Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome

Christian G Bien; Corinna I Bien; Müjgan Dogan Onugoren; Desiree De Simoni; Verena Eigler; Carl-Albrecht Haensch; Martin Holtkamp; Fatme S Ismail; Martin Kurthen; Nico Melzer; Kristina Mayer; Felix von Podewils; Helmut Rauschka; Andrea O Rossetti; Wolf-Rüdiger Schäbitz; Olga Simova; Karsten Witt; Romana Höftberger; Theodor W May

doi:10.1007/s00415-020-09814-3

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome

Christian G Bien, Corinna I Bien, Müjgan Dogan Onugoren, Desiree De Simoni, Verena Eigler, Carl-Albrecht Haensch, Martin Holtkamp, Fatme S Ismail, Martin Kurthen, Nico Melzer, Kristina Mayer, Felix von Podewils, Helmut Rauschka, Andrea O Rossetti, Wolf-Rüdiger Schäbitz, Olga Simova, Karsten Witt, Romana Höftberger, Theodor W May

Division of Neurology (University Hospital St. Pölten)

Research output: Journal article (peer-reviewed) › Journal article

31 Citations (Scopus)

Abstract

OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions.

METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters.

RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention.

CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

Original language	English
Pages (from-to)	2101-2114
Number of pages	14
Journal	Journal of Neurology
Volume	267
Issue number	7
DOIs	https://doi.org/10.1007/s00415-020-09814-3
Publication status	Published - 1 Jul 2020

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Autoantibodies/analysis
Autoimmune Diseases of the Nervous System/blood
Child
Child, Preschool
Diagnostic Techniques, Neurological/standards
Female
Glutamate Decarboxylase/immunology
HEK293 Cells
Humans
Immunologic Tests/standards
Infant
Intracellular Signaling Peptides and Proteins/immunology
Male
Membrane Proteins/immunology
Mental Disorders/blood
Middle Aged
Nerve Tissue Proteins/immunology
Neuropil/immunology
Potassium Channels, Voltage-Gated/immunology
Receptors, AMPA/immunology
Receptors, GABA-B/immunology
Receptors, Glycine/immunology
Receptors, N-Methyl-D-Aspartate/immunology
Reproducibility of Results
Retrospective Studies
Young Adult

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10.1007/s00415-020-09814-3

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Bien, C. G., Bien, C. I., Dogan Onugoren, M., De Simoni, D., Eigler, V., Haensch, C-A., Holtkamp, M., Ismail, F. S., Kurthen, M., Melzer, N., Mayer, K., von Podewils, F., Rauschka, H., Rossetti, A. O., Schäbitz, W-R., Simova, O., Witt, K., Höftberger, R., & May, T. W. (2020). Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome. Journal of Neurology, 267(7), 2101-2114. https://doi.org/10.1007/s00415-020-09814-3

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title = "Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome",

abstract = "OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions.METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters.RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention.CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Autoantibodies/analysis, Autoimmune Diseases of the Nervous System/blood, Child, Child, Preschool, Diagnostic Techniques, Neurological/standards, Female, Glutamate Decarboxylase/immunology, HEK293 Cells, Humans, Immunologic Tests/standards, Infant, Intracellular Signaling Peptides and Proteins/immunology, Male, Membrane Proteins/immunology, Mental Disorders/blood, Middle Aged, Nerve Tissue Proteins/immunology, Neuropil/immunology, Potassium Channels, Voltage-Gated/immunology, Receptors, AMPA/immunology, Receptors, GABA-B/immunology, Receptors, Glycine/immunology, Receptors, N-Methyl-D-Aspartate/immunology, Reproducibility of Results, Retrospective Studies, Young Adult",

author = "Bien, {Christian G} and Bien, {Corinna I} and {Dogan Onugoren}, M{\"u}jgan and {De Simoni}, Desiree and Verena Eigler and Carl-Albrecht Haensch and Martin Holtkamp and Ismail, {Fatme S} and Martin Kurthen and Nico Melzer and Kristina Mayer and {von Podewils}, Felix and Helmut Rauschka and Rossetti, {Andrea O} and Wolf-R{\"u}diger Sch{\"a}bitz and Olga Simova and Karsten Witt and Romana H{\"o}ftberger and May, {Theodor W}",

note = "Funding Information: Dr. CG Bien obtained honoraria for speaking engagements from UCB, Desitin (Hamburg, Germany), and Euroimmun. He receives research support from Deutsche Forschungsgemeinschaft (German Research Council, Bonn, Germany) and Gerd-Altenhof-Stiftung (Deutsches Stiftungszentrum, Essen, Germany). Dr. M Holtkamp obtained speaker{\textquoteright}s honoraria and/or consultancy fees from Arvelle, Bial, Desitin, Eisai, GW Pharmaceuticals, Novartis, and UCB. Dr. N Melzer has received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharmaceuticals, Fresenius Medical Care, Diamed, and BIAL, and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharmaceuticals, and Novartis Pharma. Dr. F von Podewils obtained honoraria for speaking engagements from UCB, Eisai, and BIAL. Dr H Rauschka obtained honoraria for speaking engagements, consulting, serving on advisory boards and funding for conference travels from Biogen, Merck, Novartis, Roche, Sanofi and Teva-Ratiopharm. Dr. R H{\"o}ftberger obtained honoraria for speaking engagements from Euroimmun and Novartis. She receives research support from the Jubil{\"a}umsfonds der {\"O}sterreichischen Nationalbank, Project 16919, and the GBS/CIDP Foundation International. The Medical University of Vienna receives payments for antibody assays. The other authors report no conflicts of interest. Publisher Copyright: {\textcopyright} 2020, Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2020",

month = jul,

day = "1",

doi = "10.1007/s00415-020-09814-3",

language = "English",

volume = "267",

pages = "2101--2114",

journal = "Journal of Neurology",

issn = "0340-5354",

publisher = "D. Steinkopff-Verlag",

number = "7",

}

Bien, CG, Bien, CI, Dogan Onugoren, M, De Simoni, D, Eigler, V, Haensch, C-A, Holtkamp, M, Ismail, FS, Kurthen, M, Melzer, N, Mayer, K, von Podewils, F, Rauschka, H, Rossetti, AO, Schäbitz, W-R, Simova, O, Witt, K, Höftberger, R & May, TW 2020, 'Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome', Journal of Neurology, vol. 267, no. 7, pp. 2101-2114. https://doi.org/10.1007/s00415-020-09814-3

TY - JOUR

T1 - Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome

AU - Bien, Christian G

AU - Bien, Corinna I

AU - Dogan Onugoren, Müjgan

AU - De Simoni, Desiree

AU - Eigler, Verena

AU - Haensch, Carl-Albrecht

AU - Holtkamp, Martin

AU - Ismail, Fatme S

AU - Kurthen, Martin

AU - Melzer, Nico

AU - Mayer, Kristina

AU - von Podewils, Felix

AU - Rauschka, Helmut

AU - Rossetti, Andrea O

AU - Schäbitz, Wolf-Rüdiger

AU - Simova, Olga

AU - Witt, Karsten

AU - Höftberger, Romana

AU - May, Theodor W

N1 - Funding Information: Dr. CG Bien obtained honoraria for speaking engagements from UCB, Desitin (Hamburg, Germany), and Euroimmun. He receives research support from Deutsche Forschungsgemeinschaft (German Research Council, Bonn, Germany) and Gerd-Altenhof-Stiftung (Deutsches Stiftungszentrum, Essen, Germany). Dr. M Holtkamp obtained speaker’s honoraria and/or consultancy fees from Arvelle, Bial, Desitin, Eisai, GW Pharmaceuticals, Novartis, and UCB. Dr. N Melzer has received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharmaceuticals, Fresenius Medical Care, Diamed, and BIAL, and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharmaceuticals, and Novartis Pharma. Dr. F von Podewils obtained honoraria for speaking engagements from UCB, Eisai, and BIAL. Dr H Rauschka obtained honoraria for speaking engagements, consulting, serving on advisory boards and funding for conference travels from Biogen, Merck, Novartis, Roche, Sanofi and Teva-Ratiopharm. Dr. R Höftberger obtained honoraria for speaking engagements from Euroimmun and Novartis. She receives research support from the Jubiläumsfonds der Österreichischen Nationalbank, Project 16919, and the GBS/CIDP Foundation International. The Medical University of Vienna receives payments for antibody assays. The other authors report no conflicts of interest. Publisher Copyright: © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2020/7/1

Y1 - 2020/7/1

N2 - OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions.METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters.RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention.CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

AB - OBJECTIVE: To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions.METHODS: Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters.RESULTS: Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-D-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (κ = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), γ-aminobutyric acid-B receptor (GABABR), and LGI1 had ≥ 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had ≤ 40% positive ratings. Of the patients with surface antibodies, 64% improved after ≥ 3 months, mostly with ≥ 1 immunotherapy intervention.CONCLUSIONS: This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Autoantibodies/analysis

KW - Autoimmune Diseases of the Nervous System/blood

KW - Child

KW - Child, Preschool

KW - Diagnostic Techniques, Neurological/standards

KW - Female

KW - Glutamate Decarboxylase/immunology

KW - HEK293 Cells

KW - Humans

KW - Immunologic Tests/standards

KW - Infant

KW - Intracellular Signaling Peptides and Proteins/immunology

KW - Male

KW - Membrane Proteins/immunology

KW - Mental Disorders/blood

KW - Middle Aged

KW - Nerve Tissue Proteins/immunology

KW - Neuropil/immunology

KW - Potassium Channels, Voltage-Gated/immunology

KW - Receptors, AMPA/immunology

KW - Receptors, GABA-B/immunology

KW - Receptors, Glycine/immunology

KW - Receptors, N-Methyl-D-Aspartate/immunology

KW - Reproducibility of Results

KW - Retrospective Studies

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85082947179&partnerID=8YFLogxK

U2 - 10.1007/s00415-020-09814-3

DO - 10.1007/s00415-020-09814-3

M3 - Journal article

C2 - 32246252

SN - 0340-5354

VL - 267

SP - 2101

EP - 2114

JO - Journal of Neurology

JF - Journal of Neurology

IS - 7

ER -

Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome

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