High Botulinum Toxin-Neutralizing Antibody Prevalence Under Long-Term Cervical Dystonia Treatment

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Abstract

<div class="section"> <a class="named-anchor" id="mdc312322-sec-0001">  </a> <h5 class="section-title" id="d4963905e174">Background</h5> <p id="d4963905e176">The aim of this study was to determine the prevalence of neutralizing antibodies in a large cohort of long‐term treated patients with cervical dystonia ( <span style="fixed-case">CD</span>) still responding to repetitive injections with botulinum toxin (Bo <span style="fixed-case">NT</span>). </p> </div><div class="section"> <a class="named-anchor" id="mdc312322-sec-0002">  </a> <h5 class="section-title" id="d4963905e185">Methods</h5> <p id="d4963905e187">Consecutively recruited <span style="fixed-case">CD</span> patients (n = 221) under long‐term Bo <span style="fixed-case">NT</span> treatment (≥2–21 years) underwent a clinical examination at the same time blood samples were taken for neutralizing antibody determination. Collected data included demographics, mean dose of the last 10 botulinum injections, treatment duration, Tsui score for <span style="fixed-case">CD</span> severity, and patients' subjective impression of treatment effect. Blood samples were screened for antibody presence by <span style="fixed-case">ELISA</span>; positive samples were further analyzed by mouse hemidiaphragm test. The two laboratories performing antibody testing were blinded to the coded samples. </p> </div><div class="section"> <a class="named-anchor" id="mdc312322-sec-0003">  </a> <h5 class="section-title" id="d4963905e202">Results</h5> <p id="d4963905e204">Antibody status could be determined for 212 patients; 39 (18.4%) were <span style="fixed-case">ELISA</span> positive and 31 (14.6%) additionally positive in the mouse hemidiaphragm test. Patients with positive neutralizing antibody titers had significantly higher Tsui scores and were treated for a significantly longer time with significantly higher doses. There were no differences between male and female patients and between onabotulinumtoxinA‐ and abobotulinumtoxinA‐treated patients. When Bo <span style="fixed-case">NT</span> preparations had been switched during the last 10 injections, a significantly higher proportion of neutralizing antibody‐positive patients was detected. </p> </div><div class="section"> <a class="named-anchor" id="mdc312322-sec-0004">  </a> <h5 class="section-title" id="d4963905e213">Conclusions</h5> <p id="d4963905e215">Neutralizing antibody prevalence in long‐term treated, still responding <span style="fixed-case">CD</span> patients is substantially higher than suggested by follow‐up studies with a shorter time frame. It should therefore be emphasized that antigenicity of Bo <span style="fixed-case">TN</span> preparations is still a relevant problem and should be taken into account in long‐term treatment decisions. </p> </div>

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Content of Botulinum Neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®

Jürgen Frevert (2010)

Background: Botulinum neurotoxin type A (BoNT/A) is the active substance in preparations used for the highly effective treatment of neurologic disorders such as cervical dystonia, blepharospasm, or spasticity, as well as other indications such as axillary and palmar hyperhidrosis, and urologic disorders. Objective: To determine the amount of BoNT/A protein present in pharmaceutical preparations of Botox®, Dysport®, and Xeomin®, which are identical with Vistabel®, Azzalure®, and Bocouture®, respectively. Methods: Rabbit and guinea pig antibodies raised against the 150kD BoNT/A neurotoxin purified from Clostridium botulinum type A, strain ATCC 3502 (‘Hall strain’), were used in a sensitive sandwich ELISA to determine the overall mean concentration of the 150kD neurotoxin present in four batches of Botox® (C2344C3, C2384C3, C2419, and C2385), two batches of Dysport® (678F and 689X) and three batches of Xeomin® (61111, 70604, and 81 208). The specific neurotoxin potency, defined as the potency or biologic activity (units) per mass of neurotoxin protein (ng), was calculated based on the overall mean concentration of BoNT/A neurotoxin. Results: Overall, the mean concentration of BoNT/A neurotoxin in Botox® was 0.73 ng per 100 unit vial (coefficient of variation [CV] = 3.5%), 3.24 ng per 500 unit vial of Dysport®, corresponding to 0.65 ng in 100 units (CV = 11.4%), and 0.44 ng per 100 unit vial of Xeomin® (CV = 1.9%). The specific potency of the 150kD BoNT/A neurotoxin was calculated as 137 units/ng for Botox®, 154 units/ng Dysport®, and 227 units/ng Xeomin®. Conclusions: The current study has shown that of the three products, Xeomin® contains the highest specific neurotoxin activity, followed by Dysport®, with Botox® having the lowest specific activity. This result suggests that Xeomin® contains only active neurotoxin in contrast with Botox®, which is likely to contain additional denatured/inactive neurotoxin.

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Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies--therapeutic consequences.

R Dengler, H Göschel, K Wohlfarth … (1997)

Although muscle-relaxant doses of botulinum A toxin (BoNT/A) are generally lower than doses stimulating the immune system, specific antibodies are raised in a substantial number of patients. As a rule, this necessitates the termination of treatment. Therefore, a reliable determination of specific anti-BoNT/A antibodies is helpful and we introduced, for this purpose, a novel in vitro toxin-neutralizing assay based on a nerve-muscle preparation. We measured the antibody titers in four groups of subjects: Group 1 comprised 75 randomly selected patients of a total of 295 who responded to treatment with Dysport in our local clinic. Five patients, in group 2, were nonresponders. Group 3 consisted of 32 untreated volunteers and group 4 of 8 subjects immunized with a toxoid more than 10 years ago. Two of the responders had marginal titers of neutralizing antibodies, while they were present in all nonresponders. The sera of all responders were also tested for nonneutralizing antibodies by ELISA. Their occurrence, however, was of no consequence to the therapeutic success. The blood samples of volunteers were free from specific antibodies, whereas antibodies persisted in the immunized subjects for longer than a decade. Patients from various clinics who had been treated unsuccessfully with the toxin-14 patients had received BOTOX, 7 had been treated with Dysport, and 7 with both products-all had neutralizing antibodies. Whether there was an antibody response depended on the amount of toxin administered. We believe, however, the effective toxin dose can be reduced by so much as to make antibody production highly improbable.

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EFNS guidelines on diagnosis and treatment of primary dystonias.

A Albanese, F Asmus, K Bhatia … (2011)

to provide a revised version of earlier guidelines published in 2006. primary dystonias are chronic and often disabling conditions with a widespread spectrum mainly in young people. primary dystonias are classified as pure dystonia, dystonia plus or paroxysmal dystonia syndromes. Assessment should be performed using a validated rating scale for dystonia. Genetic testing may be performed after establishing the clinical diagnosis. DYT1 testing is recommended for patients with primary dystonia with limb onset before age 30, and in those with an affected relative with early-onset dystonia. DYT6 testing is recommended in early-onset or familial cases with cranio-cervical dystonia or after exclusion of DYT1. Individuals with early-onset myoclonus should be tested for mutations in the DYT11 gene. If direct sequencing of the DYT11 gene is negative, additional gene dosage is required to improve the proportion of mutations detected. A levodopa trial is warranted in every patient with early-onset primary dystonia without an alternative diagnosis. In patients with idiopathic dystonia, neurophysiological tests can help with describing the pathophysiological mechanisms underlying the disorder. botulinum toxin (BoNT) type A is the first-line treatment for primary cranial (excluding oromandibular) or cervical dystonia; it is also effective on writing dystonia. BoNT/B is not inferior to BoNT/A in cervical dystonia. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for primary generalized or cervical dystonia, after medication or BoNT have failed. DBS is less effective in secondary dystonia. This treatment requires a specialized expertise and a multidisciplinary team.