Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

Marienke A.A.M. de Bruijn; Anna E.M. Bastiaansen; Hana Mojzisova; the ACES Study Group; Agnes van Sonderen; Roland D. Thijs; Marian J.M. Majoie; Rob P.W. Rouhl; Marleen H. van Coevorden-Hameete; Juna M. de Vries; Amaia Muñoz Lopetegi; Bob Roozenbeek; Marco W.J. Schreurs; Peter A.E. Sillevis Smitt; Maarten J. Titulaer

doi:10.1002/ana.26013

Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

Marienke A.A.M. de Bruijn, Anna E.M. Bastiaansen, Hana Mojzisova, the ACES Study Group, Agnes van Sonderen, Roland D. Thijs, Marian J.M. Majoie, Rob P.W. Rouhl, Marleen H. van Coevorden-Hameete, Juna M. de Vries, Amaia Muñoz Lopetegi, Bob Roozenbeek, Marco W.J. Schreurs, Peter A.E. Sillevis Smitt, Maarten J. Titulaer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2–18). Twenty patients (3.4%) had AES, of whom 3 had anti–leucine-rich glioma inactivated 1, 3 had anti–contactin-associated protein-like 2, 1 had anti–N-methyl-D-aspartate receptor, and 13 had anti–glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6–3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1–56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2–49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1–56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4–382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0–46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. Interpretation: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698–710.

Original language	English
Pages (from-to)	698-710
Number of pages	13
Journal	Annals of Neurology
Volume	89
Issue number	4
DOIs	https://doi.org/10.1002/ana.26013
Publication status	Published - Apr 2021

Bibliographical note

Acknowledgments:
This work was supported by the Dutch Epilepsy Foundation, project numbers 14‐19 and 19‐08. It is generated within the European Reference Network for Rare Immunodeficiency, Autoinflammation, and Autoimmune Diseases. H.M., and M. Elisak and P. Marusic of the ACES Study Group, were supported by the Charles University project GA UK No 746120.

Publisher Copyright:
© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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de Bruijn, M. A. A. M., Bastiaansen, A. E. M., Mojzisova, H., the ACES Study Group, van Sonderen, A., Thijs, R. D., Majoie, M. J. M., Rouhl, R. P. W., van Coevorden-Hameete, M. H., de Vries, J. M., Muñoz Lopetegi, A., Roozenbeek, B., Schreurs, M. W. J., Sillevis Smitt, P. A. E., & Titulaer, M. J. (2021). Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score. Annals of Neurology, 89(4), 698-710. https://doi.org/10.1002/ana.26013

@article{07f73bbfc7354b319dddc09a6b09dabd,

title = "Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score",

abstract = "Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2–18). Twenty patients (3.4%) had AES, of whom 3 had anti–leucine-rich glioma inactivated 1, 3 had anti–contactin-associated protein-like 2, 1 had anti–N-methyl-D-aspartate receptor, and 13 had anti–glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6–3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1–56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2–49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1–56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4–382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0–46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. Interpretation: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698–710.",

author = "{de Bruijn}, {Marienke A.A.M.} and Bastiaansen, {Anna E.M.} and Hana Mojzisova and {the ACES Study Group} and {van Sonderen}, Agnes and Thijs, {Roland D.} and Majoie, {Marian J.M.} and Rouhl, {Rob P.W.} and {van Coevorden-Hameete}, {Marleen H.} and {de Vries}, {Juna M.} and {Mu{\~n}oz Lopetegi}, Amaia and Bob Roozenbeek and Schreurs, {Marco W.J.} and {Sillevis Smitt}, {Peter A.E.} and Titulaer, {Maarten J.}",

note = "Acknowledgments: This work was supported by the Dutch Epilepsy Foundation, project numbers 14‐19 and 19‐08. It is generated within the European Reference Network for Rare Immunodeficiency, Autoinflammation, and Autoimmune Diseases. H.M., and M. Elisak and P. Marusic of the ACES Study Group, were supported by the Charles University project GA UK No 746120. Publisher Copyright: {\textcopyright} 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2021",

month = apr,

doi = "10.1002/ana.26013",

language = "English",

volume = "89",

pages = "698--710",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley & Sons Inc.",

number = "4",

}

de Bruijn, MAAM , Bastiaansen, AEM, Mojzisova, H, the ACES Study Group, van Sonderen, A, Thijs, RD, Majoie, MJM, Rouhl, RPW, van Coevorden-Hameete, MH, de Vries, JM, Muñoz Lopetegi, A, Roozenbeek, B, Schreurs, MWJ, Sillevis Smitt, PAE & Titulaer, MJ 2021, 'Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score', Annals of Neurology, vol. 89, no. 4, pp. 698-710. https://doi.org/10.1002/ana.26013

TY - JOUR

T1 - Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

AU - de Bruijn, Marienke A.A.M.

AU - Bastiaansen, Anna E.M.

AU - Mojzisova, Hana

AU - the ACES Study Group

AU - van Sonderen, Agnes

AU - Thijs, Roland D.

AU - Majoie, Marian J.M.

AU - Rouhl, Rob P.W.

AU - van Coevorden-Hameete, Marleen H.

AU - de Vries, Juna M.

AU - Muñoz Lopetegi, Amaia

AU - Roozenbeek, Bob

AU - Schreurs, Marco W.J.

AU - Sillevis Smitt, Peter A.E.

AU - Titulaer, Maarten J.

N1 - Acknowledgments: This work was supported by the Dutch Epilepsy Foundation, project numbers 14‐19 and 19‐08. It is generated within the European Reference Network for Rare Immunodeficiency, Autoinflammation, and Autoimmune Diseases. H.M., and M. Elisak and P. Marusic of the ACES Study Group, were supported by the Charles University project GA UK No 746120. Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

PY - 2021/4

Y1 - 2021/4

N2 - Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2–18). Twenty patients (3.4%) had AES, of whom 3 had anti–leucine-rich glioma inactivated 1, 3 had anti–contactin-associated protein-like 2, 1 had anti–N-methyl-D-aspartate receptor, and 13 had anti–glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6–3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1–56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2–49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1–56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4–382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0–46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. Interpretation: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698–710.

AB - Objective: Diagnosing autoimmune encephalitis (AIE) is difficult in patients with less fulminant diseases such as epilepsy. However, recognition is important, as patients require immunotherapy. This study aims to identify antibodies in patients with focal epilepsy of unknown etiology, and to create a score to preselect patients requiring testing. Methods: In this prospective, multicenter cohort study, adults with focal epilepsy of unknown etiology, without recognized AIE, were included, between December 2014 and December 2017, and followed for 1 year. Serum, and if available cerebrospinal fluid, were analyzed using different laboratory techniques. The ACES score was created using factors favoring an autoimmune etiology of seizures (AES), as determined by multivariate logistic regression. The model was externally validated and evaluated using the Concordance (C) statistic. Results: We included 582 patients, with median epilepsy duration of 8 years (interquartile range = 2–18). Twenty patients (3.4%) had AES, of whom 3 had anti–leucine-rich glioma inactivated 1, 3 had anti–contactin-associated protein-like 2, 1 had anti–N-methyl-D-aspartate receptor, and 13 had anti–glutamic acid decarboxylase 65 (enzyme-linked immunosorbent assay concentrations >10,000IU/ml). Risk factors for AES were temporal magnetic resonance imaging hyperintensities (odds ratio [OR] = 255.3, 95% confidence interval [CI] = 19.6–3332.2, p < 0.0001), autoimmune diseases (OR = 13.31, 95% CI = 3.1–56.6, p = 0.0005), behavioral changes (OR 12.3, 95% CI = 3.2–49.9, p = 0.0003), autonomic symptoms (OR = 13.3, 95% CI = 3.1–56.6, p = 0.0005), cognitive symptoms (OR = 30.6, 95% CI = 2.4–382.7, p = 0.009), and speech problems (OR = 9.6, 95% CI = 2.0–46.7, p = 0.005). The internally validated C statistic was 0.95, and 0.92 in the validation cohort (n = 128). Assigning each factor 1 point, an antibodies contributing to focal epilepsy signs and symptoms (ACES) score ≥ 2 had a sensitivity of 100% to detect AES, and a specificity of 84.9%. Interpretation: Specific signs point toward AES in focal epilepsy of unknown etiology. The ACES score (cutoff ≥ 2) is useful to select patients requiring antibody testing. ANN NEUROL 2021;89:698–710.

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JO - Annals of Neurology

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Antibodies Contributing to Focal Epilepsy Signs and Symptoms Score

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