title sub title Hyperhidrosis: Not Just A Cosmetic Problem

EXPERT MONOGRAPH ISSUE 26

Introduction

‘Hyperhidrosis’ refers to secretion of sweat in amounts greater than physiologically needed for thermoregulation. It is an extremely common yet under-recognised condition. It is typically idiopathic

and localised to certain body areas. Hyperhidrosis can have a significant impact on a patient’s self-esteem and social and occupational function, however only around one-third of sufferers seek medical advice.1 General practitioners are crucial in the detection, assessment and management of hyperhidrosis. Appropriate treatment has been shown to lead to dramatic improvements in quality of life.

Epidemiology

Prevalence estimates of hyperhidrosis are approximately 3% of individuals, depending on the population.1-3 Hyperhidrosis usually presents in childhood or adolescence and tends to persist. There

Take Home Messages ` Patients with hyperhidrosis also suffer increased

rates of chronic stress and depression; axillary disease carries the highest risk of these co-morbidities.

` Antiperspirants containing higher concentrations of aluminium chloride (e.g. aluminium chloride hexahydrate 20%) remain the most appropriate first-line therapy, especially for axillary hyperhidrosis.

` Local skin irritation is frequently encountered with aluminium chloride and may respond to a weak topical corticosteroid (e.g. hydrocortisone 1%).

` Medicare subsidises the administration of Botulinum Toxin A by dermatologists, neurologists and paediatricians for severe primary axillary hyperhidrosis, in patients aged 12 years or older who have failed, or are intolerant of, topical aluminium chloride hexahydrate after one to two months.

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This article provides an overview of the clinical approach, investigation and management of hyperhidrosis.

DR THOMAS STEWART BBioMedSc MBBS FRACGP

Dr Stewart is an unaccredited dermatology registrar at St Vincent’s hospital. He is also a fellow of the Royal Australian college of general practitioners and a conjoint associate lecturer at the University of New South Wales.

DR ROBERT ROSEN MBBS MMed FACD

Dr Rosen is a dermatologist and Managing Director at Southern Suburbs Dermatology. He is a conjoint senior lecturer at the University of New South Wales and a Lieutenant Colonel with the Australian Defence Forces.

CASSANDRA DU MARCHAND (Undergraduate, School of Nursing, University of Sydney)

title sub title

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Hormonal Contraception Trouble-shooting Part One: The Overweight Woman

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appears to be no gender disparity, however, females may be more likely to seek treatment. Hyperhidrosis is seen across all ethnicities. There may be a genetic component, as 84% of patients with palmar and 40% with axillary hyperhidrosis reported a positive family history in respective studies.4,5

Aetiology and Pathogenesis

Sweating is a normal physiological function designed to regulate body temperature. It is caused by eccrine glands that are present throughout the body, but occur in the highest concentrations in the palms, soles and axillae. Sweat glands receive innervation from sympathetic cholinergic fibres and sweating comprises both thermoregulatory and emotional pathways. Thermoregulatory sweating is affected by the hypothalamus globally across the skin surface, whereas emotional sweating receives input from higher cortical centres and usually involves the palms, axillae, soles and face. In primary hyperhidrosis, the sweat glands are normal and the cause appears to be an exaggerated sympathetic response to normal emotional stress.6 Secondary hyperhidrosis frequently has an underlying pathological aetiology (see Table 1).

Clinical Approach

It is important to make the distinction between ‘generalised’ and ‘focal’ hyperhidrosis at the outset. Generalised hyperhidrosis affects the entire body surface and may be idiopathic, but is more commonly due to an underlying medical condition or medication (see Table 1). The underlying (or secondary) cause can most often be found clinically, using history and examination alone. Investigations are sometimes needed and may be most useful in older age and/or acute severe disease.

The significant points when taking a history are age at onset of symptoms, body areas involved, symmetry, triggers (e.g. temperature, anxiety), any family history of hyperhidrosis, the effects on daily functioning, the medical history, any medications and any symptoms suggestive of secondary disease (e.g. weight loss, night sweats).

A diagnosis of primary focal hyperhidrosis can be made if a secondary cause has been

sufficiently excluded…

The physical examination should look for evidence of and the distribution of excess sweating. It is also important to examine thoroughly for signs of secondary causes (e.g. exophthalmos, lymphadenopathy, goitre, stigmata of diabetes). Physicians might

Hyperhidrosis: Not Just A Cosmetic Problem

Table 1: Secondary Causes of Hyperhidrosis

This Table is the intellectual property of the authors.

Infection Viral (e.g. HIV, Hepatitis C)

Bacterial (e.g. endocarditis, brucellosis)

Mycobacterial (e.g. tuberculosis)

Fungal infection

Endocrinopathy Carcinoid syndrome, pheochromocytoma, diabetes insipidus, hypoglycemia, post-orchiectomy

Neurological Autonomic dysreflexia/neuropathy, post-traumatic syringomyelia, stroke

Malignancy Lymphoma

Solid tumours (e.g. germ cell, medullary thyroid, prostate, renal cell carcinoma)

Medication Antidepressants (e.g. SSRIs, SNRIs)

Antihypertensives (e.g. beta-blockers, calcium channel blockers)

Analgesics (e.g. nortriptyline, tramadol, opioids)

Cholinergic agents (e.g. pilocarpine)

Hypoglycemic agents (e.g. insulin, sulfonylureas)

Hormonal agents (e.g. GnRH agonists, aromatase inhibitors, selective oestrogen receptor modulators)

Sympathomimetics (e.g. beta agonists, phenylephrine)

Substance withdrawal

Alcohol, cocaine, opioids

Other Chronic fatigue, gastrointestinal reflux, menopause, sleep apnoea, rosacea, temporal arteritis, mastocytosis

also look for complications and comorbidities of hyperhidrosis (e.g. fungal skin infection, atopic dermatitis).

A diagnosis of primary focal hyperhidrosis can be made if a secondary cause has been sufficiently excluded and the patient satisfies the following criteria (see Table 2).7

Table 2: The Diagnostic Criteria for Primary Focal Hyperhidrosis7

Focal, visible, excessive sweating of at least six months’ duration without apparent cause,

PLUS at least two of the following:

` Bilateral and relatively symmetrical distribution

` Impairment of daily activities due to symptoms

` At least one episode per week

` Onset before 25 years of age

` A family history of idiopathic hyperhidrosis

Psychosocial Considerations

Excessive sweating reduces self-esteem, leading to changes in behaviour. Social embarrassment is reported by 90% of palmar hyperhidrosis sufferers; approximately 80% avoid shaking hands and 17% resort to wearing gloves to perform daily tasks.8 Over one half of sufferers feel ‘less confident’, and more than a third ‘frustrated’ with daily activities. Up to 70% of those affected by hyperhidrosis report having to change their clothes two or more times per day.8 Patients also suffer increased rates of chronic stress and depression; axillary disease carries the highest risk of these co-morbidities.9

Investigations

Patients presenting with classical, primary, focal hyperhidrosis do not require investigation. Investigations are indicated if the history and/or examination are suggestive of a secondary cause. Any investigations should be guided by clinical suspicion, and may include thyroid function testing, blood glucose measurement, urinary catecholamines and imaging studies. Quantitative assessment of sweating is generally not required in the clinical setting. Starch-iodine testing may be useful for mapping body areas in preparation for botulinum toxin treatment.

Treatment

The treatment approach will depend primarily on location of disease (Figures 3 to 5). A variety of medical and surgical options are available for focal hyperhidrosis and the choice should be guided by severity, tolerability, and patient preference.

Figure 3: Stepwise Treatment of Palmoplantar Hyperhidrosis

These Figures are the intellectual property of the authors.

20% aluminium chloride hexahydrate for four weeks

OR

Iontophoresis

Ineffective or not tolerated

Botulinum toxin

Ineffective or not tolerated

Systemic agents or endoscopic thoracic sympathectomy

Figure 4: Stepwise Treatment of Craniofacial Hyperhidrosis

20% aluminium chloride hexahydrate for four weeks

Ineffective or not tolerated

Botulinum toxin or systemic agents

Figure 5: Stepwise Treatment of Axillary Hyperhidrosis

20% aluminium chloride hexahydrate for four weeks

Ineffective or not tolerated

Botulinum toxin or Microwave thermolysis

Ineffective or not tolerated

Suction curettage or systemic medication

Ineffective or not tolerated

Endoscopic thoracic sympathectomy

Topical treatments

Most hyperhidrosis patients have failed trials of the antiperspirants available at the supermarket by the time they consult a doctor. Antiperspirants containing higher concentrations of aluminium chloride (e.g. aluminium chloride hexahydrate 20%) remain the most appropriate first-line therapy, especially for axillary hyperhidrosis. Higher concentrations (25%) may be required for palmoplantar

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Hyperhidrosis: Not Just A Cosmetic Problem

hyperhidrosis. These agents work by obstructing the eccrine ducts, leading to glandular atrophy.10 Medicated antiperspirants should be administered daily until improvement is noted, and then once-weekly as a maintenance therapy. Local skin irritation is frequently encountered and may respond to a weak topical corticosteroid (e.g. hydrocortisone 1%).

Botulinum Toxin A

Botulinum Toxin A is an effective second-line agent that works by blocking the release of acetylcholine from the presynaptic nerve terminal, thereby inhibiting the stimulation of the eccrine sweat gland.11 It is created for medicinal purposes from the fermentation of the Hall strain of Clostridium botulinum type A. Its efficacy and safety is well-established, especially for axillary hyperhidrosis.5,11,12 An Australian study5 the author was involved with showed a mean duration of benefit of at least four months in over 80% of patients, and satisfaction with treatment in over 90% of patients. Repeated treatments also led to enhanced duration of effect.5 Standard dosing is 50 units per axilla, injected intra-dermally. Side-effects are usually minimal and the most common is pain at the injection site.

Up to 70% of those affected by hyperhidrosis report having to

change their clothes two or more times per day.8

Medicare subsidises the administration of Botulinum Toxin A by dermatologists, neurologists and paediatricians for severe primary axillary hyperhidrosis, in patients aged 12 years or older who have failed, or are intolerant of, topical aluminum chloride hexahydrate after one to two months. The procedure involves multiple intradermal injections that may be less well-tolerated in some areas (e.g. palms), requiring anesthetic, ice and/or distraction. Palmo-plantar hyperhidrosis typically requires 100 units of Botulinum Toxin A. Weakness of the intrinsic muscles of the hands is a possible adverse effect.13

Oral Agents

The most common systemic agents prescribed for primary hyperhidrosis are the oral anticholinergics oxybutynin (5mg to 15mg daily) and glycopyrrolate (1mg to 4mg daily). The dosage can generally be titrated effectively by the patient. The use of these agents is frequently limited, however, by their adverse effects (e.g. dry mouth, dry eyes, constipation, urinary retention).14,15 These medications may have highest yield in treatment-refractory cases where sweating is more generalised. Other systemic agents that have been used with some success in small series include clonidine, beta-blockers and benzodiazepines.

Iontophoresis

Iontophoresis is a reasonable second-line alternative commonly used for palmoplantar hyperhidrosis.16,17 It involves the application of an electric current to the affected area whilst the latter is immersed in tap water, or tap water plus an anticholinergic agent, typically glycopyrrolate (this is called ‘glycopyrrolate iontophoresis’). Tap water iontophoresis can be performed at home using a commercial device, whereas glycopyrrolate iontophoresis requires treatment at a specialist centre. The most frequent side-effect is discomfort during the procedure. Anticholinergic side-effects due to systemic absorption of glycopyrrolate are very uncommon. Iontophoresis is less effective in axillary disease, as it is difficult to obtain uniform contact of the electrode with axillary skin.

Microwave Therapy

Microwave thermolysis is a newer alternative to Botulinum Toxin A for treatment of axillary hyperhidrosis. Microwave energy is utilised to destroy eccrine glands.18 It is typically administered in two lots of 30-minute sessions, three months apart. The most common adverse effects are pain, swelling, altered sensation and other local reactions, and these may persist for several weeks. At present, the adverse effects, cost and availability are significant limiting factors preventing wider access to this therapy.

Surgery

Surgical treatment should be limited to patients who do not respond to medical therapy and in whom the hyperhidrosis is causing significant life impairment.

Suction Curettage

Minimally invasive suction curettage, a newer local surgical technique for removing axillary eccrine and apocrine glands, may offer superior outcomes and reduced morbidity compared with subcutaneous curettage or excision (which are associated with significant risk of permanent scarring and functional impairment).19 Currently, suction curettage is a viable option for patients who cannot be managed with topical agents or botulinum toxin, however additional studies are needed to determine its exact role as a therapeutic agent.

Endoscopic Thoracic Sympathectomy

Endoscopic thoracic sympathectomy (ETS) is reserved for patients with severe and debilitating symptoms that cannot be managed with any other therapies. It requires the surgical interruption of the upper thoracic sympathetic chain and is indicated primarily for upper extremity or cervicofacial hyperhidrosis. ETS has been widely shown to be effective in the treatment of upper extremity hyperhidrosis, but the risk of adverse effects precludes its broader use. The greatest concerns are recurrence and compensatory hyperhidrosis, the rates of which may be as high as 86%.20-22 ETS may be most appropriate in palmar hyperhidrosis.23

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When to Refer

General practitioners should consider referral to a specialist if the patient does not respond to, or is intolerant of, prescribed topical therapy (e.g. aluminium chloride 20% or equivalent). Doctors comfortable with prescribing anticholinergic agents might consider delaying referral until after exploring this option. Patients who have secondary hyperhidrosis should also be referred to the appropriate specialty if necessary.

Conclusion

Hyperhidrosis is a common and potentially debilitating disease. It is not simply a cosmetic problem, and should always be taken seriously due to its association with depression and impact on daily living. There are a number of treatments currently available that can offer life-changing results, and so general practitioners play a pivotal role in the identification and management of hyperhidrosis.

Declaration

Both main authors declared no conflict of interest.

Further Reading

Hyperhidrosis. DermNetNZ: https://www.dermnetnz.org/topics/hyperhidrosis

International Hyperhidrosis Society: https://www.sweathelp.org

References

1. Strutton DR, Kowalski JW, Glaser DA, Stang PE. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol. 2004 Aug; 51(2): 241-8.

2. Doolittle J, Walker P, Mills T, Thurston J. Hyperhidrosis: an update on prevalence and severity in the United States. Arch Dermatol Res. 2016 Dec; 308: 743-749.

3. Ricchetti-Masterson K, Symons JM, Aldridge M, et al. Epidemiology of hyperhidrosis in 2 population-based health care databases. J Am Acad Dermatol. 2018; 78(2): 358.

4. Ro KM, Cantor RM, Lange KL, Ahn SS. Palmar hyperhidrosis: evidence of genetic transmission. J Vasc Surg. 2002; 35(2): 382-6.

5. Rosen R, Stewart T. Results of a 10-year follow-up study of botulinum toxin A therapy for primary axillary hyperhidrosis in Australia. Intern Med J. 2018 Mar; 48(3): 343-347.

6. Sato K, Kang WH, Saga KT, Sato KT. Biology of sweat glands and their disorders. II. Disorders of sweat gland function. J Am Acad Dermatol. 1989 May; 20(5): 713-726.

7. Hornberger J, Grimes K, Naumann M, Glaser DA, Lowe NJ, Naver H, et al. Recognition, diagnosis and treatment of primary focal hyperhidrosis. J Am Acad Dermatol. 2004 Aug; 51(2): 274-86.

8. International Society for hyperhidrosis. About hyperhidrosis – the effect on patients’ lives – social embarrassment and psychological effects. 2018. [cited 6 March 2018]. Available from: https://www.sweathelp.org/about-hyperhidrosis/the-effects-on-patients-lives/social-embarrassment-and-psychological-effects.html

9. Gross KM, Schote AB, Schneider KK, Schulz A, Meyer J. Elevated social stress levels and depressive symptoms in primary hyperhidrosis. PLoS One. 2014 Mar; 9(3): e92412.

10. Holzle E, Braun-Falco O. Structural changes in axillary eccrine glands following long-term treatment with aluminium chloride hexahydrate solution. Br J Dermatol. 1984 Apr; 110(4): 399-403.

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Video Resources

Lichen Sclerosis: What GPs Need to Know with A/Prof Gayle Fischer

Botox and Hyperhidrosis with Dr Rob Rosen

Watch full lectures on the Healthed website. Visit www.healthed.com.au/video

11. Lakraj AAD, Moghimi N, Jabbari B. Hyperhidrosis: Anatomy, Pathophysiology and Treatment with Emphasis on the Role of Botulinum Toxins. Toxins (Basel). 2013 Apr; 5(4): 821–840.

12. 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 Sep; 323(7313): 596-9.

13. Weinberg T, Solish N, Murray C. Botulinum neurotoxin treatment of palmar and plantar hyperhidrosis. Dermatol Clin. 2014 Oct; 32(4): 505-15.

14. Wolosker N, de Campos JR, Kauffman P, Neves S, Munia MA, BiscegliJatene F, et al. The use of oxybutynin for treating axillary hyperhidrosis. Ann Vasc Surg. 2011 Nov; 25(8): 1057-62.

15. Bajaj V, Langtry JA. Use of oral glycopyrronium bromide in hyperhidrosis. Br J Dermatol. 2007; 157(1): 118-21.

16. Dolianitis C, Scarff CE, Kelly J, Sinclair R. Iontophoresis with glycopyrrolate for the treatment of palmoplantar hyperhidrosis. Australas J Dermatol. 2004 Nov; 45(4): 208-212.

17. Stolman LP, Treatment of excess sweating of the palms by iontophoresis. Arch Dermatol. 1987 Jul; 123(7): 893-6.

18. Glaser DA, Coleman WP 3rd, Fan LK, Kaminer MS, Kaminer SL, Nossa R, et al. A randomized, blinded clinical evaluation of a novel microwave device for treating axillary hyperhidrosis: the dermatologic reduction in underarm perspiration study. Dermatol Surg. 2012 Feb; 38(2): 185-91.

19. Bechara FG, Sand M, Sand D, Altmeyer P, Hoffman K. Surgical treatment of axillary hyperhidrosis: a study comparing liposuction cannulas with suction-curettage cannula. Ann Plast Surg. 2006 Jun; 56(6): 654-7.

20. Drott C, Gothberg G, Claes G. Endoscopic transthoracic sympathectomy: an efficient and safe method for the treatment of hyperhidrosis. J Am Acad Dermatol. 1995 Jul; 33(1): 78-81.

21. Cerfolio RJ, De Campos JR, Bryant AS, Connery CP, Miller DL, DeCamp MM, et al. The society of thoracic surgeons expert consensus for the surgical treatment of hyperhidrosis. Ann Thorac Surg. 2011 May; 91(5): 1642-8.

22. Gossot D, Galetta D, Pascal A, Debrosse D, Caliandro R, Girard P, et al. Long-term results of endoscopic thoracic sympathectomy for upper limb hyperhidrosis. Ann Thorac Surg. 2003 Apr; 75(4): 1075-9.

23. Herbst F, Plas EG, Függer R, Fritch A. Endoscopic thoracic sympathectomy for primary hyperhidrosis of the upper limbs. A critical analysis and long-term results of 480 operations. Ann Surg. 1994 Jul; 220(1): 86-90.

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Editorial TeamMedical Editors: Dr Linda Calabresi, Dr Vivienne Miller Managing Editor: Karina Lozada Editorial Assistant: Neil Harris Commissioning Editor: Dr Ramesh Manocha