Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy

Sukhvir Wright, Ada T. Geerts, Cornelia Maria Jol-Van Der Zijde, Leslie Jacobson, Bethan Lang, Patrick Waters, Maarten J.D. Van Tol, Hans Stroink, Rinze F. Neuteboom, Oebele F. Brouwer, Angela Vincent*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Objective In autoimmune encephalitis the etiologic role of neuronal cell-surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long-term outcomes in these patients. Methods Patients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age-matched bone-marrow donors served as controls (n = 112). All sera were tested for serum N-methyl-d-aspartate receptor (NMDAR), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin-2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)-complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years. Results Seventeen patients (9.5%) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin-2 (n = 3), compared to three (3/112; 2.6%) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell-surface antibodies), but 8 (47%) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody-positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody-positive patients were treated with standard antiepileptic drugs (AEDs); three (17%) became intractable but this was not different from the 16 (10%) of 161 antibody-negative patients. In 96 patients with available follow-up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients. Significance Neuronal antibodies were found at low levels in 9.5% of patients with new-onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long-term outcome did not differ from those of antibody-negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody-positive group, the CASPR2 and contactin-2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.

Original languageEnglish
Pages (from-to)823-831
Number of pages9
JournalEpilepsia
Volume57
Issue number5
Early online date21 Mar 2016
DOIs
Publication statusPublished - 1 May 2016

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Immunotherapy
Epilepsy
Pediatrics
Antibodies
Contactin 2
Contactins
Anticonvulsants
Contactin 1
Serum
Voltage-Gated Potassium Channels
Neurons
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Proteins
Glutamate Decarboxylase
Encephalitis
Glioma
Cerebrospinal Fluid
Comorbidity

Bibliographical note

© 2016 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Keywords

  • Autoantibodies
  • NMDA receptor
  • Pediatric epilepsy
  • Voltage-gated potassium channel complex

Cite this

Wright, Sukhvir ; Geerts, Ada T. ; Jol-Van Der Zijde, Cornelia Maria ; Jacobson, Leslie ; Lang, Bethan ; Waters, Patrick ; Van Tol, Maarten J.D. ; Stroink, Hans ; Neuteboom, Rinze F. ; Brouwer, Oebele F. ; Vincent, Angela. / Neuronal antibodies in pediatric epilepsy : Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy. In: Epilepsia. 2016 ; Vol. 57, No. 5. pp. 823-831.
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title = "Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy",
abstract = "Objective In autoimmune encephalitis the etiologic role of neuronal cell-surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long-term outcomes in these patients. Methods Patients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age-matched bone-marrow donors served as controls (n = 112). All sera were tested for serum N-methyl-d-aspartate receptor (NMDAR), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin-2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)-complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years. Results Seventeen patients (9.5{\%}) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin-2 (n = 3), compared to three (3/112; 2.6{\%}) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell-surface antibodies), but 8 (47{\%}) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody-positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody-positive patients were treated with standard antiepileptic drugs (AEDs); three (17{\%}) became intractable but this was not different from the 16 (10{\%}) of 161 antibody-negative patients. In 96 patients with available follow-up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients. Significance Neuronal antibodies were found at low levels in 9.5{\%} of patients with new-onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long-term outcome did not differ from those of antibody-negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody-positive group, the CASPR2 and contactin-2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.",
keywords = "Autoantibodies, NMDA receptor, Pediatric epilepsy, Voltage-gated potassium channel complex",
author = "Sukhvir Wright and Geerts, {Ada T.} and {Jol-Van Der Zijde}, {Cornelia Maria} and Leslie Jacobson and Bethan Lang and Patrick Waters and {Van Tol}, {Maarten J.D.} and Hans Stroink and Neuteboom, {Rinze F.} and Brouwer, {Oebele F.} and Angela Vincent",
note = "{\circledC} 2016 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.",
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Wright, S, Geerts, AT, Jol-Van Der Zijde, CM, Jacobson, L, Lang, B, Waters, P, Van Tol, MJD, Stroink, H, Neuteboom, RF, Brouwer, OF & Vincent, A 2016, 'Neuronal antibodies in pediatric epilepsy: Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy', Epilepsia, vol. 57, no. 5, pp. 823-831. https://doi.org/10.1111/epi.13356

Neuronal antibodies in pediatric epilepsy : Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy. / Wright, Sukhvir; Geerts, Ada T.; Jol-Van Der Zijde, Cornelia Maria; Jacobson, Leslie; Lang, Bethan; Waters, Patrick; Van Tol, Maarten J.D.; Stroink, Hans; Neuteboom, Rinze F.; Brouwer, Oebele F.; Vincent, Angela.

In: Epilepsia, Vol. 57, No. 5, 01.05.2016, p. 823-831.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Neuronal antibodies in pediatric epilepsy

T2 - Clinical features and long-term outcomes of a historical cohort not treated with immunotherapy

AU - Wright, Sukhvir

AU - Geerts, Ada T.

AU - Jol-Van Der Zijde, Cornelia Maria

AU - Jacobson, Leslie

AU - Lang, Bethan

AU - Waters, Patrick

AU - Van Tol, Maarten J.D.

AU - Stroink, Hans

AU - Neuteboom, Rinze F.

AU - Brouwer, Oebele F.

AU - Vincent, Angela

N1 - © 2016 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Objective In autoimmune encephalitis the etiologic role of neuronal cell-surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long-term outcomes in these patients. Methods Patients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age-matched bone-marrow donors served as controls (n = 112). All sera were tested for serum N-methyl-d-aspartate receptor (NMDAR), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin-2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)-complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years. Results Seventeen patients (9.5%) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin-2 (n = 3), compared to three (3/112; 2.6%) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell-surface antibodies), but 8 (47%) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody-positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody-positive patients were treated with standard antiepileptic drugs (AEDs); three (17%) became intractable but this was not different from the 16 (10%) of 161 antibody-negative patients. In 96 patients with available follow-up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients. Significance Neuronal antibodies were found at low levels in 9.5% of patients with new-onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long-term outcome did not differ from those of antibody-negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody-positive group, the CASPR2 and contactin-2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.

AB - Objective In autoimmune encephalitis the etiologic role of neuronal cell-surface antibodies is clear; patients diagnosed and treated early have better outcomes. Neuronal antibodies have also been described in patients with pediatric epilepsy without encephalitis. The aim was to assess whether antibody presence had any effect on long-term outcomes in these patients. Methods Patients (n = 178) were recruited between 1988 and 1992 as part of the prospective Dutch Study of Epilepsy in Childhood; none received immunotherapy. Healthy age-matched bone-marrow donors served as controls (n = 112). All sera were tested for serum N-methyl-d-aspartate receptor (NMDAR), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, leucine rich glioma inactivated 1, contactin associated protein like 2 (CASPR2), contactin-2, glutamic acid decarboxylase, and voltage gated potassium channel (VGKC)-complex antibodies by standard techniques. No cerebrospinal fluid (CSF) samples were available. Results were correlated with clinical data collected over 15 years. Results Seventeen patients (9.5%) were positive for VGKC complex (n = 3), NMDAR (n = 7), CASPR2 (n = 4), and contactin-2 (n = 3), compared to three (3/112; 2.6%) healthy controls (VGKC complex [n = 1], NMDAR [n = 2]; p = 0.03; Fisher's exact test). Titers were relatively low (≤1:100 for cell-surface antibodies), but 8 (47%) of the 17 positive samples bound to the surface of live hippocampal neurons consistent with a potential pathogenic antibody. Preexisting cognitive impairment was more frequent in antibody-positive patients (9/17 vs. 33/161; p = 0.01). Fourteen antibody-positive patients were treated with standard antiepileptic drugs (AEDs); three (17%) became intractable but this was not different from the 16 (10%) of 161 antibody-negative patients. In 96 patients with available follow-up samples at 6 and/or 12 months, 6 of 7 positive antibodies had disappeared and, conversely, antibodies had appeared for the first time in a further 7 patients. Significance Neuronal antibodies were found at low levels in 9.5% of patients with new-onset pediatric epilepsy but did not necessarily persist over time, and the development of antibodies de novo in later samples suggests they could be due to a secondary response to neuronal damage or inflammation. Moreover, as the response to standard AEDs and the long-term outcome did not differ from those of antibody-negative pediatric patients, these findings suggest that routine neuronal antibody testing is unlikely to be helpful in pediatric epilepsy. However, the higher incidence of preexisting cognitive problems in the antibody-positive group, the CASPR2 and contactin-2 antibodies in 7 of 17 patients, and the binding of 8 of 17 of serum samples to live hippocampal neurons suggest that neuronal antibodies, even if secondary, could contribute to the comorbidities of pediatric epilepsy.

KW - Autoantibodies

KW - NMDA receptor

KW - Pediatric epilepsy

KW - Voltage-gated potassium channel complex

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