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Botulinum neurotoxins (BTXs) inhibit the presynaptic release of acetylcoline causing a chemical denervation that results in sustained muscle weakness and have been used in the past 20 years to induce selective blocking of hyperactive striatal (and smooth) muscles.1 All the different seven serotypes of BTXs have in common the mechanism of action (block of the neuroexocytosis machinery inside the end plate, responsible for the release of acetylcholine into the neuromuscular junction), acting on different targets. The two commercially available serotypes, botulinum toxin type A and botulinum toxin type B (abbreviated BTX-A and BTX-B, respectively) are reported to act as zinc dependent endopeptidases on different intraneuronal target proteins.
The clinical value of BTX-A has been recognised for a long time and is widely demonstrated by hundreds of clinical reports. More recently a clinical usefulness of BTX-B has been investigated. Two controlled clinical trials have demonstrated that local intramuscular injections of BTX-B are effective in the treatment of cervical dystonia in patients with BTX-A responsive disease,2 as well as in patients with BTX-A resistant disease (secondary non-responders).3 BTX-B was found to be effective in both studies, with a significant improvement observed in all the parameters investigated (severity, disability, and pain); action was found to last as long as 16 weeks.2,3
Based on these favourable results, we investigated BTX-B treatment in blepharospasm (BLS), another common form of focal dystonia, and in hemifacial spasm (HFS). Indeed, despite BTX-A being an efficacious treatment for these conditions,4 a percentage of patients still shows a suboptimal response, particularly in long term treatments. They could, therefore, benefit from the availability of another botulinum toxin serotype.
Blepharospasm
We studied 13 subjects (10 women and 3 men; mean (SD) age at onset 51.5 (15.0) years; mean disease duration 9.1 (8.1) years) with BLS. BLS was diagnosed as idiopathic focal dystonia in 12 patients, and as tardive dystonia in one case. All patients had received BTX-A before, with a moderate to good response. Patients were excluded if they had received a BTX-A injection in the past three months for their BLS. After an informed consent was obtained, four pretarsal injections were placed around each eye; the fixed total dose for each treatment was 2500 units (0.8 ml of a solution obtained by adding 0.3 ml of saline to 0.5 ml of the commercially available BTX-B solution). Before each treatment, patients were assessed with an objective rating scale for dystonia (Burke-Fahn-Marsden scale, severity factors, items for BLS5); efficacy was assessed at the time of the peak effect (7–14 days after treatment) with the same rating scale and with a visual analogue scale assessment (Patient Global Assessment of Change), in which improvement was subjectively measured from 0% to 100%. Latency of the effect was defined as the time between the treatment and the first detectable clinical effect. Duration of effect was defined as the time between the first detectable clinical effect and the moment when that any benefit has completely worn off, both as reported by the patient. Each patient received a single treatment. Additionally, a telephone call was made to the patient each week to assess safety and duration of the effect.
Results of the trial are reported in table 1. Overall five patients rated the efficacy of BTX-B as superior to BTX-A and preferred to continue treatment with BTX-B. The drug was generally well tolerated, with the most common adverse effect of BTX-B being pain during the injection, which was reported by 11 of 13 of the patients. Other common side effects of BTX-A treatment, such as ptosis and epiphora, were mild and transient. One patient experienced an anaphylactic reaction, consisting of Quincke’s oedema, from day two after the injection, though this resolved after treatment with corticosteroids.
Response to BTX-B injections
Hemifacial spasm
We studied 11 subjects (six men and five women; mean age at onset 64.9 (10.4) years; mean disease duration 5.4 (3.9) years) with primary HFS. All patients had received BTX-A before, with a moderate to good response. Patients were excluded if they had received a BTX-A injection in the past three months for their HFS. After an informed consent was obtained, four pretarsal injections were placed around each eye, and two around the mouth; the fixed total dose of BTX-B for each treatment was 937.5 units. This was obtained taking 0.3 ml of the previously described solution. Before each treatment, patients were assessed with an objective rating scale for dystonia (Burke-Fahn-Marsden scale, severity factors, items for BLS and mouth averaged5; this scale was used in the absence of validated rating scales for HFS); efficacy was assessed at the time of the peak effect with the same objective rating scale and the subjective visual analogue scale reported above. Each patient received a single treatment. Latency and duration of the effect were assessed as above.
Results of the trial are reported in table 1. Only two patients rated the efficacy of BTX-B as superior to BTX-A and preferred to continue treatment with BTX-B. The drug was well tolerated, with the most common adverse effect being burning pain during the injection, which was reported by 7 of 11 patients. Other common side effects of BTX-A treatment were negligible.
Comment
This open pilot trial, which is the first to use BTX-B in a neurological condition other than cervical dystonia, suggests that BTX-B is an effective and safe treatment for both BLS and HFS. The time course and magnitude of the improvement observed in our study are similar to those reported in trials with BTX-A for the same conditions, while the duration of the effect appears shorter as the mean duration of effect with BTX-A in these neurological conditions is 12–16 weeks.4 The only peculiar side effect was local pain during the injection, which has not been reported before in trials with BTX-B. This event might to be related to the fact that BTX-B is available in a liquid preparation, which has different biochemical properties than the reconstituted solution of BTX-A.2–4 The severe, adverse reaction reported in a single patient with BLS has not been described in previous trials using this compound for cervical dystonia and has rarely been reported in conjunction with BTX-A use6; it should, however, not discourage the planning of further dose ranging studies of BTX-B and studies on larger series of patients designed to compare the effect of BTX-B with both placebo and BTX-A in different neurological disorders.
Competing interests: CC has been reimbursed by Elan, Allergan and Ipsen (manufacturers of different botulinum neurotoxins) for attending several conferences. MFC has been reimbursed by Elan for attendign a conference. ARB has been reimbursed by Allergan and Ipsen for attending several conferences.