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© Borgis - New Medicine 2/2004, s. 37-40
Ewa Szpringer1, 2, Krzysztof Lutnicki1
Eccrine hyperhidrosis – new therapeutic options
1 Department of Pathophysiology, Medical University, Lublin, Poland
2 ´Laser-Medic´ Dermatology and Laser Therapy Centre, Lublin, Poland
Hyperhidrosis is a severe problem for the people affected with the disorder. Until now the treatment of local eccrine hyperhidrosis (pharmacological treatment, iontophoresis, application of antiperspirants) has not been very effective or it has carried the risk of complications (surgical excision of the skin and subcutaneous tissue, endoscopic transthoracic sympathectomy). Very good therapeutic results may be achieved by injecting botulinum toxin of type A. The procedure effectively inhibits the secretion of sweat in the face, palms, soles and axillae for a few months or even longer than a year.
Maintaining proper heat balance in homeothermic organisms depends upon the balance between heat production and heat loss. The body loses heat through radiation (45-60%), conduction and convection (20-40%), and perspiration – imperceptible and perceptible evaporation of water from the skin surface (20-25%). Sweating is one of the most important mechanisms of removing excess heat from the body. Evaporation of 1 litre of sweat from the skin surface results in the utilization of more than 2400 kJ (543 kcal) of thermal energy (1).
Hyperhidrosis is excessive perspiration not resulting from normal thermoregulatory mechanisms. In terms of its localization, hyperhidrosis may be divided into local and generalized. In terms of its causes excessive sweating may be described as idiopathic, which is usually confined to the palms, soles and axillae and secondary (symptomatic), resulting from endocrine dysfunction (diabetes mellitus, hyperthyroidism, phaeochromocytoma, menopause), neoplastic disease, neurological syndromes (spinal cord and peripheral nerves damage, diabetic neuropathy) or febrile infectious diseases. Some persons develop the so-called gustatory sweating (Luckie-Frei syndrome) which is excessive perspiration of the skin of the face and the nape of the neck following ingestion of spicy foods or tyramine (an alkaloid ergot) contained, among others, in certain types of hard cheese, the Chianti wine, certain types of beer, yeast, mushrooms and herring (2).
Sweat is a weak solution of sodium chloride, containing mineral compounds (potassium, calcium, magnesium, iron) and urea, lactic acid, carbohydrates and lipids. Specific gravity of sweat is 1.002-1.003, pH ranges from 4.2 to 7.5. The number of sweat glands in the human skin is approximately 2000/cm2 on the hands and feet and from 100 to 200/cm2 on the skin of the chest and limbs. Sweat glands are divided into eccrine and apocrine. Eccrine glands are distributed all over the body, except for the breast, vermilion border and nail bed. They are most densely located on the forehead, palms, soles and axillae and most sparsely found in the skin of the eyelids. Eccrine sweat glands play a role in thermoregulation. They are also vital in the so-called emotional perspiration. Apocrine glands are not involved in thermoregulation. They are associated with hair follicles and open onto a hair root sheath just above the opening of the sebaceous gland. The secretion of apocrine glands is thicker than that of eccrine glands and contains fragrant substances (pheromones). Apocrine glands are located (together with eccrine glands) in the anogenital area, eyelids and ears, nipples, axillae, groins. They become active at puberty (3).
Sweat glands are supplied by the autonomic nervous system. The chemical nature of transmission in the fibres of the autonomic system consists in one neuron secreting only one specific chemical transmitter. Noradrenaline is the main transmitter in postganglionic sympathetic fibres, and acetylcholine in postganglionic parasympathetic fibres and in all autonomic preganglionic fibres - both parasympathetic and sympathetic. Eccrine glands are the exception in this rule as they are innervated by postganglionic sympathetic fibres, cholinergic character, releasing acetylcholine at their endings. However, the glands are controlled by the sympathetic nervous system and respond to sympathetic and parasympathetic pharmaceutical agents; their function is stimulated by muscarine, polocarpine and acetylcholine and inhibited by atropine. Apocrine glands are innervated by noradrenergic fibres (3).
Acetylcholine is produced from choline and acetyl coenzyme A in cholinergic neurons, and is the catalyst choline acetyltransferase. The synthesized acetylcholine is stored in synaptic vesicles. It is estimated that from 1000 to 50 000 acetylcholine molecules may be found in one vesicle and there are approximately 300 synaptic vesicles at one nerve ending, which clearly manifests that the activity of the acetylcholine synthesis is very high. Some quantity of acetylcholine is continuously and spontaneously released in small amounts. The quantum release is responsible for the formation of miniature postsynaptic potentials and is the source of the parasympathetic tonus which disappears when a nerve has been severed or has degenerated. Due to irritation of parasympathetic nerves and depolarization of the nerve ending, the membranes of synaptic vesicles bind with the membrane of the nerve ending, and the contents of the vesicles are emptied into the synaptic fissure. Approximately 100 or more vesicles are simultaneously opened, and from 100 000 to 5 000 000 acetylcholine molecules are released. Each of them, having bound to a receptor, alters the postsynaptic membrane potential by 3 × 10-7 V, which results in the value of 3 to 150 mV. During the acetylcholine action the system is in the state of refraction and does not respond to further stimuli. Reactivity returns after acetylcholine is removed from the bonding sites. This function is performed by acetylcholinesterase (AChE), the enzyme hydrolyzing acetylcholine to acetic acid and choline. After passing through a depolarized presynaptic membrane into the synaptic fissure, acetylcholine binds to the muscarine receptors (M) of the postsynaptic membrane. A stimulation potential is then evoked in certain organs, which leads to muscle contraction and increased glandular secretion. Acetylcholine released by cholinergic fibres also causes dilation of the vascular bed as well as coronary and pulmonary vessels, acting on muscarine receptors. It decelerates the heart action, decreases the force of myocardial contractions and reduces conduction. It increases the tonus and amplitude of contractions and the peristalsis of the stomach and intestines. It also activates the secretion of all glands released parasympathetically, including saliva, gastric juice, digestive juices, mucus in the respiratory tract and sweat (4).
Destruction of sympathetic innervation entirely stops sweat response to an increased temperature within the range of the innervation. Sweat glands, however, still respond to acetylcholine and pilocarpine. It seems important that perspiration is induced by stimuli radiating from the centres in the cerebral cortex. The beginning of muscular work, sweating is initiated by impulsation from motor centres of the cerebral cortex, as it occurs before any change in the temperature of the internal organs. Similar impulsation from the cerebral cortex may play a role in inducting perspiration by mental and emotional stimuli. For example, cold sweat may be due to psychogenic result from psychic factors, anxiety, fear, fatigue or mental effort. Cold sweat occurs especially on the forehead, palms and soles, that is in the areas which basically do not respond with sweating to an increased temperature.
For people affected with the disorder, eccrine hyperhidrosis is a serious problem, which makes it difficult or impossible for them to function in the society, begin work and maintain normal interpersonal relationships.
Antiperspirants used in the treatment of hyperhidrosis act by blocking the openings of sweat glands. Active aluminium salt contained in antiperspirants combines with the components of sweat, producing amorphous hydroxide gel. For healthy people this may be sufficient to inhibit their sweat secretion, but in those with hyperhidrosis the application of antiperspirants, particularly in the volar areas, is usually ineffective. An alternative treatment is iontophoresis which consists in rinsing the hydrotic areas with water or a solution of cholinolytic drugs and exposing them to a continuous low-intensity current. This procedure should be repeated many times and provides remission for several weeks.
Surgical options of treating hyperhidrosis include either excision of the tissue together with its sweat glands, which is possible in the axillary region, or surgical denervation of the affected site by sympathectomy. Sympathectomy results in complete blockage of the secretory action of sweat glands in a particular area of the skin, for example, in hands or feet. Subcutaneous curettage of the axillary area or complete resection of the skin with the subcutaneous tissue in the armpit carries the risk of excessive cicatrization of the area, loss of sensation and paraesthesia. Sympathectomy may lead to compensatory perspiration in different areas (approximately 65% of patients), excessive dryness of the skin of the face and hands, and bradycardia. The most dangerous complication of endoscopic transthoracic sympathectomy is pneumothorax (5).
Pharmacological therapy is an adjunctive treatment. Cholinolytic drugs are not widely used in dermatology to inhibit excessive secretion of sweat glands. Slight improvement is observed during the treatment with Bellergot, a complex preparation containing Atropa belladonna alkaloids, ergotamine tartrate and phenylethylbarbituric acid. Sedatives are applied if excessive perspiration is associated with emotional excitation.
Since the present treatment described above has proved to be unsatisfactory, more effective methods of therapy are being sought.
For several years many world centres have treated excessive perspiration with botulinum toxin. This procedure of high efficacy, with little risk of complications, may be performed on any skin area affected with hyperhidrosis on an outpatient basis. Botulinum toxin is produced by Gram-positive anaerobes Clostridium botulinum. There are seven serotypes of the toxin A-G; however, until now, therapeutic application has been found for only Botulinum toxin type A, a chemically zincdependent enzyme consisting of two polypeptide chains joined by a bisulphide bond. The botulinum toxin inhibits the release of acetylcholine from nerve endings. The mechanism of its action upon the nerve ending includes three stages. The first stage involves binding of botulinum toxin to the presynaptic membrane of the motor plate by a heavy chain; the second stage – internalization – consists in endocytosis of botulinum toxin into the inside of a neuron and its cleavage of both chains. At the third stage, botulinum toxin splits cytoplasmic protein SNAP-25, which is indispensable for the release of acetylcholine. In this way, chemical denervation of cholinergic postsynaptic effectors occurs (transversely striated muscles, sweat glands and certain blood vessels). The lack of stimulation of sweat glands to release sweat is usually maintained for several months, after which the effect disappears due to degeneration.
Randomized studies of the treatment of axillary hyperhidrosis with botulinum toxin were conducted in 17 European dermatological and neurological centres (6) and their results were reported in 2001. The patients were given injections of 50 units of Botox (Allergan) into one axilla, after a previous Minor´s test application of potassium iodide and starch to an appropriate skin area. When the skin is moist with sweat, a chromatic reaction occurs indicating the skin surface area as an injection site. Botox was injected intradermally; 10-15 injections were given into one axillary area. The control group received placebo injections of 0.9% saline following the same injection protocol. The reduction in hyperhidrosis was satisfactory, the patients considered the procedure highly efficacious, and there were no significant adverse effects. In 5% of the patients a compensatory increase in sweat secretion in areas other than the axillae was observed. The effects of the therapeutic procedure were maintained even up to 14-15 months; in the majority of the patients they were maintained for 6-8 months. No weakening of the strength of the adjacent muscles or other complaints was noted. Lowe et al. from Great Britain (7), Neuman et al. from Germany (8), Schnider et al. from Austria (9), Oddeson from the USA (10) and Sahnanopoor from Iran (11) obtained similar results. Our own observations and results of the studies are similar.
Local hyperhidrosis affects the palms and soles as frequently as the axillae. In such cases, injecting botulinum toxin type A has also produced satisfactory results, transiently decreasing perspiration. The results were confirmed by Maillard et al. (12), Blanchet et al. (13), Lowe et al. (14), Rusciani et al. (15), Sevin et al. (16), Saadie et al. (17) and our own studies. Botulinum toxin type A, at a dose of 50 to 100 units of Botox for one limb, was injected intradermally in the palmar and plantar areas. The procedure effectively reduced the sweat secretion for 4 to 10 months and in individual cases even for 18-22 months. A significant problem associated with the procedure is painfulness of the injections. Anaesthesia with Emla (Lidocaine hydrochloride and Prilocaine/Astra Zeneca) in occlusive dressing significantly reduces the patient´s discomfort during the procedure, however, it does not completely relieve pain. In particularly sensitive individuals a block of the median and ulnar nerve at the level of the wrist may be performed, but its multiple repetition may lead to nerve damage (18). An alternative method is to give local intravenous anaesthesia (Bier´s block) after tightening a cuff on the patient´s forearm (19).
Botulinum A toxin injections in the arm may lead to the weakening of strength of small muscles; although slight and transient, this may be badly tolerated by people performing precise manual work. Among the muscles of the hand most exposed to the atonic action of botulinum A toxin are those situated superficially which are, at the same time, important for precise functioning of the hand. They include: the short abductor muscle of the thumb (m. abductor pollicis brevis), the short flexor muscle of the thumb (m. flexor pollicis brevis) and the abductor muscle of the little finger (m. abductor digiti minimi). No disturbances are found in the muscles of the central part of the hand (mm. lumbricales) (20).
Intradermal injections into the sole of the foot are usually given after occlusal anaesthesia with Emla; no disturbances in the motor activity of the foot muscles are found after the procedure, and the pain is transient and accepted by the patient (21). Botulinum A toxin is also used in the treatment of gustatory sweating, mostly in the face (22).
In Poland botulinum A toxin has been approved for symptomatic treatment of blepharospasm, facial hemispasm, focal dystonia, spasticity in children with cerebral palsy and in cosmetic medicine to remove wrinkles. In the treatment of hyperhidrosis Botox has been approved for registration in Switzerland, Holland, Great Britain and Germany and it might soon be approved in Poland.
The treatment with botulinum A toxin is contraindicated in people with recognised hypersensitivity to any of its components, patients with myasthenia and amyotrophic lateral sclerosis, persons treated with antibiotics of the aminoglycoside group or spectinomycin. Botulinum A toxin is also used with caution in people treated with polymyxins, tetracycline, lincomycin and muscle relaxants. The treatment with botulinum toxin type A is not indicated in pregnant and lacting women.
To conclude, the treatment of hyperhidrosis with botulinum toxin type A is a procedure of choice in patients with local hyperhidrosis who do not intend to undergo surgical excision of glands. The treatment is safe, may be provided in outpatients´ clinics, and the effects of the procedure are satisfactory.
1. Górny D.: Termoregulacja.In: Patofizjologia. PZWL, Warszawa 1992; p.220-32. 2.Stolman L.P.: Treatment of hyperhidrosis. J. Drugs. Dermatol. 2003; 5:521-7. 3.Lutnicki W.: Układ powłokowy zwierząt domowych. PWN, Kraków 1988; p.30-35. 4.Maśliński C.: Aminy biogenne. In: Patofizjologia. PZWL, W-wa 1992; p.184-6. 5.Naumann M., Lowe N.J.: Botulinum toxin A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. B.M.J. 2001; 323:596-9. 6.Lai Y.T., Yang L.H., Chio C.C., Chen H.H.: Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. Neurosurgery 1997; 41:113-5. 7.Lowe P.L., Cerdan-sanz S., Lowe N.J.: Botulinum toxin type A in the treatment of bilateral primary axillary hyperhidrosis: efficacy and duration with repeated treatments. Dermatol. Surg. 2003; 29:545-8. 8.Naumann M., Lowe N.J., Kumar C.R., Hamm H.: Botulinum toxin type A is a safe and effective treatment for axillary hyperhidrosis over 16 months: a prospective study. Arch. Dermatol. 2003; 139:731-6. 9.Schnider P., Moraru E., Kittler H., Binder M., Krana G., Voller B., Auff E.: Treatment of focal hyperhidrosis with botulinum toxin type A: long-term follow-up in 61 patients.Br. J. Dermatol. 2001; 145:289-93. 10.Odderson I.R.: Long-term quantitative benefits of botulinum toxin type A in the treatment of axillary hyperhidrosis. Dermatol. Surg. 2002; 28:480-3. 11.Salmanpoor R., Rahmanian M.J.: Treatment of axillary hyperhydrosis with botulinum A toxin. Int. J. Dermatol. 2002; 41:428-30. 12.Maillard H., Briand N., Bara C., Celerier P.: Efficacy of botulinum toxin A in the treatment of axillary and palmar hyperhidrosis: 10 cases. Ann. Dermatol. Venereol. 2003; 130:511-3. 13.Blaheta H.J., Vollert B., Zuder D., Rassner G.: Intravenous regional anesthesia (Bier´s block) for botulinum toxin therapy of palmar hyperhidrosis is safe and effective. Dermatol. Surg. 2002; 28:666-71. 14.Lowe N.J., Yamauchi P.S., Lask G.P., Patnaik R., Iyer S.: Efficacy and safety of botulinum toxin type A in the treatment of palmar hyperhidrosis: a double-blind, randomized, placebo-controlled study. Dermato. Surg. 2002; 28: 922-7. 15.Ruscianii L., Severino E., Rusciani A.: Type A botulinum toxin: a new treatment for axillary and palmar hyperhydrosis. J. Drugs. Dermatol. 2002; 1:147-51. 16.Sevim S., Dogu O., Kaleagasi H.: Botulinum toxin A therapy for palmar and plantar hyperhydrosis. Acta. Neurol. Belg. 2002; 102:167-70. 17.Saadia D., Voustianiouk A., Wang A.K., Kaufmann H.: Botulinum Toxin type A in primary palmar hyperhidrosis: randomized, single-blind, two-dose study. Neurology 2001; 57:2095-9. 18.Almeida A.R., Kadune B.V., Oliveira E.M.: Improving botulinum toxin therapy for palmar hyperhidrosis: wrist block and technical considerations. Dermatol. Surg. 2001; 27:34-6. 19.Blaheta H.J., Deusch H., Rassner G., Vollert B.: Intravenous regional anesthesia (Bier´s block) in superior to a peripheral nerve block for painless treatment of plantar hyperhidrosis with botulinum toxin. J. Am. Acad. Dermatol. 2002; 48:302-4. 20.Swartling C., Farnstrand C., Abt G., Stalberg E., Naver H.: Side-effects of intradermal injections of botulinum A toxin in the treatment of palmar hyperhidrosis: a neurophysiological study. Eur. J. Neurol. 2001; 8: 451-6. 21.Wollina U., Karamfilov T.: Botulinum toxin A for palmar hyperhidrosis. J. Eur. Acad. Dermatol. Venereol. 2001; 15:555-8. 22.Laskawi R., Rohrbach S.: treatment of gustatory sweating with botulinum toxin: special aspects. J. Otorhinolaryngol. Relat. Spec. 2001; 63:294-7.
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