CLINICAL/SCIENTIFIC NOTES OPEN ACCESS Chronic inflammatory demyelinating polyneuropathy associated with contactin-1 antibodies in a child Laura Carrera-Garcı́a, MD, Daniel Natera-de Benito, MD, PhD, Cinta Lleixà, PhD, Carlos Ortez, MD, Correspondence Dr. Armangué Jaume Colomer, MD, PhD, Andrés Nascimento, MD, Albert Saiz, MD, PhD, Josep Dalmau, MD, PhD, tarmangue@ Luis Querol, MD, PhD, and Thaı́s Armangué, MD, PhD sjdhospitalbarcelona.org Neurol Neuroimmunol Neuroinflamm 2019;6:e602. doi:10.1212/NXI.0000000000000602 Clinical case A previously healthy 2-year and 9-month old boy was brought to the emergency department for a 6-day history of weakness in the legs and frequent falls, rendering him unable to walk 1 day before admission. He did not have pain, dysphagia, bladder dysfunction, or sensory symptoms. There was no history of trauma, but he developed diarrhea 3 days before symptom onset. Family history was negative for consanguinity or neurologic diseases. At examination, he had bilateral leg weakness requiring substantial aid to walk a few steps and was unable to stand up from the floor. He had absent tendon reflexes in the lower extremities and flexor plantar responses. Strength and reflexes in upper extremities and the rest of the examination were normal. CSF showed a protein concentration of 125 mg/dL (NR: 15–45), with normal white blood cell count and glucose concentration. Blood cell count and chemistry were normal, and stool culture was negative. Nerve conduction studies (NCSs) and EMG showed decreased amplitudes in both peroneal nerves (table e-1, links.lww.com/NXI/A131). The patient was treated with IV immunoglobulins (IVIg) 2 g/kg administered in 3 days. During the next 2 weeks, there was mild improvement in motor strength as he was able to walk and stand up with support (the Guillain-Barré syndrome disability scale [GBSds]1 score remained 3), and he was discharged home. Two weeks later (4 weeks after symptom onset), he was brought back for worsening weakness in the legs and new onset weakness in the arms. This time, the examination revealed weakness in legs and arms, generalized areflexia, and impossibility to stand up from the floor (GBSds 4). Repeat CSF studies showed a protein concentration of 148 mg/dL and normal white blood cell count and glucose level. No toxic or infectious etiologies were iden- tified, and serum was negative for ganglioside antibodies. NCSs showed prolonged distal motor latencies, conduction slowing, and decreased amplitude of compound muscle action potentials, along with EMG features of chronic denervation, fibrillation, and positive sharp waves (table e-1, links.lww.com/NXI/A131). Treatment with IVIg was ineffective, but IV methylprednis- olone (30 mg/kg/d for 5 days) resulted in substantial improvement, leaving the patient with normal strength except for mild distal lower extremity weakness (GBSds 1). One year later, after an episode of diarrhea, the patient developed similar clinical and electro- physiologic abnormalities confined to the lower extremities (GBSds 3) fulfilling clinical and electrophysiologic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). This time, the symptom recrudescence improved with IVIg, and he returned to his baseline (GBSds 1). From the Neuromuscular Unit (L.C.-G., D.N.B., C.O., J.C., A.N.), Neurology Service, Research Institute, Sant Joan de Deu Children’s Hospital, University of Barcelona; Neuromuscular Diseases Unit (C.L., L.Q.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona; Centro Investigación Biomédica en Red para Enfermedades Raras (CIBERER) (C.L., J.D., L.Q., T.A.), Madrid; Neuroimmunology Program (A.S., J.D., T.A.), Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS)-Hospital Clı́nic, University of Barcelona; Catalan Institution for Research and Advanced Studies (ICREA) (J.D.), Barcelona, Spain; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Pediatric Neuroimmunology Unit (T.A.), Sant Joan de Deu Children’s Hospital, University of Barcelona, Spain. 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 AGAUR. 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 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Figure Demonstration of anti–contactin-1 antibodies in a serum of a child with CIDP The presence of anti–contactin-1 antibodies was confirmed with contactin-1–transfected human embrionic kidney (HEK) 293 cells. Patient serum (B) showed strong reactivity against contactin-1 and colocalized with the reactivity of a commercial antibody (A) in merged images (C). Patient serum showed strong reactivity against the paranode on pig teased nerve fibers (E) and colocalized with the reactivity of a commercial antibody (D) in merged images (F). A recent follow-up, 5 years after symptom onset, showed that and EMG suggesting demyelinating features accompanied by the neurologic deficits were stable, and the patient had not had early axonal damage. However, he had a less aggressive course further relapses. Current serum studies for antibodies against compared with that described in adults. Because at the last components of the nodal and paranodal regions of peripheral follow-up, 5 years after disease onset, the patient’s deficits had nerves were negative, but analysis of archived serum and CSF remained stable for 4 years, treatment with rituximab was not samples obtained at disease onset (5 years earlier) showed considered. It is likely that an earlier recognition of the dis- intense reactivity with teased nerve fibers from pig and human order, by examining contactin-1 antibodies at disease onset, embrionic kidney (HEK) 293 cells expressing contactin-1 would have prompted treatment with rituximab and perhaps demonstrating the presence of these antibodies in both assays prevented some of his deficits. (figure). Experience with this patient indicates that contactin-1 antibody-associated CIDP can occur in children. Testing for Discussion antibodies against nodo-paranodal proteins is important in pediatric patients with CIDP refractory to conventional ther- CIDP is a rare, disabling and treatable disease in children. apies because antibody findings can help optimizing their care. Antibodies against proteins of the paranode and node of Ranvier (contactin-1, contactin-associated protein 1, and Study funding neurofascin 155 and 186) have been recently described in This study was supported in part by Instituto Carlos III/FEDER several subsets of patients with CIDP.2 In particular, CIDP (FIS 17/00234 (J.D.), FIS16/00627 (L.Q.), CM17/00054 associated with antibodies against the 155 isoform of neuro- (D.N.)); CIBERER #CB15/00010 (T.A., J.D., L.Q.); AGAUR fascin develop at younger ages, including pediatric patients.2,3 (Generalitat de Catalunya); Pla estratègic de recerca i innovació However, antibodies against contactin-1 have never been en salut (PERIS), Departament de Salut, Generalitat de Cata- reported in children. These antibodies are predominantly lunya (SLT006/17/00131, L.Q.); and Fundació CELLEX (J.D.). IgG4 subclass and associate with a form of CIDP that mani- fests with an aggressive symptom onset, resembling Guillain- Disclosure Barré syndrome, with predominant motor weakness, ataxia, J. Dalmau receives royalties from Athena Diagnostics for the use and absent or limited response to IVIg or steroids but an of Ma-2 as an autoantibody test and from Euroimmun AG for excellent response to rituximab.4,5 This disorder represents the use of NMDA, GABAB receptor, GABAA receptor, DPPX, approximately 2%–4% of all patients with CIDP. Clinical and IgLON5 as autoantibody tests and is Editor of Neurology: improvement is usually accompanied by a decrease of Neuroimmunology & Neuroinflammation. The other authors re- contactin-1 antibody titers.6,7 Our patient had a similar pre- port no relevant disclosures. Go to Neurology.org/NN for full sentation with predominant motor involvement and NCSs disclosures. 2 Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 5 | September 2019 Neurology.org/NN Publication history Received by Neurology: Neuroimmunology & Neuroinflammation Appendix (continued) April 12, 2019. Accepted in final form June 25, 2019. Name Location Role Contribution Josep University of Author Coordinated and Dalmau, MD, Pennsylvania, supervised data PhD IDIBAPS and collection and critically Appendix Authors Hospital Clinic reviewed and revised the manuscript Name Location Role Contribution Luis Querol, Hospital de la Santa Author Coordinated and Laura Sant Joan de Déu Author Data collection; MD, PhD Creu i Sant Pau supervised data Carrera Children’s Hospital interpreted the data; collection and critically Garcı́a, MD follows the patient; reviewed and revised and writing/drafting the manuscript the initial manuscript Thaı́s Sant Joan de Déu Author Designed and Daniel Sant Joan de Déu Author Interpreted the data; Armangué, Children’s Hospital, conceptualized the Natera-de Children’s Hospital follows the patient; MD, PhD IDIBAPS and study; performed the Benito, MD, and critically reviewed Hospital Clinic neuroimmunologic PhD and revised the studies; analyzed the manuscript data; follows the patient; drafted the Cinta Lleixà, Hospital de la Santa Author Performed the manuscript; and PhD Creu i Sant Pau neuroimmunologic developed the figures studies; analyzed the data; and developed the figures Carlos Ortez, Sant Joan de Déu Author Interpreted the data; MD Children’s Hospital follows the patient; and critically reviewed References and revised the 1. Hughes RA, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial prednisolone manuscript in acute polyneuropathy. Lancet 1978;2:750–753. 2. Querol L, Devaux J, Rojas-Garcia R, Illa I. Autoantibodies in chronic inflammatory Jaume Sant Joan de Déu Author Interpreted the data; neuropathies: diagnostic and therapeutic implications. Nat Rev Neurol 2017;13: Colomer, Children’s Hospital follows the patient; 533–547. MD, PhD and critically reviewed 3. Vural A, Doppler K, Meinl E. Autoantibodies against the node of ranvier in and revised the seropositive chronic inflammatory demyelinating polyneuropathy: diagnostic, manuscript pathogenic, and therapeutic relevance. Front Immunol 2018;14:1029. 4. Querol L, Nogales-Gadea G, Rojas-Garcia R, et al. Antibodies to contactin-1 in Andrés Sant Joan de Déu Author Interpreted the data; chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013;73: Nascimento, Children’s Hospital follows the patient; 370–380. MD and critically reviewed 5. Miura Y, Devaux JJ, Fukami Y, et al. Contactin 1 IgG4 associates to chronic and revised the inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015;138: manuscript 1484–1491. 6. Querol L, Rojas-Garcı́a R, Diaz-Manera J, et al. Rituximab in treatment-resistant CIDP Albert Saiz, IDIBAPS and Author Performed the with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm MD, PhD Hospital Clinic neuroimmunologic 2015;2:e149. doi:10.1212/NXI.0000000000000149. studies; and analyzed 7. Doppler K, Appeltshauser L, Wilhelmi K, et al. Destruction of paranodal architecture the data in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neuro- surg Psychiatry 2015;86:720–728. Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 6, Number 5 | September 2019 3 Chronic inflammatory demyelinating polyneuropathy associated with contactin-1 antibodies in a child Laura Carrera-García, Daniel Natera-de Benito, Cinta Lleixà, et al. Neurol Neuroimmunol Neuroinflamm 2019;6; DOI 10.1212/NXI.0000000000000602 This information is current as of July 24, 2019 Neurol Neuroimmunol Neuroinflamm is an official journal of the American Academy of Neurology. Published since April 2014, it is an open-access, online-only, continuous publication journal. Copyright Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rights reserved. Online ISSN: 2332-7812. Updated Information & including high resolution figures, can be found at: Services http://nn.neurology.org/content/6/5/e602.full.html References This article cites 7 articles, 1 of which you can access for free at: http://nn.neurology.org/content/6/5/e602.full.html##ref-list-1 Citations This article has been cited by 1 HighWire-hosted articles: http://nn.neurology.org/content/6/5/e602.full.html##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Pediatric http://nn.neurology.org//cgi/collection/all_pediatric Chronic inflammatory demyelinating polyneuropathy http://nn.neurology.org//cgi/collection/chronic_inflammatory_demyeli nating_polyneuropathy EMG http://nn.neurology.org//cgi/collection/emg Guillain-Barre syndrome http://nn.neurology.org//cgi/collection/guillainbarre_syndrome Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://nn.neurology.org/misc/about.xhtml#permissions Reprints Information about ordering reprints can be found online: http://nn.neurology.org/misc/addir.xhtml#reprintsus Neurol Neuroimmunol Neuroinflamm is an official journal of the American Academy of Neurology. Published since April 2014, it is an open-access, online-only, continuous publication journal. Copyright Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rights reserved. Online ISSN: 2332-7812.