Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis

Sialorrhoea is a socially disabling problem in bulbar amyotrophic lateral sclerosis (ALS). Botulinum toxin A (BoNT/A) was injected into the salivary glands in five patients with bulbar ALS and sialorrhoea. The effect of BoNT/A was measured by the number of paper handkerchiefs used each day and by salivary gland scintigraphy. BoNT/A ameliorated sialorrhoea and quality of life without major adverse effects. BoNT/A may be a relatively safe and effective treatment for sialorrhoea in selected patients.     

Secondary non-response due to antibody formation in a child after three injections of botulinum toxin B into the salivary glands

Botulinum toxin (BTX) offers a new treatment option to reduce drooling in adults and children. Antibody formation against BTX is known to be one reason for clinical secondary non-response to this treatment. This is a case report on the development of secondary non-response to BTX type B (BTX-B) in a 15-year-old male, with bilateral dyskinetic cerebral palsy (Gross Motor Function Classification System Level IV) with additional learning disability* and microcephaly, treated for the indication of drooling. After three successful treatment sessions, the fourth and fifth injections showed no clinical response. This was associated with the presence of antibodies against BTX-B as determined using the mouse diaphragm assay. Thus, formation of neutralizing antibodies against BTX-B appears to be an important issue, not only in patients treated for cervical dystonia but also in children treated for drooling. Subsequent injections with an adequate dose of BTX type A (BTX-A) did not show any clinical response either, although no antibodies to BTX-A were detected. Besides the unanswered questions of dosing and distribution, a second possible explanation could be that BTX-B gave rise to non-neutralizing antibodies that cross-react with BTX-A. The resulting immune complexes could be taken up by phagocytes and, thereby, impede clinical response.     

Randomized trial of botulinum toxin injections into the salivary glands to reduce drooling in children with neurological disorders

The primary aim of this randomized, controlled trial was to assess the effectiveness of botulinum toxin A (BoNT-A) injections into the submandibular and parotid glands on drooling in children with cerebral palsy (CP) and other neurological disorders. Secondary aims were to ascertain the duration of any such effect and the timing of maximal response. Of the 48 participants (27 males, 21 females; mean age 11y 4mo [SD 3y 3mo], range 6-18y), 31 had a diagnosis of CP and 15 had a primary intellectual disability; 27 children were non-ambulant. Twenty-four children randomized to the treatment group received 25 units of BoNT-A into each parotid and submandibular gland. Those randomized to the control group received no treatment. The degree and impact of drooling was assessed by carers using the Drooling Impact Scale questionnaire at baseline and at monthly intervals up to 6 months postinjection/baseline, and again at 1 year. Maximal response was at 1 month at which time there was a highly significant difference in the mean scores between the groups. This difference remained statistically significant at 6 months. Four children failed to respond to the injections, four had mediocre results, and 16 had good results. While the use of BoNT-A can help to manage drooling in many children with neurological disorders, further research is needed to fully understand the range of responses.     

Treatment of hip adductor spasticity with botulinum toxin type B

For the treatment of focal spasticity using botulinum toxin, only studies using type A have been published.Botulinum toxin type B (Neurobloc) is registered for cervical dystonia, but there is increasing interest in ist effectiveness for treating other diseases. Four patients, each with seriously disabling hip adductor spasticity of different origins, were treated with botulinum toxin type B following the failure of other therapeutic options.Total doses of 10,000 IU to 22,000 IU were injected bilaterally into the hip adductor muscles. A reduction in muscle tone or painful spasms was observed in all patients within 2 weeks, leading to an improvement in gait and increased ease of nursing care. Therefore, botulinum toxin type B may be a more cost-effective treatment for hip adductor spasticity than botulinum toxin type A.     

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.     

Clinical use of non-a botulinum toxins: botulinum toxin type B

Botulinum neurotoxin type B (BT, BT-B) has been used as NeuroBloc/MyoBloc since 1999 for treatment of cervical dystonia, hyperhidrosis, spastic conditions, cerebral palsy, hemifacial spasm, bladder dysfunction, spasmodic dysphonia, sialorrhoea, anal fissures, piriformis syndrome, various pain conditions and cosmetic applications. Generally, its therapeutic effects are comparable to BT type A (BT-A). The adverse effect profiles of BT-B and BT-A, however, differ considerably. BT-B has been found to produce more regional as well as systemic anticholinergic adverse effects, such as dryness of mouth, accommodation difficulties, conjunctival irritation, reduced sweating, dysphagia, heartburn, constipation, bladder voiding difficulties and dryness of nasal mucosa. In BT-B the relationship between autonomic and motor effects known from BT-A is substantially shifted towards autonomic effects. BT-B, therefore, should be used carefully in patients with autonomic disorders and in patients with concomitant anticholinergic therapy. If NeuroBloc/MyoBloc is used to treat cervical dystonia patients with antibody-induced failure of BT-A therapy, 86% of those will develop complete secondary therapy failure after five applications. If NeuroBloc/MyoBloc used to treat cervical dystonia patients without prior exposure to BT, 44% of those will develop complete secondary therapy failure after nine applications. NeuroBloc/MyoBloc, therefore, is associated with substantial antigenicity problems originating from a particular low specific biological potency. Systemic anticholinergic adverse effects and high antigenicity limits the clinical use of NeuroBloc/MyoBloc considerably.     

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     

Idiosyncratic adverse reactions to intramuscular botulinum toxin type a injection

Three cases of adverse reactions to repeated intramuscular botulinum toxin A (BTA) injections are described: a persistent rash on the face at the site of injection, a localized anaphylactic reaction following BTA injection into one leg, and bilateral ptosis repeatedly following BTA injection into neck muscles. The mechanisms for these idiosyncratic adverse responses are not known.     

Ptosis as a remote effect of therapeutic botulinum toxin B injection

The authors report a patient with cervical dystonia, previously treated with botulinum toxin A (BTX-A), who developed bilateral ptosis and difficulty with accommodation only after botulinum toxin B (BTX-B). High-frequency repetitive nerve stimulation of the abductor digiti minimi demonstrated a 34% increment in compound muscle action potential. No increment in 20 people injected with BTX-A and no cases of ptosis in a chart review of 1,606 BTX-A injections for cervical dystonia were found. The authors conclude that systemic spread of BTX-B can cause symptomatic involvement of autonomic neurons.     

Thickened saliva after effective management of drooling with botulinum toxin A

Aim The aim of this study was to evaluate the rheological properties of saliva after submandibular botulinum toxin type A (BoNT‐A) injections. Method We enrolled 15 children (11 males and six females; age range 3–17y, mean age 9y 10mo) diagnosed with spastic (n=9) or dyskinetic (n=6) quadriplegic cerebral palsy (CP); Gross Motor Function Classification System level IV or V; and two children with intellectual disability (IQ <70) who experienced moderate to severe drooling. Salivary flow rate and drooling quotient were measured at baseline and at different times after BoNT‐A injections up to 24 weeks. The mucin concentration of saliva was analysed before and after BoNT‐A treatment. Results Both submandibular salivary flow rate (baseline 0.38mL/min; 24wks after injection 0.26mL/min) and drooling quotient (baseline 42.5%; 24wks 28.80%) were substantially reduced, with a concomitant increase in mucin concentration within 8 weeks after BoNT‐A injection (from 0.612 to 1.830U/mL). The parents of nine children observed thickened saliva. Swallowing and chewing were problematic in seven children. Two of these children needed treatment with mucolytics because of pooling of thickened saliva in the throat. Interpretation When making decisions about the use of BoNT‐A, the risk of problems with masticatory and swallowing functions as a result of thickening of saliva after BoNT‐A treatment should be taken into account.     

局部注射A型肉毒毒素治疗Meige综合征

目的 观察A型肉毒毒素(BTX—A)治疗Meige综合征，(眼睑痉挛-口颌肌张力障碍综合征)的疗效。方法 用A型肉毒毒素对17例Meige综合征行面部肌肉局部多点注射，分析其治疗结果。结果 17例中完全缓解者9例，明显缓解者5例，部分缓解者2例，无效1例。总有效率94％。起效时间数小时至3天，疗效持续时间3～6个月。局部副反应轻微、短暂，无全身反应及过敏反应。结论 A型肉毒毒素是治疗Meige综合征最有效的方法。     

国产A型肉毒毒素治疗脑卒中后上肢痉挛的疗效

目的探讨国产A型肉毒毒素(CBTX-A)肌肉注射治疗脑卒中后上肢痉挛的疗效和安全性。方法选取43例脑卒中患者为研究对象。根据随机数字表将患者分为两组:CBTX-A +康复治疗组(治疗组)和单纯康复治疗组(对照组)。治疗组患者除康复训练外,肱二头肌肌肉注射CBTX- A。分别于治疗前及治疗后2、4、8、12周对患者上肢功能进行评价。评价内容包括改良的Ashworth计分(MAS)、关节活动度(ROM)、上肢的Fugl-Meyer(FMA-上肢)计分和上肢的FIM运动能力(mot- FIM-上肢)。结果治疗组CBTX-A局部注射治疗后,85.7%(18/21)的患者有效。两组在MAS、ROM、FMA-上肢计分和mot-FIM-上肢方面,治疗后比治疗前均有显著改善。治疗后2、4、8周MAS计分治疗组分别为1.74±0.41,1.62±0.35,1.60±0.41,对照组分别为2.50±0.51,2.27±0.53, 2.18±0.55,各期两组间差异有统计学意义(P<0.01)。但是在治疗后12周时,两组间差异无统计学意义(P>0.05)。治疗后4-12周,ROM计分治疗组分别为57.81±57.60,66.43±64.38,68.14±65.99,对照组分别为27.91±30.13,30.73±34.03,33.73±34.50,各期治疗组比对照组均有显著性增加,差异有统计学意义(P<0.05)。治疗组治疗后FMA-上肢计分和mot-FIM-上肢计分与对照组相比均无统计学意义(P>0.05)。结论通过实验可以得出CBTX-A肌肉注射结合康复治疗可以达到提前缓解局部肌张力,扩大关节活动度,减轻疼痛,改善肢体功能的目的,这种治疗方法安全有效,具有良好的耐受性。     

Clinico-immunologic aspects of botulinum toxin type B treatment of cervical dystonia

In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.     

Treatment of sialorrhoea with ultrasound guided botulinum toxin type A injection in patients with neurological disorders

OBJECTIVES: To investigate the safety and efficacy of ultrasound guided botulinum toxin type A (BTX-A) injections into salivary glands for the treatment of sialorrhoea in patients with neurological disorders. METHODS: The parotid and submandibular glands of 10 patients were injected with BTX-A using ultrasound guidance. Before injection, the baseline rate of salivation was assessed using a visual analogue scale. Postinjection, assessments were repeated at regular intervals for up to 1 year. RESULTS: Of the 10 patients treated, nine (90%) reported a subjective reduction in salivation post-treatment and one patient (10%) found no improvement. Visual analogue scale scores showed a reduction of 55% in the mean rate of salivation for all patients and a reduction of 60.8% for the group of responders. No serious adverse events occurred and no procedure related complications were reported. CONCLUSIONS: This is the first study to report (1) the injection of BTX-A (BOTOX) into both parotid and submandibular glands, and (2) the use of ultrasound guidance during the administration of BTX-A into salivary glands. The results suggest that the technique is safe and that BTX-A injections are effective for the treatment of sialorrhoea in patients with neurological disorders.