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January 01, 2019; 92 (1) Article

High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy

Philipp Albrecht, Alexander Jansen, John-Ih Lee, Marek Moll, Marius Ringelstein, Dietmar Rosenthal, Hans Bigalke, Orhan Aktas, Hans-Peter Hartung, Harald Hefter
First published November 21, 2018, DOI: https://doi.org/10.1212/WNL.0000000000006688
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Abstract

Objective To investigate the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) during long-term BoNT/A treatment in different neurologic indications.

Methods In this monocentric, observational cross-sectional study, 596 outpatients treated with BoNT/A for different indications were tested for BoNT/A binding antibodies by ELISA. Positive samples were investigated for NAbs with the mouse hemidiaphragm test. The prevalence of NAbs was analyzed for different indications: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Besides the rate of NAb-positive patients overall and per patient subgroup, a Kaplan-Meier analysis of the probability of remaining NAb negative with duration of treatment is provided, and a stepwise binary logistic regression analysis is performed to identify factors significantly contributing to the induction of NAbs.

Results Overall, 83 of 596 patients (13.9%) had measurable NAbs. The probability of developing NAbs increased with the single and cumulative dose of treatment and was influenced by the BoNT/A formulation, while all other factors analyzed, including disease entity and treatment duration, had no additional influence.

Conclusions We present the largest study to date of the prevalence of BoNT/A NAbs in a large unbiased cohort of patients including the relevant neurologic indications. Repeated injections of BoNT/A inevitably bear the risk of developing NAbs. However, in addition to avoiding booster injections and providing short intervals between injections, reducing the individual injected doses may diminish the risk of NAb induction independently of the indication for which BoNT/A is used.

Glossary

ANOVA=
analysis of variance;
BoNT/A=
botulinum neurotoxin type A;
CD=
cervical dystonia;
FHS=
facial hemispasm;
MHDA=
mouse hemidiaphragm assay;
NAb=
neutralizing antibody;
ODT=
other dystonia;
STF=
secondary treatment failure;
uDU=
unified dose units

Footnotes

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

  • CME Course: NPub.org/cmelist

  • Received April 19, 2018.
  • Accepted in final form September 7, 2018.
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Letters: Rapid online correspondence

  • Author response: Neutralizing antibodies after long-term Botulinum toxin injections: Loss of clinical benefit?
    • Philipp Albrecht, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf
    • Alexander Jansen, Resident, Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf
    • John-Ih Lee, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf
    • Orhan Aktas, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf
    • Hans Bigalke, Neurologist, Toxogen GmbH (Hannover, Germany)
    • Hans-Peter Hartung, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf
    • Harald Hefter, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf
    Submitted April 09, 2019
  • Neutralizing antibodies after long-term Botulinum toxin injections: Loss of clinical benefit?
    • Eoin Mulroy, Clinical Reserach Fellow, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology (London, UK)
    • Bettina Balint, Senior Clinical Research Fellow, Department of Neurology, University Hospital (Heidelberg, Germany)
    • Amit Batla, Consultant Neurology, Luton and Dunstable University Hospital (Luton, UK)
    Submitted January 31, 2019
  • Author response to Dr. Jankovic
    • Philipp Albrecht, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf
    • Alexander Jansen, MD, Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf
    • John-Ih Lee, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf
    • Marius Ringelstein, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf
    • Orhan Aktas, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf
    • Hans Bigalke, Neurologist, Toxogen GmbH, Hannover, Germany
    • Hans-Peter Hartung, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf
    • Harald Hefter, Neurologist, Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf
    Submitted December 28, 2018
  • Immunoresistance to botulinum toxin
    • Joseph Jankovic, Professor of Neurology, Baylor College of Medicine (Houston, TX)
    Submitted December 12, 2018
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