Neurotoxicity Research

, Volume 29, Issue 1, pp 105–117 | Cite as

Neutralizing Antibody and Botulinum Toxin Therapy: A Systematic Review and Meta-analysis

  • Margherita Fabbri
  • Giorgio Leodori
  • Ricardo M. Fernandes
  • Roongroj Bhidayasiri
  • Maria Jose Marti
  • Carlo Colosimo
  • Joaquim J. Ferreira
Original Article


The formation of neutralizing antibodies (NAbs) directed specifically against the active neurotoxin part of the botulinum neurotoxin (BoNT) complex is often cited as a major cause of secondary non-responsiveness (SnR) to treatment. This systematic and meta-analytic review evaluates the frequency of NAbs among patients treated with BoNT therapy for any clinical indication. A comprehensive database search strategy was designed to retrieve relevant clinical data from the published literature up to April 2013. All English-language publications that analyzed NAbs prevalence in more than ten patients were included, regardless of BoNT formulation, assay method, and study design. For the meta-analysis, patients were divided into three categories: secondary non-response (SnR) patients, clinically responding patients and all patients, independently of BoNT responsiveness. The meta-analysis included 61 studies reporting data for 8525 patients; 4972 dystonic patients, 1170 patients with spasticity, 294 patients with urologic indications, 396 patient with hyperhidrosis, 1659 patients with glabellar line, and 34 patients with hypersalivation. Among the “all patients” group NAbs frequency was 20 % for dystonia, 5.9 % for spasticity, and 2.7 % for urologic patients and 1.1 % for other conditions. The prevalence of NAbs was lower (3.5 %) among clinically responding patients and higher in 53.5 % SnR patients. About a half of patients with SnR do not have NAbs. NAbs was high among patients treated with RIMA but it was not associated with clinical non-responsiveness. Meta-analysis of the frequency of NAbs and SnR are limited by the heterogeneity of study design and reported outcomes. Indeed the analysis of several factors that can influence the development of NAbs, i.e., MHC of patients, frequency and site of injection, injection technique, cumulative dose, and toxin denaturation, was not specifically evaluated due to the paucity and heterogeneity of data. The identification of all these missing data should be taken into account in order to improve the methodology of future studies.


Botulinum toxin Systematic review Meta-analysis Neutralizing antibodies 

Supplementary material

12640_2015_9565_MOESM1_ESM.doc (186 kb)
Supplementary material 1 (DOC 185 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Margherita Fabbri
    • 1
  • Giorgio Leodori
    • 2
  • Ricardo M. Fernandes
    • 1
  • Roongroj Bhidayasiri
    • 3
    • 4
  • Maria Jose Marti
    • 5
  • Carlo Colosimo
    • 2
  • Joaquim J. Ferreira
    • 1
    • 6
  1. 1.Clinical Pharmacology Unit, Instituto de Medicina Molecular, Faculty of MedicineUniversity of LisbonLisbonPortugal
  2. 2.Dipartimento di Neurologia e PsichiatriaSapienza Università di RomaRomeItaly
  3. 3.Chulalongkorn Center of Excellence on Parkinson’s Disease and Related Disorders, Department of Medicine, Faculty of Medicine, Thai Red Cross SocietyChulalongkorn University and King Chulalongkorn Memorial HospitalBangkokThailand
  4. 4.Department of NeurologyGeffen School of Medicine at UCLALos AngelesUSA
  5. 5.Neurology Service, Institut Clínic de Neurociències (ICN), Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED)Hospital Clinic of BarcelonaBarcelonaSpain
  6. 6.Laboratory of Clinical Pharmacology and Therapeutics, Faculty of MedicineUniversity of LisbonLisbonPortugal

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