Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure

Recently, it was reported that botulinum toxin type B complex (BoNT/B) (NeuroBloc®, Elan Pharmaceuticals) can produce an adequate therapeutic response in patients with antibody induced failure of botulinum toxin type A complex (BoNT/A) therapy. We wanted to study whether this effect is transient or sustained. For this, 10 consecutive patients (6 males, 4 females, age 54.6 ± 14.3 years, duration of illness 15.8 ± 7.0 years) with complete BoNT/A therapy failure and BoNT/A antibody titres in excess of 10mU/ml in the mouse diaphragm assay (MDA) received BoNT/B in an initial dose of 12370 ± 1804MU. After the first BoNT/B application the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) improved from 20.1 ± 3.0 to 11.9 ± 3.4. In all patients systemic anticholinergic side effects occurred. Three patients had stable continuous responses to two, three and five subsequent BoNT/B applications. Six patients showed complete secondary therapy failure to the second or third subsequent BoNT/B applications. Side effects did no longer occur. In four of them the BoNT/B doses were doubled without producing any therapeutic benefit or any side effects. In five of them MDA testing was performed and revealed BoNT/B antibody titres in excess of 1mU/ml. One patient lost half of her initial BoNT/B responsiveness indicating partial secondary BoNT/B therapy failure. This partial therapy failure was seen on two consecutive application series and has not proceeded to complete therapy failure so far. BoNT/B seems to be only temporarily effective in the majority of patients with BoNT/A antibody induced therapy failure. Whether the formation of BoNT/B antibody points to a high antigenic potency of BoNT/B, to an increased immunoreactivity in BoNT/A antibody carriers or whether it is due to the large amount of protein applied in BoNT/B therapy needs to be studied.     

A型肉毒毒素治疗头颈部肌张力障碍的临床观察

目的观察A型肉毒毒素(BTXA)治疗偏侧面肌痉孪、睑痉孪、Meige’s综合征、痉孪性斜颈的疗效。方法治疗组(A组)用BTXA对86例患者进行头颈部肌肉多点注射,对照组(B组)50例根据诊断选用不同的药物或/和针灸、理疗、中医药治疗。观察两组疗效及副作用。结果A组治疗后当日至3d内开始见效,7～15d达高峰,疗效维持2～6月。总有效率为100%,疗效明显高于B组(P<0.001)。BTXA重复注射疗效无下降,1例HFS患者第三次注射产生耐药性,少数患者有轻微的局部副反应,未见全身副作用。B组62%(31例)的患者疗效维持5～15月后减退,需逐渐增加剂量,少数患者出现白细胞减少、肝功能损害、皮疹、共济失调等不良反应。结论A型肉毒毒素局部注射是治疗头颈部肌张力障碍的一种安全、有效、简便的方法。     

Botulinum toxin antibody type A titres after cessation of botulinum toxin therapy.

In some patients, therapy with botulinum toxin type A (BT-A) becomes ineffective due to formation of antibodies (BT-A-AB). The time course of BT-A-AB titres after cessation of BT-A therapy was quantitatively studied to determine whether and when they might drop. Thirteen patients (eight women, five men) with various dystonic syndromes and complete secondary therapy failure (CSTF) were included in this study (age at initiation of BT-A therapy, 48.2 +/- 11.3 years; number of injection series, 7.7 +/- 2.9; treatment time, 678.8 +/- 385.6 days; mean interinjection interval, 90.4 +/- 35.5 days; mean single dose, 546.7 +/- 336.9 EMU; cumulative dose, 4185.1 +/- 3375.7 EMU [1 EMU = 1 botox MU = 3 dysport MU]). During a monitoring period of at least 750 days after occurrence of CSTF, two or more BT-A-AB tests using the quantitative mouse diaphragm assay were performed. Eight of 13 BT-A-AB titres decreased. The onset of decrease could be detected after between approximately 500 and 1,750 days. After 1,250 to 2,250 days they had dropped below a level of 0.002 U/ml, where CSTF is unlikely. Five of 13 BT-A-AB titres did not decrease. For three of these five, the monitoring period was less than 1,500 days; a chance to drop remained. The other two were monitored for up to 2,400 days. Patients with decreasing and nondecreasing BT-A-AB titres did not exhibit statistically significant differences in either clinical characteristics or treatment parameters. When BT-A therapy was stopped the majority of BT-A-AB titres eventually decreased, allowing reinitiation of BT-A therapy. Application of new BT-A preparations with low antigenic potency might then become an interesting treatment option.     

The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A -- initial experiences.

The increasing use of botulinum toxin type-A, especially for focal dystonia and spasticity has highlighted the issue of secondary non-responsiveness. Within the last few years botulinum toxin type-B (Myobloc/Neurobloc) has become commercially available as an alternative to type-A. This paper discusses our initial experience of botulinum toxin type-B in a total of 63 individuals who attended our botulinum clinic. Thirty-six patients had cervical dystonia and a secondary non-response to type-A toxin. Thirteen of these patients (36%) had a reasonable clinical response to Neurobloc and continue to have injections. The other 23 patients either had no response, or a poor response, or had unacceptable side effects and ceased treatment. A small number of people with blepharospasm, hemifacial spasm and foot dystonia also had a disappointing response to injection. Twenty patients with spasticity were also type-A resistant. Seven of these show some continuing response to type-B, without unacceptable side effects. These findings demonstrate that botulinum toxin type-B has a place in the management of patients who have become non-responsive to type-A, but overall the responses to type-B toxin were disappointing.     

The use of botulinum neurotoxin type A (BoNTA) in urology

Summary The use of Botulinum neurotoxin type A (BoNT/A) in the lower urinary tract was pioneered as early as 20 years ago with injections into the urethral sphincter reducing bladder voiding pressures, urethral pressures, and post-void residual urine. Over the past 9 years, the use of BoNT/A has revolutionised the treatment of intractable symptoms associated with the neurogenic or idiopathic overactive bladder, both in adults and children. The duration of clinical improvement is 6–11 months, is accompanied by significant amelioration of patients’ quality of life and repeat bladder treatments appear to have sustained effects. Despite evidence for an effect on the afferent pathways, its mode of action in the human bladder remains largely unknown. The use of BoNT/A has also expanded into the painful bladder syndrome and in benign prostatic diseases, with promising preliminary results. This review aims to provide an insight of the use of BoNT/A in the lower urinary tract, addressing issues such as treatment outcomes and safety, mechanisms of action and potential for future research. Correspondence: Apostolos Apostolidis, 2nd Department of Urology, Papageorgiou Hospital, Aristotle University of Thessaloniki, Ring Road, Nea Efkarpia, 56429 Thessaloniki, Greece     

Single event multilevel botulinum toxin type A treatment and surgery: similarities and differences

The present study attempts to provide objective evidence of two treatment options for children with cerebral palsy (CP): multilevel botulinum toxin type A (BTX-A) injections and multilevel surgery. The purpose of the study was to clarify the differences and the similarities, and common treatment principles of both treatment strategies. Objective three dimensional gait analysis data were studied retrospectively in two patient groups pre- and post-treatment (randomly selected from a group of children that were treated between 1998 and 1999). In the first group, 29 children with CP were managed with BTX-A injections according to an integrated multilevel approach ( Molenaers et al ., 1999a ). A second group of 23 children with CP were managed by a more traditional single event multilevel surgery, also according to an integrated approach. Our aim was to evaluate the differences as well as the similarities between both patient groups, using a set of 56 parameters selected from three-dimensional gait analysis. The unifying concept between management with BTX-A injections and orthopaedic surgery was the adoption of a multilevel approach at one session. The groups demonstrated considerable differences with respect to age, pretreatment condition and amount and level of improvement after treatment. The children who received BTX-A were typically younger, and showed primary gait problems in the distal joints, whereas the children who underwent surgery demonstrated a higher frequency of gait deviations in the transverse plane and had more complications. Although the benefit of both treatments was confirmed by the present study, a difference in the amount and level of improvement was also demonstrated. In conclusion, these treatment modalities should be regarded as complementary rather than mutually exclusive treatments, with both calling for an integrated approach.     

Use of spasmography to assess the effects of botulinum toxin type A in patients with lower-limb spasticity

Lower-limb spasticity is one of the main features of advanced multiple sclerosis (MS), and botulinum toxin type A (BTX-A) is known to be effective in the treatment of lower-limb spasticity. Two hundred randomly selected MS outpatients were analysed for spasticity using clinical scores. Of the 200 randomly selected MS outpatients, 23% had marked or severe spasticity. Hence, the aims of this study were to investigate the effect of BTX-A injections in MS patients with lower-limb spasticity refractory to conventional treatment, and to evaluate the new method of spasmography for analysing muscle tone. Fifteen MS patients (mean MS duration, 11.2 years) with spasticity of the lower limbs were injected with BTX-A (BOTOX®) into the affected muscles. A control group of 15 healthy volunteers was analysed by spasmography. In the 15 MS patients, the Modified Ashworth Scale scores for the left and right legs were significantly lower than baseline values ( P < 0.05) at 3 and 6 weeks post-treatment. At 6 weeks post-treatment, the spasmography measures ( n = 12) of mean muscle tone and mean maximum muscle tone of both legs in passive mode were significantly reduced ( P < 0.05) compared with baseline. The time to walk 10 m (n = 9) was significantly reduced compared with baseline ( P < 0.05) at 3 and 6 weeks post-treatment. No adverse events were reported for any patients treated with BTX-A. These data indicate that BTX-A is effective and safe in the treatment of lower-limb spasticity, and that spasmography is a useful method for assessing therapeutic intervention in Spasticity.     

肌电图引导局部肌肉注射A型肉毒毒素治疗痉挛性斜颈的疗效观察

目的 观察肌电图(EMG)引导局部肌肉注射A型肉毒毒素(BTX-A)治疗痉挛性斜颈(CD)的疗效.方法 应用EMG检查19例CD患者头颈部152块肌肉,针对放松状态下出现的多频群放电位的114块靶肌肉进行BTX-A局部肌肉注射;治疗前后分别采用Tsui量表对病情和疗效进行评估;随访观察疗效持续时间以及不良反应.结果 治疗后EMG发现靶肌肉5块;根据Tsui量表评分,治疗后总有效率第1周为47.3%,第2周为78.9%,第3、4周均为94.7%;随访显示疗效平均保持10个月;不良反应轻微,均在4周内自行缓解.结论 EMG引导局部肌肉注射BTX-A治疗CD安全有效.     

Low-dose subcutaneous injection of botulinum toxin type A for facial synkinesis and hyperlacrimation

OBJECTIVE: To investigate the efficacy of low dose of botulinum toxin type A (BTX-A) for facial synkinesis and hyperlacrimation. MATERIAL AND METHODS: Eleven patients suffering from facial synkinesis after Bell's palsy or facial nerve injury were treated with a low dose of BTX-A, 0.5-1.25 U per point into several points. One patient showing hyperlacrimation was also treated with BTX-A. The whole observational period was 43 months. RESULTS: On average, 5.76 U of BTX-A, which was lower than that of previous reports, was injected per treatment. In seven cases, synkinesis disappeared completely after three or fewer sessions of BTX-A injection. The mean interval between treatments was 14.5 weeks. Hyperlacrimation was completely suppressed after a single subcutaneous injection of BTX-A. Only mild subcutaneous hemorrhage was observed as adverse reactions. CONCLUSION: Facial synkinesis can be treated with a lower dose of BTX-A without relevant adverse reactions.     

The use of botulinum toxin type A in spastic diplegia due to cerebral palsy

Spastic diplegia is a severely disabling condition and many current treatment options offer the patient no real therapeutic benefit. Intramuscular injection of botulinum toxin type A (BTX-A) has demonstrated the ability to decrease spasticity, improve mobility and delay the need for surgery in patients with spastic diplegia. The study described here was a pilot to a larger study and it aimed to identify the most suitable and sensitive outcome measures to detect the benefits of BTX-A injection. Five adolescents with hip spasticity due to cerebral palsy were injected with BTX-A into the psoas major muscle (for thigh adduction problems) or the soleus muscle (to correct 'toe clawing'). Assessments of gait and mobility were carried out every month for the 4-month study period. Following injection with BTX-A, improvement in patient mobility was most evident in subjects with thigh adduction problems. A reduction in 10-m walking time and an increase in stride length was also more pronounced in patients injected in the psoas. Three of the five patients treated demonstrated an improved Modified Ashworth Scale score at the end of the 4-month observation period. The results conclude that spastic diplegics with problems related to the hip, may benefit from BTX-A. Patients who experience 'toe clawing' present different problems and the measures used did not pick up on the benefits gained by the patients.     

Pharmacology of botulinum toxin: differences between type A preparations

Different types of botulinum neurotoxin (BoNT) block different proteins of the soluble N‐ethylmaleimide sensitive factor attachment protein receptor (SNARE) protein complex within cholinergic nerve terminals, producing blockade of cholinergic neuromuscular and autonomic synapses. Animal studies indicate the longest duration of action for BoNT type A (BoNTA) followed by types B, F, and E. Diffusion to adjacent and remote muscles may be related to protein composition, dilutions, volume, target muscle selection, and injection technique. A review of head‐to‐head, randomized, controlled trials of BoNTA preparations (Botox® and Dysport®) suggests that Dysport® tends to have higher efficacy, longer duration, and higher frequency of adverse effects. Conversion factors between the preparations varied, however, and remain controversial. In clinical settings, a Botox®:Dysport® conversion ratio of 1:3 may be appropriate. Animal studies suggest a conversion ratio of 1:2.5–3. When therapeutic effects between these preparations are attempting to be equalized, Dysport® seems to produce more adverse effects. In mice, Botox® appears to have a better safety margin than Dysport® and BoNTB. In rats, diffusion margins are similar for Botox® and Dysport®. Jitter derived from stimulation single‐fiber EMG of injected and remote muscles show no differences between Botox® and Dysport®. Atrophy of extrafusal muscle fibers of injected and remote muscles do not differ between the BoNTA preparations.     

Experience with long-term treatment with albumin-supplemented botulinum toxin type A

In earlier studies, we have demonstrated the efficacy of albumin-supplemented botulinum toxin type A (ASBTA) in principle. Here, we present long-term data from 106 patients who received ASTBA over 5–10 years for the treatment of cervical dystonia, blepharospasm and hemifacial spasm. Vials of Dysport^® were diluted in 0.1% albumin solution to a concentration of 25 units/ml. Overall patients and indications, the mean latency to response was 7.1 ± 2.2 days, the mean duration of response was 12.3 ± 3.1 weeks and the mean global clinical improvement (scale 0–3) was 2.6 ± 0.2. Only one patient had neutralizing antibodies against BoNT-A. Side effects were less frequent than known for conventional BoNT-A and generally mild. These findings were confirmed by analysis of data of 71 patients who have been reconverted from ASBTA to conventional dilutions of Dysport^® or Botox^®. We conclude that long-term treatment with ASBTA is effective, safe and help to reduce costs.     

Management of spasticity with botulinum toxin type A: implementing the treatment algorithm

Intramuscular injections of botulinum toxin type A (BTX-A) may successfully treat spasticity resulting from focal muscle overactivity. However, BTX-A should not be considered as a monotherapy. Physical interventions such as strengthening programmes, range-of-motion exercises or serial casting should be implemented following BTX-A injections. The likelihood of treatment success relies heavily on tailoring the treatment protocol to an individual's needs. This paper presents five case studies which describe patient management problems that have been addressed by applying an algorithm for the management of spasticity with botulinum toxin type A. The case studies are representative of patients with hand, arm, hip, leg and/or foot spasticity who have received BTX-A injections. The potential pitfalls of BTX-A treatment are presented and possible reasons for treatment failure are discussed. The case studies highlight the importance of reassessing functional objectives for each individual after treatment. The objectives of BTX-A treatment vary considerably between patients. If the treatment goals are not achieved, modification of the injection procedure and/or dose may be required. A continued failure of treatment suggests either poor patient selection or inappropriate treatment goals. Successful treatment does not obviate the need for routine re-evaluation of the goals at treatment follow-up.     

A multilevel approach to botulinum toxin type A treatment of the (ilio)psoas in spasticity in cerebral palsy

In spasticity, flexion deformity of the hip is frequently associated with contracture or hyper-reflexia of the psoas muscle. Botulinum toxin type A (BTX-A) has been used for some considerable time in the management of paediatric gait disorders. We have been using a multilevel approach to manage spasticity in cerebral palsy for several years, the combination of gait analysis and clinical evaluation being important for the selection of target muscles for BTX-A injections. Twenty cerebral palsy children (12 female) with spasticity were treated with BTX-A injections (BOTOX® mean dose, 2 U/kg body weight) into the psoas muscle. Patients were monitored using range of motion measurements of maximal hip extension, clinical estimates of hypertonia in the hip flexors, gait analysis (three-dimensional kinematics and kinetics) and surface electromyography of major lower limb muscles. Full gait analysis was carried out on 12 of the patients. Significant clinical improvements were observed following 15 of the 21 psoas treatments. Furthermore, the kinematics results of gait analysis showed improvement in one or more parameters in nine of the 12 patients. In conclusion, we have demonstrated the value of a multilevel approach to BTX-A treatment in the management of spasticity in children with cerebral palsy.     

A randomized study of combined botulinum toxin type A and casting in the ambulant child with cerebral palsy using objective outcome measures

It is recognized that objective gait analysis is of great value in planning a multilevel botulinum toxin type A (BTX-A) treatment. After BTX-A treatment, objective outcome measures can provide new and interesting information for each individual child with cerebral palsy (CP). Moreover, by studying group results, we may evaluate our treatment hypotheses. The present prospective study attempts to document the effect of integrated multilevel BTX-A treatment on objective gait parameters and to define the optimal strategy for the combined treatment of BTX-A with casting in children with cerebral palsy. Objective three-dimensional gait analysis (3DGA) data were collected pre- and 2 months post-treatment, in two randomized patient groups: a first group of 17 children treated with lower leg casting prior to BTX-A injections, and a second group of 17 patients who received casting immediately after injections. The present study demonstrates that improved gait can be achieved after a multilevel BTX-A treatment, combined with casting, using a set of 90 gait parameters. The most pronounced improvement was seen at the ankle joint. The results in the knee, hip and pelvis imply that multilevel treatment of the child with CP should start at an early age, in order to prevent development of muscle contractures. Slightly more pronounced benefits, mainly in the proximal joints, were seen for the children who were casted after injections as compared to the children who were casted before injections.     

Muscle histopathology in children with spastic cerebral palsy receiving botulinum toxin type A

Introduction: Botulinum toxin A (BoNTA) is routine treatment for hypertonicity in children with cerebral palsy (CP). Methods: This single‐blind, prospective, cross‐sectional study of 10 participants (mean age 11 years 7 months) was done to determine the relationship between muscle histopathology and BoNTA in treated medial gastrocnemius muscle of children with CP. Open muscle biopsies were taken from medial gastrocnemius muscle and vastus lateralis (control) during orthopedic surgery. Results: Neurogenic atrophy in the medial gastrocnemius was seen in 6 participants between 4 months and 3 years post‐BoNTA. Type 1 fiber loss with type 2 fiber predominance was significantly related to the number of BoNTA injections (r = 0.89, P < 0.001). Conclusions: The impact of these changes in muscle morphology on muscle function in CP is not clear. It is important to consider rotating muscle selection or injection sites within the muscle or allowing longer time between injections. Muscle Nerve 53: 407–414, 2016     

Adductor spasticity in children with cerebral palsy and treatment with botulinum toxin type A: the parents' view of functional outcome

Botulinum toxin type A (BTX-A) has been used successfully to manage spasticity in children with cerebral palsy. Little has been done to evaluate treatment outcome and satisfaction from the patients' and parents' points of view. The aim of this study was to investigate the parents' perceptions of the benefits of BTX-A on movement disorders in children with cerebral palsy. Twenty-six children with adductor spasticity were enrolled into an open-label, prospective study. Patients received intramuscular injections of BTX-A, and assessments of joint mobility (passive range of motion), degree of spasticity (Modified Ashworth Scale) and functional benefit (Gross Motor Function Measure) were made before and 12–18 weeks after treatment. Parents' assessment of treatment outcomes were evaluated using a standardised questionnaire. BTX-A was shown to be effective in reducing muscular hyperactivity and functional limitations. Parents' satisfaction with the treatment outcome was high. For non-ambulatory patients, the reported benefits included facilitation of daily care, ease of positioning and reduction of pain. For patients who were disabled to a lesser extent, improvements in gait and posture included sitting with improved comfort, standing for longer periods of time and/or walking longer distances. The parents' responses supported the impressions of the therapists, demonstrating that BTX-A produced beneficial effects on daily activities, according to both objective measures and parents' observation.