Arizona Neurology - Arizona Dystonia Institute

Antibodies to botulinum toxin

To the Editor: We read the article by Zuber et al,(1) dealing with the incidence of antibody formation after repetitive injections of botulinum toxin, with interest and concern. The article correctly points out that with repetitive injections there is a definitive incidence of sensitization that may render continued therapy with that immunotype ineffective. Recently, Hathaway and Dang(2) and Statkowski et al (3) reported significant numbers of cases in which sensitization had occurred. Hathaway and Dang relate the incidence of neutralizing antibodies to dose exposure. In the course of treatment of blepharospasm, Statkowski et al demonstrated a definitive incidence of sensitization. Clearly, sensitization can be an important issue in botulinum toxin therapy.

In treatment of adult-onset spasmodic torticollis, it is possible to clinically test a patient for sensitization using physical examination techniques. The following examination observations can be made which strongly suggest active resistance to the denervating effects of botulinum toxin: (1) lack of atrophy of stemomastoid muscle after injection, or (2) lack of depression of transverse increased lines in the forehead after a spot injection of the frontalis muscle(4). It has long been known that botulinum toxin can decrease facial creases caused by facial muscle insertions into dermis(4). Doses of botulinum toxin on the order of 10 to 15 international units will generally blunt transverse forehead creases and cause a mild nondisfiguring asymmetry and brow excursion. Presence of this stereotypic response at a remote point from the usual injection location (neck muscles) can be viewed as evidence of systemic resistance.

Both in vivo techniques and the mouse bioassay for the evaluation of antibodies to botulinum toxin have the advantage of detecting neutralizing antibodies. Indirect methods, such as those reported by Statkowski et al, and ELISA do not distinguish the neutralizing capacity of antibodies. This distinction is critical in evaluating clinically significant antibody titers in patients. It should be pointed out that, occasionally, tests for neutralizing antibodies will not consistently detect them. In such cases, regional denervation evaluation on the frontalis muscle may be helpful in making management decisions.

Incidence of resistance over many years, the effect of protein purification on botulinum toxin preparations. immunotype differences, and injection strategies are variables that may influence sensitization. Further work is needed in this area.

Gary E. Borodic, MD

Bruce Pearce, PhD Boston, MA

Drake Duane, MD Scottsdale, AZ

Eric Johnson, PhD Madison, WI

References:

1. Zuber M. Sebald M. Bathien N. de Recondo J. Rondot P. Botulinum antibodies in dystonic patients treated with type A botulinum toxin: frequency and significance. Neurology 1993:43:1715-1718.

2. Hathaway C, Dang C. Immunogenicity of the neurotoxins of Clostridium batulinum, chapter S. In: Jankovic J, Hallet M, eds. Therapy with botuiinum toxin. New York. Marcel Dekker, 1994.

3. Statkowski RM, Tyutyunikuv A. Bigian AW, et al. Serum antibody production to botulinum A toxin. Ophthalmology 1993:100:1061-1066.

4. Borodic GE. Botulinum A toxin for (expressionistic) ptosis overcorrection after frontalis sling. Ophthal Plast Reconstr Surg 1992:S:137-142.

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