Botulinum toxin type A in the treatment of focal, axillary and palmar hyperhidrosis and other hyperhidrotic conditions

Focal essential hyperhidrosis is a common and often disabling disorder mainly involving the palms, axillae, face, and soles of the feet. Focal hyperhidrosis may also arise from several neurological or internal diseases. Current therapeutic options include topical aluminium chloride salts, systemic anticholinergic drugs, tap-water iontophoresis, and a number of surgical approaches. However, none of these are entirely satisfactory. In recent studies, injection of botulinum toxin type A (BTX-A) into the hyperhidrotic area has proved very effective in reducing or abolishing focal sweating of different aetiologies without major side effects. BTX-A therefore has the potential to replace more invasive therapies.     

Botulinum A toxin improves life quality in severe primary focal hyperhidrosis

Focal hyperhidrosis is a condition that may disturb emotional, social and professional life. Treatment options for severe cases are surgical sympathectomy and local chemical sweat gland denervation by intradermal injections of botulinum toxin A (Btx A). The Dermatology Life Quality Index (DLQI) is a simple validated questionnaire designed to measure and compare disability in different skin diseases. The aim of this study was to assess quality of life with the DLQI before and after treatment with botulinum toxin injections in a group of patients with severe hyperhidrosis. DLQI was administered to 58 randomly chosen patients before and after treatment. All patients answered the DLQI questionnaire prior to treatment and 53/58 at mean 5.2 months after treatment. The mean DLQI score in the 58 patients before treatment was 10.3 (2-23). In the group of 16/53 patients who had a relapse of sweating when answering the DLQI a second time, no significant improvement was seen [score 10.6 before and 8.8 after treatment (P = 0.21)]. In patients without relapse, a 76% improvement was obtained (DLQI was reduced from 9.9 to 2.4; P < 0.0001). The study showed that focal hyperhidrosis may considerably reduce life quality and the disability experienced by the patients can be largely reversed by botulinum toxin injections.     

Botulinum toxin type A for drooling in Parkinson's disease: a double-blind, randomized, placebo-controlled study.

To investigate the safety and efficacy of botulinum toxin type A (BoNTX) treatment to reduce sialorrhea in Parkinson's disease (PD), a double-blind, randomized, placebo-controlled study enrolled 32 PD patients complaining of excessive drooling. Patients received either 50 U Botox in each parotid gland or placebo without using ultrasound guidance. Subjects treated with BoNTX experienced a reduction in both drooling frequency and familial and social disability (TimexGroup effect: P<0.01), as well as in saliva production (Time x Group effect: P<0.0001). No adverse events were recorded. BoNTX injections are safe and effective treatment for the management of PD-related drooling.     

Botulinum toxin type B for treatment of axillar hyperhidrosis

Recently, botulinum toxin type B (BT-B) became commercially available for treatment of cervical dystonia. It is the aim of this study to explore its use for treatment of bilateral axillar hyperhydrosis (HH). For this we directly compared the antihyperhydrotic effect of BT-B (NeuroBloc)/MyoBloc) with that of botulinum toxin type A (BT-A) (Botox). 9 patients (HD group) received BT-A 100MU unilaterally and BT-B 4000MU contralaterally. 10 patients (LD group) received BT-A 100MU and BT-B 2000MU. All patients were blinded as to which preparation was used in which side. All patients except one reported excellent HH improvement in both axillae. None of the patients had residual HH on clinical examination. The duration of HH improvement until first recurrence in the HD group was 16.0 +/-4.3 weeks in the BT-A treated axillar and 16.4 +/-4.5 weeks in the BT-B treated axillae (Wilcoxon rank-sum test, p = 0.336). In the LD group it was 16.4 +/-5.3 weeks in the BT-B treated axillae and 17.1 +/-5.7 weeks in the BT-A treated axillae (Wilcoxon rank-sum test, p = 0.059). There was also no difference in the duration of HH improvement between the axillae treated with BT-B 4000MU and BT-B 2000MU (Wilcoxon rank-sum test, p = 0.712). 5 out of 9 patients in the HD group (chi-square test, p = 0.025) and 7 out of 10 patients in the LD group (chi-square test, p = 0.008) reported more application discomfort in the BT-B treated axillae. In 6 out of 9 patients in the HD group (chi-square test, p = 0.014) and in 6 out of 10 patients in the LD group (chi-square test, p = 0.014) the onset of HH improvement appeared earlier in the BT-B treated axillae. One patient in the HD group reported dryness of the mouth and eyes and accomodation difficulties.BT-B is a safe and efficient treatment for axillar HH. Doses of BT-B 2000MU per axilla seem sufficient indicating a conversion factor between BT-A and BT-B in the order of 1:20. With a conversion factor for cervical dystonia in the order of 1:40 the autonomic nervous system seems to be relatively more sensitive to BT-B than to BT-A compared with the motor system.     

Botulinum toxin A and chronic low back pain: a randomized, double-blind study

OBJECTIVES: To investigate the efficacy of botulinum toxin A in chronic low back pain and associated disabilities. METHODS: Thirty-one consecutive patients with chronic low back pain who met the inclusion criteria were studied: 15 received 200 units of botulinum toxin type A, 40 units/site at five lumbar paravertebral levels on the side of maximum discomfort, and 16 received normal saline. Each patient's baseline level of pain and degree of disability was documented using the visual analogue scale (VAS) and the Oswestry Low Back Pain Questionnaire (OLBPQ). The authors reevaluated the patients at 3 and 8 weeks (visual analogue scale) and at 8 weeks (OLBPQ). RESULTS: At 3 weeks, 11 of 15 patients who received botulinum toxin (73.3%) had >50% pain relief vs four of 16 (25%) in the saline group (p = 0.012). At 8 weeks, nine of 15 (60%) in the botulinum toxin group and two of 16 (12.5%) in the saline group had relief (p = 0.009). Repeat OLBPQ at 8 weeks showed improvement in 10 of 15 (66.7%) in the botulinum toxin group vs three of 16 (18.8%) in the saline group (p = 0.011). No patient experienced side effects. CONCLUSION: Paravertebral administration of botulinum toxin A in patients with chronic low back pain relieved pain and improved function at 3 and 8 weeks after treatment.     

Botulinum toxin type A therapy during pregnancy.

Injection with botulinum toxin type A (Botox) is a safe and efficacious treatment for idiopathic cervical dystonia. We present the first case report of clinical Botox treatment during pregnancy. This patient underwent four apparently uncomplicated full-term pregnancies while receiving regular Botox treatments.     

Side-effects of intradermal injections of botulinum A toxin in the treatment of palmar hyperhidrosis: a neurophysiological study

Focal palmar hyperhidrosis can be effectively abolished by intradermal injections with botulinum toxin. Muscle weakness of finger grip has been reported as a reversible side-effect of this new treatment. The objective of this work was to measure muscular side-effects after treatment of palmar hyperhidrosis with botulinum toxin. As botulinum toxin has been used in the treatment of pain, we studied whether the toxin might influence afferent thin-fibre function by measuring temperature perception thresholds. Thirty-seven patients treated with botulinum toxin (Botox, Allergan Pharmaceuticals, Irvine, CA, USA) showed a decrease in compound muscle action potential (CMAP) for both abductor pollicis brevis (APB) and abductor digiti minimi (ADM) compared with pre-injection values on average by 64 and 36%, respectively, at 3 weeks which returned nearly to normal at 37 weeks. Muscle power for both finger abduction and finger opposition decreased to a lesser extent. Repetitive nerve stimulation and single fibre electromyography (EMG) showed a disturbed neuromuscular transmission. Thus, despite careful technique with small doses of botulinum toxin injected intradermally, the toxin diffuses to underlying muscles. With regard to the present results, one should be careful in using higher doses of Botox than 0.8 mU/cm(2) in the palmar skin above intrinsic muscles. No influence on thin-fibre function was seen.     

Botulinum toxin type A: new therapeutic directions

Intramuscular injections of botulinum toxin type A (BTX-A) have been used successfully to treat disorders such as cerebral palsy and cervical dystonia for many years. New and exciting directions for the toxin are currently under clinical investigation for a number of unlicensed indications including tension-type headache, myofascial pain and hyperhidrosis. Although research on BTX-A is prolific, there is still much to be learnt regarding the toxin's mode of action, clinical application and perhaps more importantly, its place in the overall treatment strategy implemented by physicians to ensure treatment is a success for both the patient and the physician. This review will focus on these issues, by outlining some of the future directions for BTX-A research.     

Botulinum toxin type A in chronic migraine

The use of botulinum toxin type A continues to be investigated by the US FDA for potential use in the treatment of headache. As part of this process there has been extensive research conducted by individual study sites as well as multicenter trials. To date, the majority of the focus has been on migraine headache as well as on tension-type headache. The results of these studies have been mixed. A variety of issues may contribute to the mixed results, including difference in the dose of toxin used, the number of injection sites utilized, the treatment paradigm itself, confounding medications, high and prolonged placebo response, as well as patient selection issues. Currently, the focus on botulinum toxin type A is on those patients who have chronic daily headache with a migraine component to their clinical picture. The results of two large trials in this population produced positive findings, especially when consideration is given to the a priori additional analyses of this complex patient population. The results of these studies have allowed a more focused program to be undertaken in the Phase III evaluation. At the same time, additional work has been performed to understand the mechanism by which botulinum toxin type A may work to alleviate migraine. This work may contribute substantially to improving outcomes with botulinum toxin type A. Characterization of the mechanism of action in pain may be crucial to outcomes because many issues are related to central sensitization.     

Botulinum toxin type A on oral health in treating sialorrhea in children with cerebral palsy: a randomized, double-blind, placebo-controlled study

Intrasalivary gland injection of botulinum toxin type A is known to treat sialorrhea effectively in children with cerebral palsy. However, oral health may be compromised with escalating dose. In this randomized, double-blind, and placebo-controlled pilot trial, the authors aim to determine the therapeutic effect of low-dose, ultrasonography-controlled botulinum toxin type A injection to bilateral parotid and submandibular glands on oral health in the management of sialorrhea. Twenty children diagnosed with cerebral palsy were randomly assigned to 2 groups. The treatment group received botulinum toxin type A injections, whereas the control received normal saline in the same locations. The authors evaluated subjective drooling scales, salivary flow rate, and oral health (salivary compositions and cariogenic bacterial counts). A significant decrease was found in salivary flow rate at the 1- and 3-month follow-up in the botulinum toxin-treated group. The authors suggest that current protocol can effectively manage sialorrhea while maintaining oral health.     

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 A and the cutaneous nociception in humans: a prospective,double-blind,placebo-controlled,randomized study

Aside from temporary chemodenervation of skeletal muscle and potential anti-inflammatory effects, a genuine peripheral antinociceptive effect of Botulinum Neurotoxin Type A (BoNT/A) has been suspected. To evaluate the effect of BoNT/A on cutaneous nociception in humans, 50 healthy volunteers received subcutaneous injections of 100 mouse units (MU) BoNT/A (Dysport) and placebo. Both forearms of each subject were treated in a double-blind fashion, one with verum, one with placebo. Heat and cold pain thresholds within the treated skin areas were measured with quantitative sensory testing (QST) and pain thresholds were evaluated with local electrical stimulation (ES). The tests were done before treatment, and after 4 and 8 weeks. No major side effects were noted. All participants completed the study. Heat and cold pain thresholds increased from baseline to week 4 by 1.4 degrees C for verum and by 1.1 degrees C for placebo. From baseline to week 8, the thresholds increased by 2.7 degrees C for verum and by 1.2 degrees C for placebo. Electrically induced pain thresholds shifted from baseline to week 4 by -0.07 mA for verum and by 0.01 mA for placebo. From baseline to week 8, the thresholds increased by 0.10 mA for verum and by 0.11 mA for placebo. None of these differences was statistically significant. The study shows that there is no direct peripheral antinociceptive effect of BoNT/A in humans. The efficacy of BoNT/A in various pain syndromes must be explained by other pathways such as chemodenervation or anti-inflammatory effects.     

Botulinum toxin type A treatment in neurogenetic syndromes

Purpose: To review the use of therapeutic botulinum toxin type A (BoNT-A) treatments in uncommon neurogenetic syndromes.

Method: A retrospective questionnaire and interview study of a selected case series to assess the efficacy and safety following initial BoNT-A treatment (50–400 units per subject) was conducted to determine the response of families to treatment. Twelve male and six female subjects with ages from 2–19 years were included. The reasons for treatments were based on both patient-related and caregiver-related objectives. Satisfaction with achievement of stated goals was assessed by follow-up interviews.

Results: Beneficial effects were reported in 56%, some effects in 22% and no to minimal effects in 22%. The duration of effect ranged from 10 days to 12 months with an average of 3.16 months. Ten families would repeat the injections as needed, four would not and four were not sure. Unanticipated effects of BoNT-A treatments were reported by some families. Adverse effects did not occur with the doses that were used.

Conclusions: The results suggest that obtaining family input may be useful when treating spasticity in unusual circumstances. The use of BTX-A in uncommon neurogenetic syndromes was supported by the majority of families interviewed.     

Botulinum toxin type A in experimental neuropathic pain

Summary. A peripheral application of botulinum toxin type A (7U/kg) has significantly reduced thermal and mechanical hypersensitivity in rats with the partial sciatic nerve transection as a classical model of surgical neuropathy.     

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.     

Botulinum toxin A treatment for primary hemifacial spasm: a 10-year multicenter study

BACKGROUND: Botulinum toxin A (BTX) is the currently preferred symptomatic treatment for primary hemifacial spasm (HFS), but its long-term efficacy and safety are not known. OBJECTIVE: To assess the long-term effectiveness and safety of BTX in the treatment of primary HFS. DESIGN: Retrospective review of medical records of the 1st and 10th years of treatment. SETTING: Outpatient clinics of 4 Italian university centers in the Italian Movement Disorders Study Group. PARTICIPANTS: A series of 65 patients with primary HFS who had received BTX injections regularly for at least 10 years. MAIN OUTCOME MEASURES: Mean duration of improvement and quality of the effect induced by the preceding treatment (measured using a patient self-evaluation scale) and occurrence and duration of adverse effects in the 1st and 10th years of treatment. RESULTS: Using a mean BTX dose per treatment session similar to that used by others, we obtained a 95% response rate and an overall mean duration of improvement of 12.6 weeks during year 1. The effectiveness of BTX in relieving the symptoms of primary HFS, as measured by the response rate and average duration of improvement, remained unchanged in the 1st and 10th years. Patients needed statistically similar BTX doses in the 1st and 10th years. The rate of local adverse effects (including upper lid ptosis, facial weakness, and diplopia) diminished significantly in the 10th year of treatment. CONCLUSION: Treatment with BTX effectively induces sustained relief from symptoms of HFS in the long term, with only minimal and transient adverse reactions.     

Botulinum toxin type A for treating voice tremor

BACKGROUND: Voice tremor, like spasmodic dysphonia and other tremor disorders, may respond to botulinum toxin type A injections. OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injections as treatment for voice tremor. DESIGN: A randomized study of 3 doses of botulinum toxin type A with 6 weeks of follow-up. SETTING: A single-site tertiary care center.Participants and METHODS: Thirteen subjects (11 women, 2 men; mean age, 73 years) with voice tremor and no spasmodic dysphonia or head, mouth, jaw, or facial tremor were entered into this study. Patients received 1.25 U (n = 5), 2.5 U (n = 5), or 3.75 U (n = 3) of botulinum toxin type A in each vocal cord. All patients were evaluated at baseline and postinjection at weeks 2, 4, and 6. MAIN OUTCOME MEASURES: The primary outcome measure was the patient tremor rating scale, with secondary measures including patient-rated functional disability, response rating scale, independent randomized tremor ratings, and acoustical measures. RESULTS: All patients at all dose levels noted an effect from the injection. The mean time to onset of effect was 2.3 days (range, 1-7 days). For all patients combined, mean tremor severity scale scores (rated by patients on a 5-point scale) improved 1.4 points at week 2, 1.6 points at week 4, and 1.7 points at week 6. Measures of functional disability, measures of the effect of injection, independent ratings of videotaped speech, and acoustic measures of tremor also showed improvement. The main adverse effects at all doses were breathiness and dysphagia. CONCLUSION: Voice tremor improves following injections of botulinum toxin type A.     

Botulinum A toxin for cranial-cervical dystonia: a double-blind, placebo-controlled study

We studied the effects of botulinum A toxin in 12 patients with blepharospasm and 10 patients with oromandibular-cervical dystonia received in a double-blind manner. All blepharospasm patients improved, 71.6% on a clinical rating score, 60.7% by self-assessment, and 38.9% by video-rating; there was no improvement with placebo. The beneficial effects lasted a mean of 12.5 weeks (range, 5 to 28). Only 37.5% of the patients with oromandibular-cervical dystonia improved. Patients with pharyngeal dystonia and spasmodic dysphonia also improved.