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.     

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 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.     

Safety and efficacy of botulinum toxin type B (Myobloc) in adductor spasmodic dysphonia.

This single-site, open-label, dose-finding study evaluated the safety and efficacy of botulinum toxin type B (BoNT-B; Myobloc) for the treatment of adductor spasmodic dysphonia (AdSD) in 13 patients. Three patients received a total of 50 U (25 U per vocal fold); the same three subsequently received 100 U, and then 10 more received 200 U. The primary measure of efficacy was the patient's rating of the change in the severity of spasms on a scale from -3 to +3. There were seven secondary measures of efficacy, including blinded ratings of the sound of voice recorded on audiotape. At Week 8 after injection, spasms improved in 0 of 3 patients who received 50 U, 1 of 3 patients who received 100 U, and 8 of 10 patients who received 200 U. The mean (+/- standard deviation [SD]) score for the change in spasm severity at Week 8 in the 200 U group was 1.4 (+/-1.2) points (P = 0.004). All seven secondary measures also showed improvement. Breathiness was the most common side effect but was mild in intensity and of short duration. We conclude that BoNT-B is safe and effective for the treatment of adductor spasmodic dysphonia.     

Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in parkinsonism.

Drooling is a frequent symptom in Parkinson's disease (PD), occurring in almost 75% of all patients. Although it is now well known that drooling in PD is the result of swallowing difficulties rather than excessive saliva production, few treatments have been developed to reduce it. Clinical studies suggest that botulinum toxin A (BTX) injections into salivary glands are effective in decreasing drooling in PD patients. In this double-blind, placebo-controlled study, 20 patients with parkinsonism (idiopathic PD or multiple system atrophy), were randomly assigned to receive 450 U of BTX (Dysport; Ipsen, Berkshire, UK) or 2 ml of placebo, injected into the parotids and submandibular glands under ultrasonographic guidance. Treatment efficacy and safety were assessed at baseline, 1 week and 3 months after BTX injections using clinical scales (Drooling Severity and Drooling Frequency scales) and side effects surveillance. After treatment, the average secretion of saliva in the BTX group was significantly lower than in the placebo group, as appraised by clinical measurements. No side effects were observed in either group. BTX injection into parotids and submandibular glands, under ultrasonographic guidance, is an effective and safe treatment for drooling in parkinsonism.     

Prolonged vastus lateralis denervation after botulinum toxin type A injection

Intramuscular injection of botulinum toxin (BoNT) produces reversible blockade of neuromuscular transmission. In animal experimental models, recovery begins within four weeks and is usually complete by twelve weeks. We present evidence of prolonged denervation following BoNT injection of the vastus lateralis (VL) muscle to correct quadriceps muscle imbalance in patients with chronic anterior knee pain. Needle electromyography data were obtained from 10 subjects who had received a single BoNT treatment 5 to 19 months earlier as part of a clinical trial. Insertional and spontaneous activity, recruitment, and motor unit action potentials were examined. Clear differences between the injected and non‐injected VL muscles, which correlated with the time since injection, were identified in all subjects. All 10 subjects studied with needle EMG showed evidence of persisting denervation in the BoNT‐A injected VL muscle beyond the period of neuromotor recovery expected from animal experimental studies. © 2010 Movement Disorder Society     

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。     

The course of cervical dystonia and patient satisfaction with long-term botulinum toxin A treatment

In 78 patients with idiopathic cervical dystonia (CD), we studied the course of the disease and the patients' satisfaction with long-term botulinum toxin A (BTX) treatment (median 5.5 years, range 1.5–10). On a seven-point scale ranging from excellent to worsening, the effect of treatment was scored as excellent or good by 52% of patients and moderate by 33%. The independent scores of the treating neurologists were excellent or good in 65% and moderate in 27%, respectively, and correlated well with the patients' scores. The 'Global Burden of Disease', as expressed on Visual Analog Scales (VAS, 0–10) before and at evaluation of treatment, was reduced by a median of 4 in individual patients. By combining these outcome measures, 67% of the patients were characterized as having a good effect, and 33% an unsatisfactory effect. This outcome (good or unsatisfactory effect) was independent of the severity of head deviation or complexity pattern of CD prior to treatment, the delay from onset to start of BTX treatment, or the number of treatments. The complexity pattern remained stable during treatment in 64% of the patients, became less complex in 19%, whereas 17% of the patients developed more complex patterns.     

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.     

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.     

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.     

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.     

Ninhydrin sweat test: a simple method for detecting antibodies neutralizing botulinum toxin type A.

Approximately 5% of patients with cervical dystonia receiving repeated botulinum neurotoxin A (BoNT/A) injections develop secondary loss of treatment benefit. Currently available tests to directly detect neutralizing BoNT/A antibodies (BoNT/A-AB) are either expensive or time consuming. To establish a simple, clinically useful test for antibody detection, we adapted the ninhydrin sweat test (NST). Eighteen dystonic patients with secondary nonresponse and clinically suspected BoNT/A-AB formation were tested for BoNT/A-AB in the mouse diaphragm test (MDT). In addition, the size of the anhidrotic area was determined by the NST 21 days after an intradermal dose of 10 U Dysport into the hypothenar region of the left palm. In nine patients, positive BoNT-AB titers were found in the MDT. There was a significant correlation between the BoNT/A-AB titers and the anhidrotic area (Spearman's rho = -0.9, P < 0.0001). Both tests provided comparably good results with respect to qualitative antibody detection. In the clinical situation of secondary nonresponse to BoNT/A therapy, the economical NST may be a helpful tool to detect neutralizing BoNT/A-AB.     

Mouse diaphragm assay for detection of antibodies against botulinum toxin type B.

With the advent of a commercial preparation of botulinum toxin type B (BT-B) for treatment of cervical dystonia detection of antibodies against BT-B (BT-B-AB) becomes necessary. For this purpose, we carried out a mouse diaphragm assay (MDA) by continuous measurement of the twitch force of a mouse hemidiaphragm preparation elicited by electric stimulation of its phrenic nerve. After exposing the preparation to BT-B 3 ng/ml the time to half-maximal twitch force reduction (paralysis time [PT]) was 69 +/- 4 min (n = 25). Addition of sera from patients with antibodies against BT-A produced a PT of 68 +/- 5 min (n = 24), whereas addition of sera from controls with antibodies against tetanus toxoid produced a PT of 67 +/- 6 min (n = 30). When defined amounts of BT-B-AB were added to the MDA, PT was prolonged. This prolongation was correlated closely to the amount of BT-B-AB added, thus producing a calibration curve. The threshold for BT-B-AB detection was 0.4 mU/ml. When sera from 7 patients (4 women, 3 men; age 50.6 +/- 14.2 years) with cervical dystonia (Toronto Western Spasmodic Torticollis Rating Scale score, 18.9 +/- 2.9) and complete secondary failure of BT-B therapy (NeuroBloc; Elan Pharmaceuticals, Shannon, Ireland; 12,229 +/- 2,601 MU/injection series, 1.86 +/- 0.69 injection series before complete secondary therapy failure; 100.4 +/- 15.8 days between injection series with normal therapeutic effect) were tested, BT-B-AB titers of more than 10 mU/ml were found in all of them. The MDA can be used to measure neutralizing BT-B-AB titers quantitatively and with adequate sensitivity and specificity. Further studies are necessary to understand the role of intermediate BT-B-AB titers in partial BT-B therapy failure.     

Objective measurement of clinical findings in the use of botulinum toxin type A for the management of children with cerebral palsy

Clinicians use a range of clinical and objective measures to quantify the positive and negative features (impairments) of the upper motor neurone syndrome. These measures play an important role in the assessment and selection of suitable candidates for intervention and monitoring of outcome. Intervention strategies often focus on the positive features; however, outcome may be more contingent upon the severity of the negative features. The clinical protocol for patient selection and treatment used by our multidisciplinary team is presented, together with details of the assessment procedure. Measurement tools in routine use are described, including: the Modified Ashworth Scale, the Modified Tardieu Scale ('R1'), muscle length by joint range of motion 'R2', three-dimensional gait analysis, assessments of strength by the Medical Research Council Scale, Selective Motor Control, the Gross Motor Function Measure and the Observational Gait Scale. Three case studies of children with cerebral palsy who underwent botulinum toxin type A treatment as part of their management of gait disorder are presented, a 2-year-old girl with mild hemiplegia ('true equinus'), a 3-year-old boy with moderate hemiplegia ('apparent equinus') and a 6-year-old girl with diplegia, where a targeted approach was used to treat a distal problem and resulted in correction Of a proximal problem.     

An update on the treatment of detrusor-sphincter dyssynergia with botulinum toxin type A

The aim of this study was to evaluate the relaxant effect of two preparations (BOTOX® versus Dysport®) of botulinum toxin type A (BTX-A) on the external urethral sphincter in patients with neurogenic voiding disorders. Ten male spinal cord injury patients with detrusor- external urethral sphincter dyssynergia (DSD) were clinically assessed before, and 4–6 weeks after, transurethral or transperineal BTX-A injections (BOTOX® 100 U or Dysport® 250 U) into the external urethral sphincter. Patients with persistent difficulties in voiding or high post-void residual volumes were re-injected with the same product up to three times. All patients were urodynamically examined within 120 days of injection. In total, 30 BTX-A injection cycles (one to three injections) were administered. Significant ( P < 0.05) reductions in the DSD duration post-injection, the time interval between the start of bladder contractions and voiding, and DSD seventy post-treatment were observed. All patients who presented with a residual volume pre-treatment showed a marked decrease post-treatment. These effects lasted 6 months. Improvements in urodynamic parameters were significantly better following BOTOX® than DysporP treatment ( P < 0.05), although the Dysport® dose used is now considered less potent than that of BOTOX®. Thus, injections of BTX-A into the external urethral sphincter are a valuable treatment option for DSD in spinal cord injury patients. Treatment success appears to depend on the seventy of DSD before treatment.     

A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke

OBJECTIVE: To study the efficacy and safety of botulinum toxin type A (BtxA) in the treatment of upper limb muscle spasticity, caused by stroke. METHODS: This was a randomized, controlled trial. Patients received either placebo injections or a total of 1000 IU of BtxA (Dysport) into five muscles of the affected arm. Muscle tone was assessed using the Modified Ashworth Scale (MAS). Other outcome measures were the change in the joint range of motion (ROM), the Barthel index, pain score, goal attainment and the subjective evaluation of benefit by patients and investigators. The patients were assessed blind to randomization at baseline and 4, 8, 12 and 16 weeks after treatment. RESULTS: Fifty nine patients were recruited and received treatment. One patient was lost to follow-up before the last scheduled visit of the study. The group of patients who received BtxA had a significant reduction in the summed MAS score at week 4 compared with the placebo group (P=0.004). The magnitude of benefit over the 16 week follow-up period was significantly reduced for the BtxA group in the wrist (P=0.004) and the finger joints (P=0.001) when compared with the placebo. There was no statistically significant difference between the groups in the joint ROM, muscle pain, goal-attainment or the Barthel index scores at week 4 of the study. At week 16, the BtxA group showed significantly greater improvement in the passive ROM at the elbow (P=0.036). The patients' global assessment of benefit at the end of the study showed that 16 (50%) patients in the placebo group had 'much improved' or had 'some improvement' compared with 24 (92.3%) patients in the BtxA group (P=0.007). The investigators' rating for the same item was 16 (50%) and 23 (88.4%) patients, respectively (P=0.002). Sixteen and twenty patients in the BtxA and placebo groups, respectively, had an adverse event. The most frequently reported adverse events were accidental injury, respiratory and urinary tract infections and muscle pain. CONCLUSION: The findings of the present study suggest that treatment with BtxA in a dose of 1000 units reduces muscle tone in patients with post-stroke upper limb spasticity. This effect is sustained for at least 16 weeks. BtxA is safe in the dose used in this study. IMPORTANT NOTE: The authors wish to emphasize that the botulinum toxin preparation used in this study was Dysport (Ipsen Ltd) which has a different therapeutic equivalence from other commercially available product, Botox (Allergan Inc.).     

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.