Antibodies and Botulinum Toxin Therapy

In some individuals treated with botulinum toxin, antibodies may develop, bind to the toxin, and inactivate it. This renders botulinum toxin ineffective in weakening muscle contractions associated with dystonia. It is estimated that approximately five percent or up to possibly 20 percent of individuals with cervical dystonia who have been treated regularly with relatively higher doses of botulinum toxin type A develop antibodies. Once a patient forms antibodies to a particular serotype of botulinum toxin (immunoresistance), further injections of that particular serotype of botulinum toxin are typically ineffective. Physicians should, therefore, use the smallest amount of toxin necessary to achieve therapeutic benefit and extend the time interval between treatment sessions as long as possible, with at least three months between treatments.

On occasion, a patient may not respond to therapy with botulinum toxin. So-called "primary non-responders" are patients who do not respond to their first injection of toxin. Secondary non-response may occur because of immunoresistance or as the result of a technical problem, such as an inappropriate site of injection into the wrong muscle, a dose that is inadequate to provide a clinical effect, or disease progression. The toxin may weaken the muscle; however, the degree of relaxation may not provide symptomatic relief for the patient. In addition, some patients on combination therapies for segmental or generalized dystonias may fail to take their oral medications, leading to a general increase in symptoms (masking the local effects of botulinum toxin). If failure to respond continues, it is possible that the patient has antibody-mediated resistance (immunoresistance). When a patient develops resistance to a botulinum toxin type A, MYOBLOC/Neurobloc, a botulinum toxin type B product, has been shown to be effective for the treatment of pain and disability of CD.

Antibody-based resistance is a significant concern in botulinum toxin therapy. No studies have been published thus far concerning development of resistance in patients receiving MYOBLOC. An open-label extension trial was conducted on 446 patients from the three studies described above as well as others who opted to continue to receive MYOBLOC. Serum samples were examined for presence of anti-toxin antibodies using the ELISA. Serum from patients with positive ELISA tests was then tested in a mouse neutralization assay (MNA). Interim analysis showed after 6 months of treatment, the probability of a positive ELISA test was 20%, while the probability of a positive MNA result was 0%. At one year, these figures rose to 36% and 10%, and at 18 months, to 50% and 18%.

The complex issues involved in the development of antibodies to botulinum toxins are not fully understood. The development of antibodies or immunogenicity in a patient receiving botulinum toxin treatment may be related to the relative amount of protein in the injected toxin as well as the quality of the protein (neurotoxin complex) in the product. Additional research studies are required to increase the understanding of immunogenicity. It is important that patients work with their physicians to set appropriate treatment goals and tailor the course of treatment to meet these goals. There is no formal "recipe" that works for every patient with CD. Each individual is unique and responds differently to botulinum toxin therapy.

	Botulinum Toxins and Cervical Dystonia Bibliography