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Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies

Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies Background and Objectives Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Af- fected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). Methods We retrospectively analyzed clinical data of 227 patients with chronic inflammatory de- myelinating polyradiculoneuropathy and Guillain-Barr´e syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1–associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluores- cence binding assays on human pancreatic tissue sections. Results The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31–6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Se- ropositive patients with DM most frequently harbored anti–contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal anti- bodies against pancreatic tissue was detected. Discussion We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections. From the Department of Neurology (L.A., J.M., K.S., D.H., A.-M.B., H.S., B.F., C.S., K.D.), University Hospital of Wurzburg; Department of Neurology (I.A., K.P.), St. Josef Hospital Bochum, Ruhr University of Bochum, Germany; Department of Neurology (I.A.), I.M. Sechenov First Moscow State Medical University, Russia; Department of Neurology (F.B., C.D.), University Medical Center of the Johannes Gutenberg University, Mainz; Department of Neurology (J.D., S.M.), University Hospital Ulm; German Center for Neurodegenerative Diseases (DZNE) ¨ ¨ (J.D.), Ulm; Department of Neurologic Rehabilitation (F.D.), Asklepios Schloßberg-Klinik, Bad Konig; Department of Neurology (A.G.), Tubingen University Hospital; Hans Berger Department of Neurology (A.J.), Jena University Hospital; Neuroimmunology Section (F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lubeck; De- partment of Neurology (F.L.), Kiel University; Department of Neurology (M.M.), Klinikum Wurzburg Mitte gGmbH, Standort Juliusspital; Department of Neurology (P.M.), LVR-Klinik, ¨ ¨ Bonn; Department of Pathology (M.R.), Julius Maximilian University of Wurzburg; Department of Neurology (A.-D.S.), Sachsisches Krankenhaus Altscherbitz, Schkeuditz; Department of Neurology (M.W.), Bundeswehrkrankenhaus Ulm; and Department of Neurology (G.S.W.), KRH Klinikum Nordstadt, Hannover, Germany. Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors, the Open Access Publication Fund of the University of Wurzburg ¨ and the Interdisciplinary Center of Clinical Research of the Medical Faculty of Wurzburg. ¨ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary Caspr-1 = contactin-1–associated protein 1; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; DM = diabetes mellitus; GAD = glutamate decarboxylase; GBS = Guillain-Barr´e syndrome; HbA1c = hemoglobin A1c; Ig = immunoglobulin; PE = plasma exchange. In the past decade, nodo-paranodopathy has emerged as a new Statistical Analysis concept in the spectrum of peripheral neuropathies. In this con- Descriptive and statistical data analysis were performed using text, immunoglobulin (Ig) G autoantibodies against cell adhesion SPSS Statistics version 28.0 (IBM, Armonk, NY) and Prism molecules like contactin-1, contactin-1–associated protein 1 V9.3.0 (GraphPad Software, San Diego, CA), including the (Caspr-1), and neurofascin isoforms have been described. These d’Agostino Pearson test for normality distribution and the χ proteins constitute the axoglial junction at the paranodal region of test, Student’s t test, Mann-Whitney test, and Spearman cor- the node of Ranvier and are essential for saltatory conduction. relation coefficient. Antiparanodal antibodies impair nodal integrity and function. Immunofluorescence Staining on Human The primary trigger of autoimmunity, however, has still not been Normal Pancreatic Tissue identified. The patients show a distinct phenotype, which fre- Five-micrometer sections of paraffine-embedded pancreatic tis- quently manifests with an acute onset, severe sensorimotor neu- 1,3,4 sue from the Department of Pathology of the University of ropathy, sensory ataxia, tremor, and neuropathic pain. The IgG W¨urzburg were deparaffinized, rehydrated, and steamed in subclass may influence the course of disease and response to 1,5 10 mM citrate buffer. The slides were washed and blocked. therapy. Antiparanodal antibodies thus are novel biomarkers Afterwards, double immunofluorescence staining was performed with direct implications for monitoring and treatment. with rabbit-anti-synaptophysin (AB9272; Merck, Darmstadt, Germany) as one primary antibody and either serum of a patient An axoglial dysjunction at the node of Ranvier also occurs in with anti-glutamate decarboxylase (GAD)-associated DM type diabetic neuropathy, possibly exposing antigens to the immune 1, or 2 seronegative patients, or 2 seropositive patients of each response. Diabetes mellitus (DM) has been discussed contro- paranodal target antigen or commercial antiparanodal antibodies versially as a risk factor in chronic inflammatory demyelinating (polyclonal chicken anti–pan-neurofascin 1:1,000, AF3235; polyradiculoneuropathy (CIDP) and has lately been confirmed R&D Systems, Minneapolis, MN; monoclonal mouse anti- in multicenter studies. We previously described DM as a –Caspr-1 1:100, Sc-373777 [E-8]; Santa Cruz Biotechnology, comorbidity in patients with antiparanodal antibodies. However, Dallas, TX; polyclonal goat anti–contactin-1 1:200, ab191285; little is known about the frequency of DM in nodo-para- Abcam, Cambridge, United Kingdom) as the other primary nodopathy. We therefore investigated a possible clinical associa- antibodies. After a secondary antibody incubation (Jackson tion of DM and nodo-paranodopathy in a large cohort of patients Immuno Research, West Grove, PA), sections were viewed with with immune-mediated neuropathies. a fluorescence microscope (Zeiss Axiovert 200M; Zeiss, Ober- kochen, Germany). Methods Data Availability Patients and Clinical Data Anonymized data will be made available on request from any We included 156 patients with CIDP fulfilling the European qualified investigator. Federation of Neurological Societies/Peripheral Nerve Society criteria from 2010 (n = 129 definite, n = 19 probable, and n = 8 possible) and 71 patients with Guillain-Barr´e syndrome (GBS) Results according to the Brighton criteria (n = 50level1,n= 11level2, Frequencies of Antiparanodal Antibodies in n = 2 level 3, and n = 8 level 4) whose sera had been collected the Cohort between 2005 and 2021 at multiple centers in Germany for routine Our cohort included 191 (84.1%) seronegative patients and diagnostic workup purposes and who had undergone anti- 36 (15.9%) patients IgG seropositive for antiparanodal anti- paranodal autoantibody testing via ELISA and confirmation with bodies. The predominant antibody subclass was IgG4 in 18/ cell-based assay at the University Hospital of Wur ¨ zburg as pre- 5,10 36 patients, IgG3 in 12/36 patients, IgG2 in 3/36 patients, viously described. Clinical data were collected retrospectively. IgG1 in 1/36 patients, and not determinable in 2/36 patients. Patients with/without antiparanodal antibodies are further referred Table 1 displays serostatus and demographic data. to as seropositive/seronegative. Increase in Frequency of DM in Standard Protocol Approvals, Registrations, and Patient Consents Seropositive Patients The Ethics Committee of the Medical Faculty, University of A disorder of glucose metabolism was diagnosed in 17.2% of the W¨urzburg, approved the study. The patients whose sera were entire cohort (39/227; according to the World Health Organi- used in the analysis had given written informed consent. zation criteria : n = 2 DM type 1; n = 33 DM type 2; n = 4 2 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 Neurology.org/NN Table 1 Serostatus, Diagnoses, and Demographic Data of the Cohort Total, N (%) CIDP, n (%) GBS, n (%) Age, mean (SD) Seronegative 191 (84.1) 126 (55.5) 65 (28.6) 58.09 (14.6) Seropositive 36 (15.9) 30 (13.2) 6 (2.6) 57.51 (16.5) Neurofascin-155 8 (3.5) 8 (3.5) 0 (0.0) 48.00 (21.5) Pan-neurofascin 10 (4.4) 9 (4.0) 1 (0.4) 60.00 (15.5) Contactin-1 10 (4.4) 8 (3.5) 2 (0.9) 63.70 (13.6) Caspr-1 6 (2.6) 4 (1.8) 2 (0.9) 53.67 (16.2) Caspr-1/contactin-1 2 (0.9) 1 (0.4) 1 (0.4) 63.50 (6.4) + 227 (100) 156 (68.7) 71 (31.3) 58.00 (14.9) Abbreviations: Caspr = contactin-1–associated protein; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; GBS = Guillain-Barr´ e syndrome. Numbers represent the number of patients included in the study. Frequencies are displayed in brackets as percentage of the total cohort. Mean age is shown with SD in brackets. impaired glucose tolerance). In seropositive patients, the fre- show a significant increase in the frequency of DM in the CIDP quency of DM was 33.3% and thus significantly higher compared subcohort (seropositive 33.3% vs seronegative 15.1%). In the with seronegative patients (14.1%), especially in anti–contactin- GBS subcohort, we found a similar tendency that did not reach 1-seropositive patients (58.3%; Table 2 and Figure, A). Per- statistical significance(Table2). Although patients with DM forming a subanalysis in the CIDP and GBS cohort, we could were significantly older than patients without DM in the total Table 2 Results of Statistical Testing Seropositive Seronegative p Value OR (95% CI) Frequency of DM, n (%) Total cohort, all antiparanodal antibodies 12/36 (33.3) 27/191 (14.1) 0.014 3.04 (1.31 to 6.80) CIDP subcohort 10/30 (33.3) 19/126 (15.1) 0.034 2.82 (1.14 to 6.94) GBS subcohort 2/6 (33.3) 8/65 (12.3) 0.197 3.56 (0.56 to 22.70) Anti–contactin-1 subcohort 7/12 (58.3) 27/191 (14.1) <0.001 8.50 (2.64 to 25.42) Anti-neurofascin subcohort 4/18 (22.2) 27/191 (14.1) 0.316 1.74 (0.53 to 5.67) Anti–Caspr-1 subcohort 3/8 (37.5) 27/191 (14.1) 0.102 3.64 (0.82 to 16.14) Subcohort of all patients >age 60 y 8/20 (40.0) 18/98 (18.4) 0.042 2.96 (1.01 to 7.65) Subcohort of anti–contactin-1 >age 60 y 5/9 (55.0) 18/98 (18.4) 0.021 5.56 (1.36 to 22.77) Patients with documented HbA1c only 11/19 (57.9) 22/84 (26.2) 0.013 3.88 (1.41 to 11.41) Female-to-male ratio, n (%) 11/25 (30.5) 43/148 (22.5) 0.294 0.66 (0.31 to 1.44) Mean age (SD) Total cohort 57.50 (16.68) 58.09 (14.60) 0.828 −4.77 to 5.94 DM subcohort 65.07 (11.79) 64.25 (9.40) 0.832 −7.00 to 8.65 Median HbA1c Total cohort 5.50 5.70 0.821 DM subcohort 6.50 6.45 0.985 Abbreviations: CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; DM = diabetes mellitus; HbA1c = hemoglobin A1c. Frequencies (n/total, with percentage in brackets) in the main analysis and subanalysis, female-to-male ratio, and mean/median values (including SD in brackets) of age and HbA1c are displayed in seropositive and seronegative patients of the cohort. Results of statistical tests are displayed in the last 2 rows. a 2 b c Results are considered statistically significant at p <0.05( χ test, Student’s t test, and Mann-Whitney test). OR is displayed with 95% CI. Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 3 cohort (64.82 vs 56.57, p < 0.002), the mean age and female-to- Figure Frequency of DM and Immunofluorescence Stain- male ratio did not differ between seropositive and seronegative ings on Pancreatic Tissue patients (Table 2). In patients aged >60 years, the frequency of DM was still significantly elevated in seropositive vs seronegative patients. Treatment with plasma exchange (PE), IVIg, and corticosteroids was assessed retrospectively in the last 28 days before serum withdrawal and rituximab or further immunosuppressive treat- ment until 1 year before the withdrawal. There were no significant differences in previous PE, IVIg, and corticosteroid treatment in patients with and without DM (PE 2/12 [16.6%] vs 2/24 [8.3%], p = 0.59; IVIg 2/12 [16.7%] vs 8/24 [33.3%], p = 0.44; corti- costeroids 1/12 [8.3%] vs 13/24 [54.2%], p = 0.22). Nevertheless, patients having received corticosteroids (n = 8) were excluded from the titer analysis to avoid bias. They were mainly found in the nondiabetic group because corticosteroids are often avoided in patients with diabetes. Furthermore, corticosteroid treatment in- fluences total IgG levels until 2–4 weeks after application. None of the patients had received rituximab treatment or further im- munosuppressive treatment before antibody testing. Titers in the remaining 28 seropositive patients ranged from 1:100 to 1:40,000 and were significantly higher in patients with DM than without DM (median of 1:2,000 vs 1:500, p = 0.035). Hemoglobin A1c (HbA1c) was determined at the onset of neurologic symptoms in 103 (45.4%) patients. The maximum HbA1c values were significantly higher in patients with DM compared with individuals without diabetes (mean of 6.5 vs 5.5, p < 0.001), but did not differ in seropositive and sero- negative patients with DM (Table 2). We performed a sub- analysis of the frequency of DM with patients whose HbA1c values were measured and documented at the time point of serologic testing. Here, the frequency of DM stayed signifi- cantly higher in seropositive vs seronegative patients (Table 2). Furthermore, HbA1c levels correlated significantly with the autoantibody titer (r = 0.584, p = 0.029; Figure, B) in (A) Frequency of diabetes mellitus is significantly elevated in patients n = 14 patients whose titer and HbA1c were assessed simul- seropositive for antiparanodal antibodies (33.3%) compared with sero- taneously and considered in the analysis (see above). negative patients (14.1%, p = 0.014) and with the general German pop- ulation (9.9%, p < 0.001), especially in anti–contactin-1-seropositive patients (58.3% vs 14.1% in seronegative, p <0.001 and9.9%inthe In all seropositive patients, the diagnosis of DM preceded the German population, p < 0.001). Significance levels are marked with as- terisks: *p <0.05, **p < 0.01, ***p < 0.001. (B) In seropositive patients not acute onset of nodo-paranodopathy without any close tem- having received corticosteroid treatment within the last 28 days and who were therapy naive to rituximab, HbA1c levels (y-axis, %) were de- poral connection. In 2/12 seropositive patients, the time termined in 14 patients at the time point of serum withdrawal and cor- point of diagnosis was documented >10 years before the onset related significantly with the autoantibody titer, displayed on a logarithmic scale (r =0.58, p = 0.029). (C.a–l) Photomicrographs show of neurologic symptoms. In the other patients, the exact time human pancreatic normal tissue sections with nucleus staining (DAPI) point of DM diagnosis was not documented, but all patients shown in blue (C.a, C.d, C.g, and C.j) and double staining with synapto- physin as marker for the islets of Langerhans (displayed in green, C.b, carried an established diagnosis of diabetes before the onset of C.e, C.h, and C.k) and serum or antiparanodal antibodies (displayed in magenta, C.c, C.f, C.i, and C.l). Serum of a patient with CIDP and DM type nodo-paranodopathy, and 10/12 patients had received long- 1 with GAD antibodies binds to β cells in pancreatic islets of Langerhans term antidiabetic treatment. (C.a–c), whereas serum of a patient with anti–contactin-1 antibodies (C.d–f) and commercial goat anti–contactin-1 (C.g–i) and commercial chicken anti–pan-neurofascin (C.j–l) do not show any binding. Photo- DM type 2 occurred independently of the predominant IgG micrographs of binding of the other patients’ sera or commercial anti- bodies tested in the assay are not shown. Scale bar = 10 μm. CNTN = subclass: in 1/1 (100%) patients with predominant IgG1, in contactin-1; DAPI = 49,6-diamidino-2-phenylindole; DM = diabetes mel- 1/3 (33%) patients with predominant IgG2, in 3/12 (25%) litus; HbA1c = hemoglobin A1C. patients with predominant IgG3, and in 6/18 (33.3%) 4 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 Neurology.org/NN 6,14 patients with predominant IgG4. In 1 patient, DM type 1 was suggested as promoting factors for CIDP. DM leads to a 6,15 disruption of the paranodal junction. This could expose diagnosed 15 years before the onset of nodo-paranodopathy. paranodal targets like contactin-1 to the adaptive immune re- This patient had reported normal total IgG4 levels 3 years sponse, supported by our finding of higher autoantibody titers in before the onset of nodo-paranodopathy. At the onset of patients with DM and the correlation of HbA1c levels with the neurologic symptoms, IgG4 antibodies against pan- autoantibody titers. Especially IgG4-related disease occurs after neurofascin were detected. chronic antigen exposure and might therefore be triggered by diabetes-associated long-term pathologic structural changes. Relative Risks and Comparison to Furthermore, the disruption of paranodal architecture could fa- Previous Studies cilitate the access of the autoantibodies to the paranodal com- The relative risk of DM compared with the general German plex, which is protected by the myelin barrier under physiologic population according to health insurance data was 3.4-fold conditions. We hypothesize that these factors increase the risk higher in seropositive patients (33.3% vs 9.9%, p < 0.001; of developing nodo-paranodopathy. Figure, A) and 1.88-fold higher in our entire CIDP cohort (18.6% vs 9.9%, p < 0.01). The frequency of DM in our total Patients with IgG4-related nodo-paranodopathy respond well CIDP cohort did not differ significantly from previously de- to antibody depletion with rituximab, as recommended in the scribed European CIDP cohorts (n = 29/156, 18.6% vs n = European Federation of Neurological Societies/Peripheral 48/257, 18.7%, p > 0.999). Nerve Society guidelines. Whether additional treatment should be adapted depending on the presence of DM needs to No Binding of Antiparanodal Antibodies to be addressed in further studies. Pancreatic β-Cell Islets On normal pancreatic tissue sections, commercial antibodies A possible bias when comparing frequencies in cohorts with against synaptophysin and patient anti-GAD antibodies as the general population prevalence rates in this and other positive controls bound specifically to insulin-producing β studies is the age-dependent increase of the prevalence of cells in the Langerhans islets (Figure, C). Neither the com- DM. Therefore, we used age-matched controls in our cohort mercial antibodies against nodo-paranodal antigens nor the and considered age-dependent effects by a subanalysis of patient sera with anti-contactin-1, anti-Caspr-1, and anti- patients aged >60 years, thus reducing the risk of age as a neurofascin antibodies showed any binding to β cells (Figure, possible confounder for our cohort data. C representatively illustrates binding assays with serum and commercial anti–contactin-1 and commercial anti–pan- Within seropositive patients, we found a strong association of neurofascin, other data not shown). DM and anti–contactin-1. These patients are older than pa- tients with antibodies targeting neurofascin-155. We there- fore hypothesize that in the elderly, DM and its associated Discussion conditions may potentially predispose to developing nodo- We report an association of antiparanodal antibodies and DM paranodopathy. In the young, however, other triggers still and identify DM as a possible risk factor for developing nodo- need to be investigated. paranodopathy. An approximately 2-fold increase of the rel- ative risk of DM compared with the general population has In a subanalysis, we found the frequency of DM only to be been described in European cohorts of CIDP and was con- increased in our CIDP cohort. In our GBS cohort, we found a firmed by our data. Furthermore, we detected a 3.4-fold in- similar tendency, but studies with larger GBS cohorts are needed crease of the relative risk in antibody-mediated CIDP, to study an association. Furthermore, the frequency of anti- supporting the notion of humoral immunity playing a major paranodal antibodies in our cohort is higher than previously role in the association of CIDP and DM. reported prevalences, possibly due to a selection bias as a national center for antibody diagnostics. Therefore, given the low preva- As we did not detect any binding of antiparanodal antibodies to lence of antiparanodal antibodies and the retrospective character pancreatic tissue, our data suggest that immunogenic target of this explorative analysis, larger international multicenter studies epitopes of proteins recognized by the antibodies are likely not to are needed to address the role of humoral immunity with focus on be present in the pancreas. Thus, antiparanodal antibodies do antiparanodal antibodies and DM in CIDP and GBS and in- probably not have a direct pathogenic effect on pancreatic β cells. vestigate the role of DM and its associated conditions in para- This hypothesis is supported by the fact that in the patient with nodopathy using multivariate models. Following experimental DM type 1, diagnosis preceded the onset of IgG4-related neu- studies may elucidate the exact pathoimmunologic mechanisms. rologic disease. We therefore hypothesize that nodo- paranodopathy may be associated to a preexisting DM or hy- Acknowledgment perglycemic condition. The authors thank Barbara Reuter, Hiltrud Klupfel, ¨ and Antonia Kohl for excellent technical assistance and Robert A diabetes-related blood-nerve barrier dysfunction and Blum for advice on the study conceptualization. They also upregulation of proinflammatory cytokines have been thank the patients who contributed to the study. Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 5 Study Funding Appendix (continued) This study was supported by the Open Access Publication Fund of the University of Wu¨rzburg. L. Appeltshauser and K. Doppler Name Location Contribution are supported by research fellowships by the Interdisciplinary Julia Messinger University Hospital of Data acquisition and Center of Clinical Research of the Medical Faculty of Wur ¨ zburg. Wurzburg, Germany revision of the manuscript K. Doppler is supported by a grant of the German Research for content Foundation (DFG, DO-2219/1-1). J. Messinger and D. Hein- Katharina Starz University Hospital of Data acquisition and rich are supported by a grant of the University of Wur ¨ zburg Wurzburg, Germany revision of the manuscript for content Graduate School of Life Sciences. David Heinrich University Hospital of Data acquisition and Wurzburg, Germany revision of the manuscript Disclosure for content I. Ayzenberg, A.-M.Brunder,C.Dresel, J. Dorst, F. Dvorak, B. Fiebig, A. Grimm, D. Heinrich, A. Joerk, M. M¨aurer, P. Merl, S. Anna-Michelle University Hospital of Data acquisition and Brunder Wurzburg, ¨ Germany revision of the manuscript Michels, J. Messinger,M.Rosenfeldt, A.-D.Sperfeld, K. Starz, H. for content Stengel, M. Weihrauch, and G. S. Welte report no disclosures Helena Stengel University Hospital of Data acquisition and relevant to the manuscript. L. Appeltshauser, F. Leypoldt, C. Wurzburg, ¨ Germany revision of the manuscript Sommer, and K. Doppler work for an academic institution of- for content fering commercial antibody diagnostics. F. Birklein received Bianca Fiebig University Hospital of Data acquisition and support for research as a PI from the German Research Foun- Wurzburg, Germany revision of the manuscript for content dation DFG, grants Bi 579/10 and Bi 579/11, and unrestricted educational grants from Alnylam and the workers compensation Ilya Ayzenberg, St. Josef Hospital Bochum, Data acquisition and MD Ruhr University of Bochum, revision of the manuscript insurance BGW; he has served on advisory boards for Novartis Germany; I.M. Sechenov for content and Gru¨nenthal; he received speaker honoraria from Pfizer, First Moscow State Medical University, Russia Merz, Alnylam, and Akcea; he has served as an associate editor or editorial advisory board member for Neurology, European Journal Frank Birklein, University Medical Center Data acquisition and of Pain,and Pain Medicine. K. Pitarokoili received travel funding MD of the Johannes Gutenberg revision of the manuscript University, Mainz, for content and speaker honoraria from Biogen Idec, Novartis, Grifols, CSL Germany Behring, Celgene, and Bayer Schering Pharma and funding from Christian University Medical Center Data acquisition and the Ruhr University. F. Leypoldt has served on advisory boards Dresel, MD of the Johannes Gutenberg revision of the manuscript for Biogen, Roche, and Alexion and received speaker honoraria University, Mainz, for content Germany from Roche, Biogen,Grifols,Alexion,Desitin,and Novartis.F. Leypoldt serves as editorial board member for Neurology N2.C. Johannes University Hospital Ulm, Data acquisition and Dorst, MD Germany revision of the manuscript Sommer has served on scientific advisory boards for Akcea, for content Algiax, Air Liquide, Bayer, Grifols, Ipsen, LFB, Immunic, Merz, Florian Dvorak, Asklepios Schloßberg- Data acquisition and Pfizer, Roche, and Takeda; she reports having received speaker MD Klinik, Bad Konig, Germany revision of the manuscript honoraria for educational talks from Akcea, Alnylam Amicus, for content Grifols, Pfizer, and Teva. C. Sommer serves or has served as a Alexander University Hospital Data acquisition and journal editor, associate editor, or editorial advisory board Grimm, MD Tubingen, Germany revision of the manuscript member for the European Journal of Neurology, PLoS One,and for content PAIN Reports. Go to Neurology.org/NN for full disclosures. Alexander Jena University Hospital, Data acquisition and Joerk, MD Germany revision of the manuscript for content Publication History Received by Neurology: Neuroimmunology & Neuroinflammation Frank Leypoldt, University Hospital Data acquisition and MD Schleswig-Holstein, Kiel revision of the manuscript November 12, 2021. Accepted in final form February 15, 2022. University, Germany for content Mathias Klinikum Wurzburg Mitte Data acquisition and M¨ aurer, MD gGmbH, Germany revision of the manuscript for content Appendix Authors Patrick Merl, LVR-Klinik, Bonn, Germany Data acquisition and Name Location Contribution MD revision of the manuscript for content Luise University Hospital of Study design and ¨ Sebastian University Hospital Ulm, Data acquisition and Appeltshauser, Wurzburg, Germany conception; data MD acquisition, analysis, and Michels, MD Germany revision of the manuscript for content interpretation; drafting of the first version of the Kalliopi St. Josef Hospital Bochum, Data acquisition and manuscript; and revision of the manuscript for Pitarokoili, MD Ruhr University of revision of the manuscript Bochum, Germany for content intellectual content 6 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 Neurology.org/NN 4. Devaux JJ, Miura Y, Fukami Y, et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology. 2016;86(9):800-807. Appendix (continued) 5. Appeltshauser L, Brunder AM, Heinius A, et al. Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e817. Name Location Contribution 6. Sima AA, Lattimer SA, Yagihashi S, et al. Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spon- Mathias University of Wurzburg, ¨ Data acquisition and taneously diabetic bio-breeding rat. J Clin Invest. 1986;77(2):474-484. Rosenfeldt, Germany revision of the manuscript 7. Rajabally YA, Peric S, Cobeljic M, et al. Chronic inflammatory demyelinating poly- PhD for content neuropathy associated with diabetes: a European multicentre comparative reappraisal. J Neurol Neurosurg Psychiatry. 2020;91(10):1100-1104. Anne-Dorte Sachsisches Krankenhaus Data acquisition and 8. Van den Bergh PY, Hadden RD, Bouche P, et al. European Federation of Neurological Sperfeld, MD Altscherbitz, Schkeuditz, revision of the manuscript Societies/Peripheral Nerve Society guideline on management of chronic in- Germany for content flammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society— Marc Bundeswehrkrankenhaus Data acquisition and first revision. Eur J Neurol. 2010;17(3):356-363. Weihrauch, MD Ulm, Germany revision of the manuscript 9. Fokke C, van den Berg B, Drenthen J, et al. Diagnosis of Guillain-Barre syndrome and for content validation of Brighton criteria. Brain. 2014;137(pt 1):33-43. 10. Stengel H, Vural A, Brunder AM, et al. Anti-pan-neurofascin IgG3 as a marker of fulminant Gabriel Simon KRH Klinikum Nordstadt, Data acquisition and autoimmune neuropathy. Neurol Neuroimmunol Neuroinflamm. 2019;6(5):e603. Welte, MD Hannover, Germany revision of the manuscript 11. World Health Organization. Classification of Diabetes Mellitus. World Health Organiza- for content tion; 2019. Accessed October 25, 2021. apps.who.int/iris/handle/10665/325182. Li- cence: CC BY-NC-SA 3.0 IGO. Claudia University Hospital of Data acquisition and 12. Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on immuno- Sommer, MD Wurzburg ¨ , Germany revision of the manuscript globulins. J Allergy Clin Immunol. 1978;62(3):162-166. for content 13. National Diabetes Surveillance at the Robert Koch Institute. Diabetes in Germany— National Diabetes Surveillance Report 2019. Robert Koch Institute; 2019. Accessed July Kathrin University Hospital of Study design and 7, 2021. diabsurv.rki.de/SharedDocs/downloads/DE/DiabSurv/diabetes-report_ Doppler, MD Wurzburg, Germany conception; data 2019_eng.pdf?__blob=publicationFile&v=12. acquisition; and revision of 14. Ben-Kraiem A, Sauer RS, Norwig C, et al. Selective blood-nerve barrier leakiness with the manuscript for content claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy. JMol Med (Berl). 2021;99(9):1237-1250. 15. Doppler K, Frank F, Koschker AC, et al. Nodes of Ranvier in skin biopsies of patients with diabetes mellitus. J Peripher Nerv Syst. 2017;22(3):182-190. References 16. Dalakas MC. IgG4-mediated neurologic autoimmunities. Understanding the patho- 1. Pascual-Goni E, Martin-Aguilar L, Querol L. Autoantibodies in chronic in- genicity of IgG4, ineffectiveness of IVIg, and long-lasting benefits of anti–B cell flammatory demyelinating polyradiculoneuropathy. Curr Opin Neurol. 2019;32(5): therapies. Neurol Neuroimmunol Neuroinflamm. 2022;9(1):e1116. 651-657. 17. Reinhold AK, Rittner HL. Barrier function in the peripheral and central nervous 2. Rasband MN, Peles E. The nodes of ranvier: molecular assembly and maintenance. system—a review. Pflugers Arch. 2017;469(1):123-134. Cold Spring Harb Perspect Biol. 2015;8(3):a020495. 18. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of 3. Pascual-Goñi E, Fehmi J, Lleix`a C, et al. Antibodies to the Caspr1/contactin-1 Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic complex in chronic inflammatory demyelinating polyradiculoneuropathy. Brain. inflammatory demyelinating polyradiculoneuropathy: report of a joint Task Force- 2021;144(4):1183-1196. doi:10.1136/ard.2003.001234. second revision. J Peripher Nerv Syst. 2021;26(3):242-268. Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 7 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurology Neuroimmunology & Neuroinflammation Wolters Kluwer Health

Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies

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Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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Abstract

Background and Objectives Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Af- fected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). Methods We retrospectively analyzed clinical data of 227 patients with chronic inflammatory de- myelinating polyradiculoneuropathy and Guillain-Barr´e syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1–associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluores- cence binding assays on human pancreatic tissue sections. Results The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31–6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Se- ropositive patients with DM most frequently harbored anti–contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal anti- bodies against pancreatic tissue was detected. Discussion We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections. From the Department of Neurology (L.A., J.M., K.S., D.H., A.-M.B., H.S., B.F., C.S., K.D.), University Hospital of Wurzburg; Department of Neurology (I.A., K.P.), St. Josef Hospital Bochum, Ruhr University of Bochum, Germany; Department of Neurology (I.A.), I.M. Sechenov First Moscow State Medical University, Russia; Department of Neurology (F.B., C.D.), University Medical Center of the Johannes Gutenberg University, Mainz; Department of Neurology (J.D., S.M.), University Hospital Ulm; German Center for Neurodegenerative Diseases (DZNE) ¨ ¨ (J.D.), Ulm; Department of Neurologic Rehabilitation (F.D.), Asklepios Schloßberg-Klinik, Bad Konig; Department of Neurology (A.G.), Tubingen University Hospital; Hans Berger Department of Neurology (A.J.), Jena University Hospital; Neuroimmunology Section (F.L.), Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lubeck; De- partment of Neurology (F.L.), Kiel University; Department of Neurology (M.M.), Klinikum Wurzburg Mitte gGmbH, Standort Juliusspital; Department of Neurology (P.M.), LVR-Klinik, ¨ ¨ Bonn; Department of Pathology (M.R.), Julius Maximilian University of Wurzburg; Department of Neurology (A.-D.S.), Sachsisches Krankenhaus Altscherbitz, Schkeuditz; Department of Neurology (M.W.), Bundeswehrkrankenhaus Ulm; and Department of Neurology (G.S.W.), KRH Klinikum Nordstadt, Hannover, Germany. Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors, the Open Access Publication Fund of the University of Wurzburg ¨ and the Interdisciplinary Center of Clinical Research of the Medical Faculty of Wurzburg. ¨ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary Caspr-1 = contactin-1–associated protein 1; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; DM = diabetes mellitus; GAD = glutamate decarboxylase; GBS = Guillain-Barr´e syndrome; HbA1c = hemoglobin A1c; Ig = immunoglobulin; PE = plasma exchange. In the past decade, nodo-paranodopathy has emerged as a new Statistical Analysis concept in the spectrum of peripheral neuropathies. In this con- Descriptive and statistical data analysis were performed using text, immunoglobulin (Ig) G autoantibodies against cell adhesion SPSS Statistics version 28.0 (IBM, Armonk, NY) and Prism molecules like contactin-1, contactin-1–associated protein 1 V9.3.0 (GraphPad Software, San Diego, CA), including the (Caspr-1), and neurofascin isoforms have been described. These d’Agostino Pearson test for normality distribution and the χ proteins constitute the axoglial junction at the paranodal region of test, Student’s t test, Mann-Whitney test, and Spearman cor- the node of Ranvier and are essential for saltatory conduction. relation coefficient. Antiparanodal antibodies impair nodal integrity and function. Immunofluorescence Staining on Human The primary trigger of autoimmunity, however, has still not been Normal Pancreatic Tissue identified. The patients show a distinct phenotype, which fre- Five-micrometer sections of paraffine-embedded pancreatic tis- quently manifests with an acute onset, severe sensorimotor neu- 1,3,4 sue from the Department of Pathology of the University of ropathy, sensory ataxia, tremor, and neuropathic pain. The IgG W¨urzburg were deparaffinized, rehydrated, and steamed in subclass may influence the course of disease and response to 1,5 10 mM citrate buffer. The slides were washed and blocked. therapy. Antiparanodal antibodies thus are novel biomarkers Afterwards, double immunofluorescence staining was performed with direct implications for monitoring and treatment. with rabbit-anti-synaptophysin (AB9272; Merck, Darmstadt, Germany) as one primary antibody and either serum of a patient An axoglial dysjunction at the node of Ranvier also occurs in with anti-glutamate decarboxylase (GAD)-associated DM type diabetic neuropathy, possibly exposing antigens to the immune 1, or 2 seronegative patients, or 2 seropositive patients of each response. Diabetes mellitus (DM) has been discussed contro- paranodal target antigen or commercial antiparanodal antibodies versially as a risk factor in chronic inflammatory demyelinating (polyclonal chicken anti–pan-neurofascin 1:1,000, AF3235; polyradiculoneuropathy (CIDP) and has lately been confirmed R&D Systems, Minneapolis, MN; monoclonal mouse anti- in multicenter studies. We previously described DM as a –Caspr-1 1:100, Sc-373777 [E-8]; Santa Cruz Biotechnology, comorbidity in patients with antiparanodal antibodies. However, Dallas, TX; polyclonal goat anti–contactin-1 1:200, ab191285; little is known about the frequency of DM in nodo-para- Abcam, Cambridge, United Kingdom) as the other primary nodopathy. We therefore investigated a possible clinical associa- antibodies. After a secondary antibody incubation (Jackson tion of DM and nodo-paranodopathy in a large cohort of patients Immuno Research, West Grove, PA), sections were viewed with with immune-mediated neuropathies. a fluorescence microscope (Zeiss Axiovert 200M; Zeiss, Ober- kochen, Germany). Methods Data Availability Patients and Clinical Data Anonymized data will be made available on request from any We included 156 patients with CIDP fulfilling the European qualified investigator. Federation of Neurological Societies/Peripheral Nerve Society criteria from 2010 (n = 129 definite, n = 19 probable, and n = 8 possible) and 71 patients with Guillain-Barr´e syndrome (GBS) Results according to the Brighton criteria (n = 50level1,n= 11level2, Frequencies of Antiparanodal Antibodies in n = 2 level 3, and n = 8 level 4) whose sera had been collected the Cohort between 2005 and 2021 at multiple centers in Germany for routine Our cohort included 191 (84.1%) seronegative patients and diagnostic workup purposes and who had undergone anti- 36 (15.9%) patients IgG seropositive for antiparanodal anti- paranodal autoantibody testing via ELISA and confirmation with bodies. The predominant antibody subclass was IgG4 in 18/ cell-based assay at the University Hospital of Wur ¨ zburg as pre- 5,10 36 patients, IgG3 in 12/36 patients, IgG2 in 3/36 patients, viously described. Clinical data were collected retrospectively. IgG1 in 1/36 patients, and not determinable in 2/36 patients. Patients with/without antiparanodal antibodies are further referred Table 1 displays serostatus and demographic data. to as seropositive/seronegative. Increase in Frequency of DM in Standard Protocol Approvals, Registrations, and Patient Consents Seropositive Patients The Ethics Committee of the Medical Faculty, University of A disorder of glucose metabolism was diagnosed in 17.2% of the W¨urzburg, approved the study. The patients whose sera were entire cohort (39/227; according to the World Health Organi- used in the analysis had given written informed consent. zation criteria : n = 2 DM type 1; n = 33 DM type 2; n = 4 2 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 Neurology.org/NN Table 1 Serostatus, Diagnoses, and Demographic Data of the Cohort Total, N (%) CIDP, n (%) GBS, n (%) Age, mean (SD) Seronegative 191 (84.1) 126 (55.5) 65 (28.6) 58.09 (14.6) Seropositive 36 (15.9) 30 (13.2) 6 (2.6) 57.51 (16.5) Neurofascin-155 8 (3.5) 8 (3.5) 0 (0.0) 48.00 (21.5) Pan-neurofascin 10 (4.4) 9 (4.0) 1 (0.4) 60.00 (15.5) Contactin-1 10 (4.4) 8 (3.5) 2 (0.9) 63.70 (13.6) Caspr-1 6 (2.6) 4 (1.8) 2 (0.9) 53.67 (16.2) Caspr-1/contactin-1 2 (0.9) 1 (0.4) 1 (0.4) 63.50 (6.4) + 227 (100) 156 (68.7) 71 (31.3) 58.00 (14.9) Abbreviations: Caspr = contactin-1–associated protein; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; GBS = Guillain-Barr´ e syndrome. Numbers represent the number of patients included in the study. Frequencies are displayed in brackets as percentage of the total cohort. Mean age is shown with SD in brackets. impaired glucose tolerance). In seropositive patients, the fre- show a significant increase in the frequency of DM in the CIDP quency of DM was 33.3% and thus significantly higher compared subcohort (seropositive 33.3% vs seronegative 15.1%). In the with seronegative patients (14.1%), especially in anti–contactin- GBS subcohort, we found a similar tendency that did not reach 1-seropositive patients (58.3%; Table 2 and Figure, A). Per- statistical significance(Table2). Although patients with DM forming a subanalysis in the CIDP and GBS cohort, we could were significantly older than patients without DM in the total Table 2 Results of Statistical Testing Seropositive Seronegative p Value OR (95% CI) Frequency of DM, n (%) Total cohort, all antiparanodal antibodies 12/36 (33.3) 27/191 (14.1) 0.014 3.04 (1.31 to 6.80) CIDP subcohort 10/30 (33.3) 19/126 (15.1) 0.034 2.82 (1.14 to 6.94) GBS subcohort 2/6 (33.3) 8/65 (12.3) 0.197 3.56 (0.56 to 22.70) Anti–contactin-1 subcohort 7/12 (58.3) 27/191 (14.1) <0.001 8.50 (2.64 to 25.42) Anti-neurofascin subcohort 4/18 (22.2) 27/191 (14.1) 0.316 1.74 (0.53 to 5.67) Anti–Caspr-1 subcohort 3/8 (37.5) 27/191 (14.1) 0.102 3.64 (0.82 to 16.14) Subcohort of all patients >age 60 y 8/20 (40.0) 18/98 (18.4) 0.042 2.96 (1.01 to 7.65) Subcohort of anti–contactin-1 >age 60 y 5/9 (55.0) 18/98 (18.4) 0.021 5.56 (1.36 to 22.77) Patients with documented HbA1c only 11/19 (57.9) 22/84 (26.2) 0.013 3.88 (1.41 to 11.41) Female-to-male ratio, n (%) 11/25 (30.5) 43/148 (22.5) 0.294 0.66 (0.31 to 1.44) Mean age (SD) Total cohort 57.50 (16.68) 58.09 (14.60) 0.828 −4.77 to 5.94 DM subcohort 65.07 (11.79) 64.25 (9.40) 0.832 −7.00 to 8.65 Median HbA1c Total cohort 5.50 5.70 0.821 DM subcohort 6.50 6.45 0.985 Abbreviations: CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; DM = diabetes mellitus; HbA1c = hemoglobin A1c. Frequencies (n/total, with percentage in brackets) in the main analysis and subanalysis, female-to-male ratio, and mean/median values (including SD in brackets) of age and HbA1c are displayed in seropositive and seronegative patients of the cohort. Results of statistical tests are displayed in the last 2 rows. a 2 b c Results are considered statistically significant at p <0.05( χ test, Student’s t test, and Mann-Whitney test). OR is displayed with 95% CI. Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 3 cohort (64.82 vs 56.57, p < 0.002), the mean age and female-to- Figure Frequency of DM and Immunofluorescence Stain- male ratio did not differ between seropositive and seronegative ings on Pancreatic Tissue patients (Table 2). In patients aged >60 years, the frequency of DM was still significantly elevated in seropositive vs seronegative patients. Treatment with plasma exchange (PE), IVIg, and corticosteroids was assessed retrospectively in the last 28 days before serum withdrawal and rituximab or further immunosuppressive treat- ment until 1 year before the withdrawal. There were no significant differences in previous PE, IVIg, and corticosteroid treatment in patients with and without DM (PE 2/12 [16.6%] vs 2/24 [8.3%], p = 0.59; IVIg 2/12 [16.7%] vs 8/24 [33.3%], p = 0.44; corti- costeroids 1/12 [8.3%] vs 13/24 [54.2%], p = 0.22). Nevertheless, patients having received corticosteroids (n = 8) were excluded from the titer analysis to avoid bias. They were mainly found in the nondiabetic group because corticosteroids are often avoided in patients with diabetes. Furthermore, corticosteroid treatment in- fluences total IgG levels until 2–4 weeks after application. None of the patients had received rituximab treatment or further im- munosuppressive treatment before antibody testing. Titers in the remaining 28 seropositive patients ranged from 1:100 to 1:40,000 and were significantly higher in patients with DM than without DM (median of 1:2,000 vs 1:500, p = 0.035). Hemoglobin A1c (HbA1c) was determined at the onset of neurologic symptoms in 103 (45.4%) patients. The maximum HbA1c values were significantly higher in patients with DM compared with individuals without diabetes (mean of 6.5 vs 5.5, p < 0.001), but did not differ in seropositive and sero- negative patients with DM (Table 2). We performed a sub- analysis of the frequency of DM with patients whose HbA1c values were measured and documented at the time point of serologic testing. Here, the frequency of DM stayed signifi- cantly higher in seropositive vs seronegative patients (Table 2). Furthermore, HbA1c levels correlated significantly with the autoantibody titer (r = 0.584, p = 0.029; Figure, B) in (A) Frequency of diabetes mellitus is significantly elevated in patients n = 14 patients whose titer and HbA1c were assessed simul- seropositive for antiparanodal antibodies (33.3%) compared with sero- taneously and considered in the analysis (see above). negative patients (14.1%, p = 0.014) and with the general German pop- ulation (9.9%, p < 0.001), especially in anti–contactin-1-seropositive patients (58.3% vs 14.1% in seronegative, p <0.001 and9.9%inthe In all seropositive patients, the diagnosis of DM preceded the German population, p < 0.001). Significance levels are marked with as- terisks: *p <0.05, **p < 0.01, ***p < 0.001. (B) In seropositive patients not acute onset of nodo-paranodopathy without any close tem- having received corticosteroid treatment within the last 28 days and who were therapy naive to rituximab, HbA1c levels (y-axis, %) were de- poral connection. In 2/12 seropositive patients, the time termined in 14 patients at the time point of serum withdrawal and cor- point of diagnosis was documented >10 years before the onset related significantly with the autoantibody titer, displayed on a logarithmic scale (r =0.58, p = 0.029). (C.a–l) Photomicrographs show of neurologic symptoms. In the other patients, the exact time human pancreatic normal tissue sections with nucleus staining (DAPI) point of DM diagnosis was not documented, but all patients shown in blue (C.a, C.d, C.g, and C.j) and double staining with synapto- physin as marker for the islets of Langerhans (displayed in green, C.b, carried an established diagnosis of diabetes before the onset of C.e, C.h, and C.k) and serum or antiparanodal antibodies (displayed in magenta, C.c, C.f, C.i, and C.l). Serum of a patient with CIDP and DM type nodo-paranodopathy, and 10/12 patients had received long- 1 with GAD antibodies binds to β cells in pancreatic islets of Langerhans term antidiabetic treatment. (C.a–c), whereas serum of a patient with anti–contactin-1 antibodies (C.d–f) and commercial goat anti–contactin-1 (C.g–i) and commercial chicken anti–pan-neurofascin (C.j–l) do not show any binding. Photo- DM type 2 occurred independently of the predominant IgG micrographs of binding of the other patients’ sera or commercial anti- bodies tested in the assay are not shown. Scale bar = 10 μm. CNTN = subclass: in 1/1 (100%) patients with predominant IgG1, in contactin-1; DAPI = 49,6-diamidino-2-phenylindole; DM = diabetes mel- 1/3 (33%) patients with predominant IgG2, in 3/12 (25%) litus; HbA1c = hemoglobin A1C. patients with predominant IgG3, and in 6/18 (33.3%) 4 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 Neurology.org/NN 6,14 patients with predominant IgG4. In 1 patient, DM type 1 was suggested as promoting factors for CIDP. DM leads to a 6,15 disruption of the paranodal junction. This could expose diagnosed 15 years before the onset of nodo-paranodopathy. paranodal targets like contactin-1 to the adaptive immune re- This patient had reported normal total IgG4 levels 3 years sponse, supported by our finding of higher autoantibody titers in before the onset of nodo-paranodopathy. At the onset of patients with DM and the correlation of HbA1c levels with the neurologic symptoms, IgG4 antibodies against pan- autoantibody titers. Especially IgG4-related disease occurs after neurofascin were detected. chronic antigen exposure and might therefore be triggered by diabetes-associated long-term pathologic structural changes. Relative Risks and Comparison to Furthermore, the disruption of paranodal architecture could fa- Previous Studies cilitate the access of the autoantibodies to the paranodal com- The relative risk of DM compared with the general German plex, which is protected by the myelin barrier under physiologic population according to health insurance data was 3.4-fold conditions. We hypothesize that these factors increase the risk higher in seropositive patients (33.3% vs 9.9%, p < 0.001; of developing nodo-paranodopathy. Figure, A) and 1.88-fold higher in our entire CIDP cohort (18.6% vs 9.9%, p < 0.01). The frequency of DM in our total Patients with IgG4-related nodo-paranodopathy respond well CIDP cohort did not differ significantly from previously de- to antibody depletion with rituximab, as recommended in the scribed European CIDP cohorts (n = 29/156, 18.6% vs n = European Federation of Neurological Societies/Peripheral 48/257, 18.7%, p > 0.999). Nerve Society guidelines. Whether additional treatment should be adapted depending on the presence of DM needs to No Binding of Antiparanodal Antibodies to be addressed in further studies. Pancreatic β-Cell Islets On normal pancreatic tissue sections, commercial antibodies A possible bias when comparing frequencies in cohorts with against synaptophysin and patient anti-GAD antibodies as the general population prevalence rates in this and other positive controls bound specifically to insulin-producing β studies is the age-dependent increase of the prevalence of cells in the Langerhans islets (Figure, C). Neither the com- DM. Therefore, we used age-matched controls in our cohort mercial antibodies against nodo-paranodal antigens nor the and considered age-dependent effects by a subanalysis of patient sera with anti-contactin-1, anti-Caspr-1, and anti- patients aged >60 years, thus reducing the risk of age as a neurofascin antibodies showed any binding to β cells (Figure, possible confounder for our cohort data. C representatively illustrates binding assays with serum and commercial anti–contactin-1 and commercial anti–pan- Within seropositive patients, we found a strong association of neurofascin, other data not shown). DM and anti–contactin-1. These patients are older than pa- tients with antibodies targeting neurofascin-155. We there- fore hypothesize that in the elderly, DM and its associated Discussion conditions may potentially predispose to developing nodo- We report an association of antiparanodal antibodies and DM paranodopathy. In the young, however, other triggers still and identify DM as a possible risk factor for developing nodo- need to be investigated. paranodopathy. An approximately 2-fold increase of the rel- ative risk of DM compared with the general population has In a subanalysis, we found the frequency of DM only to be been described in European cohorts of CIDP and was con- increased in our CIDP cohort. In our GBS cohort, we found a firmed by our data. Furthermore, we detected a 3.4-fold in- similar tendency, but studies with larger GBS cohorts are needed crease of the relative risk in antibody-mediated CIDP, to study an association. Furthermore, the frequency of anti- supporting the notion of humoral immunity playing a major paranodal antibodies in our cohort is higher than previously role in the association of CIDP and DM. reported prevalences, possibly due to a selection bias as a national center for antibody diagnostics. Therefore, given the low preva- As we did not detect any binding of antiparanodal antibodies to lence of antiparanodal antibodies and the retrospective character pancreatic tissue, our data suggest that immunogenic target of this explorative analysis, larger international multicenter studies epitopes of proteins recognized by the antibodies are likely not to are needed to address the role of humoral immunity with focus on be present in the pancreas. Thus, antiparanodal antibodies do antiparanodal antibodies and DM in CIDP and GBS and in- probably not have a direct pathogenic effect on pancreatic β cells. vestigate the role of DM and its associated conditions in para- This hypothesis is supported by the fact that in the patient with nodopathy using multivariate models. Following experimental DM type 1, diagnosis preceded the onset of IgG4-related neu- studies may elucidate the exact pathoimmunologic mechanisms. rologic disease. We therefore hypothesize that nodo- paranodopathy may be associated to a preexisting DM or hy- Acknowledgment perglycemic condition. The authors thank Barbara Reuter, Hiltrud Klupfel, ¨ and Antonia Kohl for excellent technical assistance and Robert A diabetes-related blood-nerve barrier dysfunction and Blum for advice on the study conceptualization. They also upregulation of proinflammatory cytokines have been thank the patients who contributed to the study. Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 5 Study Funding Appendix (continued) This study was supported by the Open Access Publication Fund of the University of Wu¨rzburg. L. Appeltshauser and K. Doppler Name Location Contribution are supported by research fellowships by the Interdisciplinary Julia Messinger University Hospital of Data acquisition and Center of Clinical Research of the Medical Faculty of Wur ¨ zburg. Wurzburg, Germany revision of the manuscript K. Doppler is supported by a grant of the German Research for content Foundation (DFG, DO-2219/1-1). J. Messinger and D. Hein- Katharina Starz University Hospital of Data acquisition and rich are supported by a grant of the University of Wur ¨ zburg Wurzburg, Germany revision of the manuscript for content Graduate School of Life Sciences. David Heinrich University Hospital of Data acquisition and Wurzburg, Germany revision of the manuscript Disclosure for content I. Ayzenberg, A.-M.Brunder,C.Dresel, J. Dorst, F. Dvorak, B. Fiebig, A. Grimm, D. Heinrich, A. Joerk, M. M¨aurer, P. Merl, S. Anna-Michelle University Hospital of Data acquisition and Brunder Wurzburg, ¨ Germany revision of the manuscript Michels, J. Messinger,M.Rosenfeldt, A.-D.Sperfeld, K. Starz, H. for content Stengel, M. Weihrauch, and G. S. Welte report no disclosures Helena Stengel University Hospital of Data acquisition and relevant to the manuscript. L. Appeltshauser, F. Leypoldt, C. Wurzburg, ¨ Germany revision of the manuscript Sommer, and K. Doppler work for an academic institution of- for content fering commercial antibody diagnostics. F. Birklein received Bianca Fiebig University Hospital of Data acquisition and support for research as a PI from the German Research Foun- Wurzburg, Germany revision of the manuscript for content dation DFG, grants Bi 579/10 and Bi 579/11, and unrestricted educational grants from Alnylam and the workers compensation Ilya Ayzenberg, St. Josef Hospital Bochum, Data acquisition and MD Ruhr University of Bochum, revision of the manuscript insurance BGW; he has served on advisory boards for Novartis Germany; I.M. Sechenov for content and Gru¨nenthal; he received speaker honoraria from Pfizer, First Moscow State Medical University, Russia Merz, Alnylam, and Akcea; he has served as an associate editor or editorial advisory board member for Neurology, European Journal Frank Birklein, University Medical Center Data acquisition and of Pain,and Pain Medicine. K. Pitarokoili received travel funding MD of the Johannes Gutenberg revision of the manuscript University, Mainz, for content and speaker honoraria from Biogen Idec, Novartis, Grifols, CSL Germany Behring, Celgene, and Bayer Schering Pharma and funding from Christian University Medical Center Data acquisition and the Ruhr University. F. Leypoldt has served on advisory boards Dresel, MD of the Johannes Gutenberg revision of the manuscript for Biogen, Roche, and Alexion and received speaker honoraria University, Mainz, for content Germany from Roche, Biogen,Grifols,Alexion,Desitin,and Novartis.F. Leypoldt serves as editorial board member for Neurology N2.C. Johannes University Hospital Ulm, Data acquisition and Dorst, MD Germany revision of the manuscript Sommer has served on scientific advisory boards for Akcea, for content Algiax, Air Liquide, Bayer, Grifols, Ipsen, LFB, Immunic, Merz, Florian Dvorak, Asklepios Schloßberg- Data acquisition and Pfizer, Roche, and Takeda; she reports having received speaker MD Klinik, Bad Konig, Germany revision of the manuscript honoraria for educational talks from Akcea, Alnylam Amicus, for content Grifols, Pfizer, and Teva. C. Sommer serves or has served as a Alexander University Hospital Data acquisition and journal editor, associate editor, or editorial advisory board Grimm, MD Tubingen, Germany revision of the manuscript member for the European Journal of Neurology, PLoS One,and for content PAIN Reports. Go to Neurology.org/NN for full disclosures. Alexander Jena University Hospital, Data acquisition and Joerk, MD Germany revision of the manuscript for content Publication History Received by Neurology: Neuroimmunology & Neuroinflammation Frank Leypoldt, University Hospital Data acquisition and MD Schleswig-Holstein, Kiel revision of the manuscript November 12, 2021. Accepted in final form February 15, 2022. University, Germany for content Mathias Klinikum Wurzburg Mitte Data acquisition and M¨ aurer, MD gGmbH, Germany revision of the manuscript for content Appendix Authors Patrick Merl, LVR-Klinik, Bonn, Germany Data acquisition and Name Location Contribution MD revision of the manuscript for content Luise University Hospital of Study design and ¨ Sebastian University Hospital Ulm, Data acquisition and Appeltshauser, Wurzburg, Germany conception; data MD acquisition, analysis, and Michels, MD Germany revision of the manuscript for content interpretation; drafting of the first version of the Kalliopi St. Josef Hospital Bochum, Data acquisition and manuscript; and revision of the manuscript for Pitarokoili, MD Ruhr University of revision of the manuscript Bochum, Germany for content intellectual content 6 Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 Neurology.org/NN 4. Devaux JJ, Miura Y, Fukami Y, et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology. 2016;86(9):800-807. Appendix (continued) 5. Appeltshauser L, Brunder AM, Heinius A, et al. Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e817. Name Location Contribution 6. Sima AA, Lattimer SA, Yagihashi S, et al. Axo-glial dysjunction. A novel structural lesion that accounts for poorly reversible slowing of nerve conduction in the spon- Mathias University of Wurzburg, ¨ Data acquisition and taneously diabetic bio-breeding rat. J Clin Invest. 1986;77(2):474-484. Rosenfeldt, Germany revision of the manuscript 7. Rajabally YA, Peric S, Cobeljic M, et al. Chronic inflammatory demyelinating poly- PhD for content neuropathy associated with diabetes: a European multicentre comparative reappraisal. J Neurol Neurosurg Psychiatry. 2020;91(10):1100-1104. Anne-Dorte Sachsisches Krankenhaus Data acquisition and 8. Van den Bergh PY, Hadden RD, Bouche P, et al. European Federation of Neurological Sperfeld, MD Altscherbitz, Schkeuditz, revision of the manuscript Societies/Peripheral Nerve Society guideline on management of chronic in- Germany for content flammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society— Marc Bundeswehrkrankenhaus Data acquisition and first revision. Eur J Neurol. 2010;17(3):356-363. Weihrauch, MD Ulm, Germany revision of the manuscript 9. Fokke C, van den Berg B, Drenthen J, et al. Diagnosis of Guillain-Barre syndrome and for content validation of Brighton criteria. Brain. 2014;137(pt 1):33-43. 10. Stengel H, Vural A, Brunder AM, et al. Anti-pan-neurofascin IgG3 as a marker of fulminant Gabriel Simon KRH Klinikum Nordstadt, Data acquisition and autoimmune neuropathy. Neurol Neuroimmunol Neuroinflamm. 2019;6(5):e603. Welte, MD Hannover, Germany revision of the manuscript 11. World Health Organization. Classification of Diabetes Mellitus. World Health Organiza- for content tion; 2019. Accessed October 25, 2021. apps.who.int/iris/handle/10665/325182. Li- cence: CC BY-NC-SA 3.0 IGO. Claudia University Hospital of Data acquisition and 12. Settipane GA, Pudupakkam RK, McGowan JH. Corticosteroid effect on immuno- Sommer, MD Wurzburg ¨ , Germany revision of the manuscript globulins. J Allergy Clin Immunol. 1978;62(3):162-166. for content 13. National Diabetes Surveillance at the Robert Koch Institute. Diabetes in Germany— National Diabetes Surveillance Report 2019. Robert Koch Institute; 2019. Accessed July Kathrin University Hospital of Study design and 7, 2021. diabsurv.rki.de/SharedDocs/downloads/DE/DiabSurv/diabetes-report_ Doppler, MD Wurzburg, Germany conception; data 2019_eng.pdf?__blob=publicationFile&v=12. acquisition; and revision of 14. Ben-Kraiem A, Sauer RS, Norwig C, et al. Selective blood-nerve barrier leakiness with the manuscript for content claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy. JMol Med (Berl). 2021;99(9):1237-1250. 15. Doppler K, Frank F, Koschker AC, et al. Nodes of Ranvier in skin biopsies of patients with diabetes mellitus. J Peripher Nerv Syst. 2017;22(3):182-190. References 16. Dalakas MC. IgG4-mediated neurologic autoimmunities. Understanding the patho- 1. Pascual-Goni E, Martin-Aguilar L, Querol L. Autoantibodies in chronic in- genicity of IgG4, ineffectiveness of IVIg, and long-lasting benefits of anti–B cell flammatory demyelinating polyradiculoneuropathy. Curr Opin Neurol. 2019;32(5): therapies. Neurol Neuroimmunol Neuroinflamm. 2022;9(1):e1116. 651-657. 17. Reinhold AK, Rittner HL. Barrier function in the peripheral and central nervous 2. Rasband MN, Peles E. The nodes of ranvier: molecular assembly and maintenance. system—a review. Pflugers Arch. 2017;469(1):123-134. Cold Spring Harb Perspect Biol. 2015;8(3):a020495. 18. Van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of 3. Pascual-Goñi E, Fehmi J, Lleix`a C, et al. Antibodies to the Caspr1/contactin-1 Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic complex in chronic inflammatory demyelinating polyradiculoneuropathy. Brain. inflammatory demyelinating polyradiculoneuropathy: report of a joint Task Force- 2021;144(4):1183-1196. doi:10.1136/ard.2003.001234. second revision. J Peripher Nerv Syst. 2021;26(3):242-268. Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 9, Number 3 | May 2022 7

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