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August 02, 2016; 87 (5) Article

The clinical spectrum of Caspr2 antibody–associated disease

Agnes van Sonderen, Helena Ariño, Mar Petit-Pedrol, Frank Leypoldt, Peter Körtvélyessy, Klaus-Peter Wandinger, Eric Lancaster, Paul W. Wirtz, Marco W.J. Schreurs, Peter A.E. Sillevis Smitt, Francesc Graus, Josep Dalmau, Maarten J. Titulaer
First published July 1, 2016, DOI: https://doi.org/10.1212/WNL.0000000000002917
Agnes van Sonderen
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Helena Ariño
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Mar Petit-Pedrol
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Frank Leypoldt
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Peter Körtvélyessy
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Klaus-Peter Wandinger
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Eric Lancaster
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Paul W. Wirtz
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Marco W.J. Schreurs
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Peter A.E. Sillevis Smitt
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Francesc Graus
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Josep Dalmau
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Maarten J. Titulaer
From the Departments of Neurology (A.v.S., P.A.E.S.S., M.J.T.) and Immunology (M.W.J.S.), Erasmus University Medical Center, Rotterdam; Department of Neurology (A.v.S., P.W.W.), Haga Teaching Hospital, the Hague, the Netherlands; Department of Neurology (H.A., F.G.), Hospital Clinic, University of Barcelona; Neuroimmunology Program (H.A., M.P.-P., F.G.) and Department of Neurology, Hospital Clinic (J.D.), Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Neuroimmunology (F.L.), Institute of Clinical Chemistry, Christian-Albrechts-University; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel; Department of Neurology (P.K.), University Hospital Magdeburg; Neuroimmunology (K.-P.W), Institute of Clinical Chemistry, University Medical Center Schleswig-Holstein Campus Lübeck; Department of Neurology (K.-P.W), University of Lübeck, Germany; Department of Neurology (E.L.), University of Pennsylvania (J.D.), Philadelphia; and Department of Neurology (J.D.), Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
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Citation
The clinical spectrum of Caspr2 antibody–associated disease
Agnes van Sonderen, Helena Ariño, Mar Petit-Pedrol, Frank Leypoldt, Peter Körtvélyessy, Klaus-Peter Wandinger, Eric Lancaster, Paul W. Wirtz, Marco W.J. Schreurs, Peter A.E. Sillevis Smitt, Francesc Graus, Josep Dalmau, Maarten J. Titulaer
Neurology Aug 2016, 87 (5) 521-528; DOI: 10.1212/WNL.0000000000002917

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Abstract

Objective: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder.

Methods: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients' informed consent.

Results: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses.

Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.

GLOSSARY

Caspr2=
contactin-associated protein-like 2;
CBA=
cell-based assay;
FLAIR=
fluid-attenuated inversion recovery;
IgG=
immunoglobulin G;
IHC=
immunohistochemistry;
IVIg=
IV immunoglobulin;
LE=
limbic encephalitis;
LGI1=
leucine-rich glioma-inactivated 1;
MG=
myasthenia gravis;
NMDAR=
NMDA receptor;
PNH=
peripheral nerve hyperexcitability;
RIA=
radioimmunoassay;
VGKC=
voltage-gated potassium channel

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received December 4, 2015.
  • Accepted in final form April 25, 2016.
  • © 2016 American Academy of Neurology
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Letters: Rapid online correspondence

  • Author response: Morvan syndrome and severe hyponatremia
    • Agnes van Sonderen, Neurologist, Erasmus University Medical Center, Rotterdam, the Netherlandsm.titulaer@erasmusmc.nl
    • Helena Arino, Josep Dalmau, Maarten J Titulaer
    Submitted September 13, 2016
  • Morvan syndrome and severe hyponatremia
    • Han Chen, Physician, Department of Neurology, Third Xiangya Hospital, Central South University, Chang Sha, Chinahchen_xy3yy@sina.com
    Submitted August 24, 2016
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