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Correspondence to: S. Tierney, Department of Surgery, Adelaide and Meath Hospital, Tallaght, Dublin 24 Email: sean.tierney@amnch.ie

Introduction

Medical Treatments

Primary hyperhidrosis affects up to 1% of the population and has a significant negative impact on quality of life. It affects the axillae in approximately 80% of cases. Hyperhidrosis results from excessive sympathetic stimulation of the eccrine sweat glands: the various treatment modalities available target points along the pathway between the central nervous system and the peripheral gland. The first line of treatment is topical aluminium chloride, which is effective in the majority of cases. Alternative treatments such as systemic anti-cholinergics and iontophoresis have significant disadvantages, while surgical sympathectomy has been regarded as the gold-standard in treatment of this condition. Recently, attention has focused on the use of intradermal botulinum toxin for the treatment of axillary hyperhidrosis. This is a highly effective, minimally-invasive treatment with few side effects, and is now recommended as the treatment of choice in isolated axillary hyperhidrosis

Keywords: Hyperhidrosis Surg J R Coll Surg Edinb Irel., 1 December 2004, 311-314

Hyperhidrosis may be primary or secondary; the former is relatively common, affecting between 0.6% and 1% of the general population.¹ It may be generalised or localised, with palmar, plantar, axillary, truncal, and facial variants. The palms, soles and axillae are the most commonly affected sites. In upper limb hyperhidrosis, the axillae alone are affected in 37%, the hands and axillae in 43% and the hands alone in 20 per cent.² The typical patient presents in their second or third decade of life, with a positive family history in 30% to 50% of cases.³ While clearly not life threatening, this is a socially disabling condition, associated with significant negative impact on quality of life.⁴

Sweating is a centrally-mediated physiological process, with thermo sensitive neurons in the pre-optic area of the hypothalamus playing an important role. Impulses pass from the hypothalamus, via the medulla, to the lateral horn of the spinal ganglia and, thence, to the sympathetic ganglia and on to the eccrine sweat glands, where acetylcholine is the principal terminal neurotransmitter.⁵ Patients with hyperhidrosis have over-functioning of the sympathetic nerve fibres and increased sympathetic outflow.⁶ Patients with sympathetic nerve lesions have isolated areas of anhydrosis, as is classically seen in Horner’s syndrome. Apocrine sweat glands are also present in the axilla, and produce a viscous fluid rich in precursors of odiferous substances. Patients with axillary hyperhidrosis rarely have excessive axillary odour, suggesting that secretory activity of apocrine glands does not parallel that of eccrine glands.⁷ Excessive secretion by the apocrine glands results in malodorous bromhidrosis, and is treatable by removing the subcutaneous axillary tissue in which these glands are located.⁸

Treatment approaches are based on modifications of various stages in the pathway of sweat production. Therapeutic interventions may occur at the level of the sympathetic chain, at the neuroglandular junction or at the gland itself. This article examines the options available in the treatment of isolated axillary hyperhidrosis, which include invasive and non-invasive modalities. The most commonly used are topical antiperspirants, sympathectomy and, increasingly, intradermal injection of botulinum toxin.

Topical antiperspirants are the first line of therapy, and generally sufficient for cases of light to moderate hyperhidrosis although more severe cases may not respond adequately.⁹ Aluminium chloride is the most widely used topical agent, with concentrations of 10-15% recommended for use in the axillae.¹⁰ The product is applied to dry axillae at bedtime to take advantage of the relative inactivity of the sweat glands through the night, and washed off in the morning. The affected areas are treated every night initially, with weekly or fortnightly applications usually sufficient once symptoms have been controlled.¹¹ The mechanism of action is either mechanical obstruction of the eccrine gland sweat pore or induction of atrophy of the secretory cells.^12,13 This treatment is most effective for isolated axillary hyperhidrosis, with one study finding a successful outcome in 64 of 65 patients treated for isolated axillary hyperhidrosis with aluminium chloride salts.^20-22

Anticholinergic agents block sweat production at the level of the neuroglandular junction by competing with acetylcholine. They may be administered topically, via a transdermal patch or systemically (orally or intravenously). Central anticholinergic side effects such as xerostomia, mydriasis, glaucoma, drowsiness, urinary retention and constipation are significant, at the doses required to treat hyperhidrosis, and often render these medications unacceptable to patients.¹¹

First used as a treatment for hyperhidrosis in 1952, iontophoresis is a technique that involves the transport of charged molecules into a tissue.¹⁵ Direct electrical current is passed through an electrolyte solution, containing ions for delivery. The skin is in contact with the electrolyte solution, with pads applied to the axillae, (or with the hands placed in basins in the case of palmar hyperhidrosis). The mechanism of action is obstruction of the sweat glands via reversible disruption of the ion channel in the secretory glomeruli of the sweat glands and poral plugging.³⁰ Tap water iontophoresis is used initially, with the addition of an anticholinergic agent such as hexopyrronium bromide reserved as a second line treatment due to associated anticholinergic side effects. This non-invasive treatment may be associated with skin reactions, and is cumbersome, time-consuming and costly.¹⁷ It may be self-administered with equipment available for home use.

Botulinum toxins are derived from the anaerobic sporeforming bacterium clostridium botulinum. The neurotoxin rapidly and irreversibly binds to the presynaptic neuron at the neuromuscular junction, preventing the release of vesicle-bound acetylcholine.¹⁸ This results in a temporary chemodenervation and loss or reduction of activity in the target organ. The neuron responds by sending sprouts from the nerve terminal and nodes of Ranvier which eventually form functional synapses, resulting in a return of activity in the target organ.¹⁹ Thus, any therapeutic effect is temporary, and treatments must be repeated at regular intervals. Since the approval of the first botulinum toxin-based therapeutic product (Botox ^®, Allergan, Irvine, CA, USA) in 1989, botulinum toxin has been used in the treatment of various neurological disorders including spasticity, spasmodic torticollis and hemifacial spasm.^20-22 Studies of botulinum toxin use for various disorders have shown that long-term regular treatments maintain efficacy. Calace et al (2003) described treatment of blepharospasm over a twenty-one year period, and found that repeated treatments with botulinum toxin provided long-lasting relief of symptoms in the majority of patients. Defazio et al (2002) found that treatment of hemifacial spasm over a ten-year period offered sustained relief from symptoms.

The first reported use of botulinum toxin for the treatment of hyperhidrosis was in 1997, in a patient with palmar hyperhidrosis.²⁵ The benefit of botulinum toxin A on reducing axillary hyperhidrosis has since been clearly demonstrated by several open studies and two randomised, double-blind, placebo-controlled trials.^1,26,27,28 As this is a relatively new treatment for hyperhidrosis, no long-term data on its success exist. It is reasonable to expect that patients will require retreatment at regular intervals, in the same manner as patients treated for neurological conditions have done.

The toxin is diluted with normal saline and delivered as a number of intradermal injections (typically ten 0.1ml aliquots) to the hair-bearing area of the axilla, which has been shaved prior to the procedure. Doses used in the literature vary, and units are not interchangeable between different products. Heckmann et al (2001) used 200U of Dysport^®(Ipsen-Pharma, Efflingen, Germany) per axilla, while Naumann et al (2001) used 50U of Botox^® (Allergan, Irvine, CA, USA) per axilla.²⁷ High levels of treatment satisfaction, rapid and sustained effect, and few adverse events were reported. Improved quality of life has been demonstrated in patients who have received this treatment.^4,29 Intradermal botulinum toxin A injections have been recommended as the treatment of choice in isolated axillary hyperhidrosis.³⁰

The main side effect found with the use of this therapy is pain at the injection site, which is usually transitory.³¹ Due to the growth of new synapses at the end-plate, the therapeutic effect gradually wanes, with patients requesting re-treatment at 4-17 months.²⁶ Small muscle wasting has been reported when the toxin is used in the treatment of palmar hyperhidrosis, although this has not been reported as a problem in the treatment of axillae. Compensatory hyperhidrosis has rarely been reported.³²

Surgery offers definitive treatment of hyperhidrosis, but is not without risks of morbidity and mortality. Sympathectomy involves ablation of the sympathetic nerve supply to the sweat glands. In the case of axillary hyperhidrosis, the second, third, and fourth thoracic ganglia are ablated.³³ For palmar hyperhidrosis, it is sufficient to ablate the sympathetic supply at the level of the second rib and, in the case of plantar hyperhidrosis, ablation of the second, third and fourth lumbar ganglia results in denervation of the distal third of the leg.³⁴ Lumbar sympathectomy may result in sexual dysfunction in male patients and is, therefore, rarely used. The sympathetic chain is locally excised, ablated with electrocautery, laser, or clipped. The first thoracoscopic sympathectomy was performed in 1942, but the technique remained relatively rare until the development of the technique of video-assisted thoracoscopy and endoscopic thoracic sympathectomy (ETS).³⁵ The technique is effective, with success rates of close to 100% in palmar hyperhidrosis.³⁶ It is regarded as the gold standard in the treatment of palmar hyperhidrosis but it seems to be less effective in axillary than in palmar hyperhidrosis.³⁷

Complications associated with this procedure include Horner’s syndrome (0-0.1% of patients experience a permanent form, and 0-0.8% a transient form), and clinically significant pneumothorax and haemothorax (which are extremely rare).³³A significant minority of patients have one or more other complications. In addition, the procedure requires general anaesthesia with its attendant risks.

Compensatory hyperhidrosis is the commonest side effect, and by far the commonest reason for patient dissatisfaction post-operatively.³⁸ It occurs in 37% to 75% of patients in whom the T2 to T4 ganglia are ablated, with the incidence paralleling the extent of the ablation (where T2 alone is ablated, the incidence is 16% to 20%).³⁹ A severe form occurs in approximately 1% of patients.⁴⁰ Recurrence of hyperhidrosis may occur, and may be immediate, where ablation is inadequate (1% of open procedures and 2% of endoscopic procedures). It may also occur later, usually within two to eighteen months of surgery, and in up to 5% of cases (both open and endoscopic).⁴¹ The postulated mechanisms include partial denervation, nerve regeneration and anatomic variation.

Other surgical treatment options include local excision of the sweat glands, and suction-assisted lipolysis.^42,43Percutaneous techniques have also been used, aiming to disrupt the sympathetic nerve supply to the glands. Agents used include alcohol, phenol, radiofrequency ablation and thermocoagulation.^44-47 Blind percutaneous needle insertion was initially used, with radiologically-guided techniques developed later.^48,49 The latter has fallen from favour despite good immediate results, as long-term follow-up showed a failure rate of up to 40 per cent.⁵⁰

Less invasive methods such as topical aluminium compounds should initially be tried, before consideration of more invasive procedures. Sympathectomy has been regarded as the gold standard in definitive treatment of the condition. This invasive treatment may have adverse consequences, however, and the decision to embark upon it must be taken with a degree of caution. The advent of intradermal botulinum toxin injections has changed the approach to treatment, offering a highly effective, minimally invasive option in treatment of isolated axillary hyperhidrosis. It has been recommended as the treatment of choice, and should at least be considered in those patients in whom topical agents have failed.

1. Quraishy MS, Giddings AEB. Treating hyperhidrosis: endoscopic transthoracic sympathectomy may be the best treatment. Br Med J 1993; 1221-22.

2. Moran KT, Brady MP. Surgical management of primary hyperhidrosis. Br J Surg 1991; 78: 279-83.

3. Mosek A, Korczyn A. Hyperhidrosis in the palms and soles. In: Korczyn A, editor. Handbook of Autonomic System Dysfunction. New York: Marcel Dekker; p.167-77.

4. Fitzgerald E, McCormick PH, Tierney S, Feeley TM.Botulinum toxin treatment for hyperhidrosis. IJMS 2003; 172 (1) [Suppl 1]: S28.

5. Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands and their disorders I. Normal sweat gland function. J Am Acad Dermatol 1989; 20:537-65.

6. Shih CJ, Wu JJ, Lin MT. Autonomic dysfunction in palmar hyperhidrosis. J Auton Nerv Syst 1983; 8 (1):33-43.

7. Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands and their disorders II. Disorders of sweat gland function. J Am Acad Dermatol 1989; 20:713-26.

8. Hafner J, Beer GM. Axillary sweat gland excision. Curr Probl Dermatol 2002; 30, 57-63.

9. Cheung JS, Soloman BA. Disorders of sweat glands: hyperhidrosis: unapproved treatments. Clin Dermatol 2002; 20: 628-42.

10. Togel B, Greve B, Raulin C. Current treatment strategies for hyperhidrosis: a review. Eur J Dermatol 2002; 12: 219-23.

11. Stolman LP. Treatment of hyperhidrosis. Dermatol Clin 1998 Oct; 16(4) 863-69.

13. Holzle E, Braun-Falco O. Structural changes in axillary eccrine glands following long-term treatment with aluminium chloride hexahydrate solution. Br J Dermatol 1984; 110: 399-403

14. Scholes KT, Crow KD, Ellis JP, Harman RR, Saihan EM. Axillary hyperhidrosis treated with alcoholic solution of aluminium chloride hexahydrate. Br Med J 1978; 2: 84-85.

15. Bouman HD, Lentzer EM. The treatment of hyperhidrosis of hands and feet with constant current. Am J Phys Med 1952; 31: 158-69.

16. Hill AC, Baker GF, Jansen GT. Mechanism of action of iontophoresis in the treatment of palmar hyperhidrosis. Cutis 1981; 28: 69-70.

17. Holzle E, Alberti N. Long-term efficacy and side effects of tap water iontophoresis of palmoplantar hyperhidrosis - the usefulness of home therapy. Dermatologica 1987;175: 126-35.

18. Simpson LL. Kinetic studies on the interactions between botulinum toxin type A and the cholinergic neuromuscular junction. J Pharmacol Exp Ther 1980; 212: 16-21.

19. Aoki KR. Physiology and pharmacology of therapeutic botulinum neurotoxins. Curr Probl Dermatol 2002; 30: 107-16.

20. Grazko MA, Polo KB, Jabbari B. Botulinum toxin A for spasticity, muscle spasms, and rigidity. Neurology 1995; 45: 712-17.

21. Kang U, Greene P, Fahn S, Brin M, Moskowitz C, Flaster E. Double-blind placebo-controlled study of botulinum toxin injection for torticollis. Neurology 1990; 40: 1213-18.

22. Brin MF, Fahn S, Moskowitz C, Friedman A, Shale HM, Greene PE et al. Localised injections of botulinum toxin for the treatment of focal dystonia and hemifacial spasm. Mov Disord 1987; 2: 237-54.

23. Calace P, Cortese G, Piscopo R, Della Volpe G, Gagliardi V, Magli A, De Berardinis T. Treatment of blepharospasm with botulinum neurotoxin A: long-term results. Eur J Ophthalmol 2003; May: 13 (4):331-36.

24. Defazio G, Abbruzzese G, Girlanda P, Vacca L, Curra A, De Salvia R, Marchese R, Raineri R, Roselli F, Livrea P, Berardelli A. Botulinum toxin A treatment for preimary hemifacial spasm: a 10-year multicentre study. Arch Neurol 2002; 59 (3): 418-20.

25. Naumann M, Flachenecker P, Broker EB, Toyka KV, Reiners K. Botulinum toxin for palmar hyperhidrosis. Lancet 1997; 349: 252.

26. Heckmann M. Hyperhidrosis of the axilla. Curr Probl Dermatol 2002; 30: 149-55.

27. Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel-group, double-blind, placebo-controlled trial. BMJ 2001; 323: 596-99.

28. Heckmann M, Ceballos-Baumann A, Plewig G. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med 2001; 344: 488-93.

29. Naumann MK, Lowe NJ, Hamm H. Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: a randomised controlled trial. Br J Dermatol 2002; 147 (6): 1218-26.

30. Collin J, Whatling P. Treating hyperhidrosis. Surgery and botulinum toxin are treatments of choice in severe cases. BMJ. 2000; 320: 1221-22.

31. Solomon BA, Hayman R. Botulinum toxin type A therapy for palmar and digital hyperhidrosis. J Am Acad Dermatol 2000; 42: 1026-29.

32. Tan SR, Solish N. Long-term efficacy and quality of life in the treatment of focal hyperhidrosis with botulinum toxin A. Dermatol Surg 2002; 28 (6): 495-99.

33. Kestenholz PB, Weder W. Thoracic sympathectomy Curr Probl Dermatol 2002; 30: 64-76.

34. Orteu CH, McGregor JM, Almeyda JR, Rustin MHA. Recurrence of hyperhidrosis after endoscopic transthoracic sympathectomy - case report and review of the literature. Clin Exp Dermatol 1995; 20: 230-33.

36. Rex LO, Drott C, Claes G, Gothberg G, Dalman P. The Boras experience of endoscopic thoracic sympathicotomy for palmar, axillary, facial hyperhidrosis and facial blushing. Eur J Surg Suppl 1998; 580: 23-26.

37. Chaudhuri N, Birdi I, Ritchie AJ. Current practice in thoracic sympathectomy. Hosp Med 1999; 60: 807-11.

38. Kux M. Thoracic endoscopic sympathectomy in palmar and axillary hyperhidrosis. Arch Surg 1978; 113: 264-66.

39. Edmondson RA, Banerjee AK, Rennie JA. Endoscopic transthoracic sympathectomy in the treatment of hyperhidrosis. Ann Surg 1992; 215: 289-93.

40. Adar R. Compensatory hyperhidrosis after thoracic sympathectomy. Lancet 1998; 351: 231-32.

41. Byrne J, Walsh TN, Hederman WP. Endoscopic transthoracic electrocautery of the sympathetic chain for palmar and axillary hyperhidrosis. Br J Surg 1990; 77: 1046-49.

42. Bisbal J, del Cacho C, Casalots J. Surgical treatment of axillary hyperhidrosis. Ann Plast Surg 1987; 18: 429-36.

43. Shenaq SM, Spira M, Christ J. Treatment of bilateral axillary hyperhidrosis by suction-assisted lipolysis technique. Ann Plast Surg 1987; 19: 548-51.

44. Levine IM, Harris OJ. Chemical sympathectomy. New approach to the treatment of localised hyperhidrosis. AMA Arch Derm 1955; 71: 226-30.

46. Wilkinson HA. Percutaneous radiofrequency upper thoracic sympathectomy: a new technique. Neurosurgery 1984; 15: 811-14.

47. Chuang KS, Liou NH, Liu JC. New stereotactic technique for percutaneous thermocoagulation upper thoracic ganglionectomy in cases of palmar hyperhidrosis. Neurosurgery 1988; 22: 600-4.

48. Walker PM, Key JA, MacKay IM, Johnston KW. Phenol sympathectomy for vascular occlusive disease. Surg Gynecol Obstet 1978; 146: 741-44.

49. Dondelinger RF, Kurdziel JC. Percutaneous phenol block of the upper thoracic sympathetic chain with computed tomography guidance. A new technique. Acta Radiol 1987; 28: 511-15.

50. Adler OB, Engel A, Saranga D. Palmar hyperhidrosis treated by percutaneous transthoracic chemical sympathicolysis. Eur J Radiol 1994; 4: 57-62.

• The isolated palmar variant is commoner than isolated axillary hyperhidrosis

• Topical aluminium chloride is effective in the majority of cases of axillary hyperhidrosis

• Intradermal botulinum toxin is as effective as sympathectomy for axillary hyperhidrosis