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Botulinum toxins in the treatment of primary focal dystonias
Journal of the Neurological Sciences 316 (2012) 9–14
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Review article
Botulinum toxins in the treatment of primary focal dystonias Daniel Truong ⁎ The Parkinson's and Movement Disorder Institute, Fountain Valley, CA, USA
a r t i c l e
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Article history: Received 6 July 2011 Received in revised form 5 January 2012 Accepted 19 January 2012 Available online 14 February 2012 Keywords: Dystonia Focal dystonia Blepharospasm Botulinum toxin OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA RimabotulinumB
a b s t r a c t Focal dystonia, such as cervical dystonia, blepharospasm, oromandibular dystonia, largyngeal dystonia, and limb dystonia, is often observed in adult-onset primary dystonia syndromes that affect a specific area of the body and tend to have little or no spread. This review will examine the past, present, and future approaches to the treatment of focal dystonia. Botulinum toxin (BoNT) has emerged as the treatment of choice for the majority of focal dystonias. Currently four products are widely available commercially, three of BoNT/A type and one of BoNT/B type. Each has important pharmacological differences that give rise to markedly different dosing recommendations. The four approved BoNTs are safe and effective for treating focal dystonias, including long-term treatment. Adverse events are limited and transient and, for the most part, mild in severity. Potential problems with the use of BoNT agents are diffusion and neutralizing antibody formation; the latter can lead to treatment resistance. Because each BoNT product is developed from distinct purification and manufacturing procedures and has varying toxin complex size and structures, physicians need to be aware of these differences when choosing an agent. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . Botulinum toxins. . . . . . . . . . . . . . . . Clinical studies — efficacy . . . . . . . . . . . . 3.1. OnabotulinumtoxinA . . . . . . . . . . 3.2. AbobotulinumtoxinA. . . . . . . . . . . 3.3. OnabotulinumtoxinA/AbobotulinumtoxinA 3.4. IncobotulinumtoxinA . . . . . . . . . . 3.5. RimabotulinumB . . . . . . . . . . . . 3.6. Other BoNT preparations . . . . . . . . . 4. Clinical studies — safety . . . . . . . . . . . . 4.1. Long-term efficacy and safety . . . . . . 4.2. Immunoresistance . . . . . . . . . . . . 5. Treatment alternatives . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . Conflict . of interest . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . comparison studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Dystonia is a neurological movement disorder that causes sustained, involuntary, and sometimes painful muscular contraction, ⁎ Parkinson's and Movement Disorder Institute, 9940 Talbert Avenue, Suite 204, Fountain Valley, CA 92708, USA. Tel.: + 1 714 378 5062; fax: + 1 714 378 5061. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.01.019
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twisting, repetitive movements, or abnormal postures [1]. Dystonia may be primary (idiopathic), considered to be of genetic origin in some cases [2–5], or it may be the result of environmental factors (secondary or symptomatic dystonia). In the 2010 European Federation of Neurological Societies (EFNS) Guidelines on the Diagnosis and Treatment of Primary Dystonias, primary dystonias are classified as pure dystonia, dystonia plus, or paroxysmal dystonia syndromes [2].
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D. Truong / Journal of the Neurological Sciences 316 (2012) 9–14
Focal dystonia is often observed in adult-onset primary pure dystonia syndromes that affect a specific area of the body and tend to have little or no spread. The most common presentations are cervical dystonia (spasmodic torticollis; abnormal head twisting), blepharospasm (involuntary, forcible closure of the eyelids), oromandibular dystonia (forceful contractions of the face, jaw, and/or tongue), largyngeal dystonia (spasmodic dysphonia), and limb dystonia (abnormal limb-muscle movement) [6]. Although there is no cure for primary dystonia, symptomatic treatments are available that can minimize the symptoms [2]. The indications for and challenges in using botulinum neurotoxins (BoNTs) will be reviewed here. 2. Botulinum toxins BoNT is considered the treatment of choice for the majority of focal dystonias [2,7–9]. There are seven antigenically distinct toxins (A through G) produced by different strains of Clostridium botulinum bacteria; only types A and B are approved for use in the treatment of focal dystonia. The most common type A formulations are Botox® (OnabotulinumtoxinA; Allergan Inc., Irvine CA, USA), Dysport® (AbobotulinumtoxinA; Ipsen Ltd., Slough, UK), and Xeomin® (IncobotulinumtoxinA; Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany). The commercially available type B BoNT is rimabotulinumB (RimabotulinumB; Solstice Neurosciences Inc., Malvern, PA, USA), which is sold in the United States and Canada as Myobloc® Injection and as NeuroBloc® in the EU, Norway, and Iceland and as Myobloc® Injectable Solution in Korea. In the United States, onabotulinumtoxinA is approved for the treatment of cervical dystonia in adult patients and blepharospasm associated with dystonia in patients ≥12 years of age [10], while abobotulinumtoxinA is approved for the treatment of adults with cervical dystonia [11], and incobotulinumtoxinA is approved for the treatment of adults with cervical dystonia and blepharospasm [12]. RimabotulinumB is indicated for the treatment of adults with cervical dystonia [13]. Beginning in 2009 all botulinum toxin products were required by the FDA to carry a boxed warning cautioning that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism [14]. In onabotulinumtoxinA and abobotulinumtoxinA, the BoNT component is formed by botulinum neurotoxin and by nontoxic proteins known as complexing proteins [15], whereas the purification and manufacturing process for incobotulinumtoxinA removes the complexing proteins [16]. The three type A products differ for the size of BoNT component, potentially affecting diffusion characteristics, adverse-event (AE) profile, and therapeutic properties. Although each of these agents consists of the BoNT component and excipients, it is important to note that they are unique drugs [17] that differ in molecular weight and complexing proteins, onset of action and diffusion, approved indications and clinical use, and importantly dosing, which is not interchangeable. A full comparison of the differences among the BoNT formulations is beyond the scope of this publication; however, we refer the reader to a comparison recently published by Gollomp [18] and to a Table provided by Albanese that presents differences in the manufacturing, potency, and dosing of the most common formulations [17]. Since the first report of improvement of abnormal movements and pain in BoNT-treated cervical dystonia [19,20] and blepharospasm patients [21], approximately 80 studies have been published [22]. Eight of these meet the criteria for Class I evidence as defined by the EFNS Scientific Task Force [23] indicating that treatment with BoNT improves the symptoms of cervical dystonia (see Box 1) [24–31]. Studies in both animals [32,33] and humans [34–36] have indicated a possible relationship between increased activity and BoNT uptake at the nerve terminal (e.g., with electrical stimulation or exercise).
3. Clinical studies — efficacy 3.1. OnabotulinumtoxinA In one of the first clinical trials to evaluate the efficacy of BoNT for the treatment of spasmodic torticollis/cervical dystonia, treatment with onabotulinumtoxinA produced both subjective and objective improvements (p b .05), including significant reductions in pain (p b .02) [20]. Side effects were few, and no significant systemic adverse reactions were noted [20]. These results have since been confirmed in numerous short- [27,37,38] and long-term studies [39]. Greene and colleagues reported that treatment with onabotulinumtoxinA was associated with significant improvement in the severity of torticollis (p = .001), disability (p = .0097), pain (p = .0029), and degree of head turning at rest (p = .0001) and while walking (p = .0016). There were no serious side effects; 61% of treated patients improved during the double-blind phase and 74% improved during a subsequent open-label phase at a higher dose of onabotulinumtoxinA [27]. In the long-term study, which followed 205 patients with medically intractable cervical dystonia for at least 3 months and up to 4 years, the average peak-effect score was 3.0 ± 1.2, and the average global rating score was 2.9 ± 1.2; 76.4% of patients who originally reported neck pain obtained complete relief. Peak effect was determined by a review of the patient's diary, the results of interviews conducted with the spouse or friends, and by the patient's perception of response and rated on a scale of 0 to 4. The global rating score was derived from the peak-effect score by subtracting 1 point for a mild complication and 2 points for a disabling complication [39]. OnabotulinumtoxinA has also been shown to be an effective treatment for blepharospasm. In a study composed of 101 patients with idiopathic blepharospasm treated with onabotulinumtoxinA, symptoms were relieved in 78 patients for an average of 9 weeks. The severity/duration of the blepharospasm did not influence outcome. Side effects, particularly a temporary partial ptosis, were common but were well tolerated [40]. In a more recent study, treatment with onabotulinumtoxinA was associated with a significant reduction in Jankovic Rating Scale (JRS) sum score and patient-reported improvement in global response (both p b .0001). OnabotulinumtoxinA was well tolerated; AEs were mostly mild or moderate. The most common AE was ptosis [41]. The onset of the onabotulinumtoxinA effect occurs within 24 to 72 h, peaks at 2 to 4 weeks, and lasts 3 to 6 months [42]. 3.2. AbobotulinumtoxinA In both short- [29,31,43] and long-term double-blind placebocontrolled studies [30,44], patients treated with abobotulinumtoxinA experienced significant improvement in disease-severity scores in patients with cervical dystonia. In the latest study to evaluate the efficacy and safety of abobotulinumtoxinA in the treatment of cervical dystonia, abobotulinumtoxinA produced a significant decrease from baseline in mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores compared with placebo at week 4 (–5.6 vs. –6.7; p b .001). Significant improvements were also seen in TWSTRS subscale scores, visual analog scale (VAS) pain scores, and subject/investigator's VAS symptom assessments compared with placebo (all p b .05) [30]. In treating bilateral benign essential blepharospasm, abobotulinumtoxinA improved functional impairment, and reduced frequency and intensity of facial spasms. There were fewer withdrawals because of lack of efficacy in the abobotulinumtoxinA treatment group compared with placebo. Truong et al. reported sustained efficacy and a favorable safety profile with 80 U of abobotulinumtoxinA/eye [45]. The onset of action is usually evident within 2 weeks of treatment, the peak effect occurs at 4 to 8 weeks, and most patients require retreatment after 10 to 16 weeks [46].
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3.3. OnabotulinumtoxinA/AbobotulinumtoxinA comparison studies A number of studies have compared onabotulinumtoxinA and abobotulinumtoxinA. Nüssgens and Roggenkämper reported results from an early double-blind study in patients with blepharospasm who received one injection of onabotulinumtoxinA and one injection of abobotulinumtoxinA. The results indicated similar efficacy and no significant difference in the duration of the treatment effect between the two preparations, although there were significantly (p b .05) fewer side effects with onabotulinumtoxinA (particularly ptosis; p b .01) [47]. However, in a recent long-term study that assessed the use of onabotulinumtoxinA and abobotulinumtoxinA for the treatment of blepharospasm, Bentivoglio and colleagues noted that the mean duration of improvement was significantly (p b .01) longer for abobotulinumtoxinA. As in the Nüssgens study, the rate of side effects was significantly (p b .01) higher with abobotulinumtoxinA [48]. In another early study that compared onabotulinumtoxinA with abobotulinumtoxinA at three times the onabotulinumtoxinA dose for the treatment of predominantly rotational cervical dystonia, both treatments were equally effective and had a similar safety profile. The duration of effect, assessed by time to retreatment, was also similar [46]. However, a more recent study showed abobotulinumtoxinA to be more effective than onabotulinumtoxinA for both impairment (Tsui score) and pain (TWSTRS pain score). AEs were higher with abobotulinumtoxinA, although none required withdrawal of therapy or specific management [49]. Results of a recent study that evaluated the safety, efficacy, and duration of effect of onabotulinumtoxinA after switching from abobotulinumtoxinA in patients with blepharospasm, cervical dystonia, hemifacial spasm dystonia, or hemifacial spasm showed that onabotulinumtoxinA was more efficacious and had a longer duration of effect than abobotulinumtoxinA regardless of diagnosis [50]. 3.4. IncobotulinumtoxinA IncobotulinumtoxinA has been shown to be noninferior to onabotulinumtoxinA for the treatment of patients with cervical dystonia [51] or blepharospasm [41] with no difference between the two preparations in efficacy, safety profile, onset of action, or duration and waning of effect [52,53]. It is important to note that in the study conducted by Roggenkämper and colleagues [41], the finding of noninferiority was based on a clear prespecified set of clinically relevant criteria, such as those suggested in published recommendations [54]. The primary efficacy variable was the change from baseline in the sum score of the JRS [55] at the control visit. Secondary efficacy variables included the change from baseline in the sum score of the JRS at the final visit and the changes from baseline in the mean total score of the Blepharospasm Disability Index (BSDI) [56] at the control visit and the final visit. Global response to study treatment was also evaluated at both visits using an adaptation of a scale developed by Wissel [57]. In a study of 233 patients with cervical dystonia who received 120 or 240 U of incobotulinumtoxinA or placebo, treatment with either dose of incobotulinumtoxinA was associated with a significant (p b .001) improvement in total TWSTRS score after 4 weeks. AEs occurred in 41.9% of the placebo group, 56.4% of the 120-U group, and 55.6% of the 240-U group. AEs were similar to those reported in other studies of BoNT/A products [58]. A subanalysis of these data showed similar efficacy and safety among treatment-naïve [59] and previously treated [60] patients. Preliminary results for 153 of 217 patients with cervical dystonia participating in a long-term study (up to 88 weeks) indicate that repeated treatments with incobotulinumtoxinA were effective and well tolerated [61]. TWSTRS total score was significantly improved at 4 weeks after each injection (p b .05 vs. injection-visit score), as well as at the study-termination visit (12–13 weeks after the final injection) vs. the first injection visit of the extension phase (p b .001).
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One or more AEs were experienced by 118 of the participants (77.1%). The most frequently reported AEs were dysphagia, neck pain, and sinusitis. No serious AEs were considered to be related to BoNT/A. The overall incidence of AEs decreased with each injection interval, indicating no cumulative effect with repeated doses. The clinical effect of incobotulinumtoxinA begins to appear within 1 week after injection, peaks at approximately 4 to 6 weeks, and is sustained for several months. The duration of effect is about 110 days [53]. The safety and efficacy of incobotulinumtoxinA has also been shown in patients with blepharospasm. Results of a study that evaluated the efficacy and safety of incobotulinumtoxinA compared with placebo in 109 previously treated subjects with blepharospasm showed a significant (p b .0001) treatment effect in favor of incobotulinumtoxinA, as evidenced by improvements in the JRS severity subscore. AEs were reported in 70.3% of subjects in the incobotulinumtoxinA group and 61.8% of subjects in the placebo group. The most commonly reported AEs were eyelid ptosis, dry eye, and dry mouth [62]. 3.5. RimabotulinumB RimabotulinumB is a type B BoNT — an antigenically distinct form of BoNT that has unique physical and clinical properties that distinguish it from BoNT/A. Early studies showed rimabotulinumB to be an efficacious treatment for patients with cervical dystonia regardless of whether they are responsive or resistant to BoNT/A [28,63]. More recently, rimabotulinumB was reported to be noninferior to onabotulinumtoxinA for the treatment of cervical dystonia in treatment-naïve patients randomized to receive either 150 U of onabotulinumtoxinA or 10,000 U of rimabotulinumB [64]. In a head-to-head study, both BoNT/A and /B showed equivalent benefit at 4 weeks in subjects with cervical dystonia, although BoNT/A was associated with fewer AEs (dysphagia and dry mouth) and had a marginally longer (BoNT/ A, 14 weeks vs. BoNT/B, 12.1 weeks; p = .033) duration of effect in subjects showing a clinical response [65]. Two important factors differentiate these head-to-head studies. Pappert [64] used a higher dose ratio of 1:66.7 (BoNT/A:B), which was based on practice utilization datasheets from several European countries for BoNT/A and the European Commission Summary of Product Characteristic for BoNT/ B; while the earlier study conducted by Comella used a ratio of 1:40 reflecting usual practice in North America. In addition, patients in the Pappert study were treatment naïve, whereas those in the Comella study had prior exposure (and response) to BoNT/A. Both of these factors may have contributed to the different side-effect profiles and duration of treatment effect seen in these two studies. Other studies have noted equivalence in efficacy between BoNT/A and BoNT/B [66]. BoNT/B may be an alternative treatment for cervical dystonia patients who have developed resistance to BoNT/A [26]. However, a report of a high frequency of botulinum toxin B antibody-induced therapy failure in toxin-naïve cervical dystonia patients after a relatively short exposure may limit its use in these patients [67]. 3.6. Other BoNT preparations Chinese botulinum toxin A (CBTX-A) (Lanzhou Biological Products Institute, China), sold as Prosigne in Brazil, has been compared with onabotulinumtoxinA in four studies. In a comparison study in cervical dystonia patients, both drugs had equivalent efficacy, safety, and tolerability profiles at a dose equivalence of 1:1 [68]. Another study comparing CBTX-A and onabotulinumtoxinA in patients with dystonia and muscle spasm reported no significant differences in clinical effects including the latency of response, maximal benefit, and duration of improvement, although a higher dose of Prosigne was needed [69]. Similar efficacy has been reported in the treatment of blepharospasm and hemifacial spasm. In two studies, there were no significant
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differences between Prosigne and onabotulinumtoxinA in subjective global improvement, response onset, efficacy duration, and incidence and severity of AEs [70,71]. Meditoxin®/Neuronox®, a BoNT/A complex produced by Medy-Tox (Seoul, South Korea), is currently available in Asia, the Middle East, and Africa. It is manufactured as 100-U vials of neurotoxin along with 0.5 mg of serum albumin and 0.9 mg of sodium chloride [72]. Results of a study that compared the efficacy and safety of Meditoxin/Neuronox and onabotulinumtoxinA in the treatment of essential blepharospasm, showed no significant differences between treatment groups in the changes in eyelid closing force, functional visual status post-injection, or spasm severity. AEs were reported in 16.1% of the Meditoxin group and 27.6% of the onabotulinumtoxinA group, but no serious AEs were found in either group [73]. 4. Clinical studies — safety BoNT/A has a generally favorable safety and tolerability profile across a broad spectrum of therapeutic uses with a similar AE profile among all products. The majority of AEs reported with BoNT/A treatment are due to expected effects on the target or diffusion into adjacent muscles. Some are due to systemic spread to distant sites, resulting in mild generalized muscle weakness or malaise [74]. Diffusion of BoNT is believed to be influenced by a number of factors including injection technique, concentration, and volume. Clinicians inexperienced with BoNT injections should consider referral to a specialist experienced with proper injection technique. Another option to improve targeting is the use of electromyograph-guided injections, particularly to reach deep muscles [75]. Results of a meta-analysis of 36 randomized controlled studies conducted between 1996 and 2003 and composed of 1425 subjects who received treatment with onabotulinumtoxinA, reported a rate of mild-to-moderate AEs of approximately 25% in the onabotulinumtoxinA-treated group (353/1425 patients) compared with 15% in the control group (133/884 patients, p b .001). No severe AEs were reported [76]. The most common AEs related to cervical dystonia treatment include dysphagia, dry mouth, neck-muscle weakness and pain, injection-site pain, and flulike symptoms [29,39,44,77]. Because it is a long-term treatment, the safety of repeated BoNT injections is an important consideration. The Cervical Dystonia Patient Registry for the Observation of Botulinum Toxin Type A Efficacy Study (CD-PROBE) is an ongoing registry intended to understand the use of onabotulinumtoxinA in the treatment of cervical dystonia. Recently presented preliminary results from CD-PROBE suggest that repeated injections of onabotulinumtoxinA are well tolerated, have a low rate of AEs [78], and are associated with significant and sustained relief of cervical dystonia pain (Pain Numeric Rating Scale and TWSTRS pain scale) and improved patient-reported quality of life, as measured by the Cervical Dystonia Impact Profile (CIDP-58) [79]. The CDIP-58 is a relatively new rating scale for measuring the health impact of cervical dystonia that includes patients' perceptions and complements existing observer-dependent clinician rating scales [80]. 4.1. Long-term efficacy and safety As there is no known cure for dystonia, treatment with BoNT is often long term. Studies in patients with dystonia have consistently shown that the efficacy and safety of BoNT products are maintained. In a study in patients with spasmodic torticollis, Anderson [81] reported that as many as 95% of patients had moderate or excellent benefit after receiving treatment over a median period of 15 months (range 3 to 42 months). In patients with hemifacial spasm, injection of onabotulinumtoxinA into the orbicularis oculi muscle effectively induced sustained relief from symptoms for as long as 10 years with only minimal and transient adverse reactions [82]. Other studies
have reported efficacy of up to 10 years in study populations consisting of patients with cervical dystonia, hemifacial spasm, hyperhidrosis, or blepharospasm [61,83,84]. 4.2. Immunoresistance Different studies show that the risk of developing BoNT/A neutralizing antibodies is low [77,85], particularly in patients who began treatment with the current formulation of BoNT/A (i.e., after 2000) [86], which is thought to be less immunogenic than the previous formulation [87]. In one long-term follow-up study of 45 patients, there was a low incidence of immunogenicity, even after 18 years of use. In this study, patients (n = 22) who exhibited a poor response to their BoNT injection at two consecutive visits were tested for antibodies. Blocking antibodies were confirmed in four tested patients. Responsiveness resumed in 16 of the antibody-negative patients after a dose adjustment; two patients whose nonresponsiveness persisted were switched to treatment with BoNT/B [77]. Brin et al. reported immunogenicity rates as low as 1.2% [85]. The formation of neutralizing antibodies is one reason for lack of or loss of response. Recently Garcia Ruiz et al. reported the results of a retrospective, multicenter study to determine the mean dose of BoNT/A per session and the appearance of resistance during the first 5 years of treatment for cervical dystonia [86]. The study included cervical dystonia patients (n = 275) with a good initial response to BoNT/A, who received their first injection between 1989 and 2002. During the 5 years of follow-up there was a significant (p b .0001) increase in dose over time (year 1: 180 ± 65 U; year 5: 203 ± 63 U) for the entire group. In addition, secondary nonresponse was noted in 6.9% (n = 19/275) of patients. However, because this study took place during a period of time when two different formulations of BoNT/A were in use, the investigators were able to examine the results for the two formulations separately. When they did so, they found no increase in dose over time (year 1: 181.8 ± 75 U; year 5: 181.7 ± 75 U) for 49 patients treated exclusively after 2000 (i.e., with the newer dose of BoNT/A). Furthermore, only one subject (2%) in this group developed resistance compared with 18 (7.9%; 18/226) of the patients who began treatment prior to 2000. It has been suggested that the current formulation of BoNT/A has an improved immunogenic profile compared with the product in use prior to 2000; and while acknowledging that this may have contributed to these results, the authors also suggested that other factors, such as increased experience on the part of clinicians, improved injection technique, and lower variability of BoNT/A dose per vial could have played a part. Although there are not as many long-term studies for BoNT/B, it may be a useful alternative for patients who develop resistance to BoNT/A [88]. In one study, the effect of BoNT/B was sustained for up to 2.5 years in type A-resistant patients, but the magnitude of response diminished over time [89]. 5. Treatment alternatives Although both the EFNS [2] and the American Academy of Neurology (AAN) consider BoNTs to be first-line treatment for cervical dystonia, these are not the only available treatments. Potential alternatives include oral medications, deep brain stimulation (DBS), and peripheral denervation [2,7]. Among the oral medications are levodopa, the anticholinergics, and benzodiazepines. Surgery includes DBS and peripheral denervation. DBS was first used in patients with dystonia in the year 2000. Long-term studies have shown that DBS is safe [90,91] with improvements lasting as long as 8 years [91]. Selective peripheral denervation has been used for patients with cervical dystonia [92,93]. Early studies showed modest, long-term, functional improvement with a reduction in dystonia scores of approximately 30% [94]. This technique is currently of limited use [7].
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6. Conclusions BoNT therapy is the first-line approach for treating focal dystonia. Currently four brands are widely available commercially, three of BoNT/A and one of BoNT/B. Each has important pharmacological differences that give rise to markedly different dosing recommendations. The four approved BoNTs are safe and effective for treating focal dystonias, even for long-term treatment, while AEs are limited and transient and, for the most part, mild in severity. Potential problems with the use of BoNT agents are diffusion and the formation of neutralizing antibody formation, which can lead to treatment resistance. Because each BoNT product is developed from distinct purification and manufacturing procedures and have varying toxin-complex sizes and structures, physicians need to be aware of these differences when choosing and using an agent.
[10] [11] [12] [13] [14]
[15] [16] [17] [18] [19] [20]
Box 1
[21] [22]
The EFNS recommendations state that BoNT can be regarded as first-line treatment for blepharospasm or cervical dystonia (Level A), and that it is effective for writer's cramp (Level A) and other types of upper-limb dystonia [2]. Although not specifically recommended, electromyography-assisted injection appears to have added benefits [75,95]. The American Academy of Neurology recommends the use of BoNT for the treatment of cervical dystonia (Level A) and blepharospasm, focal upper-extremity dystonia, adductor laryngeal dystonia, and upper-extremity essential tremor (Level B) [9].
Conflict of interest Daniel Truong served as a speaker for GSK, Allergan, and Teva; as an advisor/consultant for Teva, Novartis, Ipsen, Schering-Plough, and Merz; and as a researcher for Teva, Boehringer Ingelheim, NIH, Merz, Solvay, UCB, Chelsea Therapeutics International, Ipsen, Allergan, and Schering-Plough.
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
Acknowledgments Editorial support, consisting of substantive editing, copy editing, and styling of Dr. Truong's draft, as well as assistance with literature searches was provided by Linnéa Elliott and Maria Vinall of The Curry Rockefeller Group, LLC, Tarrytown, NY. Funding for editorial support was provided by Merz Pharmaceuticals, LLC, Greensboro, NC.
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Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Review article
Botulinum toxins in the treatment of primary focal dystonias Daniel Truong ⁎ The Parkinson's and Movement Disorder Institute, Fountain Valley, CA, USA
a r t i c l e
i n f o
Article history: Received 6 July 2011 Received in revised form 5 January 2012 Accepted 19 January 2012 Available online 14 February 2012 Keywords: Dystonia Focal dystonia Blepharospasm Botulinum toxin OnabotulinumtoxinA AbobotulinumtoxinA IncobotulinumtoxinA RimabotulinumB
a b s t r a c t Focal dystonia, such as cervical dystonia, blepharospasm, oromandibular dystonia, largyngeal dystonia, and limb dystonia, is often observed in adult-onset primary dystonia syndromes that affect a specific area of the body and tend to have little or no spread. This review will examine the past, present, and future approaches to the treatment of focal dystonia. Botulinum toxin (BoNT) has emerged as the treatment of choice for the majority of focal dystonias. Currently four products are widely available commercially, three of BoNT/A type and one of BoNT/B type. Each has important pharmacological differences that give rise to markedly different dosing recommendations. The four approved BoNTs are safe and effective for treating focal dystonias, including long-term treatment. Adverse events are limited and transient and, for the most part, mild in severity. Potential problems with the use of BoNT agents are diffusion and neutralizing antibody formation; the latter can lead to treatment resistance. Because each BoNT product is developed from distinct purification and manufacturing procedures and has varying toxin complex size and structures, physicians need to be aware of these differences when choosing an agent. © 2012 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . Botulinum toxins. . . . . . . . . . . . . . . . Clinical studies — efficacy . . . . . . . . . . . . 3.1. OnabotulinumtoxinA . . . . . . . . . . 3.2. AbobotulinumtoxinA. . . . . . . . . . . 3.3. OnabotulinumtoxinA/AbobotulinumtoxinA 3.4. IncobotulinumtoxinA . . . . . . . . . . 3.5. RimabotulinumB . . . . . . . . . . . . 3.6. Other BoNT preparations . . . . . . . . . 4. Clinical studies — safety . . . . . . . . . . . . 4.1. Long-term efficacy and safety . . . . . . 4.2. Immunoresistance . . . . . . . . . . . . 5. Treatment alternatives . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . Conflict . of interest . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . comparison studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Dystonia is a neurological movement disorder that causes sustained, involuntary, and sometimes painful muscular contraction, ⁎ Parkinson's and Movement Disorder Institute, 9940 Talbert Avenue, Suite 204, Fountain Valley, CA 92708, USA. Tel.: + 1 714 378 5062; fax: + 1 714 378 5061. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.01.019
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twisting, repetitive movements, or abnormal postures [1]. Dystonia may be primary (idiopathic), considered to be of genetic origin in some cases [2–5], or it may be the result of environmental factors (secondary or symptomatic dystonia). In the 2010 European Federation of Neurological Societies (EFNS) Guidelines on the Diagnosis and Treatment of Primary Dystonias, primary dystonias are classified as pure dystonia, dystonia plus, or paroxysmal dystonia syndromes [2].
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Focal dystonia is often observed in adult-onset primary pure dystonia syndromes that affect a specific area of the body and tend to have little or no spread. The most common presentations are cervical dystonia (spasmodic torticollis; abnormal head twisting), blepharospasm (involuntary, forcible closure of the eyelids), oromandibular dystonia (forceful contractions of the face, jaw, and/or tongue), largyngeal dystonia (spasmodic dysphonia), and limb dystonia (abnormal limb-muscle movement) [6]. Although there is no cure for primary dystonia, symptomatic treatments are available that can minimize the symptoms [2]. The indications for and challenges in using botulinum neurotoxins (BoNTs) will be reviewed here. 2. Botulinum toxins BoNT is considered the treatment of choice for the majority of focal dystonias [2,7–9]. There are seven antigenically distinct toxins (A through G) produced by different strains of Clostridium botulinum bacteria; only types A and B are approved for use in the treatment of focal dystonia. The most common type A formulations are Botox® (OnabotulinumtoxinA; Allergan Inc., Irvine CA, USA), Dysport® (AbobotulinumtoxinA; Ipsen Ltd., Slough, UK), and Xeomin® (IncobotulinumtoxinA; Merz Pharmaceuticals GmbH, Frankfurt am Main, Germany). The commercially available type B BoNT is rimabotulinumB (RimabotulinumB; Solstice Neurosciences Inc., Malvern, PA, USA), which is sold in the United States and Canada as Myobloc® Injection and as NeuroBloc® in the EU, Norway, and Iceland and as Myobloc® Injectable Solution in Korea. In the United States, onabotulinumtoxinA is approved for the treatment of cervical dystonia in adult patients and blepharospasm associated with dystonia in patients ≥12 years of age [10], while abobotulinumtoxinA is approved for the treatment of adults with cervical dystonia [11], and incobotulinumtoxinA is approved for the treatment of adults with cervical dystonia and blepharospasm [12]. RimabotulinumB is indicated for the treatment of adults with cervical dystonia [13]. Beginning in 2009 all botulinum toxin products were required by the FDA to carry a boxed warning cautioning that the effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism [14]. In onabotulinumtoxinA and abobotulinumtoxinA, the BoNT component is formed by botulinum neurotoxin and by nontoxic proteins known as complexing proteins [15], whereas the purification and manufacturing process for incobotulinumtoxinA removes the complexing proteins [16]. The three type A products differ for the size of BoNT component, potentially affecting diffusion characteristics, adverse-event (AE) profile, and therapeutic properties. Although each of these agents consists of the BoNT component and excipients, it is important to note that they are unique drugs [17] that differ in molecular weight and complexing proteins, onset of action and diffusion, approved indications and clinical use, and importantly dosing, which is not interchangeable. A full comparison of the differences among the BoNT formulations is beyond the scope of this publication; however, we refer the reader to a comparison recently published by Gollomp [18] and to a Table provided by Albanese that presents differences in the manufacturing, potency, and dosing of the most common formulations [17]. Since the first report of improvement of abnormal movements and pain in BoNT-treated cervical dystonia [19,20] and blepharospasm patients [21], approximately 80 studies have been published [22]. Eight of these meet the criteria for Class I evidence as defined by the EFNS Scientific Task Force [23] indicating that treatment with BoNT improves the symptoms of cervical dystonia (see Box 1) [24–31]. Studies in both animals [32,33] and humans [34–36] have indicated a possible relationship between increased activity and BoNT uptake at the nerve terminal (e.g., with electrical stimulation or exercise).
3. Clinical studies — efficacy 3.1. OnabotulinumtoxinA In one of the first clinical trials to evaluate the efficacy of BoNT for the treatment of spasmodic torticollis/cervical dystonia, treatment with onabotulinumtoxinA produced both subjective and objective improvements (p b .05), including significant reductions in pain (p b .02) [20]. Side effects were few, and no significant systemic adverse reactions were noted [20]. These results have since been confirmed in numerous short- [27,37,38] and long-term studies [39]. Greene and colleagues reported that treatment with onabotulinumtoxinA was associated with significant improvement in the severity of torticollis (p = .001), disability (p = .0097), pain (p = .0029), and degree of head turning at rest (p = .0001) and while walking (p = .0016). There were no serious side effects; 61% of treated patients improved during the double-blind phase and 74% improved during a subsequent open-label phase at a higher dose of onabotulinumtoxinA [27]. In the long-term study, which followed 205 patients with medically intractable cervical dystonia for at least 3 months and up to 4 years, the average peak-effect score was 3.0 ± 1.2, and the average global rating score was 2.9 ± 1.2; 76.4% of patients who originally reported neck pain obtained complete relief. Peak effect was determined by a review of the patient's diary, the results of interviews conducted with the spouse or friends, and by the patient's perception of response and rated on a scale of 0 to 4. The global rating score was derived from the peak-effect score by subtracting 1 point for a mild complication and 2 points for a disabling complication [39]. OnabotulinumtoxinA has also been shown to be an effective treatment for blepharospasm. In a study composed of 101 patients with idiopathic blepharospasm treated with onabotulinumtoxinA, symptoms were relieved in 78 patients for an average of 9 weeks. The severity/duration of the blepharospasm did not influence outcome. Side effects, particularly a temporary partial ptosis, were common but were well tolerated [40]. In a more recent study, treatment with onabotulinumtoxinA was associated with a significant reduction in Jankovic Rating Scale (JRS) sum score and patient-reported improvement in global response (both p b .0001). OnabotulinumtoxinA was well tolerated; AEs were mostly mild or moderate. The most common AE was ptosis [41]. The onset of the onabotulinumtoxinA effect occurs within 24 to 72 h, peaks at 2 to 4 weeks, and lasts 3 to 6 months [42]. 3.2. AbobotulinumtoxinA In both short- [29,31,43] and long-term double-blind placebocontrolled studies [30,44], patients treated with abobotulinumtoxinA experienced significant improvement in disease-severity scores in patients with cervical dystonia. In the latest study to evaluate the efficacy and safety of abobotulinumtoxinA in the treatment of cervical dystonia, abobotulinumtoxinA produced a significant decrease from baseline in mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores compared with placebo at week 4 (–5.6 vs. –6.7; p b .001). Significant improvements were also seen in TWSTRS subscale scores, visual analog scale (VAS) pain scores, and subject/investigator's VAS symptom assessments compared with placebo (all p b .05) [30]. In treating bilateral benign essential blepharospasm, abobotulinumtoxinA improved functional impairment, and reduced frequency and intensity of facial spasms. There were fewer withdrawals because of lack of efficacy in the abobotulinumtoxinA treatment group compared with placebo. Truong et al. reported sustained efficacy and a favorable safety profile with 80 U of abobotulinumtoxinA/eye [45]. The onset of action is usually evident within 2 weeks of treatment, the peak effect occurs at 4 to 8 weeks, and most patients require retreatment after 10 to 16 weeks [46].
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3.3. OnabotulinumtoxinA/AbobotulinumtoxinA comparison studies A number of studies have compared onabotulinumtoxinA and abobotulinumtoxinA. Nüssgens and Roggenkämper reported results from an early double-blind study in patients with blepharospasm who received one injection of onabotulinumtoxinA and one injection of abobotulinumtoxinA. The results indicated similar efficacy and no significant difference in the duration of the treatment effect between the two preparations, although there were significantly (p b .05) fewer side effects with onabotulinumtoxinA (particularly ptosis; p b .01) [47]. However, in a recent long-term study that assessed the use of onabotulinumtoxinA and abobotulinumtoxinA for the treatment of blepharospasm, Bentivoglio and colleagues noted that the mean duration of improvement was significantly (p b .01) longer for abobotulinumtoxinA. As in the Nüssgens study, the rate of side effects was significantly (p b .01) higher with abobotulinumtoxinA [48]. In another early study that compared onabotulinumtoxinA with abobotulinumtoxinA at three times the onabotulinumtoxinA dose for the treatment of predominantly rotational cervical dystonia, both treatments were equally effective and had a similar safety profile. The duration of effect, assessed by time to retreatment, was also similar [46]. However, a more recent study showed abobotulinumtoxinA to be more effective than onabotulinumtoxinA for both impairment (Tsui score) and pain (TWSTRS pain score). AEs were higher with abobotulinumtoxinA, although none required withdrawal of therapy or specific management [49]. Results of a recent study that evaluated the safety, efficacy, and duration of effect of onabotulinumtoxinA after switching from abobotulinumtoxinA in patients with blepharospasm, cervical dystonia, hemifacial spasm dystonia, or hemifacial spasm showed that onabotulinumtoxinA was more efficacious and had a longer duration of effect than abobotulinumtoxinA regardless of diagnosis [50]. 3.4. IncobotulinumtoxinA IncobotulinumtoxinA has been shown to be noninferior to onabotulinumtoxinA for the treatment of patients with cervical dystonia [51] or blepharospasm [41] with no difference between the two preparations in efficacy, safety profile, onset of action, or duration and waning of effect [52,53]. It is important to note that in the study conducted by Roggenkämper and colleagues [41], the finding of noninferiority was based on a clear prespecified set of clinically relevant criteria, such as those suggested in published recommendations [54]. The primary efficacy variable was the change from baseline in the sum score of the JRS [55] at the control visit. Secondary efficacy variables included the change from baseline in the sum score of the JRS at the final visit and the changes from baseline in the mean total score of the Blepharospasm Disability Index (BSDI) [56] at the control visit and the final visit. Global response to study treatment was also evaluated at both visits using an adaptation of a scale developed by Wissel [57]. In a study of 233 patients with cervical dystonia who received 120 or 240 U of incobotulinumtoxinA or placebo, treatment with either dose of incobotulinumtoxinA was associated with a significant (p b .001) improvement in total TWSTRS score after 4 weeks. AEs occurred in 41.9% of the placebo group, 56.4% of the 120-U group, and 55.6% of the 240-U group. AEs were similar to those reported in other studies of BoNT/A products [58]. A subanalysis of these data showed similar efficacy and safety among treatment-naïve [59] and previously treated [60] patients. Preliminary results for 153 of 217 patients with cervical dystonia participating in a long-term study (up to 88 weeks) indicate that repeated treatments with incobotulinumtoxinA were effective and well tolerated [61]. TWSTRS total score was significantly improved at 4 weeks after each injection (p b .05 vs. injection-visit score), as well as at the study-termination visit (12–13 weeks after the final injection) vs. the first injection visit of the extension phase (p b .001).
11
One or more AEs were experienced by 118 of the participants (77.1%). The most frequently reported AEs were dysphagia, neck pain, and sinusitis. No serious AEs were considered to be related to BoNT/A. The overall incidence of AEs decreased with each injection interval, indicating no cumulative effect with repeated doses. The clinical effect of incobotulinumtoxinA begins to appear within 1 week after injection, peaks at approximately 4 to 6 weeks, and is sustained for several months. The duration of effect is about 110 days [53]. The safety and efficacy of incobotulinumtoxinA has also been shown in patients with blepharospasm. Results of a study that evaluated the efficacy and safety of incobotulinumtoxinA compared with placebo in 109 previously treated subjects with blepharospasm showed a significant (p b .0001) treatment effect in favor of incobotulinumtoxinA, as evidenced by improvements in the JRS severity subscore. AEs were reported in 70.3% of subjects in the incobotulinumtoxinA group and 61.8% of subjects in the placebo group. The most commonly reported AEs were eyelid ptosis, dry eye, and dry mouth [62]. 3.5. RimabotulinumB RimabotulinumB is a type B BoNT — an antigenically distinct form of BoNT that has unique physical and clinical properties that distinguish it from BoNT/A. Early studies showed rimabotulinumB to be an efficacious treatment for patients with cervical dystonia regardless of whether they are responsive or resistant to BoNT/A [28,63]. More recently, rimabotulinumB was reported to be noninferior to onabotulinumtoxinA for the treatment of cervical dystonia in treatment-naïve patients randomized to receive either 150 U of onabotulinumtoxinA or 10,000 U of rimabotulinumB [64]. In a head-to-head study, both BoNT/A and /B showed equivalent benefit at 4 weeks in subjects with cervical dystonia, although BoNT/A was associated with fewer AEs (dysphagia and dry mouth) and had a marginally longer (BoNT/ A, 14 weeks vs. BoNT/B, 12.1 weeks; p = .033) duration of effect in subjects showing a clinical response [65]. Two important factors differentiate these head-to-head studies. Pappert [64] used a higher dose ratio of 1:66.7 (BoNT/A:B), which was based on practice utilization datasheets from several European countries for BoNT/A and the European Commission Summary of Product Characteristic for BoNT/ B; while the earlier study conducted by Comella used a ratio of 1:40 reflecting usual practice in North America. In addition, patients in the Pappert study were treatment naïve, whereas those in the Comella study had prior exposure (and response) to BoNT/A. Both of these factors may have contributed to the different side-effect profiles and duration of treatment effect seen in these two studies. Other studies have noted equivalence in efficacy between BoNT/A and BoNT/B [66]. BoNT/B may be an alternative treatment for cervical dystonia patients who have developed resistance to BoNT/A [26]. However, a report of a high frequency of botulinum toxin B antibody-induced therapy failure in toxin-naïve cervical dystonia patients after a relatively short exposure may limit its use in these patients [67]. 3.6. Other BoNT preparations Chinese botulinum toxin A (CBTX-A) (Lanzhou Biological Products Institute, China), sold as Prosigne in Brazil, has been compared with onabotulinumtoxinA in four studies. In a comparison study in cervical dystonia patients, both drugs had equivalent efficacy, safety, and tolerability profiles at a dose equivalence of 1:1 [68]. Another study comparing CBTX-A and onabotulinumtoxinA in patients with dystonia and muscle spasm reported no significant differences in clinical effects including the latency of response, maximal benefit, and duration of improvement, although a higher dose of Prosigne was needed [69]. Similar efficacy has been reported in the treatment of blepharospasm and hemifacial spasm. In two studies, there were no significant
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differences between Prosigne and onabotulinumtoxinA in subjective global improvement, response onset, efficacy duration, and incidence and severity of AEs [70,71]. Meditoxin®/Neuronox®, a BoNT/A complex produced by Medy-Tox (Seoul, South Korea), is currently available in Asia, the Middle East, and Africa. It is manufactured as 100-U vials of neurotoxin along with 0.5 mg of serum albumin and 0.9 mg of sodium chloride [72]. Results of a study that compared the efficacy and safety of Meditoxin/Neuronox and onabotulinumtoxinA in the treatment of essential blepharospasm, showed no significant differences between treatment groups in the changes in eyelid closing force, functional visual status post-injection, or spasm severity. AEs were reported in 16.1% of the Meditoxin group and 27.6% of the onabotulinumtoxinA group, but no serious AEs were found in either group [73]. 4. Clinical studies — safety BoNT/A has a generally favorable safety and tolerability profile across a broad spectrum of therapeutic uses with a similar AE profile among all products. The majority of AEs reported with BoNT/A treatment are due to expected effects on the target or diffusion into adjacent muscles. Some are due to systemic spread to distant sites, resulting in mild generalized muscle weakness or malaise [74]. Diffusion of BoNT is believed to be influenced by a number of factors including injection technique, concentration, and volume. Clinicians inexperienced with BoNT injections should consider referral to a specialist experienced with proper injection technique. Another option to improve targeting is the use of electromyograph-guided injections, particularly to reach deep muscles [75]. Results of a meta-analysis of 36 randomized controlled studies conducted between 1996 and 2003 and composed of 1425 subjects who received treatment with onabotulinumtoxinA, reported a rate of mild-to-moderate AEs of approximately 25% in the onabotulinumtoxinA-treated group (353/1425 patients) compared with 15% in the control group (133/884 patients, p b .001). No severe AEs were reported [76]. The most common AEs related to cervical dystonia treatment include dysphagia, dry mouth, neck-muscle weakness and pain, injection-site pain, and flulike symptoms [29,39,44,77]. Because it is a long-term treatment, the safety of repeated BoNT injections is an important consideration. The Cervical Dystonia Patient Registry for the Observation of Botulinum Toxin Type A Efficacy Study (CD-PROBE) is an ongoing registry intended to understand the use of onabotulinumtoxinA in the treatment of cervical dystonia. Recently presented preliminary results from CD-PROBE suggest that repeated injections of onabotulinumtoxinA are well tolerated, have a low rate of AEs [78], and are associated with significant and sustained relief of cervical dystonia pain (Pain Numeric Rating Scale and TWSTRS pain scale) and improved patient-reported quality of life, as measured by the Cervical Dystonia Impact Profile (CIDP-58) [79]. The CDIP-58 is a relatively new rating scale for measuring the health impact of cervical dystonia that includes patients' perceptions and complements existing observer-dependent clinician rating scales [80]. 4.1. Long-term efficacy and safety As there is no known cure for dystonia, treatment with BoNT is often long term. Studies in patients with dystonia have consistently shown that the efficacy and safety of BoNT products are maintained. In a study in patients with spasmodic torticollis, Anderson [81] reported that as many as 95% of patients had moderate or excellent benefit after receiving treatment over a median period of 15 months (range 3 to 42 months). In patients with hemifacial spasm, injection of onabotulinumtoxinA into the orbicularis oculi muscle effectively induced sustained relief from symptoms for as long as 10 years with only minimal and transient adverse reactions [82]. Other studies
have reported efficacy of up to 10 years in study populations consisting of patients with cervical dystonia, hemifacial spasm, hyperhidrosis, or blepharospasm [61,83,84]. 4.2. Immunoresistance Different studies show that the risk of developing BoNT/A neutralizing antibodies is low [77,85], particularly in patients who began treatment with the current formulation of BoNT/A (i.e., after 2000) [86], which is thought to be less immunogenic than the previous formulation [87]. In one long-term follow-up study of 45 patients, there was a low incidence of immunogenicity, even after 18 years of use. In this study, patients (n = 22) who exhibited a poor response to their BoNT injection at two consecutive visits were tested for antibodies. Blocking antibodies were confirmed in four tested patients. Responsiveness resumed in 16 of the antibody-negative patients after a dose adjustment; two patients whose nonresponsiveness persisted were switched to treatment with BoNT/B [77]. Brin et al. reported immunogenicity rates as low as 1.2% [85]. The formation of neutralizing antibodies is one reason for lack of or loss of response. Recently Garcia Ruiz et al. reported the results of a retrospective, multicenter study to determine the mean dose of BoNT/A per session and the appearance of resistance during the first 5 years of treatment for cervical dystonia [86]. The study included cervical dystonia patients (n = 275) with a good initial response to BoNT/A, who received their first injection between 1989 and 2002. During the 5 years of follow-up there was a significant (p b .0001) increase in dose over time (year 1: 180 ± 65 U; year 5: 203 ± 63 U) for the entire group. In addition, secondary nonresponse was noted in 6.9% (n = 19/275) of patients. However, because this study took place during a period of time when two different formulations of BoNT/A were in use, the investigators were able to examine the results for the two formulations separately. When they did so, they found no increase in dose over time (year 1: 181.8 ± 75 U; year 5: 181.7 ± 75 U) for 49 patients treated exclusively after 2000 (i.e., with the newer dose of BoNT/A). Furthermore, only one subject (2%) in this group developed resistance compared with 18 (7.9%; 18/226) of the patients who began treatment prior to 2000. It has been suggested that the current formulation of BoNT/A has an improved immunogenic profile compared with the product in use prior to 2000; and while acknowledging that this may have contributed to these results, the authors also suggested that other factors, such as increased experience on the part of clinicians, improved injection technique, and lower variability of BoNT/A dose per vial could have played a part. Although there are not as many long-term studies for BoNT/B, it may be a useful alternative for patients who develop resistance to BoNT/A [88]. In one study, the effect of BoNT/B was sustained for up to 2.5 years in type A-resistant patients, but the magnitude of response diminished over time [89]. 5. Treatment alternatives Although both the EFNS [2] and the American Academy of Neurology (AAN) consider BoNTs to be first-line treatment for cervical dystonia, these are not the only available treatments. Potential alternatives include oral medications, deep brain stimulation (DBS), and peripheral denervation [2,7]. Among the oral medications are levodopa, the anticholinergics, and benzodiazepines. Surgery includes DBS and peripheral denervation. DBS was first used in patients with dystonia in the year 2000. Long-term studies have shown that DBS is safe [90,91] with improvements lasting as long as 8 years [91]. Selective peripheral denervation has been used for patients with cervical dystonia [92,93]. Early studies showed modest, long-term, functional improvement with a reduction in dystonia scores of approximately 30% [94]. This technique is currently of limited use [7].
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6. Conclusions BoNT therapy is the first-line approach for treating focal dystonia. Currently four brands are widely available commercially, three of BoNT/A and one of BoNT/B. Each has important pharmacological differences that give rise to markedly different dosing recommendations. The four approved BoNTs are safe and effective for treating focal dystonias, even for long-term treatment, while AEs are limited and transient and, for the most part, mild in severity. Potential problems with the use of BoNT agents are diffusion and the formation of neutralizing antibody formation, which can lead to treatment resistance. Because each BoNT product is developed from distinct purification and manufacturing procedures and have varying toxin-complex sizes and structures, physicians need to be aware of these differences when choosing and using an agent.
[10] [11] [12] [13] [14]
[15] [16] [17] [18] [19] [20]
Box 1
[21] [22]
The EFNS recommendations state that BoNT can be regarded as first-line treatment for blepharospasm or cervical dystonia (Level A), and that it is effective for writer's cramp (Level A) and other types of upper-limb dystonia [2]. Although not specifically recommended, electromyography-assisted injection appears to have added benefits [75,95]. The American Academy of Neurology recommends the use of BoNT for the treatment of cervical dystonia (Level A) and blepharospasm, focal upper-extremity dystonia, adductor laryngeal dystonia, and upper-extremity essential tremor (Level B) [9].
Conflict of interest Daniel Truong served as a speaker for GSK, Allergan, and Teva; as an advisor/consultant for Teva, Novartis, Ipsen, Schering-Plough, and Merz; and as a researcher for Teva, Boehringer Ingelheim, NIH, Merz, Solvay, UCB, Chelsea Therapeutics International, Ipsen, Allergan, and Schering-Plough.
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
Acknowledgments Editorial support, consisting of substantive editing, copy editing, and styling of Dr. Truong's draft, as well as assistance with literature searches was provided by Linnéa Elliott and Maria Vinall of The Curry Rockefeller Group, LLC, Tarrytown, NY. Funding for editorial support was provided by Merz Pharmaceuticals, LLC, Greensboro, NC.
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