As measured by standardized questionnaires, primary focal hyperhidrosis negatively affects many fields of daily life to a significant extent, including emotional status, personal hygiene, work and productivity, leisure activities and self-esteem (Hamm et al., 2006). The so-called Hyperhidrosis Disease Severity Scale (HDSS) (Box 22.2), a single-item question allowing four gradations of the tolerability of sweating and its interference with daily activities, offers a simple and useful way to estimate the impairment of quality of life (Lowe et al., 2007).

History taking is the most important tool in the diagnosis of primary focal hyperhidrosis and the exclusion of secondary types. Physical examination should focus on visible evidence of excessive sweating in the characteristic locations and on detection of signs that suggest a secondary cause. Laboratory tests are not needed if the presentation is characteristic and if evidence of secondary causes is lacking. In contrast, generalized forms of sweating and asymmetric patterns have to be evaluated for underlying disorders (Hornberger et al., 2004). Gravimetric quantification of sweat production in predominantly involved sites is not routinely performed but may be helpful to support the diagnosis, to rate the severity and in clinical research. Minor’s iodine–starch test is used to outline the sweating area prior to botulinum neurotoxin (BoNT) treatment or local surgery (see below).

Conventional treatment options

There are a large number of treatment options for primary focal hyperhidrosis, the utility of which partly depends on the site involved (Hoorens and Ongenae, 2012).

When seeking medical advice, most patients with primary axillary hyperhidrosis have already tried over-the-counter antiperspirants without success. The majority of them, particularly those with mild to moderate hyperhidrosis, can be treated effectively with topical aluminum chloride salts, which mechanically obstruct the sweat gland ducts. We prefer aluminum chloride hexahydrate 15% in aqueous solution thickened with methylcellulose (aluminum chloride hexahydrate 15 ml, methylcellulose 1.5 ml, distilled water to 100 ml) and bottled in a roll-on flask; others recommend absolute alcohol or salicylic acid gel as base for the preparation. To minimize skin irritation, the solution should be applied to dry, clean armpits at bedtime and washed off after getting up in the morning. Initially, it is used every other evening until euhidrosis is achieved. The frequency of application can often be tapered to once every 1–3 weeks to maintain the effect. Continued treatment may even lead to atrophy of the secretory cells. If ineffective, every evening application or higher concentrations may be tried, but this will often not be tolerated by the patient. In contrast, the irritative potential of aluminum chloride salts is less severe on palms and soles and so concentrations may possibly be increased to 25–35%. Nevertheless, this treatment has proved less potent and less feasible in other than the axillary region.

Tap water iontophoresis using direct current or direct plus alternating current is regarded as the most effective non-invasive therapy for palmar and plantar hyperhidrosis. Iontophoresis is thought to work by transient disruption of ion transport in the sweat gland, but its exact mode of action is unclear. Hands or feet are placed in a shallow basin filled with tap water through which an electric current at 15–20 mA is passed for 15–30 minutes. Initially, patients undergo five to seven treatments per week, and six to ten treatments are usually required to achieve euhidrosis. Side effects include burning, tingling (“pins and needles”), irritation, erythema, skin dryness, transient paresthesia and rarely vesicles. Such reactions are best prevented by petrolatum. To maintain the effect, regular sessions about once or twice a week are necessary, which is why many patients refrain from continuation of the time-consuming procedure. The method is less practical for axillary hyperhidrosis and it is contraindicated in pregnancy and in patients with a pacemaker or metal implant.

Oral anticholinergic drugs such as methantheline bromide, propantheline bromide and bornaprine are able to suppress sweating for a short time but their effect is often accompanied by side effects, such as dry mouth, blurred vision, dizziness, urinary retention and constipation. Glycopyrrolate, oxybutynin, quetiapine, diazepam, amitriptyline, beta-blockers, diltiazem, clonidine, gabapentin and indomethacin are further oral agents that have been tried in a limited number of patients with hyperhidrosis, with variable success.

Surgery can be offered as a last choice in severe cases. Various techniques of local elimination or destruction of sweat glands have been proposed to treat axillary hyperhidrosis. En bloc excision of the entire sweating area as the simplest and most effective method has largely been abandoned since it inevitably leads to large unsightly scars. Nowadays, curettage, liposuction and combined techniques (suction curettage) performed under local or tumescent local anesthesia are favored as they have far better cosmetic results. However, bleeding, hematomas, seromas, wound infection, skin necrosis, prolonged wound healing, paresthesiae, prominent scars and wound contractures interfering with arm mobility are possible complications, and only about 70% of patients benefit from these local procedures in the long run. Microwave devices causing irreversible thermolysis of eccrine sweat glands at the interface between skin and subcutaneous tissue are an evolving treatment option that deserves further research (Glaser et al., 2012).

Endoscopic thoracic sympathectomy interrupts the transmission of sympathetic nerve impulses from ganglia to nerve endings and is the most efficient but also the most invasive method to treat focal hyperhidrosis. Usually, thoracic sympathetic ganglia T₃ and T₄ are destroyed or cut through by electrocautery for treatment of palmar hyperhidrosis and, in addition, T₂ in craniofacial hyperhidrosis. In about 98% of patients with palmar hyperhidrosis, immediate complete anhidrosis occurs, with only low rates of recurrence; the results in axillary hyperhidrosis are less convincing. Acute and early complications are rare but include bleeding; hemo-, pneumo- and chylothorax; pleural adhesion or effusion; neuralgia; and complete or incomplete Horner’s syndrome. However, compensatory sweating mainly of the back, abdomen and legs develops regularly some weeks to months after surgery, as well as gustatory sweating, in up to half of the patients. Incapacitating compensatory sweating is claimed by about 5–10% of patients. Therefore, endoscopic thoracic sympathectomy should be reserved for patients with severe palmar hyperhidrosis who have not responded to any other treatments available.

Treatment algorithms for primary axillary and primary palmar hyperhidrosis worked out in an international consensus conference are presented in Boxes 22.3 and 22.4, respectively (Hornberger et al., 2004).

Botulinum neurotoxin therapy

At the turn of this century, BoNT type A (BoNT-A) evolved as a novel, minimally invasive therapeutic modality for focal hyperhidrosis. When injected intradermally, the neurotoxin blocks the release of acetylcholine from the sympathetic nerve fibers that stimulate eccrine sweat glands and causes a localized, long-lasting but reversible abolishment of sweating.

Use of BoNT-A has been evaluated most extensively in primary axillary hyperhidrosis. Three large randomized, placebo-controlled, double-blind studies and numerous open-label studies clearly document its effectiveness and safety in this indication. In a European study enrolling 320 patients, 94% of patients treated with 50 U onabotulinumtoxinA per axilla were treatment responders at week 4 (>50% reduction in sweat production from baseline gravimetric measurement), with an average reduction in sweat production of 83.5% (Naumann and Lowe, 2001). In a 12-month follow-up study, 207 of these patients received up to three further BoNT-A injections. Response rates and satisfaction with treatment remained consistently high with no diminution of effect and no confirmed positive results for neutralizing antibodies to BoNT-A with repeated treatments (Naumann et al., 2003). Mean duration of benefit was about 7 months after a single treatment and 28% of patients did not require more than one injection, indicating a long-lasting benefit of at least 16 months. No major side effects occurred, with subjective increase in non-axillary sweating perceived by 4% of the patients being the most frequent complaint. Treatment with BoNT-A also markedly improved the quality of life of patients (Naumann et al., 2002).

In a multicenter North American trial in 322 patients comparing 50 U onabotulinumtoxinA per axilla with 75 U onabotulinumtoxinA per axilla and placebo, responders were defined as having at least a 2-grade reduction in their HDSS score. There was a 75% response rate in the treatment groups compared with a 25% response rate in the placebo-treated patients, but without significant difference between the groups treated with different onabotulinumtoxinA doses (Lowe et al., 2007). In the treatment groups, 80–84% had at least a 75% reduction in sweat production, compared with only 21% in the placebo group. Median duration of the BoNT-A effect was again approximately 7 months. These studies led to the licensing of Botox (onabotulinumtoxinA) for axillary hyperhidrosis in many countries worldwide. Currently, it is the only BoNT formulation licensed for use in hyperhidrosis.

A randomized, placebo-controlled, double-blind study in 145 German patients with one axilla being treated with either 100 or 200 U abobotulinumtoxinA and the contralateral one with placebo obtained similar results with regard to efficacy and safety (Heckmann et al., 2001). A significant decrease in sweat production compared with placebo was observed after 2 weeks and maintained 24 weeks after injection. The two doses proved equally effective in reducing axillary sweating.

So far, only one single-center study on the effect of the novel BoNT-A preparation incobotulinumtoxinA has been performed in hyperhidrosis. Double-blind, intraindividual side-to-side comparison of 50 U onabotulinumtoxinA and 50 U incobotulinumtoxinA in 46 patients showed no differences in onset, extent and duration of effect, as evaluated by patient and physician (Dressler, 2010). Of note, the decrease in sweat production was not assessed by gravimetrical assessment.

There are a number of smaller controlled and observational studies showing that BoNT-A (onabotulinumtoxinA, abobotulinumtoxinA) is also a valuable treatment option in palmar hyperhidrosis (Saadia et al., 2001; Simonetta Moreau et al., 2003). However, treatment is more complex, injections are considerably more painful, higher doses are needed, and the effect is less pronounced and less long-lasting than in axillary hyperhidrosis.

Reduction or elimination of pain during palmar injections can be achieved by median and ulnar nerve blocks performed a few centimeters proximal to the wrist. However, transient paresthesiae and the potential risk of permanent nerve damage, particularly associated with repeated treatments, are major disadvantages. In addition, patients are bothered by the sensation of disabled hands for several hours. Therefore, cryoanalgesia with ice cubes, frozen gel packs, forced cold air, liquid ethylchloride or dichlorotetrafluoroethane (Frigiderm) is preferred by most colleagues because of its convenience, low risk and minimal cost (Doft et al., 2012). Precooling the hand in iced water for several minutes may have an additional benefit. Moreover, topical lidocaine cream, vibratory anesthesia, intravenous regional anesthesia (Bier block) and general sedation have been advocated to reduce or eliminate the pain.

Manufacturers generally recommend reconstitution of BoNT products in unpreserved saline. However, limited experience suggests that the use of preserved saline and solutions with local anesthetics such as lidocaine may reduce injection pain without affecting efficacy of the BoNT (Trindade de Almeida et al., 2011).

The usual dose is 100 U onabotulinumtoxinA or equivalent per palm but 150 U or more may be required depending on its size. Sweating is reduced to about half the pretreatment amount, and the effect lasts about 4 months on average (Lowe et al., 2002). Longer disease history seems to predict shorter duration of effect (Campanati et al., 2011). Mild weakness of the intrinsic hand muscles, particularly of the thumb–index finger pinch strength, may occur in a minority of patients for up to 4–6 weeks and is usually insignificant. This most frequent side effect should be particularly pointed out to manual workers.

Injection pain and decreased hand muscle strength may be overcome by delivery of BoNT-A via iontophoresis. Two pilot studies in eight patients each showed a significant decrease of sweating in the palm treated by BoNT-A iontophoresis compared with the palm treated by normal saline iontophoresis until week 12 (Kavanagh and Shams, 2006; Davarian et al., 2008). In the absence of larger studies, the relevance of this observation has to be awaited.

According to a few smaller studies injections of BoNT type B (BoNT-B) seem to be similarly effective as BoNT-A in axillary and palmar hyperhidrosis. Doses used were 2000–5000 U rimabotulinumtoxinB per axilla and 5000 U per palm. Compared with BoNT-A, side effects occur considerably more often with BoNT-B, particularly systemic adverse events, including dryness of the mouth and throat, dryness of eyes, indigestion and heartburn (Dressler et al., 2002; Baumann et al., 2005).

In axillary hyperhidrosis, BoNT-A treatment is now the treatment of choice if topical treatments prove ineffective. In palmar hyperhidrosis, it should be considered if topical treatments and iontophoresis have failed. Another excellent indication for BoNT-A treatment is gustatory sweating (Frey’s syndrome), which is discussed in more detail in Chapter 12.

Primary hyperhidrosis of other sites has also been treated with BoNT-A, such as the scalp (Fig. 22.1) (Anders et al., 2008), forehead (Kinkelin et al., 2000), nose, anal fold, groins and soles (Campanati et al., 2007); it has also been used in certain types of regional secondary hyperhidrosis, such as Ross syndrome (Fig. 22.2), residual limb hyperhidrosis in amputees (Charrow et al., 2008), congenital eccrine nevus and compensatory sweating (Kim et al., 2009). Experience in these indications is much more limited than in axillary and palmar hyperhidrosis, and no general recommendations can be given.

Fig. 22.1 Cranial hyperhidrosis 4 weeks after treatment with botulinum neurotoxin type A injections. Areas in which sweating is abolished are visualized by iodine–starch test.

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