larger series.

Conformation-stabilizing ELISA and cell-based assays reveal patient subgroups targeting three different epitopes of AGO1 antibodies.

Autoantibodies (Abs) are biomarkers for many disease conditions and are increasingly used to facilitate diagnosis and treatment decisions. To guarantee high sensitivity and specificity, the choice of their detection method is crucial. Via cell-based assays, we recently found 21 patients with neurological diseases positive for antibodies against argonaute (AGO), 10 of which having a neuropathy (NP). Here, we established a simple and conformation-sensitive ELISA with the aim to distinguish between AGO1 Abs against conformational epitopes and non-conformational epitopes and to reveal further characteristics of AGO1 antibodies in NP and autoimmune disease (AID). In a retrospective multicenter case/control and observational study, we tested 434 patients with NP, 274 disease controls with AID, and 116 healthy controls (HC) for AGO1 Abs via conformation-stabilizing ELISA. Seropositive patients were also tested for conformation-specificity via comparative denaturing/stabilizing ELISA (CODES-ELISA), CBA positivity, AGO1 titers and IgG subclasses, and AGO2 reactivity. These parameters were statistically compared among different epitope-specific patient groups. We found Abs in 44 patients, including 28/434 (6.5%) NP, 16/274 (5.8%) AID, and 0/116 (0%) HC. Serum reactivity was consistently higher for AGO1 than AGO2. Globally among the 44 AGO1 Abs-positive patients, 42 were also tested in CBA for AGO1 Abs positivity and 15 (35.7%) were positive. Furthermore, 43 were tested for conformation-specificity and 32 (74.4%) bound a conformational epitope. Among the subgroups of highly positive patients (ELISA z-score >14) with sera binding conformational epitopes (n=23), 14 patient sera were also CBA positive and 9 bound a second conformational but CBA-inaccessible epitope. A third, non-conformational epitope was bound by 11/43 (15.6%). Among the epitope-specific patient subgroups, we found significant differences regarding the Abs titers, IgG subclass, and AGO2 reactivity. When comparing AGO1 Abs-positive NP versus AID patients, we found the conformation-specific and CBA inaccessible epitope significantly more frequently in AID patients. We conclude that 1) conformational ELISA was more sensitive than CBA in detecting AGO1 Abs, 2) serum reactivity is higher for AGO1 than for AGO2 at least for NP patients, 3) AGO1 Abs might be a marker-of-interest in 6.5% of NP patients, 4) distinguishing epitopes might help finding different patient subgroups.

Sensory neuronopathies, diagnostic criteria and causes.

PURPOSE OF REVIEW: To stress on the diagnostic strategy of sensory neuronopathies (SNN), including new genes and antibodies. RECENT FINDING: SNN involve paraneoplastic, dysimmune, toxic, viral and genetic mechanisms. About one-third remains idiopathic. Recently, new antibodies and genes have reduced this proportion. Anti-FGFR3 and anti-AGO antibodies are not specific of SNN, although SNN is predominant and may occur with systemic autoimmune diseases. These antibodies are the only marker of an underlying dysimmune context in two-thirds (anti-FGFR3 antibodies) and one-third of the cases (anti-AGO antibodies), respectively. Patients with anti-AGO antibodies may improve with treatment, which is less clear with anti-FGFR3 antibodies. A biallelic expansion in the RFC1 gene is responsible for the cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) in which SNN is a predominant manifestation. Most of the patients have an adult onset and are sporadic. The RFC1 mutation may represent one-third of idiopathic sensory neuropathies. Finally, the criteria for the diagnosis of paraneoplastic SNN have recently been updated. SUMMARY: The diagnostic of SNN relies on criteria distinguishing SNN from other neuropathies. The strategy in search of their cause now needs to include these recent findings.

Usefulness and prognostic value of diagnostic tests in patients with possible chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION/AIMS: Recent guidelines define chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and possible CIDP. The aims of our study were to evaluate the value of diagnostic tests to support the diagnosis of CIDP in patients with possible CIDP and to identify prognostic factors of therapeutic success. METHODS: We conducted an observational retrospective two-center study between 2014 and 2019. We selected patients with a clinical presentation suggesting CIDP, but whose electrodiagnostic (EDX) test results did not meet the EFNS/PNS 2021 criteria. We analyzed epidemiologic and clinical features, axonal loss on EDX, cerebrospinal fluid (CSF), somatosensory evoked potentials (SSEPs), plexus magnetic resonance imaging (MRI), nerve biopsy, and therapeutic response. RESULTS: We selected 75 patients, among whom 30 (40%) responded to treatment. The positivity rates of CSF analysis, MRI and SSEPs were not influenced by the clinical presentation or by the delay between symptom onset and medical assessment. A high protein level in CSF, female gender, and a relapsing-remitting course predicted the therapeutic response. DISCUSSION: It is important to properly diagnose suspected CIDP not meeting EFNS/PNS 2021 EDX criteria by using supportive criteria. Specific epidemiological factors and a raised CSF protein level predict a response to treatment. Further prospective studies are needed to improve diagnosis and the prognostic value of diagnostic tests in CIDP.

Prognostic Factors and Treatment Efficacy in Spinal Cord Sarcoidosis: An Observational Cohort With Long-term Follow-up.

BACKGROUND AND OBJECTIVES: Spinal cord sarcoidosis is a rare manifestation of sarcoidosis with a consequent risk of neurologic sequelae for the patient. We investigated prognostic factors and efficacy of immunosuppressive treatments in a longitudinal cohort. METHODS: We retrospectively studied patients with spinal cord sarcoidosis followed between 1995 and 2021 in 7 centers in France. Patients with definite, probable, or possible spinal cord sarcoidosis according to the Neurosarcoidosis Consortium Consensus Group criteria and with spinal cord involvement confirmed by MRI were included. We analyzed relapse or progression rate with a Poisson model, initial Rankin score with a linear model, and change in the Rankin score during follow-up with a logistic model. RESULTS: A total of 97 patients were followed for a median of 7.8 years. Overall mean relapse or progression rate was 0.17 per person-year and decreased over time. At last visit, 46 (47.4%) patients had a loss of autonomy (Rankin score ≥2). The main prognostic factors significantly associated with relapse or progression rate were gadolinium enhancement (relative rate [95% CI] 0.61 [0.4, 0.95]) or meningeal involvement (relative rate [95% CI] 2.05 [1.31, 3.19]) on spinal cord MRI and cell count (relative rate [95% CI] per 1 log increase 1.16 [1.01, 1.33]) on CSF analysis. Relapse or progression rate was not significantly associated with initial Rankin score or Expanded Disability Status Scale. Tumor necrosis factor-α (TNF-α) antagonists significantly decreased relapse or progression rate compared with corticosteroids alone (relative rate [95% CI] 0.33 [0.11, 0.98]). Azathioprine was significantly less effective than methotrexate on relapse or progression rate (relative rate [95% CI] 2.83 [1.04, 7.75]) and change in Rankin score (mean difference [95% CI] 0.65 [0.23, 1.08]). DISCUSSION: Regarding the relapse or progression rate, meningeal localization of sarcoidosis was associated with a worse prognosis, TNF-α antagonists resulted in a significant decrease compared to corticosteroids alone, and methotrexate was more effective than azathioprine. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with spinal cord neurosarcoidosis, TNF-α antagonists were associated with decreased relapse or progression rate compared to corticosteroids alone, but other therapies showed no significant benefit.

Anti-FGFR3 antibody epitopes are functional sites and correlate with the neuropathy pattern.

Antibodies against FGFR3 define a subgroup of sensory neuropathy (SN). The aim of this study was to identify the epitope(s) of anti-FGFR3 autoantibodies and potential epitope-dependent clinical subtypes. Using SPOT methodology, five specific candidate epitopes, three in the juxtamembrane domain (JMD) and two in the tyrosine kinase domain (TKD), were screened with 68 anti-FGFR3-positive patients and 35 healthy controls. The identified epitopes cover 6/15 functionally relevant sites of the protein. Four patients reacted with the JMD and 11 with the TKD, partly even in a phosphorylation-state dependent manner. The epitope could not be identified in the others. Patients with antibodies recognizing TKD exhibited a more severe clinical and electrophysiological impairment than others.

A multicenter cross-sectional French study of the impact of COVID-19 on neuromuscular diseases.

BACKGROUND: Due to their health condition, patients with neuromuscular diseases (NMD) are at greater risk of developing serious complications with COVID-19. The objective of this study was to analyze the prevalence of COVID-19 among NMD patients and the risk factors for its impact and severity during the first wave of the pandemic. Clinical data were collected from NMD-COVID-19 patients, between March 25, 2020 and May 11, 2020 in an anonymous survey carried out by expert physicians from the French Health Care Network Filnemus. RESULTS: Physicians reported 84 patients, including: 34 with myasthenia gravis, 27 with myopathy and 23 with neuropathy. COVID-19 had no effect on NMD for 48 (58%) patients and 48 (58%) patients developed low COVID-19 severity. COVID-19 caused the death of 9 (11%) NMD patients. Diabetic patients were at greater risk of dying. Patients with diabetes, hypertension or severe forms of NMD had a higher risk of developing a moderate or severe form of COVID-19. In our cohort, corticosteroids and other immunosuppressants were not significantly associated with higher COVID-19 severity for acquired NMD. CONCLUSION: During this period, a small percentage of French NMD patients was affected by COVID-19 compared to the general French population and COVID-19 had a limited short-term effect on them. Diabetes, hypertension and a severe degree of NMD were identified as risk factors of unfavorable outcome following COVID-19. Conversely, in our cohort of patients with acquired NMD, corticosteroids or other immunosuppressants did not appear to be risk factors for more severe COVID-19.

Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases.

OBJECTIVE: To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases. METHODS: Two distinct approaches (immunoprecipitation/mass spectrometry-based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples. RESULTS: Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments. CONCLUSIONS: AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls.

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.

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.

Impact of a frequent nearsplice SOD1 variant in amyotrophic lateral sclerosis: optimising SOD1 genetic screening for gene therapy opportunities.

OBJECTIVE: Mutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic. METHODS: We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases. RESULTS: We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation. CONCLUSIONS: Our results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.

Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis.

OBJECTIVE: To describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among patients with myasthenia gravis (MG) and identify factors associated with COVID-19 severity in patients with MG. METHODS: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS (Filière Neuromusculaire) network (between March 1, 2020, and June 8, 2020), including patients with MG with a confirmed or highly suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a PCR test from a nasopharyngeal swab or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology, thoracic CT scan, or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes. RESULTS: Among 3,558 patients with MG registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ± 19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p = 0.004); factors that were not associated included sex, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity. CONCLUSIONS: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes (odds ratio, 102.6 [4.4-2,371.9]). These results are important for establishing evidence-based guidelines for the management of patients with MG during the COVID-19 pandemic.

CIDP Antibodies Target Junction Proteins and Identify Patient Subgroups: An Autoantigenomic Approach.

OBJECTIVE: To discover systemic characteristics in the repertoires of targeted autoantigens in chronic inflammatory demyelinating polyneuropathy (CIDP), we detected the entire autoantigen repertoire of patients and controls and analyzed them systematically. METHODS: We screened 43 human serum samples, of which 22 were from patients with CIDP, 12 from patients with other neuropathies, and 9 from healthy controls via HuProt Human Proteome microarrays testing about 16,000 distinct human bait proteins. Autoantigen repertoires were analyzed via bioinformatical autoantigenomic approaches: principal component analysis, analysis of the repertoire sizes in disease groups and clinical subgroups, and overrepresentation analyses using Gene Ontology and PantherDB. RESULTS: The autoantigen repertoires enabled the identification of a subgroup of 10/22 patients with CIDP with a younger age at onset and a higher frequency of mixed motor and sensory CIDP. IV immunoglobulin therapy responders targeted 3 times more autoantigens than nonresponders. No CIDP-specific autoantibody is present in all patients; however, anchoring junction components were significantly targeted by 86.4% of patients with CIDP. There are potential novel CIDP-specific autoantigens such as the myelination- or axo-glial structure-related proteins actin-related protein 2/3 complex subunit 1B, band 4.1-like protein 2, cadherin-15, cytohesin-1, epidermal growth factor receptor, ezrin, and radixin. CONCLUSIONS: The repertoire of targeted autoantigens of patients with CIDP differs in a systematic degree from those of controls. Systematic autoantigenomic approaches can help to understand the disease and to discover novel bioinformatical tools and novel autoantigen panels to improve diagnosis, treatment, prognosis, or patient stratification.

Proper definition of the set of autoantibody-targeted antigens relies on appropriate reference group selection.

Autoimmune diseases are frequently associated with autoantibodies. Recently, large sets of autoantibody-targeted antigens ("autoantigen-omes") of patient and control sera have been revealed, enabling autoantigen-omic approaches. However, statistical standards for defining such autoantigen-omes are lacking. The z-score indicates how many standard deviations an antigen reactivity of a given sample is from the mean reactivity of the corresponding antigen in a reference group. Hence, it is a common measure to define significantly positive reactivity in autoantigen profiling approaches. Here, we address the risk of biased analyses resulting from unbalanced selection of the reference group. Three study groups were selected. Patients-of-interest were chronic inflammatory demyelinating polyneuropathy (CIDP); controls were other neuropathies (ONP); and healthy controls (HC). Each serum was screened for significant autoantigen reactivity using HuProt™ protein arrays. We compared three possible selections of reference groups for statistical z-score calculations: method#1, the control groups (ONP + HC); method #2, all groups together; method #3, the respective other groups (e.g., CIDP + HC for the ONP autoantigen-ome). The method selection seriously affected the size of the autoantigen-omes. Method #1 introduced a bias favoring significantly more antigens per patient in the CIDP group (for z >4: 19 ±â€¯3 antigens) than in the control groups (ONP: 2 ±â€¯1; HC: 0 ±â€¯0). The more balanced methods #2 and #3 did not result in significant differences. This contribution may help to avoid interpretation biases and to develop guidelines for population studies revealing autoantigen-omes via high throughput studies such as protein microarrays, immunoprecipitation with mass spectrometry, or phage display assays.

CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell-targeted therapies.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies.

OBJECTIVE: To describe the main syndrome and clinical course in a large cohort of patients with anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS). METHODS: Twenty-year retrospective nationwide study and systematic review of the literature. RESULTS: Thirty-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. CONCLUSIONS: Ri-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.

Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteins.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) with antibodies against neurofascin 155 (Nfasc155) or contactin-1 (CNTN1) have distinctive clinical features. Knowledge on their electrophysiological characteristics is still scarce. In this study, we are investigating whether these patients have specific electrophysiological characteristics. METHODS: The electrophysiological data from 13 patients with anti-Nfasc155 IgG4 antibodies, 9 with anti-CNTN1 IgG4 antibodies were compared with those of 40 consecutive CIDP patients without antibodies. RESULTS: All the patients with antibodies against Nfasc155 or CNTN1 fulfilled the EFNS/PNS electrodiagnostic criteria for definite CIDP. There was no electrophysiological difference between patients with anti-CNTN1 and anti-Nfasc155 antibodies. Nerve conduction abnormalities were heterogeneously distributed along nerves trunks and roots. They were more pronounced than in CIDP without antibodies. Motor conduction velocity on median nerve <24 m/s or motor velocity on ulnar nerve <26 m/s or motor distal latency on ulnar nerve >7.4 ms were predictive of positive antibodies against the node of Ranvier with a sensitivity of 59% and a specificity of 93%. CONCLUSIONS: Marked conduction abnormalities may suggest the presence of positive antibodies against the node of Ranvier. SIGNIFICANCE: Anti-Nfasc155 and anti-CNTN1 antibodies target the the paranodal axo-glial domain but are associated with nerve conduction abnormalities mimicking a "demyelinating" neuropathy.

Autoantigenomics: Holistic characterization of autoantigen repertoires for a better understanding of autoimmune diseases.

Autoimmune diseases are mostly characterized by autoantibodies in the patients' serum or cerebrospinal fluid, representing diagnostic or prognostic biomarkers. For decades, research has focused on single autoantigens or panels of single autoantigens. In this article, we advocate to broaden the focus by addressing the entire autoantigen repertoire in a systemic "omics-like" way. This approach aims to capture the enormous biodiversity in the sets of targeted antigens and pave the way toward a more holistic understanding of the concerted character of antibody-related humoral immune responses. Ongoing technological progress permits high-throughput screenings of thousands of autoantigens in parallel, e.g., via protein microarrays, phage display, or immunoprecipitation with mass spectrometry. We argue that the time is right for combining omics and autoantibody screening approaches into "autoantigenomics" as a novel omics subcategory. In this article, we introduce the concept of autoantigenomics, describe its roots and application options, and demarcate the method from related holistic approaches such as systems serology or immune-related transcriptomics and proteomics. We suggest the following extendable method set to be applied to autoantigen repertoires: (1) principal component analysis, (2) hierarchical cluster analysis, (3) partial least-square discriminant analysis or orthogonal projections to latent structures discriminant analysis, (4) analysis of the repertoire sizes in disease groups and clinical subgroups, (5) overrepresentation analyses using databases like those of Gene Ontology, Reactome Pathway, or DisGeNET, (6) analysis of pathways that are significantly targeted by specific repertoires, and (7) machine learning approaches. In an unsupervised way, these methods can identify clusters of autoantigens sharing certain functional or spatial properties, or clusters of patients comprising clinical subgroups potentially useful for patient stratification. In a supervised way, these methods can lead to prediction models that may eventually assist diagnosis and prognosis. The untargeted autoantigenomics approach allows for the systematic survey of antibody-related humoral immune responses. This may enhance our understanding of autoimmune diseases in a more comprehensive way compared to current single or panel autoantibodies approaches.