Primary focal hyperhidrosis

INTRODUCTION — Hyperhidrosis (excessive sweating) is a common condition rarely due to significant underlying pathology that may have serious social, emotional, and professional consequences.

The diagnosis and treatment of primary focal hyperhidrosis is reviewed here. Night sweats and menopausal hot flashes are discussed separately. (See "Evaluation of the patient with night sweats or generalized hyperhidrosis" and "Menopausal hot flashes".)

DEFINITION — Hyperhidrosis is the secretion of sweat in amounts greater than physiologically needed for thermoregulation. It is most commonly a chronic idiopathic (primary) condition; however, secondary medical conditions or medications should be excluded. Idiopathic hyperhidrosis localized to certain areas of the body is called primary focal hyperhidrosis. Primary focal hyperhidrosis usually affects the axillae, palms, and soles. The condition may also affect other sites, such as the face, scalp, inguinal, and inframammary areas.

A consensus panel suggested the following diagnostic criteria for primary focal hyperhidrosis [1]:

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

Plus at least two of the following characteristics:

●Bilateral and relatively symmetric

●Impairs daily activities

●At least one episode per week

●Onset before age 25

●Family history of idiopathic hyperhidrosis

●Focal sweating stops during sleep

SYMPTOMS — Patients with primary focal hyperhidrosis generally develop symptoms in childhood or adolescence that persist throughout life. Patients have focal symptoms most often localized to the palms, soles, and axillae [2-4]. Less commonly, primary focal hyperhidrosis may affect the scalp and face, or other sites [4]. While primary focal hyperhidrosis is made worse by heat or emotional stimuli, it is not considered a psychologic disorder.

Patients with axillary hyperhidrosis report skin maceration and staining of clothes. Palmar hyperhidrosis often leads to a fear of shaking hands and soiling of papers, and patients may have difficulty with work or recreational tasks that require a dry grip. Patients report that hyperhidrosis often results in social problems on both a private and professional level.

Hyperhidrosis is associated with an increased incidence of other cutaneous disorders. In a retrospective case-control study involving 387 patients with primary focal hyperhidrosis, patients with hyperhidrosis were more likely to suffer from dermatophytosis, pitted keratolysis, and viral warts at the sites of hyperhidrosis [4]. In addition, atopic dermatitis and other eczematous dermatitides were present at a greater frequency in subjects with hyperhidrosis. The reason for this association is unknown; one theory is that hyperhidrosis is an exacerbating factor for dermatitis [4].

EPIDEMIOLOGY — Hyperhidrosis prevalence estimates range from 1 to 5 percent of the population [3,5-8].

A study of patients with primary palmar hyperhidrosis who had been treated with thoracoscopic sympathectomy found that 49 of 58 patients and none of 20 controls reported a family history of hyperhidrosis [9], which suggests a genetic component to the disease.

PATHOGENESIS — Sweating assists thermoregulation, skin hydration, and fluid and electrolyte balance. Three types of sweat glands, eccrine, apocrine, and apoeccrine glands have been described in humans [10]. Eccrine sweat glands are responsible for hyperhidrosis, although apoeccrine glands might play a role in axillary hyperhidrosis [11].

The primary function of eccrine sweat glands is thermoregulation, with cooling resulting from evaporation of eccrine sweat. Eccrine sweat glands are located throughout the body, but they are found in greatest quantity in the palms, soles, and (to a lesser degree) axillae. Sweating on the face, chest, and back is generally due to heat stimuli, while sweating of the palms and soles is due to emotional stress. The axillae have eccrine, apocrine, and apoeccrine glands. Thermal sweating can occur throughout the day, but emotional sweating (palms, soles, and to some degree axillae) stops while sleeping [12,13].

Eccrine glands are innervated by the sympathetic nervous system but utilize acetylcholine as the primary neurotransmitter. Thermal and emotional sweating are controlled by different regions of the brain. Thermal sweating is controlled by the hypothalamus via the thermosensitive preoptic sweat center, while emotional sweating is regulated by the cerebral cortex. A sympathetic signal is carried to endocrine glands via cholinergic autonomic neurons. In patients with primary focal hyperhidrosis, the sweat glands are usually histologically and functionally normal. Rather, the cause of hyperhidrosis appears to be an abnormal or exaggerated central response to normal emotional stress.

DIFFERENTIAL DIAGNOSIS — Patients with primary focal hyperhidrosis generally have hyperhidrosis involving the face, scalp, palms, soles, or axillae. Generalized sweating suggests an etiology other than primary focal hyperhidrosis.

Secondary hyperhidrosis — The most common cause of generalized sweating is excessive heat. Generalized hyperhidrosis can be due to systemic diseases or medications. Unlike primary focal hyperhidrosis, patients with generalized, secondary hyperhidrosis usually present as adults and report sweating that occurs both while awake and sleeping. A history of generalized hyperhidrosis requires a careful evaluation for systemic causes. The differential diagnosis for generalized hyperhidrosis is similar to the differential diagnosis of night sweats (see "Evaluation of the patient with night sweats or generalized hyperhidrosis"). One should evaluate for signs and symptoms of an infectious cause such as tuberculosis [14], HIV [15], or endocarditis; a malignant etiology such as lymphoma [16,17]; or an endocrinopathy such as carcinoid syndrome [18], pheochromocytoma [19], or hyperthyroidism [20].

Medications should be carefully reviewed, as many can cause generalized sweating (table 1).

While menopause is a common cause of excessive sweating, clinicians should perform a careful history and examination before concluding that excessive sweating in a woman of perimenopausal age is due to hot flashes. (See "Menopausal hot flashes".)

Other causes of excessive sweating include:

●Patients with previous spinal cord injuries may occasionally develop episodes of diffuse sweating long after their injury. These sweating episodes can be due to an autonomic dysreflexia, orthostatic hypotension, or a posttraumatic syringomyelia. Hyperhidrosis attributed to autonomic dysreflexia is caused by an exaggerated autonomic response to normal stimuli such as bowel and bladder distention or skin irritation. In addition to sweating of the face, neck, and trunk, patients generally have flushing of the face and a throbbing headache. Their spinal cord lesion is usually at or above the sixth thoracic level. A post-traumatic syringomyelia may occur months to years after the development of paraplegia from a spinal cord injury of any level. The syrinx may develop above or below the level of the transection and may be associated with progressive numbness of the hyperhidrotic areas [12,13].

●Gustatory sweating (mild sweating around the lips, nose, and forehead) occurs normally with the consumption of hot, spicy foods. However, pathologic gustatory sweating may be caused by sympathetic nerve damage, either due to invasion (such as a Pancoast tumor), or by sympathectomy (see 'Sympathectomy' below). It can also be due to a diabetic neuropathy, herpes zoster of the preauricular region, or misdirection of autonomic nerve fibers following parotid surgery (Frey's syndrome) [12,13].

Colored sweat — Chromhidrosis is an uncommon, idiopathic, nonhyperhidrotic condition in which apocrine glands secrete colored sweat (eg, yellow, blue, green, or black). Chromhidrosis can occur on the face (particularly malar cheeks), axillae, areolae, groin, and other areas [21-23]. Chromhidrosis is reviewed in detail separately. (See "Chromhidrosis".)

TREATMENT — Selection of the appropriate approach to treatment begins with consideration of the location of involvement (ie, axillary, palmar, plantar, or craniofacial location). Additional factors, such as the patient's goals, expectations, and preferences, as well as safety concerns, disease severity, cost, and treatment availability also impact treatment selection.

Axillary hyperhidrosis — The major therapeutic options for axillary hyperhidrosis include antiperspirants, botulinum toxin, microwave thermolysis, topical glycopyrronium, oral medications, and surgery.

First-line therapy — Topical antiperspirants are the preferred initial treatment for axillary hyperhidrosis because they are widely available, inexpensive, and well-tolerated therapies. Topical glycopyrronium is an alternative first-line treatment and an option for patients who present with a history of poor responses to prescription antiperspirants.

Antiperspirants — Most commercially available nonprescription antiperspirants contain a low-dose metal salt (usually aluminum) that physically obstructs the opening of sweat gland ducts. Nonprescription products are only successful in treating patients with very mild hyperhidrosis.

Treatment with prescription antiperspirants, such as 20% aluminum chloride hexahydrate or 6.25% aluminum chloride hexahydrate, may provide adequate therapy for patients with axillary hyperhidrosis that fails to respond to nonprescription antiperspirants [24,25]. (See 'Palmar or plantar hyperhidrosis' below.)

●Efficacy – The mechanism through which aluminum salts are thought to improve hyperhidrosis involves precipitation of the metal ions with mucopolysaccharides after application to the skin, leading to damage of epithelial cells within of the lumina of sweat ducts and the formation of plugs that occlude the ducts [26].

●Administration – Prescription strength antiperspirants should be applied nightly to the area of hyperhidrosis until improvement is noted; significant improvement may be noted within one week. The interval between applications then can be gradually lengthened. Once-weekly applications are typically needed for maintenance therapy [27].

Unfortunately, treatment with strong antiperspirants is often limited by skin irritation, especially in the axillary region. Low-potency corticosteroid creams (such as 2.5% hydrocortisone cream) can help alleviate axillary irritation.

To reduce the risk of irritation, these products should be applied to dry skin between episodes of sweating. Ideally, aluminum chloride hexahydrate should be applied at bedtime when hyperhidrosis is at a minimum, allowed to remain in place for six to eight hours, and washed off in the morning [26]. Others have recommended using a hair dryer to quickly dry the skin before application and immediately after application, or to use baking soda powder in the morning to neutralize any remaining aluminum chloride [13].

We do not instruct patients to occlude treated areas with plastic wrap or other occlusive materials after the application of prescription antiperspirants. Occlusion is not necessary and may increase risk for irritation.

Use of an additional antiperspirant product during the daytime also is not necessary. Patients who desire to use a fragranced product may apply a nonmedicated deodorant to the axillae in the morning after bathing [26].

Topical glycopyrronium — Topical glycopyrronium is an anticholinergic drug that inhibits sweating through inhibiting the action of acetylcholine on sweat glands. Topical glycopyrronium 2.4% is applied once daily to the axillae using a premoistened cloth. Local skin irritation and anticholinergic symptoms are potential adverse effects.

Randomized trial data support benefit of topical glycopyrronium. The identical ATMOS-1 (n = 344) and ATMOS-2 (n = 353) trials randomly assigned patients ≥9 years of age with primary axillary hyperhidrosis to once-daily application of either glycopyrronium tosylate 3.75% (equivalent to 2.4% glycopyrronium) or vehicle in a 2:1 ratio [28]. Primary endpoints were assessed after four weeks and included the rate of response (≥4 point improvement from baseline) on patient-reported sweating severity in the Axillary Sweating Daily Diary (ASDD) and the mean absolute change from baseline in axillary gravimetric sweat production. Both trials found that more patients in the glycopyrronium tosylate groups achieved the specified ASDD measure of response than in the vehicle groups; pooled response rates were 60 versus 28 percent. In ATMOS-2, patients in the glycopyrronium tosylate group had a greater mean absolute change in sweat production compared with the vehicle group (-110±131 versus -92±153 mg/5 min). In ATMOS-1, the difference in the mean reduction in sweat production (105±285 versus 92±128 mg/5 min) was not statistically significant; a sensitivity analysis suggested a single analysis center with extreme outlier data may have contributed. Treatment-emergent adverse effects were more frequent in the glycopyrronium tosylate groups but were generally transient and mild to moderate in severity. Dry mouth and mydriasis were the most common anticholinergic adverse effects.

Second-line therapy — Patients who do not achieve sufficient improvement in axillary hyperhidrosis with topical antiperspirants may benefit from botulinum toxin injections or microwave thermolysis.

Botulinum toxin — Periodic botulinum toxin injection into affected skin is a safe and effective method for improving axillary hyperhidrosis. However, treatment can be painful and expensive.

●Efficacy – Botulinum toxin blocks the release of neuronal acetylcholine from the presynaptic junction of both neuromuscular and cholinergic autonomic neurons. By blocking the release of acetylcholine, botulinum toxin can temporarily reduce sweat production.

Although other formulations of botulinum toxin may improve hyperhidrosis, most studies have used onabotulinumtoxinA or abobotulinumtoxinA [29]. Dosing of these agents is not equivalent; 1 unit of onabotulinumtoxinA is equal to approximately 3 units of abobotulinumtoxinA [30]. US Food and Drug Administration (FDA) approval for botulinum toxin for hyperhidrosis is limited to onabotulinumtoxinA for axillary hyperhidrosis.

Several studies support the efficacy of BTX-A in the treatment of axillary hyperhidrosis [30-36]. Examples include:

•In a randomized trial involving 320 patients with bilateral primary axillary hyperhidrosis, response rates after four weeks were significantly higher with onabotulinumtoxinA, 50 units per axilla, than placebo (94 versus 36 percent) [33]. After 16 weeks, 82 percent of the onabotulinumtoxinA group still had an effective response compared with 21 percent of the placebo group.

•In a randomized trial involving 145 patients with primary axillary hyperhidrosis unresponsive to topical therapy with aluminum chloride, patients were injected with 200 units of abobotulinumtoxinA in one axilla and placebo in the other; after two weeks, the treatments were revealed, and the axilla that had been treated with placebo was injected with 100 units of abobotulinumtoxinA [30]. Two weeks after the initial injection, the rate of sweat production was significantly less on the side treated with abobotulinumtoxinA (24 versus 144 mg/min). Two weeks after the injection with 100 U, the rate of sweat production decreased from 144 to 32 mg/min. The mean reduction in sweating was greater with the 200 units injection (81.4 versus 76.5 percent).

Although the above study found a statistically greater reduction in sweating with 200 units of abobotulinumtoxinA, it is not clear that this difference is clinically important. A study of 43 patients found no difference in the degree or duration of reduction in sweating with 100 or 200 units of abobotulinumtoxinA [37].

A response to treatment is usually evident within two to four days and improvement in sweating typically persists for three to nine months or longer [29]. The duration of efficacy may increase with subsequent injections. In a retrospective study of 83 patients given an average of four abobotulinumtoxinA injection sessions for axillary hyperhidrosis (range 2 to 17 sessions) and followed for an average of 2.7 years (range 3 months to 9 years), the median duration of effect (as reported by patients) was 5.5 months after the initial injection and 8.5 months after the last injection [38]. An increase in the duration of effect of botulinum toxin may result from lengthening of the time required for regrowth of the axon terminal [38]. Additional studies are needed to confirm the findings of this study.

Neutralizing antibody development, which occasionally has been linked to reduced therapeutic effectiveness in patients treated with botulinum toxin for other indications [39,40], appears to be infrequent among patients treated for axillary hyperhidrosis and does not necessarily result in a failure to respond to treatment. In an analysis of data from trials of onabotulinumtoxinA therapy for various indications, only 4 of 871 patients (0.5 percent) treated for axillary hyperhidrosis developed neutralizing antibodies against botulinum toxin, and the two patients who received subsequent injections after developing neutralizing antibodies continued to respond to treatment [41].

●Administration – Optimal treatment of hyperhidrosis with botulinum toxin is dependent upon accurate identification of the specific areas of hyperhidrosis. Hyperhidrotic areas of the axilla do not necessarily correlate with the distribution of terminal axillary hair [29]. The Minor iodine starch test, a simple method to identify the responsible areas, is performed with the following steps:

•Dry the affected region with absorbent paper

•Apply a 3 to 5% iodine solution to the axilla and adjacent skin

•Apply dry starch over the area of iodine application

•Note areas in which a dark purple color appears (areas of sweat production)

•Mark the areas of sweat production with a marking pen

A 30-gauge needle is used to inject the botulinum toxin into the dermis or superficial fat. Typically 10 to 20 injections spaced 1 to 2 cm apart are performed in each axilla. For onabotulinumtoxinA, the typical initial dose used per axilla is 50 units; abobotulinumtoxinA treatment usually requires 100 to 200 units per axilla [29].

Pain during injections is one of the most common complaints with this therapy. A topical anesthetic may be applied after the Minor iodine starch test to reduce pain. Cryoanalgesia (refrigerant sprays or ice packs) or vibration anesthesia also may be of some benefit in decreasing pain [42-46].

Microwave thermolysis — Microwave energy can be utilized to destroy eccrine glands and relieve hyperhidrosis in the axilla [47-51]. A commercial device designed to focus microwave energy onto the dermal-adipose interface has been approved by the FDA and is commercially available. Limited availability and cost may limit access to this therapy.

The use of microwave energy for axillary hyperhidrosis is supported by a randomized trial of 120 adults with primary axillary hyperhidrosis who were given one to three treatments with a microwave energy device (n = 81) or a sham device (n = 39) [49]. Patients treated with the microwave device were more likely to notice a subjective reduction in the severity of axillary hyperhidrosis 30 days after treatment than patients in the sham treatment group (89 versus 54 percent). The difference in favor of active treatment remained statistically significant for up to six months. In addition, more patients in the active group achieved at least a 50 or 75 percent reduction in a gravimetric measurement of sweat production through six months after treatment. However, this difference was only statistically significant for patients who achieved ≥75 percent improvement at the 30 day time point (62 versus 39 percent).

Microwave thermolysis is typically administered in two 20- to 30-minute treatment sessions separated by three months [52]. The most common side effects of treatment are altered skin sensation (median duration 25 days, range 4 to 225 days), discomfort, and other local reactions. Transient median and ulnar neuropathy after microwave thermolysis also has been reported in a patient treated for axillary hyperhidrosis [53].

Other therapies — Additional therapies that may improve axillary hyperhidrosis include systemic agents, surgical interventions, and iontophoresis. Concern for adverse effects or limited efficacy data make these agents less favorable options for initial therapy.

We agree with the stepwise approach outlined by the International Hyperhidrosis Society for patients who cannot be managed with first-line and second-line therapies. Patients are first considered for an alternative local treatment (suction curettage), followed by systemic agents, then endoscopic thoracic sympathectomy (ETS) [54].

Suction curettage — For many years axillary hyperhidrosis was surgically treated with subcutaneous curettage or excision of the skin containing eccrine glands. However, this procedure has a significant failure rate and is associated with permanent scarring and the risk of restricted arm movement [55]. Minimally invasive suction curettage, a newer local surgical technique for removing axillary eccrine and apocrine sweat glands, may have improved outcomes and decreased morbidity [56-64].

Suction curettage involves the use of tumescent anesthesia followed by cannula suction of the superficial subcutis to remove sweat glands. Additional studies are necessary to determine the role of suction curettage in the therapeutic algorithm for hyperhidrosis. We consider suction curettage as a therapeutic option for patients who cannot be managed with topical therapies or botulinum toxin injection and as an alternative to thoracic sympathectomy.

The first randomized trial to evaluate the efficacy of suction curettage compared suction curettage to botulinum toxin injection and found a trend towards better results with botulinum toxin treatment [62]. In this study, 20 patients with axillary hyperhidrosis were randomly assigned to receive suction curettage in the right axilla and injection of 50 units of onabotulinumtoxinA in the left axilla or vice versa. Three months after treatment, there were nonstatistically significant trends toward greater reductions in resting and exercise-induced sweat rates in axillae treated with botulinum toxin (72 and 74 percent reductions, respectively) than in axillae treated with suction curettage (60 and 59 percent reductions, respectively). In a subgroup of "heavy sweater" axillae, exercise-induced sweat rates were significantly lower after botulinum toxin injection than after suction curettage, indicating a better response to botulinum toxin treatment. Among all patients, a validated quality of life questionnaire revealed significantly greater patient satisfaction with botulinum toxin therapy three and six months after treatment.

Ideally, the permanent removal of axillary sweat glands via suction curettage would result in permanent improvement of hyperhidrosis, unlike nonsurgical local interventions. However, the limited amount of outcomes data on suction curettage and variation in surgical technique among studies preclude definitive conclusions about the long-term efficacy of the procedure. The potential for long-term benefit is supported by a prospective study of 28 patients that found reductions in resting and exercise-induced sweat rates of 70 and 86 percent one month after treatment, and 58 and 87 percent, respectively, after one year [61]. Treatment results at one year were graded as excellent, good, or satisfactory by 25, 14, and 24 percent of patients, respectively.

Continued hyperhidrosis after suction curettage may occur as a result of skipped areas or compensatory sweating. The skill of the surgeon performing the procedure also may influence treatment efficacy. Recurrences of hyperhidrosis may be related to reinnervation of remaining sweat glands [64].

Posttreatment soreness is a transient and expected side effect of suction curettage. Additional potential side effects include bruising, infection, hematoma, scar, hyperpigmentation at incision sites, compensatory sweating, and dysesthesia [61,62,65].

Systemic agents — Systemic therapies (anticholinergics, clonidine, beta-blockers, and benzodiazepines) can be effective for primary focal hyperhidrosis. The potential adverse effects of systemic agents inhibit the routine use of these therapies.

The most common anticholinergic agents prescribed for primary focal hyperhidrosis are oral glycopyrrolate (glycopyrronium bromide) and oral oxybutynin [66-69]. Glycopyrrolate is utilized more frequently than oxybutynin. However, only oxybutynin has been evaluated in randomized trials [70,71].

●Oral glycopyrrolate – The use of oral glycopyrrolate for hyperhidrosis is supported by retrospective case series [67,68,72]. In one retrospective series in which 45 patients with primary hyperhidrosis (axillary, palmoplantar, generalized, or craniofacial) received treatment with glycopyrrolate alone (11 patients) or in combination with local therapies (34 patients), 67 percent of patients reported symptomatic improvement [68]. In addition, a retrospective study of 31 children with hyperhidrosis (mean age of 15 years) found that 71 percent achieved major improvement in symptoms during treatment with glycopyrrolate (with or without concomitant topical aluminum chloride) [73]. The children in this study were treated with an average total dose of 2 mg of glycopyrrolate per day. Typical doses for adults range from 1 to 2 mg once or twice daily (ie, 1 to 4 mg per day). However, doses of up to 8 mg per day occasionally are required for improvement in symptoms [74].

●Oral oxybutynin – The efficacy of oxybutynin for hyperhidrosis was documented in a six-week randomized trial of 50 patients with palmar or axillary hyperhidrosis [70]. At six weeks, great or moderate improvement in symptoms occurred in 48 and 26 percent of patients treated with oxybutynin (2.5 mg per day for one week, 2.5 mg twice daily for two weeks, and 5 mg twice daily for three weeks), respectively. In contrast, great or moderate improvement was reported by 0 and 27 percent of patients treated with placebo, respectively. Uncontrolled studies performed by the same authors also support the efficacy of oxybutynin for facial, palmar, and axillary hyperhidrosis [75-77]. In addition, a placebo-controlled randomized trial in which most study participants had generalized hyperhidrosis involving more than one body area (among palms, plantar feet, axillae, face, and trunk) demonstrated efficacy of oxybutynin for primary hyperhidrosis [71]. Typical adult doses of oxybutynin are a total dose of 5 to 10 mg per day; this is given in two divided doses for immediate-release oxybutynin or once daily for extended-release oxybutynin [74]. However, doses up to 20 mg per day have been utilized [74].

Responses to systemic anticholinergics usually take about one week for the maximum effect. Dose adjustments may be needed to achieve sufficient improvement for individual patients; dosing is typically titrated to achieve satisfactory improvement in sweating while minimizing adverse effects. Continued treatment is necessary to maintain the response to treatment.

Potential adverse effects of anticholinergic agents include dry mouth (most common), blurred vision, headache, and urinary retention [67,73]. Although the side effects of glycopyrrolate and oxybutynin are often tolerable, discontinuation of glycopyrrolate may be necessary in up to one-third of treated patients [67]. Additional studies are necessary to confirm the long-term efficacy and safety of anticholinergic drugs when utilized for this indication.

As noted above, other drugs have been employed for the treatment of hyperhidrosis. Evidence for the efficacy of clonidine, an alpha-2 adrenergic agonist that reduces sympathetic outflow, for hyperhidrosis is limited to case reports and a small retrospective case series [68,78,79]. A typical dose for adults is 0.1 mg twice daily [74]. Reduced blood pressure is a potential adverse effect of this agent.

In patients with hyperhidrosis related to specific emotional events, beta-blockers or benzodiazepines may be useful in reducing the emotional stimulus that leads to the excessive sweating [27,74,80,81].

Iontophoresis — Iontophoresis, a treatment based upon the use of electrical current to inhibit sweating, is most often used for palmar and plantar hyperhidrosis. Although a special axillary electrode can be used to treat axillary hyperhidrosis [82], treatment of the axillae is often less effective because it is difficult to obtain uniform contact of the electrode with axillary skin. (See 'Iontophoresis' below.)

Sympathectomy — The endoscopic thoracic sympathectomy (ETS) procedure for upper extremity or cervicofacial involves the interruption of the upper thoracic sympathetic chain through cauterization, cutting, or clipping.

ETS is primarily reserved for patients with severe and debilitating symptoms that cannot be managed with other therapies. Based upon review of the literature, a Society for Thoracic Surgeons expert panel proposed that the ideal candidates for ETS also possess the following characteristics:

●Onset before age 16 years and younger than 25 years at the time of surgery

●Body mass index (BMI) <28

●Absence of sweating during sleep

●Absence of significant comorbidities

●Resting heart rate greater than 55 beats per minute

Numerous studies have shown ETS to be effective for upper extremity hyperhidrosis, but the potential for adverse effects (particularly the development of compensatory hyperhidrosis) is a concern and precludes the use of ETS as an initial therapy [83-92]. Reported rates for recurrent primary focal hyperhidrosis and postsurgical compensatory hyperhidrosis after ETS vary widely, ranging from 0 to 65 percent and 3 to 98 percent, respectively [93]. Patients with palmar hyperhidrosis may be the most likely to be satisfied with outcomes from ETS procedures [85].

Examples of studies that have evaluated ETS for upper extremity hyperhidrosis include:

●In a series, 850 patients with upper extremity hyperhidrosis were treated with bilateral ETS [83]. After a median follow-up of 31 months, 98 percent of patients reported satisfactory results, with only 2 percent developing recurrent symptoms. Compensatory sweating, primarily of the trunk, occurred in 55 percent of patients, but only 2 percent considered this to be as bothersome as their original hyperhidrosis symptoms. Horner's syndrome occurred in three patients. (See "Horner syndrome".)

●In a review of 480 sympathectomies, there were no major complications requiring surgical reintervention and no postoperative deaths [85]. Initially, 95.5 percent were satisfied with the results of surgery. However, satisfaction waned over time; after a mean follow-up of 14.6 years, 66.7 percent were satisfied and 26.7 percent were partially satisfied despite a recurrence rate of only 1.5 percent. Patients with axillary hyperhidrosis without palmar involvement were the least satisfied. Compensatory and gustatory sweating, which occurred in 67.4 percent and 50.7 percent of patients, respectively, were the most frequently stated reasons for dissatisfaction.

●A study evaluating long-term results (median follow-up 3.8 years) in 125 patients who underwent ETS for treatment of upper limb hyperhidrosis found a much higher recurrence rate for axillary than palmar symptoms (65 versus 6.6 percent) [84]. Eighty-six percent developed compensatory sweating; however, 61 percent of these patients considered this only a minor disturbance, and only 6.3 percent of patients reported regret in having the surgery. Horner's syndrome occurred in three patients.

Some patients treated with clipping technique experience improvement of compensatory hyperhidrosis after surgical reversal via removal of the clips. In a prospective study of 727 patients treated with endoscopic thoracic sympathetic clipping for hyperhidrosis or facial flushing, 15 out of 31 patients (48 percent) followed after a reversal procedure reported a substantial reduction in compensatory sweating [90]. Oral anticholinergic agents may also help to improve compensatory sweating [94].

In addition to compensatory hyperhidrosis and Horner's syndrome, potential adverse effects of ETS include paresthesia, pneumothorax, hemothorax, hyperthermia, and bradycardia [95].

Emerging therapy — Limited data suggest that topical botulinum toxin [96], ultrasound [97,98], and laser therapy [99-102] can be useful for the treatment of axillary hyperhidrosis. Further study is necessary to determine the role of these therapies.

Palmar or plantar hyperhidrosis — Although many of the same treatments used for axillary hyperhidrosis are effective for palmar or plantar hyperhidrosis, the approach to treatment is slightly different. In particular, iontophoresis plays a greater role in treatment.

First-line therapy — Topical antiperspirants and iontophoresis are common treatments based upon the safety of these therapies. Topical antiperspirant treatment is typically tried first because of the ease of administration of this therapy.

Antiperspirants — Prescription-strength topical antiperspirants can improve palmar and plantar hyperhidrosis, albeit with a lower likelihood for success than for axillary hyperhidrosis [26]. We typically prescribe a trial of 20% aluminum chloride hexahydrate. Treatment protocols for palmoplantar and axillary hyperhidrosis are similar. (See 'Antiperspirants' above.)

Iontophoresis — Iontophoresis is the introduction of ionized substances through intact skin by the application of direct current (also called electromotive drug administration or transdermal electromotive drug administration). Iontophoresis for hyperhidrosis is typically performed with tap water. The exact mechanism of action is unclear, but treatment may temporarily block sweat glands [13,27]. Iontophoresis equipment is available for home use.

Treatment involves placing the hands or feet in a tray with just enough water to cover the hands or feet. The iontophoresis machine is then turned on and the current administered as directed. Ideally, treatment with iontophoresis begins under the direction of a healthcare professional to ensure that the patient understands and can perform the correct technique. Once improvement has occurred or the patient has a good understanding of the treatment protocol, the patient may begin home treatments [103].

Although there are only limited data from randomized trials, iontophoresis appears to alleviate symptoms in approximately 85 percent of patients with palmar or plantar hyperhidrosis and is safe and simple to perform [104-107]. Reductions in sweating are usually noted by the patient within two to four weeks when treatment is given three times per week. If tap water iontophoresis is ineffective, an anticholinergic agent (eg, a crushed 2 mg glycopyrrolate tablet) may be added to the treatment tray [27,103].

Potential side effects include dry, cracked hands (which can be relieved with moisturizers), skin erythema, skin discomfort, and transient vesiculation [103]. Pretreatment application of petrolatum to the hands or feet may help to reduce risk for erythema and vesiculation.

The biggest issue for patients with this treatment modality is generally the time required to perform the treatments. Initial treatment is generally 20 to 30 minutes per day or three times per week; however, the frequency of treatments can often be reduced after only 10 to 15 treatments. While some studies have found that a reduction in sweating can be maintained with therapy every two weeks [104], some patients find that shorter duration treatments three times a week are required for maintenance.

Supportive measures — Additional interventions that may help with the management of symptoms of plantar hyperhidrosis include changes in foot care [54]. Frequent sock and shoe changes, as well as use of absorbent shoe insoles and absorbent foot powder, may be helpful. Patients should also avoid occlusive footwear. Leather shoes and cotton, wool, or other moisture-wicking socks are beneficial. Synthetic materials that may allow moisture to accumulate are not recommended.

Second-line therapy — Botulinum toxin injections can be very effective for palmar and plantar hyperhidrosis.

Botulinum toxin — The efficacy of botulinum toxin for palmar hyperhidrosis is supported by multiple studies, including a few small randomized trials [108-115]. Data on plantar hyperhidrosis are more limited [116-119]. As an example, in a randomized trial of 19 patients with palmar hyperhidrosis, placebo injections were given in one hand and botulinum toxin A injections in the other [109]. After four weeks, among the 17 patients not lost to follow-up, all rated the botulinum toxin injections a success, while only 12 percent rated the placebo injections a success.

The Minor starch iodine test may be performed prior to treatment to identify areas of pronounced sweating, although some clinicians find the test more useful for identifying residual areas of sweating after treatment (see 'Botulinum toxin' above) [120]. Injections are made intradermally and are usually spaced 1 to 1.5 cm apart [120]. Between 50 and 100 units of onabotulinumtoxinA or between 100 and 240 units of abobotulinumtoxinA is typically given per hand for palmar hyperhidrosis [120].

The pain during injection into the palms and soles can be significant. Techniques such as nerve blocks, topical anesthetics, cryoanalgesia (refrigerant sprays or ice packs), and vibration analgesia may be used to reduce pain [120].

Benefit from botulinum toxin injection for hyphidrosis is typically noted within the first 7 to 10 days after treatment and often persists for approximately six months [120]. Durations of effect between 2 and 22 months have been reported [121]. The duration of efficacy may increase with repeated injections [121].

A common complication associated with treatment of palmar hyperhidrosis is temporary weakness in the muscles of the thenar eminence. In an uncontrolled study in which 20 patients with palmar hyperhidrosis received botulinum toxin treatment, 21 percent of the 19 patients available for follow-up developed mild muscle weakness that lasted an average of three weeks [108]. Bruising may also occur after treatment.

Other therapies — Other therapies associated with greater risk for side effects are available for patients who cannot be managed with local, nonsurgical therapies. As with axillary hyperhidrosis, systemic agents are effective therapies for palmar and plantar hyperhidrosis [68,70,72,73,77]. Surgical options include endoscopic thoracic sympathectomy (ETS) for palmar symptoms and endoscopic lumbar sympathectomy for plantar hyperhidrosis [122,123]. For unclear reasons, some patients with both palmar and plantar hyperhidrosis experience improvement in both palmar and plantar hyperhidrosis following ETS [124]. (See 'Systemic agents' above and 'Sympathectomy' above.)

Craniofacial hyperhidrosis — The location of craniofacial hyperhidrosis is a limiting factor for some hyperhidrosis therapies. The major treatment options include topical therapies, systemic drugs, botulinum toxin injections, and surgery. Data on these treatments specifically for craniofacial hyperhidrosis are limited.

First-line therapy — Topical antiperspirants are first-line therapies based upon ease of administration and relative safety.

Topical antiperspirants — Topical nonprescription or prescription antiperspirants can be used as an initial treatment for craniofacial hyperhidrosis. We often prescribe 20% aluminum chloride hexahydrate. However, irritation may be a limiting factor for the treatment of facial areas.

Second-line therapy — Second-line effective treatment options for craniofacial hyperhidrosis include botulinum toxin injections and systemic medications. The side effects of these therapies must be considered and discussed with the patient prior to treatment.

●Botulinum toxin – Improvement following treatment with botulinum toxin has been documented in patients treated for facial hyperhidrosis in uncontrolled studies and case reports [125-129]. Botulinum toxin therapy for craniofacial hyperhidrosis must be carefully administered to avoid functional or cosmetic defects secondary to inadvertent muscle weakening [125,127,129]. The precautions vary according to the locations requiring treatment. As examples, brow ptosis is a potential complication of forehead treatment and drooping or weakening of the lips may occur after treatment for hyperhidrosis involving the upper lip [130].

●Systemic agents – Systemic agents, such as oral glycopyrrolate and oral oxybutynin, are occasionally used for craniofacial hyperhidrosis. These drugs are associated with risk for multiple side effects related to their anticholinergic effects [67,73]. (See 'Systemic agents' above.)

Other therapies

●Topical glycopyrrolate – Glycopyrrolate (glycopyrronium bromide) is an anticholinergic agent that is used as an oral drug for the treatment of hyperhidrosis (see 'Systemic agents' above). Limited data suggest that topical administration of glycopyrrolate can be effective for craniofacial hyperhidrosis [131-134].

A split-face trial of 25 patients with severe facial hyperhidrosis found that a single topical application of glycopyrrolate using pads containing 2% glycopyrrolate significantly reduced forehead sweat production in patients with primary craniofacial or secondary gustatory hyperhidrosis [131]. The effects were transient; most patients noted a return to baseline sweating within one to two days. A subsequent nine-day, split-face, placebo-controlled trial of 2% glycopyrrolate for facial hyperhidrosis (n = 39) also found that glycopyrrolate was an effective therapy [132]. Additionally, in a small uncontrolled study, topical 2% glycopyrrolate solution appeared effective for compensatory sweating after sympathectomy [133].

Adverse effects such as mydriasis, xerostomia, and other anticholinergic effects related to systemic absorption of topical glycopyrrolate are potential side effects of therapy [133,134]. Additional studies are necessary to explore the safety and efficacy of topical glycopyrrolate therapy.

●Endoscopic thoracic sympathectomy – Endoscopic thoracic sympathectomy (ETS) is an option for patients with severe craniofacial hyperhidrosis who cannot be managed effectively with other therapies. However, persistent side effects such as compensatory sweating and Horner's syndrome may result from ETS. (See 'Sympathectomy' above.)

EDUCATION AND SUPPORT — Hyperhidrosis can have a significant negative effect on quality of life. In addition to medical treatment, patients may benefit from educational and supportive resources. The International Hyperhidrosis Society provides information about hyperhidrosis and access to educational tools for patients and clinicians. In addition, information about product discount programs as well as insurance and reimbursement tools are available on the website.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary focal hyperhidrosis".)

SUMMARY AND RECOMMENDATIONS

●Overview – Individuals with primary focal hyperhidrosis typically have excessive sweating of the palms, soles, and axillae and can suffer significant psychologic, social, educational, and occupational consequences. (See 'Symptoms' above.)

●Generalized hyperhidrosis – Patients with generalized hyperhidrosis not limited to the palms, soles, and axillae are likely to have hyperhidrosis secondary to medications or a systemic illness, and the evaluation is similar to that done for night sweats. (See 'Secondary hyperhidrosis' above and "Evaluation of the patient with night sweats or generalized hyperhidrosis".)

●Treatment – When choosing treatments for primary focal hyperhidrosis, the patient's goals in therapy should be understood and the side effects associated with each therapy should be carefully discussed. Conservative measures should be tried before progressing to more invasive treatments. The severity and location of hyperhidrosis helps guide the choice of therapies (see 'Treatment' above):

•Axillary, palmar, and plantar hyperhidrosis:

-First-line treatment – Patients with axillary, palmar, or plantar hyperhidrosis should initially be treated with topical antiperspirants such as 20% aluminum chloride hexahydrate or 6.25% aluminum chloride hexahydrate. Skin irritation is a common side effect that may be reduced with proper application technique or a low-potency topical corticosteroid. Topical glycopyrronium is an alternative initial treatment for patients with axillary hyperhidrosis. Iontophoresis is an alternative initial treatment for patients with palmar or plantar hyperhidrosis. (See 'Axillary hyperhidrosis' above and 'Palmar or plantar hyperhidrosis' above.)

-Second-line treatment – Second-line treatments for axillary hyperhidrosis include botulinum toxin injection and microwave thermolysis. Palmar and plantar hyperhidrosis can also be treated with botulinum toxin, but the injections are quite painful on the hands and feet, and a significant percentage of patients develop temporary local muscle weakness. (See 'Second-line therapy' above.)

-Refractory hyperhidrosis – Patients with axillary hyperhidrosis who cannot be managed effectively with first- or second-line treatments may benefit from suction curettage, a local surgical intervention. If this is not feasible or effective, our preferred next therapy is systemic medication. Endoscopic thoracic sympathectomy (ETS) is an additional option. The selection of these treatments should follow careful consideration of the associated risks and side effects. (See 'Other therapies' above.)

Patients with palmar hyperhidrosis who cannot be managed effectively with antiperspirants, iontophoresis, or botulinum toxin are candidates for systemic medications or sympathectomy. (See 'Other therapies' above.)

•Craniofacial hyperhidrosis – First-line therapies for craniofacial hyperhidrosis include topical antiperspirants. Patients who cannot be managed with topical therapy may benefit from botulinum toxin injections or oral medication. (See 'Craniofacial hyperhidrosis' above.)