Clinical presentation and management of antibody-induced failure of botulinum toxin therapy

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Abstract
Therapy with botulinum toxin (BT) can fail due to numerous reasons, including failure due to formation of antibodies against BT (BT‐AB, AB‐TF). AB‐TF is a secondary therapy failure, i.e. it occurs during the course of an ongoing BT therapy. It can be subjective or objective, temporary or permanent, and partial or complete. Complete AB‐TF is usually preceded by injection series with partial AB‐TF in which the therapeutic effect is reduced in its intensity and duration. AB‐TF usually occurs within 2 or 3 years after initiation of BT therapy. After 4 years it is rare. BT‐AB are neutralising or blocking by definition, i.e. they are directly interfering with BT's biological mechanism of action. Non‐neutralizing or non‐blocking antibodies occur. BT‐AB can be detected by the mouse diaphragm assay, the mouse protection assay, and by patient‐based tests such as the sternocleidomastoid test, the extensor digitorum brevis test, and the frowning test. Enzyme‐linked immunosorbent assays (ELISA) have a low specificity and a low sensitivity for detection of BT‐AB. BT‐AB titres drop spontaneously after cessation of BT therapy but latencies are too long to be compatible with an effective BT therapy. BT dosage increase can be successful to overcome AB‐TF when AB‐TF is partial and when BT‐AB titres are low. Usage of alternative BT type A preparations fail to overcome AB‐TF. Alternative BT types, such as BT type B and BT type F, are initially successful in AB‐TF, but stimulate formation of antibodies against the alternative BT types after few applications. BT‐AB reduction with immunosuppressants and inactivation of BT‐AB by intravenous immunoglobuline application has not yet been achieved. Extraction of BT‐AB by plasmapheresis and immunoadsorption is possible but is associated with substantial logistic problems. Prevention of BT‐AB formation, therefore, is of paramount importance. Identified risk factors for BT‐AB formation must be taken into account when BT therapy is planned. The most interesting perspective seems to be the development of new BT preparations with reduced antigenicity. © 2004 Movement Disorder Society