Neutralising botulinum A Toxin Antibodies - Clinical Observations in Cervical Dystonia Patients

ABSTRACT: Formation of neutralising antibodies poses a problem in a substantial number of cervical dystonia (CD) patients treated with botulinum A toxin (BoNT/A). Presence of these antibodies may lead to a secondary non-response to BoNT/A injections. Methods: We studied six antibody positive (Ab+) CD patients and six antibody negative (Ab-) non-responders. Results: Both groups only differed with respect to total cumulative BoNT/A dose (Ab+: 5984 MU, SD=3151; Ab-: 1938 MU, SD=1294; p=0.016). After a break of six months Ab+ subjects responded favorably to approx. three subsequent injections before a definite non-response set in. Conclusions: In order to avoid antibody formation in BoNT/A treatment the dose should be as low as possible. When a secondary non-response occurs, an antibody assay should be performed to identify Ab+ patients. These patients can be treated again (after a break) but a definite non-response seems to be inevitable.

Keywords: botulinum A toxin, antibodies, cervical dystonia, therapy

Neutralising botulinum A Toxin Antibodies - Clinical Observations in Cervical Dystonia Patients
by Jens D. Rollnik, M.D., Kai Wohlfarth, M.D., Reinhard Dengler, M.D., Hans Bigalke, M.D.

Forum--Reviews, Comments & Criticisms

posted 19 January 2001
Factors contributing to the formation of neutralizing antibodies (AB) against botulinum toxin type A (BTX-A) are of high clinical interest. However, there are some doubts and arguments concerning the results of this interesting study.

First of all, there is no clear definition of therapy failure to BTX-A injections. How is a secondary non responder defined in this study? In a previous work of the same group (Rollnik et al. 2000 Eur Neurology 43: 9-12) failure to treatment was at least documented by a clinical self-rating of the patients.

In a recent publication, the mouse diaphragm test has shown the same high specifity as the mouse lethality test and it seems to be a little more sensitive and relevant to BTX-A therapy (Dressler et al. 2000 Mov Disord 15: 973-6). In vitro tests like ELISA, Western blot and others failed to correlate with clinical response because they can not differentiate between neutralizing and non neutralizing antibodies (AB). The authors cite the work of Siatkowski et al. (1993) and related the lack of difference of BTX-A effect between their groups (AB+ versus AB-) to the extensive clinical variations of the study groups. However, the test used by Siatkowski et al. does not distinguish the neutralizing capacity of AB as already argued by Borodic et al. (1995, Neurology 45: 204).

Cumulative doses of BTX-A are documented in this study, but there is no information about the used products (Botox®, DysportŪ). The authors conclude, that higher cumulative doses are related to a higher risk for AB production. Do they also mean that the use of Dysport® is associated with a higher risk due to the equal clinical potency of 1 unit Botox® to 3-5 units Dysport®? Up to 1998 we used exclusively Dysport® in the dystonic patients of our clinic. The rate of secondary non response in our patients is <5%. This rate is in accordance to the results of other studies where Dysport® (Kessler KR et al. 1999, J Neurol 246:265-76) or Botox® were used (Greene et al. 1994 Mov Disord 9: 213-7; Jankovic et al. 1995 Neurology 45:1743-6). In our clinic secondary non responders were defined as patients previously responded well (more than 3 points in a modified TSUI scale and/or atrophy of an injected muscle and/or reported BTA-therapy associated adverse events) and subsequently failed to respond (Kessler KR et al. 1999, J Neurol 246:265-76). We found 15 cervical dystonia patients with secondary failure to BTX-A therapy (not published data). Six of them showed AB+ results in the mouse diaphragm test. Patients of both groups received Dysport® in similar cumulative doses (AB+: mean 8308.3 units; AB-: mean 7913.3 units). The mean age, the duration of treatment before the AB test, and the mean number of treatments of the whole group (50 a, 62.1 months, 14.4 treatment sessions) did not differ substantially between the subgroups. Despite the fact, that statistical analysis of data from small groups are critical, we could not find a definite correlation between the mentioned factors.

Further, it is not surprising, that there is no benefit in the treatment of a patient after changing the product.

In their conclusion, the authors recommend AB assay in all patients with secondary non response. We are missing a clear concept on the management of patients with secondary non response. A clinical reassessment and documentation of treatment failure by rating scales, clinical tests like the eyebrow test, the frontalis test (Hanna et al. 1998, Neurology 50: 1624-9) or the EDB test (Kessler KR 1997 Mov Disord 12: 95-9) are recommended. We agree, that an additional AB assay seems to be useful.

bernhard.voller@akh-wien.ac.at and peter.schnider@univie.ac.at

posted 19 January 2001
The paper of Rollnik and co-workers has an important message for the clinician: Botox has opened new therapeutic strategies but one should keep in mind that "less could be more" for the patient. This message is not lessened here by the number of patients, althought further study with a larger group of patients might be helpful in the future to better clarify the role of antibodies in Botox-therapy.

Kropp.Stefan@mh-hannover.de

posted 20 December 2000
Over the last years, the use of Botulinum A Toxin has become more frequent in clinical neurology. This paper gives important information on the outcome determinants. If cumulative dose is the most revant factor for inducing neutralissing antibodies, this has implications for cost-benefit analysis. To my mind, this paper on a small clinical sample size stimulates new questions in this field.

Joachim Kugler, M.D.
Professor for Public Health
Dresden Medical School, Germany
Jokugler@aol.com

posted 18 December 2000
The research reported in this paper deals with patients treated with botox A. It contains an interesting aspect of botox A treatment, but the results should interpreted more cautiously according to the small number of patients.

U. Schneider, MD
Schneider.Udo@MH-Hannover.de

posted 18 December 2000
This is an interesting paper. The authors studied the treatment of BoNT/A. The data are of clinical relevance since conflicting data have been reported on conditions supporting the development of BoNT/A antibodies. However, there are some restrictions regarding the sample size. Although it is very difficult to investigate such a study with an apropriate sample size, a statistical significance test for n=12 patients seems not appropriate. The authors should focus on the exploratory character of the study. Nevertheless, the results are of clinical importance and may result in a stimulating discussion.

Dr. Norbert Schmitz
schmitzn@uni-duesseldorf.de n.schmitz@mail.lvr.de

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