Primary axillary hyperhidrosis is a medical condition characterized by excessive underarm sweating that is thought to result from localized hyperstimulation of sweat glands by cholinergic sympathetic nerve fibers. It can be associated with significant professional, physical, and emotional impairment as well as considerable difficulties in social situations and in personal relationships. Available therapies have been limited by short-lived effectiveness and in some cases significant adverse effects that can put patients at risk for potentially serious complications. Chemodenervation of sweat glands using botulinum toxin type A (BTX-A), which has long-lasting therapeutic efficacy with minimal adverse effects, has emerged as a unique therapy for treating primary axillary hyperhidrosis. This article reviews the chemodenervation procedure, including patient preparation, BTX-A administration, and patient assessment and follow-up.
Primary axillary hyperhidrosis is a pathologic condition characterized by excessive underarm sweating. While the exact cause is not known, it is thought to result from hyperstimulation of eccrine glands by the cholinergic sympathetic nerve fibers that innervate them. The etiology of primary hyperhidrosis also appears to have a genetic component, as the frequency of patient-reported family history is consistent with autosomal dominant transmission (1). The onset of axillary hyperhidrosis is typically in adolescence (2) or young adulthood (3), and its prevalence is highest in the prime working years (ages 18-64 years) (3).
Because of the intensity of its symptoms, primary axillary hyperhidrosis can result in significant impairment in both personal and professional activities and is associated with substantially reduced quality of life (4-7). Excessive sweating can further result in skin maceration and can be associated with secondary microbial infections in severely affected persons. The emotional disturbance associated with hyperhidrosis may be amplified by the persistence of wetness, staining, and damage to clothing (8). Consistent with these observations, the quality-of-life burden with primary axillary hyperhidrosis is comparable to or worse than that observed in patients with severe acne, pruritus, or psoriasis (4).
Published data indicate that the prevalence of primary hyperhidrosis is between 0.6% and 2.8% (3,9,10). Data on the prevalence of hyperhidrosis by focal location and symptom severity are scant. However, a recent study estimated that 0.5% of the US population is afflicted with severe axillary hyperhidrosis, defined as sweating that is barely tolerable or intolerable and that frequently or always interferes with the person's daily activities (3).
Primary axillary hyperhidrosis is treated with a number of therapies, ranging from topical agents to systemic oral medications to surgical sympathectomy. Successful treatment of hyperhidrosis results in substantial improvements in patient functioning and quality of life (11). However, available treatments have been limited by one or a number of factors, including short-lived effects (12,13) and substantial compensatory sweating (13-15), as well as poor tolerability (16) and potentially serious complications (such as pneumothorax or Horner's syndrome) (13-15,17).
Chemodenervation using botulinum toxin type A (BTX-A) has emerged as a safe and effective treatment for primary axillary hyperhidrosis. This procedure has also been used extensively for the treatment of strabismus, blepharospasm, and head and neck pain associated with cervical dystonia. Botulinum toxin type A acts by blocking neuronal acetylcholine release at the neuromuscular junction and in cholinergic autonomic neurons (18). When administered at sites of excessive sweating, BTX-A produces temporary denervation of the sweat glands, resulting in local reduction in sweating (2).
Randomized controlled studies conducted in Europe and the United Kingdom demonstrate that chemodenervation of sweat glands with BTX-A results in rapid and substantial reductions in axillary sweating, as quantified by gravimetric measurement of sweat production (6,19,20). These findings have recently been confirmed and extended in a 52-week North American study showing that chemodenervation using BTX-A dramatically reduces axillary sweat production and markedly improves the impairment associated with hyperhidrosis (21). The primary efficacy end point in this double-blind placebo-controlled trial was the Hyperhidrosis Disease Severity Scale (HDSS), a psychometrically validated single-item 4-point scale in which patients rate how hyperhidrosis interferes with their daily activities and its perceived tolerability (22) (Table 1). Ninety percent of the patients reported that after treatment their hyperhidrosis was tolerable or not noticeable and, at worst, only sometimes interfered with their daily activities. In addition, greater than 80% of patients treated with BTX-A showed a 75% or greater reduction in sweating, measured gravimetrically. The majority of the side effects of BTX-A treatment were mild and transient.
This article reviews the procedures and best clinical practices for treating primary axillary hyperhidrosis by chemodenervation of sweat glands using BTX-A.
Both axillae are generally treated at the same office visit. There can be considerable variation from patient to patient in the area of excessive sweating within the axillary vault. In some patients, it is confined to the hair-bearing skin and in others it extends beyond this area. In addition, the areas of excessive sweating may vary in the same patient. Because of this inter- and intrapatient variability, mapping the area of excessive sweating is a very important first step in the chemodenervation procedure.
The first step in mapping the hyperhidrotic area is to perform Minor's iodine-starch test, which makes direct visualization of the area possible. Specifically, the axillae are first cleaned and dried thoroughly. The area is then painted with an iodine solution (2 g of iodine in 10 mL of almond oil or castor oil and 90 mL of alcohol). An alternative is to use povidone-iodine with alcohol (eg, Betadine) swabs. After the solution has dried, fine starch powder is evenly dusted over the site. After several minutes, the presence of sweat causes the mixture to turn a dark blue-purple color, making the location of the sweating readily discernible. The hyperhidrotic areas are then outlined with a surgical or dermographic pen and are reprepped with antimicrobial solution.
Reconstitution and dosing of BTX-A
Vacuum-dried purified BTX-A (BOTOX[R], Allergan, Irvine, Calif; 100 U per vial) is reconstituted with 4 mL of sterile 0.9% saline solution (25 U/mL). The total injection volume (4 mL) is then drawn into 4 separate 1 mL syringes with a 20- to 22-gauge needle. To minimize patient discomfort, the needle should be replaced with a higher gauge (eg, 30-gauge) needle before injection. On the basis of the results in clinical studies, the recommended dose is 50 U/axilla (6,20,21). Recent data indicate that there are no significant differences in efficacy or duration of effect between 50-U/axilla and 75-U/axilla doses (21). Some physicians have suggested that high-dose treatment (200 U/axilla) may be associated with a longer duration of effect (23); however, this study was preliminary and not well controlled. Since the 50-U/axilla dose is highly effective, well tolerated, and is associated with a durable effect (6 to 7 months) (6,24) clinicians should opt for it in most patients. As shown in Table 2, the injection volume varies according to the number of sites that have been mapped, and 12 to 15 sites is typical in an average patients. Approximately 0.13 mL of BTX-A is given per injection when there are 15 separate injection sites in the hyperhidrotic area of the axilla.
Since each treatment site has a ring of effect of approximately 2 cm in diameter, the points of injection should be evenly spaced 1.5 cm apart and be marked before proceeding. To minimize the area of no effect, the sites should be positioned in a staggered manner rather than in a linear fashion (Figure 1). Alternatively, the area can be divided into 1.5-cm squares, with the site of injection in the center of each square (5). BTX-A is injected slowly and carefully into the intradermal plane of each axilla. The physician should try to obtain a visible wheal that confirms the placement of the drug in the proper plane of the skin. Pressure should then be applied to facilitate hemostasis. After treatment, the hyperhidrotic areas are cleaned and the patient is observed for potential side effects for approximately 20 minutes.
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Resources and service time required
A service time of 40 minutes to 1 hour should be reserved for the chemodenervation procedure--10 to 20 minutes for visualizing and mapping the hyperhidrotic areas, 10 to 20 minutes for administering BTX-A, and 20 minutes for monitoring the patient. Table 3 shows the personnel time and medical equipment necessary for the procedure.
Patient assessment and follow-up
A diagnosis of primary axillary hyperhidrosis is indicated when the patient exhibits focal, visible, excessive sweating that has been ongoing for at least 6 months and is characterized by at least two of the following: bilateral and relatively symmetric, impairs daily activities, frequency of at least 1 episode per week, age of onset less than 25 years, positive family history, and cessation during sleep (25). The HDSS (Table 1) can be used to determine the extent to which hyperhidrosis interferes with daily activities. Treatment with BTX-A is recommended for patients who have failed initial therapy with topical high-strength antiperspirants (ie, aluminum chloride hexahydrate). Clinicians should educate patients on proper use of these agents to maximize tolerability (25).
Determining the severity of hyperhidrosis and assessing the efficacy of treatment over time is key in treating patients with hyperhidrosis. Generally, patients are assessed at the initial office visit and then 7 to 10 days after treatment. Baseline assessments can help to determine hyperhidrosis severity and thus the type of treatment needed. Post-treatment assessments provide information on the efficacy of the treatment and the need for re-treatment. In rare instances patients may show incomplete results by 7 to 10 days after treatment. This generally indicates that some areas of sweating were missed during BTX-A administration or that the injection was placed in the wrong plane of the skin. If this occurs, the axillary vault should be remapped using Minor's iodine-starch test to visualize the hyperhidrotic area and the patient should be re-treated.
The HDSS is a validated and reliable single-item 4-point scale for assessing the severity of hyperhidrosis in which patients or physicians rate the patient's tolerability of hyperhidrosis symptoms and the extent to which it interferes with daily activities (22) (Table 1). A score of 3 or 4 (hyperhidrosis is barely tolerable or intolerable and frequently or always interferes with daily activities) indicates hyperhidrosis that requires treatment. The goal of treatment is to move patients to a 1 or 2 on this scale (sweating is tolerable and interferes, at worst, only sometimes with daily activities). Since the HDSS consists of only one question, it can be completed rapidly and easily. As such, it is a practical tool for diagnosing the severity of hyperhidrosis and determining the efficacy of treatment and when re-treatment is needed.
Other assessment tools
The Hyperhidrosis Impact Questionnaire (HHIQ), the Dermatology Life Quality Index (DLQI), and the Illness Intrusiveness Rating Scale (IIRS) are additional validated patient-reported assessments that may be useful in clinical practice and in clinical research with patients with hyperhidrosis. The HHIQ is a comprehensive hyperhidrosis-specific index that evaluates the impairment associated with hyperhidrosis in four domains--occupational, physical, emotional, and social--using a 41-item baseline module and a 10-item follow-up module (completed at various times) (26). The DLQI is a self-reported questionnaire that is widely used to assess the effect of dermatologic diseases on health-related quality of life (27). The IIRS is a more general measure of health-related quality of life. However, it has been validated in a population of patients with hyperhidrosis (28).
Gravimetric measurement of sweat production
Gravimetric measurement uses filter paper to quantify the secretion of sweat. With this method, preweighed filter paper is applied to the affected area and the rate of sweat production is calculated as the change in the mass of the filter paper over time (generally 5 minutes). This type of measurement is time intensive and is not routinely or practically performed in clinical practice, being reserved almost exclusively for research purposes. While it appears that this method should provide a quantitative assessment of sweating, it has features that can make it unreliable in clinical practice. First, since there can be considerable intrapatient variability in sweating, this isolated measurement may not accurately reflect the patient's symptoms; sweating can even be totally absent in some patients at some assessment times (4). In addition, gravimetric measurements may underestimate or overestimate sweating, depending on the surface area covered by the filter paper, and, because there is no established normal range of sweating based on gravimetric assessment, the results can be difficult to interpret.
Chemodenervation of sweat glands with BTX-A is a valuable treatment option in the dermatologist's treatment armamentarium, as it fills a large unmet need in the treatment of primary focal hyperhidrosis by providing a safe and effective therapy for this often debilitating medical condition. The components of BTX-A treatment include visualizing and mapping the hyperhidrotic area, properly placing the injections, and monitoring the patient. This procedure is a learned skill that will require that the physician be well-versed in cutaneous anatomy and be trained on the proper mapping procedure and injection techniques. This is crucial, as improper mapping and administration can result in a lack of efficacy or an incomplete benefit. After proper training, however, the physician can expect reliable and long-lasting results in patients with primary axillary hyperhidrosis.
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DEE ANNA GLASER MD
DEPARTMENT OF DERMATOLOGY, ST. LOUIS UNIVERSITY SCHOOL OF MEDICINE, ST. LOUIS, MO
ADDRESS FOR CORRESPONDENCE:
Dee Anna Glaser MD
Associate Professor, Department of Dermatology
Saint Louis University School of Medicine
1402 South Grand Boulevard
St. Louis, MO 63104
Phone: (314) 256-3430
Fax: (314) 256-3431
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