Introduction

Botulinum toxin is a safe, well-established, and effective treatment for focal axillary hyperhidrosis. This chapter will present the principles and common techniques for its practical application in this clinical setting.

Epidemiology

The prevalence of HH was reported by Strutton et al to be 2.8%, though it may be underestimated due to undiagnosed cases. The prevalence is similar for men and women, although interestingly, Lear and colleagues reported that women are more likely to seek evaluation and treatment. Trigger factors include emotional stress, higher environmental temperatures, and stimulants such as caffeine. However, episodes of excessive sweating can occur without any known trigger. The body areas most often affected are the axilla, palms, soles, craniofacial, inframammary and groin (Table 23.1).

Table 23.1 Hyperhidrosis site prevalence in a patient population reported with respect to each site*

^* Data from Lear W, Kessler E, Solish N, et al 2007 An epidemiological study of hyperhidrosis. Dermatologic Surgery 33:S69–S75.

Quality of life

Hyperhidrosis has a negative impact on physical, psychological, and occupational aspects of a patient’s daily living. Hamm and colleagues found that the greatest impact of HH is the significant reduction in the quality of life and alteration of daily function. Patients report a lack of confidence and depressed mood. They refrain from meeting new people and avoiding intimate activity. Excess sweat may force patients to change clothes several times before the end of the day.

The hyperhidrosis disease severity scale (HDSS) is a validated scale that is used in selecting patients appropriate for therapy and assessing effectiveness of treatment. The HDSS is based on one question the patient can answer in the office: ‘Which best describes the impact of sweating on your daily activity?’ The answer is rated with a single value 1–4, with 3–4 corresponding to uncontrolled severe HH (Table 23.2). It is frequently used in clinical practice to assess the need for therapy and response to it.

Table 23.2 Hyperhidrosis disease severity scale question:
Which best describes the impact of sweating on your daily activity?

Clinical assessment of hyperhidrosis

The starch iodine test is a simple way to detect the presence of sweat and identify the surface area involved, however it is not quantitative. The test is effective on both shaved and non-shaved skin. To perform, the skin to be tested is completely dried using a towel. An iodine solution (commonly Betadine^®) is painted over the field and allowed to dry (Fig. 23.1). After the solution is thoroughly dry, a starch powder such as plain cooking corn starch is sprinkled on the surface. Various tools may be used to accomplish the distribution of starch such as loose gauze, cosmetic brushes or a fine-opening shaker (Fig. 23.2). Accurate colormetric results are achieved when the amount of powder is minimized. Moisture from sweat dissolves the iodine and starch followed by a chemical reaction producing a purple to black color. True positive reactions have a speckled appearance as moisture is released from duct openings (Fig. 23.3). For iodine-sensitive patients, Alizarin or Ponceau red dye and starch can be used instead. Regardless of which is used, a colorimetric outline of the sweating area is achieved.

Figure 23.1 Iodine is applied to a clean dry surface.

Figure 23.2 Cornstarch is applied sparingly after iodine has dried.

Figure 23.3 True positive starch iodine results.

False positives occur if the skin has not been thoroughly dried of sweat or if iodine solution is not thoroughly dry prior to starch application. This appears as streaks or smears of dark pigment (Fig. 23.4). False negatives may occur if starch is applied too heavily (Box 23.2).

Figure 23.4 If residual sweat or moist iodine is not dried before starch is applied, darkened smearing is the result and should be considered as artifact.

Botulinum toxin therapy

Contraindications to botulinum toxin A include prior allergic reaction, injection into areas of infection or inflammation, pregnancy (category C), or breastfeeding. Relative contraindications include diseases of the neuromuscular junction (e.g. myasthenia gravis, Eaton-Lambert) cautiously because underlying generalized weakness can be exacerbated. Some medications decrease neuromuscular transmission and would be prudent to avoid in patients treated with botulinum toxin. These include aminoglycosides, penicillamine, quinine, and calcium channel blockers.

Botulinum toxin A has been used for several decades to treat AHH. In 2004, onabotulinumtoxinA was FDA approved for treatment of AHH. It is a purified neurotoxin produced by clostridium botulinum. The toxin prevents the release of acetylcholine from the nerve axon at the neuroglandular junction producing a state of denervation. Since sweating is mediated by acetylcholine, the use of botulinum toxin (BoNT) to treat AHH is a logical choice. When injected intradermally, the chemodenervation is localized, reversible, and yet long lasting.

OnabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA are derived from Botulinum toxin type A (BoNT-A). OnabotulinumtoxinA and abobotulinumtoxinA have been most extensively studied for HH. Botulinum toxin type B can be effective, but Dressler et al and Frasson et al reported that the side effect profile is quite different from BoNT-A. Given its effectiveness and safety profile, onabotulinumtoxinA has emerged as the clinically preferred treatment. As dosing is different among the BoNT-A products, these agents cannot be used interchangeably.

The foremost principle for using BoNTs to treat excessive sweating is, as discussed, to treat any underlying etiology first. The area of involvement should be objectively identified using a colorimetric test such as a starch iodine test. Sweat glands are typically located at the junction of the dermis and subcutaneous fat. For optimal BoNT interaction at the neuron–eccrine interface, it should be placed as a deep intradermal injection. Injections are generally placed 1–2 cm apart to allow to diffusion into the entire area. It is important to avoid injecting deeper structures to prevent unwanted denervation. This basic technique used to treat axillae can be applied to most areas of the body with minor variations.

Different philosophies exist for choosing a dilution volume. The prevailing sentiment seems to be that a high volume (lower concentration) will diffuse to treat more area. Locations where high volume would be appropriate are axillae, scalp, inframammary, and inguinal skin. In an area such as the forehead, a large diffusion field increases the risk of developing brow ptosis, thus a lower volume (higher concentration) may be employed.

Reisfeld and colleagues reported that compensatory hyperhidrosis is a common side effect of endoscopic thoracic sympathectomy (ETS). This phenomenon is considered rare in BoNT injection therapy. Occasionally patients report the perception of increased sweating in untreated anatomical locations after having the primary site treated. The authors have never seen clinically significant compensatory HH after onabotulinumtoxinA treatment. However, some patients will notice the sweat more from other body areas after their primary location has been treated and is dry.

Axillary hyperhidrosis

No area of the body has been studied as extensively as the axillae. Numerous studies show the benefit of BoNT-A, including large, multicenter, randomized, placebo-controlled trials in Europe and the United States. One study by Naumann & Lowe reported on 320 patients with AHH who received 50 units of Botox^® (onabotulinumtoxinA) per axilla or placebo. At 4 weeks, 94% of the onabotulinumtoxinA group had responded compared with 36% of the placebo group. Response was determined by ≥50% reduction in sweat production from baseline. By 16 weeks, the response rates were 82% and 21%, respectively. The mean duration between onabotulinumtoxinA treatments was approximately 7 months.

Similar results were published in a large Phase III double-blind trial in North America by Lowe and co-workers. Subjects with AHH (HDSS of 3 or 4) were randomized to receive placebo, 50 units, or 75 units onabotulinumtoxinA into each axilla. A successful response occurred in 75% of patients in both treatment groups compared with 25% in the placebo group (defined as ≥2 point reduction in HDSS). No significant differences were noted between the two doses of onabotulinumtoxinA and the durability of therapy was approximately 7 months for both.

Although studies have consistently shown that 50 units onabotulinumtoxinA per axilla provides safe and durable results, there is some debate whether higher doses of onabotulinumtoxinA can provide prolonged efficacy. When Wollina used 200 units of onabotulinumtoxinA per hand in 10 patients, his relapse time varied from 3 to 22 months. In one small open label study by Heckmann and colleagues, 250 units of abobotulinumtoxinA in each axilla resulted in prolonged benefit; 83% of which remained symptom free after 9 months. Moreover, 58% remained symptom free for a full 12 months.

Currently the US standard dose listed in the package insert for onabotulinumtoxinA is 50 units per axilla. This achieves excellent results, high patient satisfaction, and helps to keep cost down. If the response is not adequate or of short duration, it is the authors’ practice to repeat the starch iodine test to assess the possibility of inadequately treated area. Then if indicated, touch up areas or simply increase the dose of onabotulinumtoxinA to 100 units per axilla. There is no such dosing consensus on other brands of BoNT-A products.

To concentrate the BoNT-A into the affected area and optimize treatment, the area of involvement should be identified by a starch iodine test (as previously reviewed). Injection points may be marked with a pen to ensure adequate treatment (Fig. 23.5). The axilla does not need to be shaved prior to performing a starch iodine test or before injecting BoNT-A. The BoNT-A is injected into the deep dermis at the dermal subcutaneous level. Each injection is placed 1–2 cm apart. Thin axillary skin allows for visualization of a wheal at each site (Fig. 23.6). An average of 10–15 injections per axilla are required, but will depend on the size of the axilla and hyperhidrodic area. In the event that a starch iodine test cannot be performed prior to treatment or the test is equivocal, the physician should treat the hair-bearing areas using the same technique (Box 23.3).

Figure 23.5 Injection points are marked 1.5–2 cm apart in a staggered arrangement for efficient coverage after medication diffusion.

Figure 23.6 Depth of injection is at the dermal–subcutaneous junction. In the axilla, a small wheal can be visualized.

Should symptoms fail to improve within 2 weeks, the patient should return to the office for a repeat starch iodine test to identify any persistently ‘active’ eccrine glands (Fig. 23.7). The skin should be injected with 3–5 units of BoNT-A for each centimeter surface area identified.

Figure 23.7 If treatment is incomplete, a repeat starch iodine test can help identify small areas of active sweat production that may have been missed.

Pain is minimal and the axillary procedure is well tolerated. Despite the package insert describing the use of unpreserved saline to reconstitute BoNT-A, many physicians (e.g. Alam and colleagues, Sarifakioglu & Sarifakioglu) have found the use of preserved saline reduces pain without altering efficacy. Side effects noted in studies include pain, hematoma, bruising, headache, muscle soreness, increased facial sweating, perceived compensatory sweating, and axillary pruritus.

Retreatment with onabotulinumtoxinA will average every 6–7 months, but can vary depending on the patient’s response. In order to extend the interval between injections, Lowe and colleagues advocate patient use of a topical antiperspirant twice a week when sweating starts to return.

Use of botulinum toxin type B for hyperhldrosis

Botulinum toxin type B (BoNT-B) use has been primarily limited to treatment of cervical dystonia, but there are reports of its use for treating HH. Birklein and co-workers found that injection of BoNT-B can induce focal anhidrosis in a dose-dependent fashion. Dressler reported that 100 units onabotulinumtoxinA, 2000 units BoNT-B, and 4000 units BoNT-B were equally effective in blocking axillary sweating when studying 19 HH patients. The duration of relief was similar (16 weeks) in all groups. In general, the onset of action occurs earlier with BoNT-B.

Despite its ability to induce anhidrosis, Schlereth and colleagues found that the use of BoNT-B is limited by the occurrence of systemic adverse events. Additionally, there was greater discomfort with the BoNT-B compared with onabotulinumtoxinA. In a study by Nelson and co-workers, patients treated with 5000 units BoNT-B in each axilla achieved excellent reduction in sweating, but the incidence of side effects was high and included dry mouth, headache, and sensory motor symptoms of the hand. Due to the incidence of systemic side effects using BoNT-B and the high safety profile using BoNT-A to treat focal hyperhidrosis, to date BoNT-A is the neurotoxin of choice.

Techniques for non-axillary hyperhidrosis

Aside from axillary hyperhidrosis, onabotulinumtoxinA may be used to treat a wide variety of sweating disorders. However, it should be noted that its use to treat these conditions is off-label. The principles for treating other areas of the body generally parallel the techniques described above for axillae, but with minor variations.

The optimum dose of BoNT-A to control palmar HH is unknown and the issue is complicated by large variations in hand size. Published data by Saadia et al and Wollina et al report doses as low as 50 units per hand and as high as 200 units onabotulinumtoxinA per hand. Naumann’s group used 2 units every 1.5 cm on the palm but 3 injections per fingertip and 2 injections into each of the middle and proximal phalanx using 1–2 units per injection. The authors inject 2.5 units of onabotulinumtoxinA in the pattern described above. Additionally, pain is much more a factor in palmar treatment procedures. Various methods may be used during injection to attain acceptable pain control. Some of which include cold anesthesia, vibratory sensory interference, topical anesthesia, and nerve blocks.

There is a paucity of literature published on BoNT-A therapy for craniofacial hyperhidrosis. It is the observation of the authors that patients typically present with forehead sweating that may be combined with scalp sweating in a diffuse pattern or in an ophiasis pattern. OnabotulinumtoxinA reconstituted at 50 units/mL (twice the concentration used in axillae) may be used in an effort to limit the diffusion into the frontalis muscle and reduce the risk of brow ptosis. Injections are performed with 2–3 units every 1–2 cm avoiding the inferior 1–2 cm of the forehead to again reduce the risk of brow ptosis. Typical doses of onabotulinumtoxinA used by the authors are 50–100 units to treat the forehead and frontal hairline, 200 units to treat the forehead and the perimeter of the scalp, and 300 units when treating the forehead and entire scalp.

OnabotulinumtoxinA is the treatment of choice for gustatory sweating and Frey syndrome. The starch iodine test is performed on the patient’s face in the fashion previously described. For accurate results, it is helpful to have the patient eat or chew a food that typically induces sweating. OnabotulinumtoxinA is injected using 2.5 units every 1.5–2 cm to cover the area indicated by the starch iodine test. As when treating craniofacial hyperhidrosis, OnabotulinumtoxinA reconstituted at 50 units/mL may be used in an effort to limit the diffusion area and risk of facial asymmetry.

Reisfeld et al reported that compensatory sweating is the most common complication of endoscopic transthoracic sympathectomy (ETS). Treatment is particularly difficult, but reports have noted success using BoNT-A. Huh and colleagues used 300 units abobotulinumtoxinA to treat the chest and abdomen after identifying the area with a starch iodine test. Each 100 units of onabotulinumtoxinA were diluted in 10 mL saline and injected 0.1 mL into each square centimeter.

Future directions

The use of botulinum toxins has revolutionized the treatment of AHH and other secretory disorders. Compared with other treatments, it is unmatched in its efficacy, ease of administration, and patient satisfaction. New delivery devices are being researched to provide the most comfortable and efficient therapy. Kavanagh and colleagues have successfully used a small iontophoresis machine to deliver BoNT-A to two patients with severe palmar hyperhidrosis, sparing them injections. Glogau demonstrated that onabotulinumtoxinA can be successfully delivered into the axillary skin when combined with a proprietary transport peptide molecule. For the present, BoNT therapy is a valuable, well-tolerated therapy and can provide meaningful improvement in the quality of life of patients with AHH and other secretory disorders.