Key Words

Introduction

Axillary hyperhidrosis (AH) is a disease that impacts social and occupational lives of lots of people all over the world (Doft et al. 2011; Glaser et al. 2007). It begins at adolescence and affects men and women similarly (Hornberger et al. 2004). When associated with axillary malodor, it is called bromhidrosis.

The pathophysiology of primary focal hyperhidrosis is not well understood. It can be a result of hyperstimulation of eccrine glands, but some authors also believe that apoeccrine sweat glands may be involved (Hamm et al. 2006).

Eccrine glands are distributed over almost the entire body surface (Sato et al. 1989a) and are most numerous on the palms, soles, forehead, axillae, and cheeks (Kreyden and Scheidegger 2004). They are innervated by cholinergic postganglionic sympathetic nerve fibers, excrete sweat, and also contribute for the body temperature regulation (Mota and Sotto 2004). When patients with excessive sweating were compared to normal controls, histological studies have not shown morphological alterations nor increase in the number or size of the sweating glands (Bovell et al. 2001). However, preliminary findings of an interesting study suggest that the eccrine gland’s secretory clear cell exerts a main role at the fluid transport. Only this cell is equipped with a co-transporter and aquaporin channels, and for this reason, it is probably the source of excessive sweating in this form of hyperhidrosis (Bovell et al. 2011).

For the other hand, apocrine glands are selectively located at the urogenital regions and the axillae and are stimulated by epinephrine and norepinephrine (Bovell et al. 2011; Lindsay et al. 2008). They produce a viscid secretion that can become malodorous due to bacterial breakdown (Atkins and Butler 2002).

Apoeccrine glands as described by Sato et al. in 1989 share morphological characteristics from its eccrine and apocrine counterparts corresponding to 10–45 % of all axillary glands. It was also suggested that they would respond to cholinergic stimuli and, intensely, to epinephrine and isoproterenol infusion (Sato et al. 1989; Mota and Sotto 2004; Atkins and Butler 2002). However, subsequent histological studies were not able to demonstrate evidence of apoeccrine glands at the axillary sample tissues (Bovell et al. 2001, 2011). The occurrence of these glands remains controversial (Bechara 2008; Bovell et al. 2011, 2007).

History of Botulinum Toxin and Classification

Botulinum toxin (BoNT) injections have been safely and effectively used as a treatment option for focal hyperhidrosis since 1996, with high levels of patient satisfaction (Glaser et al. 2007; Kalner 2011). Two types of botulinum toxins – BoNT type A (BoNT-A) and BoNT type B (BoNT-B) – were studied in axillary HH, and both demonstrated effectiveness in temporarily inhibiting sweating, although acting at different target sites. BoNT-A binds to and cleaves the 25-kDa synaptosomal-associated protein (SNAP-25), while BoNT-B acts on the vesicle-associated membrane protein (VAMP or synaptobrevin) (Rosell et al. 2013; Trindade De Almeida et al. 2011), both blocking the acetylcholine release from cholinergic neurons innervating sweat glands (Lowe et al. 2007; Trindade De Almeida et al. 2011).

The use of BoNT type A (BoNT-A) for the treatment of axillary hyperhidrosis was approved in 2004 by the US FDA (Grunfeld et al. 2009), and since then, a plenty of studies have confirmed its efficacy, beneficial effects, and paucity of side effects (Heckmann et al. 2001; Naumann and Lowe 2001; Scamoni et al. 2012; Lakraj et al. 2013; Lecouflet et al. 2013).

Many commercial BoNT-A products are available around the world. The formulations are not identical, presenting individual potencies, and caution is necessary to ensure proper use. To reinforce these differences, the FDA established specific drug names to those products approved for use in the US medical market. A summary of them is presented in Table 1.

Table 1 Commercially available BoNT-A
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There is no exact ratio globally accepted among different formulations. Reviewing the related published literature, the most commonly accepted dose correlation among products are 1U OnaA = 1U IncoA = 1U BoNT-A (Lanzhou) = 1U Medy-Tox = 2.5–3u AboA.

The available BoNT-B (rimabotulinumtoxinB) products are NeuroBloc® in the EU and Myobloc® in the USA. Unlike BoNT-A, it is not commercially available worldwide, and probably for this reason, a limited number of studies of axillary hyperhidrosis being treated with this toxin type were published. Few articles describe a long distance side effects of the toxin, such as dry eyes and dry mouth, which are not commonly observed after the use of BoNT-A. Dose correlation found between BoNT-A and BoNT-B varied from 20 to 100u RimaB/1U OnaA (Baumann et al. 2005; Dressler et al. 2002; Frasson et al. 2011; Nelson et al. 2005).

Naumann et al. in a evidence-based review of hypersecretory disorders and botulinum toxins found two Class I (prospective, randomized, controlled, and with masked outcome assessment clinical trial with strict requirements) studies – one with OnaA (Naumann et al. 2001) and one with AboA (Heckmann et al. 2001) – and five Class II (similar to Class I trials but lacking one or some of the required criteria) studies of BoNT-A as a treatment for axillary hyperhidrosis (Naumann et al. 2013). They concluded that the evidence supports a Level A recommendation for BoNT-A in general and Level B recommendation for OnaA and AboA individually, for axillary hyperhidrosis. RimaB and IncoA received Level U recommendation (insufficient data).

Some BoNT comparative trials for axillary hyperhidrosis will be discussed in detail in the following paragraphs.

Studies comparing BoNT-A products:

Kalner performed a prospective same-patient comparison between OnaA in one axilla and AboA in the other, using a conversion factor of 1OnaAu:3AboAu. She observed that OnaA resulted in a faster onset of action, within 1 week, against 2 weeks for AboA and had a longer duration of benefits (9 months), while the axilla treated with AboA maintained the results for 6 months.(Kalner 2011) In another comparative trial performed in 2007 with 10 patients, Talarico-Filho et al. did not find statistically significant differences in the onset of sweating reduction or in the duration of the benefits, using the same conversion factor. (Talarico-Filho et al. 2007)

Dressler, in a double-blind comparative study of 46 patients, used 50U of OnaA in one axilla and 50U of IncoA in the contralateral one and found no difference in efficacy, onset of action, duration, or side effects between the two formulations. Both 100U/vial products were reconstituted in 10 mL of saline (10U/mL) (Dressler 2010).

Studies comparing BoNT-A and BoNT-B products:

In 2011, Frasson et al. treated ten patients using 2500U of RimaB in one axilla and 50U of OnaA in the contralateral one (50UB:1UA). They considered BoNT-B more effective than BoNT-A in reducing sweating production, with faster onset, longer duration of benefit, and higher treatment satisfaction scores. No systemic adverse effects were described. According to the authors, their findings differed from those found in the literature because other studies used lower toxin ratios (40:1 or 20:1) and higher dilutions (Frasson et al. 2011).

In another recent study (2015), An et al. treated 24 patients using 1500U of RimaB in one axilla and 50U of OnaA contralaterally. At a conversion ratio of 1:30, they considered that both neuromodulators had equally effective anhidrotic effects through 20 weeks after a single injection. There was no difference in onset or duration of action between them, nor any significant motor or autonomic side effects were observed. Patient satisfaction was equivalently high to both toxins (An et al. 2015).

In order to reduce side effects and to improve benefits, further studies are still required to treatment standardization. The toxin product will be selected at the physician’s discretion and experience according to its safety and availability.

Toxin Solution

A review about handling botulinum toxins found no standardized dilution for the use of neuromodulators in the treatment of focal hyperhidrosis (Trindade De Almeida et al. 2011). Reported dilutions found in the literature vary from 1 to 10 mL of saline for onabotulinumtoxinA (with the majority of physicians using between 2 and 5 mL), while for abobotulinumtoxinA the reconstitution volumes vary from 1.25 to 10 mL (with the use of 2.5–5 mL being the most frequent). In the only study with incobotulinumtoxinA for hyperhidrosis, the dilution used was 10U/mL. Table 2 summarizes the dilution volumes described in the literature.

Table 2 Reported dilutions for hyperhidrosis
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The present authors prefer to reconstitute the 100U vial of onabotulinumtoxinA (Botox) in 2 mlL of saline, achieving a dose of 50U per mL.

It was also reviewed that several different substances can be added to the toxin solution, with no harm to the toxin, such as hyaluronidase, lidocaine, epinephrine, etc.

Among these substances, the most interesting one for axillary hyperhidrosis treatment is lidocaine. A recent double-blind, randomized, comparative study treated eight patients with 50U of OnaA diluted in 0.5 mL of saline plus 1 mL of 2 % lidocaine into one axilla and 50U of OnaA diluted in 1.5 mL of saline into the other axilla (Gülec 2012). Vadoud-Seyedi also treated 29 patients in a similar manner in 2007 – with a dilution of 5 mL (Vadoud-Seyedi and Simonart 2007). Both studies showed equal effectiveness of BoNT-A reconstituted in saline or lidocaine. However, the toxin diluted in lidocaine caused less pain and may be preferable for treating axillary hyperhidrosis.

When reconstituted with saline admixed with hyaluronidase, onabotulinumtoxinA has its efficacy maintained after 2 weeks and shows enhanced diffusion, as observed by Goodman, in 2003 (Goodman 2003).

Evaluation Methods

After the selection of the toxin, it is important to identify the area to be treated. Minor’s iodine-starch test is a useful method to map the extension of the affected area (Cohen et al. 2007), as well as the posttreatment residual sweating, but it does not provide accurate information on the amount of sweat produced.

The test is not expensive, is very easy to apply, and is usually performed before any topical or regional anesthesia (Glogau 2004). The first step is to remove any wetness of the affected area with an absorbent paper. Then, a 3–5 % iodine solution is applied to the underarm and neighboring region and allowed to dry for a little while. In some patients, the continuous sweat must be wiped again just before the starch application to avoid false reactions (Fig. 1). In contact with starch plus iodine, the sweat acquires a dark purple color, being clearly visible. It is important to note that the commercialized PVPI topical solution with 10 % iodopovidone contains only 1 % of free iodine. Therefore, when using this substance, Minor’s test results could not be satisfactory (Burks 1998).

Fig. 1
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In contact with starch plus iodine, the sweat acquires a dark purple color, which is clearly visible at the center. Normal areas need to be kept dry in order to avoid false positive, visible at lower region

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Another important detail to take into account is that the axillary hyperhidrotic area does not always coincide with the hairy underarm region. For example, if the excessive sweating location is confined to small sites contained in the hairy region (Figs. 2 and 3), the treatment of the whole hair-bearing location will require the use of excessive and unnecessary amount of botulinum toxin units. For the other hand, in some individuals the hyperhidrotic region exceeds or is located outside the hairy area, as observed in Fig. 4. In such cases, if the botulinum toxin treatment is confined to the terminal follicular area, the response will be unsatisfactory, as some regions will be left untreated. It is also not uncommon that the distribution of the affected areas may assume bizarre shapes, like “M,” “S,” “8,” etc., but even these cases will be easily highlighted by the iodine-starch test. For this reason, Minor’s test is mandatory to precisely identify the real affected area in order to optimize the injection of the toxin and ensure effective treatment response.

Fig. 2
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In this individual, the iodine-starch test shows that the hyperhidrotic region is smaller than the hairy area

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Fig. 3
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A patient with the hyperhidrotic area smaller than the hairy area. At the center, the marked area treated with 44U of onabotulinumtoxinA (22 points of 2U each) and after the treatment

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Fig. 4
figure 4

In this patient, the excessive sweating areas are not limited to the hair-bearing regions. The delimitation of the area being treated ensures the effectiveness of the treatment

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For iodine-sensitive patients, Ponceau’s red tincture is an alternative described in the literature (Bushara and Park 1994). This tincture when mixed with starch and in contact with sweat develops a pinkish color. For both techniques, the distribution and maximal perspiration sites must be recorded in photographs for future comparison.

Another useful method for research trials is the gravimetric testing. In daily practice, it is not often applied, because it is time-consuming and requires a precision scale. Under controlled temperature conditions, the produced sweat volume is measured over a fixed period of time. Initially, the affected area is dried using absorbent tissue, and then, a previous weighed filter paper is applied and left on place for a certain period of time. The volume of produced sweat during this time interval is quantified by measuring the weight of the paper before and after contact to the sweating area. There are variations in the evaluation period among authors. Heckmann et al. (2001) prefer one-minute contact with the affected area, while Naumann and Lowe and Hund et al. consider 5 (Hund et al. 2002; Naumann and Lowe 2001); Bahmer and Sachser, 10 (Bahmer and Sachse 2008); and Odderson, 15 min (Odderson 2002).

The Hyperhidrosis Area and Severity Index (HASI) is the association of the two previous methods, gravimetry and Minor’s test, and was proposed by Bahmer et al. It uses a transparent square-lattice grid and a counting system where one centimeter (cm) represents one point. After estimation of the sweating area, the volume of secretion weighed through gravimetry after 10 min is divided by the number of sites in the affected area. The HASI score is given in mg of sweat by cm2 per minute. They consider hyperhidrosis when HASI reaches values above 1 mg/cm2 per minute.

Evaluation of Impact on Quality of Life

Hyperhidrosis impacts routine life in several aspects like interpersonal relationships, work, leisure activities, and self-esteem and is considered by many as a stigmatizing condition. Feelings of shame, intrusiveness, and depression are frequent among sufferers.

The quality of life (QoL) of focal idiopathic hyperhidrosis affected individuals may be measured through several tests. The most frequently used is the Hyperhidrosis Disease Severity Scale (HDSS), in which a score of 3 or 4 indicates severe hyperhidrosis; of 2, moderate; and of 1, absence of it. The HDSS evaluates the impact of the disease in daily life using a single question: “How would you rate the severity of your hyperhidrosis?” with four possible answers as the following: my sweating is never noticeable and never interferes with my daily activities (score 1), my sweating is tolerable but sometimes interferes with my daily activities (score 2), my sweating is barely tolerable and frequently interferes with my daily activities (score 3), and my sweating is intolerable and always interferes with my daily activities (score 4) (Strutton et al. 2004).

Another instrument described by Campos and colleagues was termed the clinical protocol for quality of life. This questionnaire includes one general question asking for overall QoL reduction and 20 questions belonging to four domains covering compromising effects on function and social activities, personal limitations with partners, emotional impairment, and restrictions under special circumstances. The answers are scored, and the result is ranked to one of the five QoL levels (De Campos et al. 2003; Wolosker et al. 2010).

The most frequent questionnaire used to measure the effects of dermatologic diseases on QoL is the Dermatologic Life Quality Index (DLQI). It is general and consists of ten items covering symptoms and feelings, daily leisure, work and school activities, personal relationships, and treatment. Each item has four assortments, between 0 and 3, and the total score ranges from 0 to 30 (Finlay and Khan 1994).

Some other tools to measure the HH impact on QoL had been described, but so far, there is no consensus among different medical specialties in the use of one specific instrument whose final score would facilitate comparison between different populations and/or therapeutic modalities.

Injection Technique

When the affected area was identified and recorded by photographs, its contour is then delimited, and the distribution of injection points is chosen using a marker pen or gentian violet. At this moment, it is possible to apply a local topical anesthetic, which will improve patient’s comfort during the procedure. If applied before, the anesthetic cream might impair the test.

Skiveren et al. investigated whether the use of a 30G versus a 27G needle influenced pain intensity in 38 patients treated with BoNT-A for axillary hyperhidrosis. The pain scores recorded after the first five injections were significantly lower for the 30G needle than for the 27G needle. For this reason, smaller needles are preferable to improve patient comfort (Skiveren et al. 2011).

The injection should be intradermal using a 30G needle attached to the syringe (0.3- or 0.5-mL syringes, Ultrafine II 30U or 50U insulin syringes; Becton Dickinson Co, New Jersey, USA), which eliminates the dead space between the needle and the syringe, as well as the risk of expelling the needle during injection. The number of injections and the total dose will depend on the involved surface area.

Once injected, it is noted that the toxin concentration will be higher at the central point, with a decreasing gradient along the peripheral areas (Glogau 2004). The aim of the treatment is to create overlapping and confluent anhidrotic halos in order to achieve maximum outcome (Klein 2003).

Table 3 summarizes the usual BoNT doses for axillary hyperhidrosis as described in the literature.

Table 3 Reported mean dose per axilla for each BoNT
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Approximately 10–20 intradermal injections in 0.1–0.2-mL aliquots (total dose: 50–100U onabotulinumtoxinA) are used for each axilla, spaced 1–2 cm apart. Injections may also be performed in the superficial fat without adverse events or significant reduction in efficacy.

The vast majority of patients have excellent treatment results. The effects begin 2–4 days after injection and last approximately 6–9 months; however, in some cases, it may last more than 1 year. In our experience, the longest duration outcomes are obtained when the excessive sweating location could be precisely delimitated. Only when the patient could not sweat during iodine-starch test, the hair-bearing area is injected, and in some of these cases, longer duration could not be warranted.

A recent publication by Brehmer et al. recently describes what some authors were perceiving in daily practice: that repetitive botulinum toxin treatments led to a significant increase in the anhidrotic effects in axillary hyperhidrosis. In a retrospective analysis in 101 patients with axillary hyperhidrosis confirmed and quantified by gravimetric analysis and Minor tests, injected with 50U of onabotulinumtoxin type A/per axilla that received at least three sessions of treatment, the efficacy duration was evaluated after the first, second, and last treatment. The median duration of efficacy was 4.0 months, 4.5 months, and 5.0 months after the first, second, and last injection, respectively. However, the amount of axillary hyperhidrosis by gravimetric analysis was not quantified prior to every botulinum toxin retreatment session (Brehmer et al. 2015).

Alternative Techniques

Other techniques have been used as a variation of the traditional needles punctures.

A multi-injection round plate with five or seven 27G device used for intralesional steroid therapy of alopecia areata was described. According to the authors, a rapid application in uniform and homogeneous manner was obtained, avoiding repeated punctures (Grimalt et al. 2001).

A multiple-site marking grid made of flexible silicon sheet with holes punched out at a 1-cm distance was also described (Exmoor Plastics Ltd –Taunton, UK). After the location of the excessive sweating, the grid is positioned on the affected area, and the site is marked through the holes in the grid with a skin marker pen (Jain 2006).

Singh et al. suggest the use of microneedling as an emerging technique for delivering botulinum toxin in a safe and pain-free way (Singh et al. 2015).

However the use of these alternative techniques implies in availability of the devices, while traditional injections only depend on easily available materials, in addition to well-trained professionals.

Table 4 provides a summary of all practical information needed for a good performance of BoNT treatment of excessive underarm sweating .

Table 4 Practical information for BoNT treatment of axillary hyperhidrosis
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Transcutaneous Botulinum Toxin

The botulinum toxin A molecule directly applied to the skin is not absorbed due to its large molecular size. For this reason, the development of a noninvasive, effective, and safe method to deliver botulinum toxin through the skin has been objective of recent research (Glogau 2007).

A biopharmaceutical company (Revance Therapeutics, Inc.) developed a mechanism that allows a transepidermal absorption of large molecules. It is composed of a peptide derived from residues of the transactivator of transcription protein that allowed the creation of the first topical formulation of BoNT-A (RT001) to date (Carruthers and Alastair 2015). The use of this transport peptide vehicle allowed successful transcutaneous penetration of BoNT-A (Chow and Wilder 2009; Glogau et al. 2012).

In a small controlled clinical trial, Chow and Wilder found statistically significant reduction of sweat production in 12 cases of axillary hyperhidrosis using 200U of onabotulinumtoxinA reconstituted with saline admixed with the transport peptide. The duration of effect was not mentioned (Chow and Wilder 2009).

This innovative method promises a revolution in the treatment of hyperhidrotic affected areas and may be useful in the future for other indications as well.

Conclusion

Botulinum toxin proved to be safe and effective for hyperhidrosis treatment, although its pathophysiology remains controversial. Nevertheless, according to evidence-based review, the beneficial effect of type A neuromodulators in inhibiting localized sweating temporarily supports a Level A recommendation, for axillary hyperhidrosis.

Take-Home Messages

  1. 1.

    Axillary hyperhidrosis impacts social and occupational lives of lots of people in all continents, and its real incidence is probably underestimated. Botulinum toxin is a safe and effective treatment option for axillary hyperhidrosis.

  2. 2.

    The BoNT-A formulations are not identical, presenting individual potencies, and caution is necessary to ensure proper use.

  3. 3.

    Reported dilutions found in the literature vary from 1 to 10 mL of saline for onabotulinumtoxinA (with the majority of physicians using between 2 and 5 mL), while for abobotulinumtoxinA, the reconstitution volumes vary from 1.25 to 10 mL (with the use of 2.5–5 mL being the most frequent). In the only study with incobotulinumtoxinA for hyperhidrosis, the dilution used was 10U/mL.

  4. 4.

    Hyperhidrosis causes impact at the everyday life in several aspects like interpersonal relationships, work and leisure activities, and self-esteem and is considered by many as a stigmatizing condition. Feelings of shame, intrusiveness, and depression are frequent among sufferers.

  5. 5.

    Botulinum toxin proved to be safe and effective for hyperhidrosis treatment, although its pathophysiology remains showing some controversial topics.