Clinical presentation and management of antibody-induced failure of botulinum toxin therapy.
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.
Dressler
Dirk
D
Department of Neurology, Rostock University, Rostock, Germany. dirk.dressler@med.uni-rostock.de
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000276:immunology / Q000627:therapeutic use*; D000906:Antibodies / Q000276:immunology*; D000917:Antibody Formation / Q000187:drug effects / Q000502:physiology; D001905:Botulinum Toxins / Q000276:immunology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004576:Electromyography; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D009132:Muscles / Q000187:drug effects; D011930:Reaction Time; D013997:Time Factors; D014103:Torticollis / Q000188:drug therapy* / Q000503:physiopathology; D017211:Treatment Failure
D018726:Anti-Dyskinesia Agents; D000906:Antibodies; D001905:Botulinum Toxins