In some patients treated with botulinum toxin type A (BT) therapy failure occurs due to the formation of antibodies against BT (BT-AB). We investigated whether increased BT doses can overcome this form of therapy failure. Eight patients with cervical dystonia, secondary BT therapy failure and evidence of BT-AB formation in the mouse diaphragm bioassay received BT test doses (Dysport®, Ipsen Ltd., Maidenhead, Berks, UK) into one of their sternocleidomastoid muscles. Test doses were increased in three steps at 3-month intervals and their effect on the amplitude of the electromyographic activity of the sternocleidomastoid muscle under maximal isometric activation (M-EMG) was measured and compared to a control group. In step 1 (200 or 300 MU) the M-EMG reduction was 12 ± 13% compared to 85 ± 10% (200 MU) and 83 ± 9% (300 MU) in the control group. In step 2 (400, 600 or 800 MU) the M-EMG reduction was 25 ± 21% compared to 78 ± 7% (400 MU) in the control group. In step 3 (1,600 or 1,800 MU) the M-EMG reduction was 24 ± 10%. Side effects were not observed in any of the patients studied. In 1 patient with partial secondary BT therapy failure, with a low BT-AB titre (0.0015 U/ml) and with a moderately pathological M-EMG reduction of 40% with 200 MU a normal M-EMG reduction of 71% could be regained with 800 MU. In three subsequent therapeutic injection series with quadrupled BT doses in all target muscles the original therapy outcome could be regained and maintained. Side effects or increasing BT-AB titres were not observed. Even massively increased BT doses cannot overcome BT-AB-induced complete secondary therapy failure. However, in patients with partial secondary therapy failure, low BT-AB titres and a moderately pathological M-EMG reduction, increased BT doses might regain and maintain normal BT efficacy without induction of side effects or increasing BT-AB titres.

Keywords:
Botulinum toxin therapy, Antibodies, Therapy failure
1.
Frueh BR, Felt DP, Wojno TH, Musch DC: Treatment of blepharospasm with botulinum toxin: A preliminary report. Arch Ophthalmol 1984;102:1464–1468.
2.
Jankovic J, Hallett M (eds): Therapy with Botulinum Toxin. New York, Dekker, 1994.
3.
Dressler D: Botulinum Toxin Therapy. Stuttgart, Thieme, 2000.
4.
Jankovic J, Schwartz KS: Clinical correlates of response to botulinum toxin injections. Arch Neurol 1991;48:1253–1256.
5.
Anderson TJ, Rivest J, Stell R, Steiger MJ, Cohen H, Thompson PD, Marsden CD: Botulinum toxin treatment of spasmodic torticollis. J R Soc Med 1992;85:524–529.
6.
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.
7.
Greene P, Fahn S, Diamond B: Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord 1994;9:213–217.
8.
Jankovic J, Schwartz K: Response and immunoresistance to botulinum toxin injections. Neurology 1995;45:1743–1746.
9.
Dressler D: Botulinum toxin therapy failure: Causes, evaluation procedures and management strategies. Eur J Neurol 1997;4(suppl 2):S67–S70.
10.
Goeschel H, Wohlfahrt K, Frevert J, Dengler R, Bigalke H: Botulinum A toxin: Neutralizing and nonneutralizing antibodies – therapeutic consequences. Exp Neurol 1997;147:96–102.
11.
Dressler D, Rothwell JC: Electromyographic quantification of the paralysing effect of botulinum toxin. Eur Neurol 2000;43:13–16.
12.
Dressler D, Bigalke H: Botulinum toxin antibody titres after cessation of botulinum toxin therapy. Mov Disord 2000;15(suppl 3):146–147.
13.
Naumann M, Toyka KV, Mansouri Taleghani B, Ahmadpour J, Reiners K, Bigalke H: Depletion of neutralising antibodies resensitises a secondary non-responder to botulinum A neurotoxin. J Neurol Neurosurg Psychiatry 1998;65:924–927.
14.
Dressler D, Zettl U, Bigalke H, Benecke R: Can intravenous immunoglobulin improve antibody mediated botulinum toxin therapy failure? Mov Disord 2000;15:1279–1281.
15.
Brin MF, Lew MF, Adler CH, Comella CL, Factor SA, Jankovic J, O’Brien C, Murray JJ, Wallace JD, Willmer-Hulme A, Koller M: Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 1999;53:1431–1438.
16.
Dressler D, Rothwell JC, Bigalke H: The sternocleidomastoid test: An in-vivo assay to investigate botulinum toxin antibody formation in man. J Neurol 2000;247:1–3.
© 2002 S. Karger AG, Basel
2002
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