Treatment of cervical dystonia with botulinum toxins

Transcription

1 European Journal of Neurology 2006, 13 (Suppl. 1): Treatment of cervical dystonia with botulinum toxins C. L. Comella a and P. D. Thompson b a Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA; and b Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia Keywords: botulinum toxin, cervical dystonia, spasmodic torticollis Botulinum toxin (BoNT) treatment has been used extensively for the treatment of cervical dystonia. In most studies, there is significant improvement following treatment for head posture and pain. The common side effects following treatment include dysphagia, dry mouth, and neck weakness. There are five brands and two serotypes of BoNT available. The dosing of each serotype and brand differs. Perhaps more importantly, each brand and serotype may differ in immunogenic potential and occurrence of secondary unresponsiveness, an issue that is currently under active investigation. Although many aspects of the technique of injection have not been adequately studied, general guidelines are available. Introduction Cervical dystonia (CD), also known as spasmodic torticollis, is a focal dystonia arising from asymmetric, involuntary contraction of muscles in the neck and shoulders, causing turning, tilting, flexion or extension movements of the head, sometimes combined with elevation or anterior shifting of the shoulders. Intermittent spasms and tremor can occur superimposed upon the longer muscle contractions. Rhythmic movements may be mistaken for head tremor, except that CD has sustained contractions causing deviation of the head in predominantly one direction. Pain is present in up to 60% of patients, and is sometimes the most disabling feature of CD [1]. Although transient remission of symptoms may occur, typically CD is a life-long disorder that waxes and wanes in severity. A variety of oral medications have been used to treat CD, including anticholinergic agents, baclofen, and benzodiazepines [2]. Unfortunately, benefit from oral medications is usually complicated by the occurrence of side effects. Botulinum toxin (BoNT) treatment is the most effective approach to CD, providing relief for up to 85% of patients. Improvement is reported for head posture, pain, and range of motion. Botulinum toxin treatment for cervical dystonia efficacy and safety Both commercially available serotypes, BoNTA and BoNTB, have been evaluated in randomized controlled trials with sufficient evidence to demonstrate safety and Correspondence: Cynthia L. Comella, MD, Department of Neurological Sciences, Rush University Medical Center, 1725 West Harrison, Chicago, IL 60612, USA (fax: ; ccomella@rush.edu). efficacy for CD. However, the methodologies employed in these studies have been variable. Many of the technical aspects of BoNT treatment have not been adequately studied to provide precise recommendations as to number of muscles to inject, optimal dosing and number of injection sites for specific muscles, or best means of muscle selection and injection. The first report of BoNT for CD included 12 patients and was single-blinded using electromyography guidance and a total maximum dose of 200 U of BoNTA as OculinumÒ (Smith-Kettlewell, San Francisco, CA, USA) [3]. Improvement occurred in 92% of the patients and lasted 4 8 weeks with 25% reporting transient neck weakness [3]. A double-blind, placebo-controlled, crossover study of 21 patients using 100 U confirmed these early results [4] and showed improvement in investigator ratings and patient assessments of CD severity. In this study, only the two most active muscles were treated. An open-label study using blinded video ratings also confirmed the efficacy of injections into two neck muscles using a different formulation of BoNTA from the Vaccine Research and Production Laboratory, Porton Down, UK (the precursor of DysportÒ) [5]. Subsequently, there have been approximately 80 studies that have evaluated BoNT in CD. Most of these are uncontrolled studies. There are seven prospective, double-blind, randomized controlled clinical trials meeting the criteria for classification as class I evidence [6 12]. BoNTA was evaluated in four studies and BoN- TB was assessed in three studies. These studies are separated into studies of de novo CD patients and those in previously treated patients. The first study in de novo patients [6] evaluated 55 CD subjects comparing BoNTA [BotoxÒ (Allergan, Inc., Irvine, CA, USA)] to placebo over a 12-week study period. Subjects were stratified by primary type of torticollis and randomized to BoNTA or placebo. Subjects received standardized injections based 16 Ó 2006 EFNS

2 Treatment of CD with BoNTs 17 on their primary type, with dose range from 140 to 165 U. Maximal benefit following injection occurred at 6 weeks with significant improvement in functional capacity, head turning, pain and subjective assessment. The greatest improvement was in head turning. Adverse events included dysphagia and neck weakness. A second study [9] compared three doses (250, 500, 1000) of BoNTA [DysportÒ (Ipsen Ltd., Slough, Berkshire, UK)] to placebo in 75 de novo CD subjects with rotational torticollis in an 8-week study. After injection, significant improvement was seen only at week 4 in the Tsui scale with a 25 30% benefit in the 500 and 1000 U dose groups. Subjective improvement occurred in 45 50% and was significant at weeks 4 and 8 for the1000 U arm, and at week 8 for the 500 U arm. Adverse events were greater in the 1000 U group, with neck weakness (19%) and voice changes (11%). Dysphagia (24%) was greatest in the 1000 U group, but did not reach statistical significance. The third study [7] of de novo CD patients compared 554 U (range U) BoNTA (DysportÒ) to 16.5 mg (range 4 24 mg) trihexyphenidyl at 12 weeks following treatment. This study showed significant improvement with BoNTA, and demonstrated the superiority of BoNTA over trihexyphenidyl for Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) disability (2 points), Tsui scale (5 points), TWSTRS pain (2 points), and general health perception (6 points). The trihexyphenidyl group had significantly more adverse events. Four studies enrolled subjects with previous exposure to BoNT. Three studies assessed BoNTB [MyoblocÒ/ NeuroBlocÒ (Solstice Neurosciences, Inc., South San Francisco, CA, USA)] [8,10,11] and one assessed BoNTA (DysportÒ) [12]. In one study, 109 CD subjects with benefit from BoNTA were randomized to placebo, 5000 or U of BoNTB [10]. At 4 weeks, there was improvement in total TWSTRS scores for all groups (10% placebo; 20% in 5000 U, 25% U), with greater improvement in the BoNTB groups compared with placebo. The TWSTRS subscales for severity and pain, and the patient and physician global scales showed similar benefit with BoNT. These improvements were no longer present at week 12. Adverse events were greater in the combined BoNTB-treated groups for dry mouth (38%), dysphagia (33%), pain (30%), and headache (39%), but were largely mild in intensity. A second study used a similar design, assessing the effects of BoNTB at U compared with placebo in 77 CD patients who were secondarily resistant to BoNTA. At 4 weeks following injection, the BoNTB group had more improvement in TWSTRS score (21% vs. 4% in placebo). Improvement in BoN- TB was also found for severity, disability, and pain subscales, and physician and patient global scores [11]. A recent study evaluated 500 U BoNTA (DysportÒ) compared with placebo in 80 CD subjects previously treated with BoNTA (BotoxÒ). This study showed improvement in TWSTRS total score at week 4 with only blurred vision and neck weakness occurring more frequently than placebo [12]. A recent double-blind, randomized study compared NT 201(XeominÒ; Merz Pharmaceuticals, Frankfurt, Germany), a new BoNTA that is free of complexing proteins, to available BoNTA as BotoxÒ in 463 CD subjects [13]. This study showed that both formulations of BoNTA provided similar benefit. Whether there are advantages of a complex protein-free formulation of BoNTA in preventing antibody formation will necessitate additional longitudinal investigations. Botulinum toxin injection technique The key elements to using BoNT for the treatment of CD include accurate selection of muscles, anatomy of the neck, dosing of BoNTs depending on serotype and localization of muscles for injection. CD arises from the involuntary activation of neck muscles. The anatomy of the neck muscles includes more than 26 muscle pairs [14]. The posture of the head is determined by the combination of activated cervical muscles and may be tonic, or have a spasmodic component that can be similar to tremor but usually has a directional component [15,16]. The primary head postures include torticollis (horizontal turn), laterocollis (tilt to the shoulder), anterocollis (forward flexion), or retrocollis (extension). CD may be simple, with activation of two muscles, or more complex with multi-directional components and involvement of several muscles [15]. Selecting muscles for injection requires a familiarity with the major neck muscles and their primary and secondary actions [17]. Botulinum toxin doses The total dose of BoNT used for CD varies depending on serotype and brand of BoNT. A dose finding study for DysportÒ recommended that a starting dose of 500 U results in significant benefit for most patients and minimizes the occurrence of dose-related adverse effects [18]. This is lower than the earlier doses of DysportÒ used in patients. A recent open-label study followed the results of DysportÒ for CD over a 10-year span (mean dose 833 U) and found that 63% of patients continued treatment, and that efficacy was sustained over repeated injections [19]. In contrast, the BotoxÒ dose used in clinical trials that showed efficacy suggested doses ranging from 100 to 300 U. In the pivotal trials of

3 18 C. L. Comella and P. D. Thompson BoNTB (MyoblocÒ/NeuroBlocÒ), doses ranging from 2500 to U were found to be safe and effective [10]. Long-term open-label studies suggest that in some patients, doses of BoNTB (MyoblocÒ/NeuroBlocÒ) of up to U can be administered without serious adverse effects [20]. Although published recommendations for the doses of BotoxÒ (21) and DysportÒ are available for individual muscles, the optimal dosing in a particular muscle has only been assessed for the sternocleidomastoid muscle (SCM) using quantitative electromyography (EMG). In two studies, doses as small as 20 U BoNTA (as BotoxÒ) reduced dystonic activity in SCM whilst doses greater than 20 U offered minimal additional improvement [23,24]. Similarly, for BoNTA as DysportÒ, 100 U was sufficient to reduce SCM activity [24]. Doses of BotoxÒ greater than 100 U in SCM were associated with a greater occurrence of dysphagia [25]. Target muscle selection The role of EMG has not been defined. EMG has been evaluated both as an adjunct to the clinical examination for planning injections and targeting the injections into overactive muscles. Investigators using EMG guidance have reported increased benefits in their patients and the potential to use smaller doses of toxin for treatment [26 29]. A single blinded study of consecutive CD patients randomized to injection with or without EMG assistance demonstrated that there was a greater magnitude of improvement and a greater number of patients with a marked improvement when EMG was used [27]. These results may be due to increased accuracy of injection into muscle [30] or to enhancing the clinical examination in the process of muscle selection [24,31]. The number of injection sites into cervical muscles ranges from one site in smaller muscles to eight sites in larger cervical muscles. However, there is little evidence available to guide clinicians in selecting the optimal number. A single study suggested that multiple point injections were more likely to improve outcome for a greater percentage of patients [32], but these results have not been further evaluated. Duration of benefit The duration of benefit following BoNT injections in CD has been assessed both prospectively and retrospectively. A prospective assessment of 37 patients treated with DysportÒ showed continued benefit with repeated injections with a mean duration of benefit of 95 days [22]. A retrospective chart review [33,34] from two research centers that included 60 patients treated for at least 1 year showed a mean clinical response lasting 15.6 weeks, with a range of weeks. Duration of benefit tended to last the longest in patients experiencing moderate symptoms [34]. The mean (±standard deviation) duration of benefit assessed to time of retreatment, and measured by Tsui scores, in a randomized double-blind study was 83.9 ± 13.6 days for DysportÒ and 80.7 ± 14.4 days for BotoxÒ [35]. Another study of patients treated with DysportÒ on six or more occasions showed the greatest degree of improvement following the first injection, although improvement was sustained following subsequent injections [36]. Closer scrutiny of the data showed that this Ôfirst treatmentõ effect could be attributed to patientsõ unwillingness to allow the benefit from BoNT to dissipate completely before returning for repeat treatment. Accordingly, they received their next injection whilst still experiencing residual benefit from the previous injections [36]. Approximately 20% of patients treated at least one time chose not to continue long-term treatment with BoNT. The most common reason for discontinuing BoNT was an unsatisfactory response or lack of effect. The occurrence of adverse events, most frequently dysphagia, was the second most common reason for discontinuation. In addition, 15% reported sustained improvement of symptoms, suggesting a coincident partial or complete remission of CD, although the possibility that BoNT treatment may increase the chances of remission in CD has been proposed [37]. In a similar survey, 155 patients receiving BoNT injections for CD at a single center were asked to complete a questionnaire related to their decisions to continue or discontinue treatment. The response rate was high, with 86.6% of the patients returning the survey. Of these, 21.8% discontinued treatment with the major reasons cited being lack of efficacy, high cost of treatment, or no advantage over oral medications [34]. In this series, adverse events from treatment were not cited as a major reason for treatment cessation. A recent double-blind, multicenter study compared BoNTA (BotoxÒ) to BoNTB (MyoblocÒ/Neuro- BlocÒ) for efficacy, side effects and duration of effect in 139 CD patients. This study showed that at maximal efficacy, both serotypes had similar results, with significant improvement in CD. Dry mouth and dysphagia were more frequent with BoNTB, but were mild to moderate in severity. Duration of effect was 14 weeks for BoNTA and 12.1 weeks for BoNTB [38]. Treatment failures Cervical dystonia patients who never benefit from BoNT are considered primary non-responders. This occurs in approximately 15 30% of CD patients and

4 Treatment of CD with BoNTs 19 may arise for a number of reasons. In some patients, anterocollis is the primary head posture. Although injection of anterior neck muscles, such as the sternocleidomastoid, scalene complex, and digastric muscles, may improve anterocollis, frequently there is involvement of the pre-vertebral muscles that are not safely accessible for injection. In addition to the occurrence of primary BoNT treatment failure (patients never responding to injection), secondary BoNT failure may also occur. These patients with initial improvement from treatment fail to respond to subsequent injections. The prevalence of secondary non-response has not been investigated systematically in prospective studies. Retrospective studies suggest that secondary BoNT failure affects approximately 10 15% of CD patients. One study found that 9.9% of patients reported a secondary non-response [36]. A second study of 242 patients with adequate follow-up showed that 16% were non-responders and, of these, 35.7% were found to have antibodies to BoNT by the mouse neutralization assay [39]. In the pivotal clinical trials included in the package inserts for commercially available serotypes of BoNT, 17% of those patients who report benefit to BoNTA were found to have neutralizing antibodies to the original formulation and did not show objective clinical benefit following treatment [40]. In 1998, the preparation of BoNTA was altered to reduce the proteins contained in the toxin. Initial investigations have shown that the occurrence of immunity to the new formulation is markedly reduced [41]. In the package insert for MyoblocÒ/NeuroBlocÒ (BoNTB), the extrapolated occurrence of neutralizing antibodies to BoNTB occurred in approximately 18% of patients after 18 months. These observations are now under investigation in prospective studies. In patients who develop resistance to one serotype, treatment with another serotype may restore clinical efficacy [11]. Conclusions Botulinum toxin has been shown to be safe and effective for the treatment of CD. Currently, there are five brands commercially available, four of BoNTA and one of BoNTB. Of the brands that have been most studied (BotoxÒ, DysportÒ, and MyoblocÒ/NeuroBlocÒ), each has important pharmacologic differences that give rise to markedly different dosing recommendations. Currently, there is little evidence to suggest significant differences in the results obtained using the two widely available formulations of BoNTA (BotoxÒ and DysportÒ) [35]. As studies assessing immunogenicity of each brand become available, this may change. The different techniques of BoNT injections for CD have not been adequately studied to allow specific recommendations for dosing into individual muscles, use of EMG or number of injection sites per muscle. 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