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.     

Isolated high-frequency jaw tremor relieved by botulinum toxin injections.

Jaw tremor can be seen as a component of various neurological disorders such as essential tremor, Parkinson's disease, dystonia, branchial myoclonus, hereditary geniospasm, task-specific tremor, and Whipple's disease, as well as in normal situations such as shivering, and subclinical physiological jaw tremor. In most of these conditions, the jaw tremor is usually associated with tremor or other abnormal involuntary movements affecting additional body parts, and its frequency is lower than 12 Hz. Schrag and colleagues reported a patient with a high-frequency idiopathic jaw tremor, and they speculated it could be related to orthostatic tremor affecting the masseter muscles. We encountered a similar patient with intermittent rapid focal jaw tremor that was successfully treated with botulinum toxin injections to the masseters.     

Clinical value of botulinum toxin in neurological indications

Botulinum toxin type-A (BoNT-A) prevents the release of acetylcholine at cholinergic junctions, thereby causing temporary muscle weakness lasting 3–4 months. It is now widely used to treat a broad range of clinical disorders characterized by muscle hyperactivity. BoNT-A has proved effective in the management of several neurological conditions and, in particular, in the management of movement disorders (e.g. blepharospasm, cervical dystonia, laryngeal dystonia, limb dystonia, hemifacial spasm, focal tics, tremor and other hyperkinetic disorders). As a treatment of spasticity, BoNT-A can improve mobility and dexterity as well as preventing the development of distressing and costly secondary complications. In cerebral palsy, BoNT-A is of value, being able to delay or even avoid surgery until motion patterns have become established.     

Botulinum toxin therapy of migraine and tension‐type headache: comparing different botulinum toxin preparations

Most of the initial reports on botulinum toxin in tension‐type headache (TTH) and in migraine were positive. Unfortunately, these results were not reproduced in well‐designed, randomized controlled trials. So far, doses from 20 U (Botox®) to 500 U (Dysport®) have been studied in patients with chronic TTH, and doses from 16 to 200 U (Botox®) in patients with migraine. Overall, there is no evidence for a beneficial effect of botulinum toxin, although trends favoring botulinum toxin were reported. Experience with botulinum toxin type B (Myobloc®/NeuroBloc®) is limited and similar to the experience with the type A. Thus, a widespread use of botulinum toxin therapy in headache can currently not be recommended.     

Effects of botulinum toxin A therapy and multidisciplinary rehabilitation on upper and lower limb spasticity in post-stroke patients

Objectives. The purpose of this study was to examine the effects of combined botulinum toxin type A (BoNT-A) and inpatient multidisciplinary (MD) rehabilitation therapy on the improvement of upper and lower limb function in post-stroke patients. Methods. In this retrospective study, a 12-day inpatient treatment protocol was implemented on 51 post-stroke patients with spasticity. Assessments were performed on the day of admission, at discharge, and at 3 months following discharge. Results. At the time of discharge, all of the evaluated items showed a statistically significant improvement. Only the Functional Reach Test (FRT) showed a statistically significant improvement at 3 months. In subgroup analyses, the slowest walking speed group showed a significantly greater change ratio of the 10 Meter Walk Test relative to the other groups, from the time of admission to discharge. This group showed a greater FRT change ratio than the other groups from the time of admission to the 3-month follow-up. Conclusion. Inpatient combined therapy of simultaneous injections of BoNT-A to the upper and lower limbs and MD may improve motor function.     

Treatment of idiopathic hemifacial spasm with botulinum toxin

Twelve patients with idiopathic hemifacial spasm received treatment with botulinum toxin A over a period of 18 months. Of 76 treatments given, most (94.7%) led to successful relief of eyelid spasms and all treatments were successful for perioral and lower facial muscle spasms. An average dose of 9.3 units of toxin per session was given to produce a mean interval of relief of 10.8 weeks. Blepharoptosis was the only ocular side effect; it was mild, reversible and occurred in 2 patients. However, lower facial palsy was frequent (9 patients); it was mild to moderate in severity but only partially reversible in 8 patients. Dosage for lower facial muscles should therefore be reduced.     

Severe amphethamine-induced bruxism: treatment with botulinum toxin

While chewing and grinding movements have been observed in amphetamine addicts, recognition and management of this problem have rarely been highlighted. Botulinum toxin (BTX) has previously been demonstrated to be effective for bruxism associated with movement disorders, such as cranial-cervical dystonia. However, there is little information on its use in tardive bruxism. Here we report an amphetamine addict who presented with medically intractable bruxism, and discuss its pathophysiology and successful treatment with BTX.     

Electromyographic evaluation of cervical dystonia for planning of botulinum toxin therapy

The success of botulinum toxin (BT) injections for treatment of cervical dystonia depends on precise identification of dystonic muscles and on quantification of their dystonic involvement. Conventionally, this is attempted by clinical examination analysing the dystonic head position. In this presentation, a more systematic approach is sought by using an electromyography (EMG)-based evaluation procedure. In 10 consecutive patients with cervical dystonia not previously exposed to BT clinical examination, analysing the dystonic head position was performed to classify patients into four groups with similar dystonic head positions. Additionally, a 2-channel concentric needle EMG was used to measure the amplitudes of dystonic and maximal voluntary activities in sternocleidomastoid (SCM), splenius capitis (SC) and trapezius/semispinalis capitis (T/SS) muscles bilaterally. The ratio between both amplitudes, the dystonia ratio, was used to quantify dystonic muscle involvement. In all patients dystonia ratios could be calculated. In patients with similar head positions, EMG evaluation revealed different qualitative and quantitative dystonic involvement patterns. In six patients, there were discrepancies in identification of dystonic muscles between clinical examination and EMG evaluation. EMG evaluation excluded dystonic involvement in five patients. All excluded muscles were SCM. In one of these patients, additional T/SS involvement was detected by EMG evaluation. In one patient, SC involvement was revealed by EMG evaluation. All dystonic muscle involvement detected by EMG evaluation represented genuine dystonic muscle coactivation rather than compensatory muscle activity. The EMG evaluation presented allows quantitative and qualitative identification of dystonic muscle involvement which cannot be achieved by clinical examination. Both pieces of information may be helpful for optimization of BT therapy.     

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.     

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。     

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.     

Botulinum toxin type B de novo therapy of cervical dystonia

Botulinum toxin induced therapy failure type B antibody (BT–B, BT–B–AB) has so far only been reported after previous formation of antibodies against botulinum toxin type A (BT–A, BTA– AB).We wanted to explore the risk of BT-B-AB-induced therapy failure in patients who were exposed to botulinum toxin for the first time. For this purpose we followed nine patients with cervical dystonia receiving BT-B (NeuroBloc^®/Myo- Bloc™, Elan Pharmaceuticals) in a dose of 11435 ± 2977MU during 4.9 ± 3.0 injection series. All patients showed a satisfactory initial therapeutic response as documented by a Toronto Western Spasmodic Torticollis Rating Scale score reduction from 17.7 ± 9.4 to 5.3 ± 4.8 and an overall subjective improvement of 56.1 ± 28.3%. Seven patients experienced systemic anticholinergic side effects. Five patients had stable therapeutic responses over subsequent injection series. Four patients experienced complete therapy failure with BT–B–AB titres in excess of 10mU/ml on the mouse diaphragm assay. Doubling the last effective BT–B dose produced neither therapeutic effects nor side effects. Subsequent applications of botulinum toxin type A produced a continued therapeutic response in one patient and complete therapy failure in the other.Despite the small sample size a frequency of 44 % indicates a high risk for BT–B–AB-induced complete therapy failure. The high amount of neurotoxin administered when NeuroBloc^®/MyoBloc™ is used might be a contributory factor. Further prospective comparative studies are necessary to monitor the frequency and time course of BT–B–AB formation.     

Moving ear syndrome: The role of botulinum toxin

We report a 30‐year‐old man with moving ear syndrome caused by focal myoclonic jerks of the right temporal muscle. This focal myoclonus would disappear while the patient was sleeping, swallowing, or speaking. He was treated with botulinum toxin type A with a favorable outcome. Previous reports of this condition and possible therapeutic approaches are discussed. © 2007 Movement Disorder Society     

Botulinum toxin in blepharospasm and oromandibular dystonia: comparing different botulinum toxin preparations

Amongst all regions of the body, the craniocervical region is the one most frequently affected by dystonia. Whilst blepharospasm – involuntary bilateral eye closure – is produced by spasmodic contractions of the orbicularis oculi muscles, oromandibular dystonia may cause jaw closure with trismus and bruxism, or involuntary jaw opening or deviation, interfering with speaking and chewing. Both forms of dystonia can be effectively treated with botulinum toxin injection. This article summarizes injection techniques in both forms of dystonia and compares doses, potency and efficacy of different commercially available toxins, including Botox®, Dysport®, Xeomin® and Myobloc®/NeuroBloc®.     

Unusual position-sensitive jaw tremor responsive to botulinum toxin.

We report on a woman with a focal position-sensitive jaw tremor present with the jaw held slightly open or while drinking from a cup. Electromyography demonstrated a rhythmic 5 Hz alternating tremor involving masseter and digastric muscles with normal reciprocal inhibition. The tremor was markedly reduced with botulinum toxin injections.