Recurrent CNTN1 antibody-positive nodopathy: a case report and literature review.

Contactin-1 (CNTN1) antibody-positive nodopathy is rare and exhibits distinct clinical symptoms such as tremors and ataxia. However, the mechanisms of these symptoms and the characteristics of the cerebral spinal fluid (CSF) remain unknown. Here, we report a case of recurrent CNTN1 antibody-positive nodopathy. Initially, a 45-year-old woman experiencing numbness in the upper limbs and weakness in the lower limbs was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Eleven years later, her symptoms worsened, and she began to experience tremors and ataxia. Tests for serum CNTN1, GT1a, and GQ1b antibodies returned positive. Subsequently, she was diagnosed with CNTN1 antibody-positive nodopathy and underwent plasmapheresis therapy, although the treatment's efficacy was limited. To gain a deeper understanding of the disease, we conducted a comprehensive literature review, identifying 52 cases of CNTN1 antibody-positive nodopathy to date, with a tremor prevalence of 26.9%. Additionally, we found that the average CSF protein level in CNTN1 antibody-positive nodopathy was 2.57 g/L, with 87% of patients exhibiting a CSF protein level above 1.5 g/L. We present a rare case of recurrent CNTN1 antibody-positive nodopathy. Our findings indicate a high prevalence of tremor (26.9%) and elevated CSF protein levels among patients with CNTN1 antibody-positive nodopathy.

Zhao M ，Chen G ，Li S ，Li X ，Chen H ，Lou Z ，Ouyang H ，Zhan Y ，Du C ，Zhao Y ... -  《Frontiers in Immunology》

Autoimmune nodopathy with anti-contactin 1 antibody characterized by cerebellar dysarthria: a case report and literature review.

Autoimmune nodopathy (AN) has emerged as a novel diagnostic category that is pathologically different from classic chronic inflammatory demyelinating polyneuropathy. Clinical manifestations of AN include sensory or motor neuropathies, sensory ataxia, tremor, and cranial nerve involvement. AN with a serum-positive contactin-1 (CNTN1) antibody usually results in peripheral nerve demyelination. In this study, we reported a rare case of AN with CNTN1 antibodies characterized by the presence of CNTN1 antibodies in both serum and cerebrospinal fluid, which is associated with cerebellar dysarthria. A 25-year-old man was admitted to our hospital due to progressive dysarthria with limb tremors. The patient was initially diagnosed with peripheral neuropathy at a local hospital. Three years after onset, he was admitted to our hospital due to dysarthria, apparent limb tremor, and limb weakness. At that time, he was diagnosed with spinocerebellar ataxia. Eight years post-onset, during his second admission, his condition had notably deteriorated. His dysarthria had evolved to typical distinctive cerebellar characteristics, such as tremor, loud voice, stress, and interrupted articulation. Additionally, he experienced further progression in limb weakness and developed muscle atrophy in the distal limbs. Magnetic resonance imaging (MRI), nerve conduction studies (NCS), and autoimmune antibody tests were performed. The results of the NCS suggested severe demyelination and even axonal damage to the peripheral nerves. MRI scans revealed diffuse thickening of bilateral cervical nerve roots, lumbosacral nerve roots, cauda equina nerve, and multiple intercostal nerve root sheath cysts. Furthermore, anti-CNTN1 antibody titers were 1:10 in the cerebrospinal fluid (CSF) and 1:100 in the serum. After one round of rituximab treatment, the patient showed significant improvement in limb weakness and dysarthria, and the CSF antibodies turned negative. Apart from peripheral neuropathies, cerebellar dysarthria (central nervous system involvement) should not be ignored in AN patients with CNTN1 antibodies.

Chen J ，Liu L ，Zhu H ，Han J ，Li R ，Gong X ，Fu H ，Long J ，Li H ，Meng Q ... -  《Frontiers in Immunology》

Antibodies to the Caspr1/contactin-1 complex in chronic inflammatory demyelinating polyradiculoneuropathy.

Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

Pascual-Goñi E ，Fehmi J ，Lleixà C ，Martín-Aguilar L ，Devaux J ，Höftberger R ，Delmont E ，Doppler K ，Sommer C ，Radunovic A ，Carvajal A ，Smyth S ，Williams L ，Mazanec R ，Potočková V ，Hinds N ，Cassereau J ，Viala K ，Lefilliatre M ，Nicolas G ，Foley P ，Leypoldt F ，Keddie S ，Lunn MP ，Zimprich F ，Nunkoo VS ，Löscher WN ，Martínez-Martínez L ，Díaz-Manera J ，Rojas-Garcia R ，Illa I ，Rinaldi S ，Querol L ... -  《-》

Effect of low-dose rituximab treatment on autoimmune nodopathy with anti-contactin 1 antibody.

Autoimmune nodopathy with anti-contactin-1 (CNTN1) responds well to rituximab instead of traditional therapies. Although a low-dose rituximab regimen was administered to patients with other autoimmune diseases, such as myasthenia gravis and neuromyelitis optica spectrum disorders, and satisfactory outcomes were obtained, this low-dose rituximab regimen has not been trialed in anti-CNTN1-positive patients. Anti-CNTN1 nodopathy patients were enrolled in this prospective, open-label, self-controlled pilot study. A cell-based assay was used to detect anti-CNTN1 antibodies and their subclasses in both serum and cerebrospinal fluid. Clinical features were evaluated at baseline, 2 days, 14 days, and 6 months after single low-dose rituximab treatment (600 mg). The titers of the subclasses of anti-CNTN1 antibody and peripheral B cells were also evaluated at baseline, 2 days, and 6 months after the rituximab regimen. Two patients with anti-CNTN1 antibodies were enrolled. Both patients had neurological symptoms including muscle weakness, tremor, sensory ataxia, numbness and mild nephrotic symptoms. In the field of neurological symptoms, sensory ataxia markedly improved, and the titer of anti-CNTN1 antibody as well as CD19+ B cells decreased only two days following low-dose rituximab treatment. Other neurological symptoms improved within two weeks of rituximab treatment. At the 6-month follow-up, all neurological symptoms steadily improved with steroid reduction, and both the anti-CNTN1 antibody titer and CD19+ B cells steadily decreased. No adverse events were observed after this single low-dose rituximab treatment. We confirmed the clinical efficacy of low-dose rituximab by B cell depletion in autoimmune nodopathy with anti-CNTN1 antibody. This rapid and long-lasting response suggests that low-dose rituximab is a promising option for anti-CNTN1 nodopathy.

Hou Y ，Zhang C ，Yu X ，Wang W ，Zhang D ，Bai Y ，Yan C ，Ma L ，Li A ，Ji J ，Cao L ，Wang Q ... -  《Frontiers in Immunology》

Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype.

To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role. Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay. Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex. Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment. This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).

Cortese A ，Lombardi R ，Briani C ，Callegari I ，Benedetti L ，Manganelli F ，Luigetti M ，Ferrari S ，Clerici AM ，Marfia GA ，Rigamonti A ，Carpo M ，Fazio R ，Corbo M ，Mazzeo A ，Giannini F ，Cosentino G ，Zardini E ，Currò R ，Gastaldi M ，Vegezzi E ，Alfonsi E ，Berardinelli A ，Kouton L ，Manso C ，Giannotta C ，Doneddu P ，Dacci P ，Piccolo L ，Ruiz M ，Salvalaggio A ，De Michelis C ，Spina E ，Topa A ，Bisogni G ，Romano A ，Mariotto S ，Mataluni G ，Cerri F ，Stancanelli C ，Sabatelli M ，Schenone A ，Marchioni E ，Lauria G ，Nobile-Orazio E ，Devaux J ，Franciotta D ... -  《Neurology-Neuroimmunology & Neuroinflammation》