Department of Dermatology, University Hospital, Zurich, Switzerland
Focal hyperhidrosis of axillae, palms or soles is a frequent, socially debilitating condition, triggered by various emotional stimuli. There are several treatment options such as local application of metal salts (aluminum chloride) or tap water iontophoresis, which provide temporary relief for some patients. More recently, local intradermal injections of botulinum toxin A (BTX-A), a neurotoxin blocking the cholinergic stimulus of eccrine sweat glands, offer an effective treatment option with few side-effects. Patient satisfaction rates are high, although treatment effects only last a few months. For definite cure, surgical procedures have to be considered.
Key Words: hyperhidrosis, botulinum toxin, BTX-A
Hyperhidrosis is a condition with a tremendous psychosocial and occupational impact for the patients affected. In axillary hyperhidrosis, the slightest emotional or mental activity leads to wet armpits, showing up as stains on clothes, which can be socially embarrassing. Furthermore, skin maceration and subsequent microbial infection lead to discomfort, and body odors can impede social contacts. Palmar hyperhidrosis leads to a slippery grip and to a cold, wet handshake. Certain occupations are impossible because of staining of paper or other materials handled. There also is an increased risk for developing delayed type hypersensitivity to nickel and other contact allergens. Patients spend large amounts of their time and energy hiding their condition in social contexts.
Several treatments have been offered to patients suffering from hyperhidrosis but they were either of limited effectiveness or had numerous side-effects. With the discovery of botulinum toxin A for the treatment of hyperhidrosis, a treatment is available which relieves the symptoms in a relatively simple and safe fashion, although only for a limited time.
Types and Diagnosis of Hyperhidrosis
Hyperhidrosis can be focal (axillary, palmar, plantar or forehead) or generalized. It can be classified according to the stimuli inducing the sweating response. These stimuli correlate with the sites of origin of the neuronal impulses for sweating— emotional, mental or sensory hyperhidrosis (cortical reflex), thermoregulatory sweating (hypothalamic), gustatory sweating (medullary), hyperhidrosis following spinal cord transsection, injury or disease (spinal), and localized sweating (axon reflex).
The most frequent triggers of focal hyperhidrosis affecting axillae or palmoplantar areas are emotional (cortical) stimuli. Hyperhidrosis is usually idiopathic, resulting from a neurogenic overactivity of the sweat glands.1 Only rarely is it associated with psychiatric disorders such as social anxiety disorder.2 Generalized hyperhidrosis can be secondary to a number of causes such as diabetes, hyperthyroidism, chronic infections or malignancy. Emotional sweating is always diurnal whereas thermoregulatory sweating may be diurnal or nocturnal.3 A history of “night sweats” always points to secondary hyperhidrosis.
The sweat glands responsible for focal hyperhidrosis are eccrine glands innervated with anatomically sympathetic, but functionally cholinergic fibers. The neurotransmitter involved is therefore acetylcholine.
The diagnosis of primary focal hyperhidrosis can usually readily be made based upon the patient’s history of wet armpits and massive sweating of the palms and soles after emotional stress. Causes of secondary hyperhidrosis should be excluded by careful history and appropriate laboratory investigations. The areas affected can be visualized with Minor’s Iodine starch test (Fig. 1). The extent of hyperhidrosis can be quantified with gravimetric methods, but this is usually unnecessary, as the diagnosis is obvious and the decision to treat is based on the subjective perception of the suffering by the patient.
There are various treatment modalities for hyperhidrosis. Medications for generalized hyperhidrosis, such as anticholinergics and antidepressants, are often disappointing because the dose necessary to inhibit sweating is high enough to cause substantial side effects (see Table 1).
|Mode of application||Mechanism of action||Duration of effect||Major advantages||Major drawbacks|
|Metal salts (aluminum chloride, zirconium)||Local application under oclusion at bedtime||Plugging of sweat glands||As long as applied||Easy application,|
few side effects
|Tap water iontophoresis||Immersion of affected sites 3-5 times weekly for 10 minutes||Unknown||As long as applied||Few side effects||Availability and cost of equipment, time consuming|
|Botulinum toxin A||Intradermal injection||Inhibition of exocytosis of acetylcholine||Several (3-17) months||Very effective||Costs, repetitive treatments necessary, anesthesia|
|Surgical procedures||Local excision of axillary sweat glands in tumescence anesthesia||Reduction of sweat glands||Lasting||Long term effectiveness||Complications of surgery|
|Thoracal sympathectomy||Denervation of sweat glands||Lasting||Long term effectiveness||Compensatory sweating, (rarely) complications|
A first line treatment for localized hyperhidrosis, both axillary and palmoplantar, is the local application of metal salts, usually aluminum chloride or zirconium salts, in an aqueous or ethanolic solution.4 These metal salts penetrate the acrosyringium of the sweat glands and form a plug, thereby reducing the amount of sweat. They are best applied in the evening, before a period of relative inactivity of the sweat glands. Applications are initially needed daily, followed by a maintenance therapy with once or twice weekly applications. The effect only lasts as long as the maintenance dose is applied, although the sweat glands may definitively involute after prolonged application.5
Another form of treatment achieving a substantial reduction of sweating, particularly for palmoplantar hyperhidrosis, is tap water iontophoresis.6 The hands or feet are immersed in tap water and a low current is applied for approximately ten minutes. Treatments should initially be performed 3-5 times per week. For maintenance therapy, which can be performed 1-3 times per week, patients sometimes prefer to buy their own iontophoresis equipment.
For a more definitive cure, surgical treatments have to be considered. Local excision of axillary sweat glands can be performed in tumescence local anesthesia and usually shows good results.7 Thoracal sympathectomy reduces palmar hyperhidrosis effectively but carries the risk of compensatory sweating.8
Botulinum Toxin A
Botulinum toxin (BTX) is a neurotoxin produced by the anaerobic bacterium clostridium botulinum. It inhibits the release of acetylcholine at the presynaptic nerve endings of the motor endplates. At the end of the 18th century, it was recognized as the cause of botulism, a frequently fatal form of food poisoning.9 Therapeutic use of the poison started in the 1960s, when ophthalmologists recognized that minute amounts of BTX could effectively paralyze eye muscles in patients with strabism and blepharospasm. Clinical use for other muscle disorders, such as cramped sphincters in anal fissures and urogenital dystonias followed quickly. In the early 1990s, after clinicians observed that patients treated with BTX for hemifacial spasms no longer sweated in the treated area, the idea arose to use the toxin to treat hyperhidrosis. In the meantime, BTX has become widely established for the treatment of hyperhidrosis and hyperfunctional facial lines.
Seven serotypes of BTX exist; of these, serotype A is the one most often used to treat hyperhidrosis. By preventing the exocytosis of acetylcholine, BTX-A exerts an inhibitory effect on the cholinergically innervated eccrine secretory cells and thus reduces sweat production. BTX-A is available in two commercial forms (BOTOX® [Allergan] in the USA and Europe and Dysport® [Ipsen] in Europe), whereby 1 unit of BOTOX® is about equal to 3-4 units of Dysport®. The affected area is first visualized with Iodine starch staining (Minor test). Then 50-200 units of BOTOX® are injected intradermally; the dose is divided into 10-15 aliquots injected at spatial intervals of approximately 2 cm, enough to cover the entire affected area. Injection in the axillae is usually well tolerated without anesthesia. Injections in palms and soles can be very painful and are therefore best performed under regional anesthesia (median and ulnar nerve block for palms, sural and posterior tibial nerve block for soles). Alternatively, the area can be rendered relatively pain free by prior application of anesthetic cream (EMLA, AstraZeneca) under occlusion, iontophoretic application of lidocaine, or cryospray.
The anhidrotic effect of BTX-A, which can be perceived after 2-4 days, is usually very satisfying. Several studies have reported it to be effective in more than 90% of patients, compared to response rates around 35% for placebo. This is true both for axillary10-12 and palmoplantar13,14 hyperhidrosis. Quality-of-life assessments showed a substantial reduction of the adverse impact of hyperhidrosis.15,16 Although apocrine sweat glands are innervated by adrenergic fibers, treatment with BTX-A showed marked improvement of unpleasant body odor (bromhidrosis).17 The mechanism of action for this effect may be a reduction of the moist environment favorable for bacterial growth, or the inhibition of cholinergic apocrine glands. In patients with dyshidrotic hand dermatitis, treatment of the palms with BTX-A may reduce the severity of the eczema, as hyperhidrosis is considered to be a precipitating factor in this condition.18
A drawback of the treatment with BTX-A when compared to surgical approaches is the limited duration of its effect. After one treatment, anhidrosis lasts between 3 and 17 months with a median duration of approximately 7 months. Higher doses of BTX-A seem to lead to a slightly longer duration of effect,19 outweighed by the higher costs and the higher risk of antibody formation. Repeat treatments can be performed at intervals guided by the patient’s requests and lead to sustained good results.10 For many patients this may be preferable to the ongoing treatments required by metal salts and tap water iontophoresis. However, a definitivecessation of the symptoms has not been observed even after multiple treatments, and histological examination of sweat glands shows no involution due to inactivity. A treatment algorithm for axillary and palmoplantar hyperhidrosis is proposed in Fig. 2.
Adverse effects of the treatment with BTX-A are minor and very rare. Hematomas at injection sites are usually of little concern. Injection into the palms can lead, by diffusion of the toxin, to a transient weakness of the small muscles in the hand. Subjectively increased sweating at non-treated sites has been reported. Especially when higher doses of BTX-A are used, antibody formation (leading to ineffectiveness of the treatment) can theoretically occur, but this has been observed only very rarely. Contraindications include pregnancy and lactation, and special precautions should be applied in patients with motor neuron disease, myasthenia gravis, Eaton-Lambert syndrome, patients on aminoglycoside antibiotics or with hypersensitivity to BTX-A or any ingredient in the formulation.
Intradermal application of Botulinum toxin A (BTX-A) has added a valuable and very effective option to the hitherto available treatments of focal hyperhidrosis. While the effect is only of limited duration and repetitive treatments are necessary, it has a very good safety profile. It can add significantly to patients’ quality of life, especially when other treatment options have proven ineffective.