The Place of Botulinum Toxin Type A in the Treatment of Focal Hyperhidrosis

N. Lowe; A. Campanati; I. Bodokh; S. Cliff; P. Jaen; O. Kreyden; M. Naumann; A. Offidani; J. Vadoud; H. Hamm

Disclosures

The British Journal of Dermatology. 2004;151(6) 

In This Article

Axillary Hyperhidrosis

Topical Treatments. Topical medications are the least invasive treatments, and as such should be used as first-line therapy where practical. Topical use of aluminium salts is the preferred method and this treatment is effective for many patients, particularly those with moderate hyperhidrosis, when used in the evening before going to bed. The effect of topical aluminium salts is thought to be caused by mechanical obstruction of the eccrine sweat gland, although atrophy of the secretory cells is also thought to contribute to the effect following long-term use.[3,7] However, this treatment only lasts approximately 48 h and it can cause skin irritation in up to 50% of patients as contact with water results in hydrochloric acid formation (Evidence levels: 1b, IIb).[3,6] Minor irritation can be relieved by use of hydrocortisone cream. Alternatively, aluminium chlorhydroxide in purified water rather than aluminium chloride in alcoholic solution can be used, which avoids this problem.

Oral Treatments. Oral anticholinergic drugs can be used to treat hyperhidrosis, although response to treatment is variable and systemic side-effects are common, such as dry mouth and blurred vision (Evidence level: IIb).[1,7] Glycopyrrolate (glycopyrronium bromide) has been found to be useful as an adjunct to other therapies and iontophoresis (Evidence level: IIb).[3] Phenoxybenzamine, an α-adrenergic blocking agent, has also been used with some success, with its mechanism thought to be via blockage of cholinergic stimulation of the sweat glands and inhibition of the uptake of neurochemical transmitters, such as norepinephrine, at the postsynaptic site.[3] However, side-effects include orthostatic hypotension and inhibition of ejaculation, as well as general lethargy and nausea.

Where hyperhidrosis is stress-induced, diazepam can have an ameliorating effect (Evidence level: IIb).[7] The nonsteroidal anti-inflammatory drug indomethacin has also caused a reduction in sweating, possibly due to its effect on prostaglandin E (Evidence level: IIb).[7] Clonidine, a centrally active α-adrenergic autoreceptor stimulant, has also proved useful in the treatment of tricyclic-induced hyperhidrosis and also in hyperhidrosis linked to menopause (Evidence level: IIb).[7] Oral propoxyphene hydrochloride, a narcotic and weak ganglionic blocking agent, may also improve hyperhidrosis in patients with autonomic dysreflexia (Evidence level: III).[14]

Surgery/Curettage/Liposuction. Local surgery, subcutaneous curettage and liposuction may be performed under local anaesthesia and have been shown to be effective in reducing axillary hyperhidrosis, with patients experiencing a subsequent reduction in sweating. Direct excision, though, can create unacceptable scarring and contractures which are associated with significant morbidity, prolonged recovery and limitations to mobility.[1,3] Subcutaneous curettage and liposuction offer permanent efficacy but far fewer side-effects and less scarring compared with local excisional procedures (Evidence level: IIa).[15,16]

Botulinum Toxin Type A. Botulinum toxin is produced by the anaerobic bacillus Clostridium botulinum and is the cause of the clinical signs and symptoms of botulism.[17] Its mechanism of action is to inhibit the release of acetylcholine at the presynaptic membrane of cholinergic neurones.[18] This is achieved by the injection of the drug in areas of excessive sweating, causing a localized, long-lasting but reversible decrease in cholinergic transmission.

Botulinum toxin type A has been used for a variety of conditions, ranging from the treatment of spasticity to blepharospasm and strabismus and it has been shown to have substantial benefits in the treatment of axillary hyperhidrosis, where it should be considered the treatment of choice if topical treatments prove ineffective. Currently BOTOX® (Allergan Inc.) is the only botulinum toxin type A formulation to be licensed for axillary hyperhidrosis and as such the majority of the data below and the recommendations refer to BOTOX® only. Given differences in dosing and safety profiles of different botulinum toxin formulations, the results should not be extrapolated to other botulinum toxin formulations or serotypes.

In a large multicentre, double-blind, placebo-controlled study patients treated with botulinum toxin type A (BOTOX®) 50 U per axilla or placebo were assessed for 16 weeks following treatment. A total of 320 patients were randomized (242 treated with botulinum toxin type A and 78 treated with placebo), with results showing a consistently high and rapid response rate in the botulinum toxin type A group at all time points (from 81·8% to 95·0%) compared with the placebo group (response rates ranging from 20·5% to 37·2%). Subjects also rated their satisfaction with the treatment following botulinum toxin type A highly (Evidence level: Ib).[19]

In an extension to this study, patients were followed for a further 12 months, during which time a further three botulinum toxin type A treatments could be given if required by the subject, with a minimum of 16 weeks between each treatment. A high response rate was seen following each treatment, with the outcome being similar after successive treatments (mean reduction in sweat production of 82% at week 4 following the first treatment and 80% following the second treatment). Patient satisfaction with treatment remained high following subsequent treatment cycles. Analysis of the duration of effect showed that the mean time between the first and second treatments was 30·6 weeks (range 15·4–51·3 weeks). However, it should be noted that this calculation applies only to subjects who received at least two botulinum toxin type A treatments: 28% of subjects did not qualify for retreatment, based on subject demand and sweat production, thus indicating that in a substantial proportion of patients the duration of effect may be considerably longer (Evidence level: Ib).[20]

Lowe et al. also demonstrated long-term efficacy of botulinum toxin type A (BOTOX®) in the suppression of axillary hyperhidrosis, with five of 20 patients requiring only one injection in 18 months of follow-up, without emergence of significant side-effects. The mean duration of effect between consecutive treatments was approximately 6 months and the duration of benefit conferred by the first injection could provide a broad guideline to the patient as to the expected frequency of reinjection (Evidence level: IIa).[21]

The efficacy of botulinum toxin type A (Dysport®; Ipsen) in axillary hyperhidrosis has been shown in a multicentre trial in 145 patients previously unresponsive to topical therapy where a significant (P < 0·001) decrease in sweat production compared with placebo occurred 2 weeks postinjection and was maintained 24 weeks postinjection (Evidence level: IIa).[22] Treatment was well tolerated and 98% of patients said they would recommend botulinum toxin therapy to others.

Treatment with botulinum toxin type A in axillary hyperhidrosis was also seen to have a significant favourable impact on patient QOL. In a study carried out to assess the effects of axillary hyperhidrosis on daily life using the HHIQ, 68% of patients felt it interfered when they met new people, 55% felt it interfered with their personal relationships, 58% felt it limited them at work and 39% felt they were less effective at work as a result of their hyperhidrosis.[6] Fifty percent of patients had to change clothes twice or more each day and 20% had to shower or bath twice or more per day because of their hyperhidrosis. Importantly, 72% of patients said it made them feel less confident and 51% of patients had changed their leisure activities as a result of their condition. Following treatment with botulinum toxin type A (BOTOX®), significant improvements in all QOL measures were noted compared with placebo treatment, with the most dramatic changes being seen in the degree of limitation on being in public places and on meeting people for the first time. The positive effects of treatment were observed within 1 week of treatment, and the effects were carried over from one treatment to the next. In fact, botulinum toxin type A treatment resulted in a greater level of overall treatment satisfaction than any other hyperhidrosis treatment (Evidence level: Ib).[6]

The positive benefits of botulinum toxin type A on QOL in patients with axillary, palmar or plantar hyperhidrosis have also been demonstrated using the Dermatology Life Quality Index (DLQI). In a study by Swartling et al., 53 patients were assessed before and after treatment with botulinum toxin type A (Evidence level: IIa).[23] This study showed that treatment resulted in a clinically significant improvement in QOL (mean reduction in DLQI from 9·9 to 2·4) for patients who had not relapsed at a median of 5 months post-treatment. Similar results were seen in a study by Campanati et al. where 41 patients with focal hyperhidrosis were treated with botulinum toxin type A and showed a significant improvement in QOL following assessment pretreatment and post-treatment using the DLQI (Evidence level: IIa).[24]

Botulinum toxin type A injections have been shown to be generally well tolerated (Evidence level: IIb),[25] with no unexpected adverse events being noted in the trials to date. In studies of axillary hyperhidrosis, isolated cases of perceived increases in nonaxillary sweating have been noted but in a very small number of individuals (< 5%). Occasional, transient, generalized muscle weakness in the hands has been reported following treatment for axillary hyperhidrosis. No severe allergic reactions have been reported.[25]

The development of neutralizing antibodies against botulinum toxin has been reported in patients administered long-term treatment (up to 10 years); however, Schnider et al. found that repeated botulinum toxin type A injections over 3 years were as effective as the first set of injections and the production of neutralizing antibodies did not play a major role (Evidence level: IIa).[26] Lowe et al. also found that repeated botulinum toxin type A injections provided the same duration of benefits without development of disease resistance or serum antibody production (Evidence level: IIa).[21] Despite this finding, the authors recommend using the most appropriate dose that achieves efficacy while minimizing the risk of antibody formation.[27]

A simple algorithm has been developed for the treatment of patients presenting with axillary hyperhidrosis based on published data:

topical

botulinum toxin type A
(BOTOX® 50 U per axilla)

botulinum toxin type A
plus topical

Local surgery

The current recommended initial dose for axillary hyperhidrosis is 50 U BOTOX® per axilla, which has been shown in clinical trials to be an efficacious and safe dose. However, it should be noted that dose adjustments may be required for subsequent treatments, dependent upon patient response (Evidence level: Ib).[28] There is little evidence for recommending a higher initial dose, and there are also cost implications for increasing the dose. From clinical experience to date the injection interval seems to be consistent for an individual patient, which is very valuable from a patient management perspective. Patients should be retreated when the sweating returns at a level of concern for the patient, although retreatment within 16 weeks is not recommended. When sweating starts to return, it is initially recommended the patients use a topical preparation twice a week, which can extend the time interval between injections.

It is very important to identify areas of hyperhidrosis objectively before commencing treatment with botulinum toxin type A. Minor's iodine starch test or gravimetric tests should be used to delineate both the hyperhidrotic area and symptom intensity and will distinguish between those patients with severe hyperhidrosis requiring treatment with botulinum toxin type A from those with delusional hyperhidrosis (e.g. botulinophilia) who display no significant objective dermatological pathology.[29] Although these techniques are not difficult, there are tricks to performing them accurately and the nursing team should be trained to do the preparatory work. The development of a practical guide and checklists are also a useful part of the training plan.

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