Todd Wechter, BSc1; Steven R. Feldman, MD, PhD2; Sarah L. Taylor, MD, MPH2

1Stony Brook University School of Medicine, Stony Brook, NY, USA
2Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, USA

Conflict of interest:
Steven Feldman has received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Baxter, Boeringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Taro, Abbvie, Cosmederm, Anacor, Astellas, Janssen, Lilly, Merck, Merz, Novartis, Regeneron, Sanofi, Novan, Parion, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. He is founder and majority owner of www.DrScore.com and founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. Sarah Taylor and Todd Wechter have no conflicts to disclose.

Abstract
Primary focal hyperhidrosis is a relatively common disease that has a significant impact on afflicted patient’s quality of life. The pathogenesis of the disease is thought to stem from increased cholinergic activity on eccrine sweat glands. Topical aluminum chloride based antiperspirants are good first-line agents for all affected body sites. Anticholinergic agents are emerging as effective topical alternatives. Iontophoresis passes an electrical current through the skin and is an excellent treatment option for palmoplantar disease. Botulinum toxin type A injections remain a mainstay second-line treatment. Local procedural advances including microwave thermolysis, laser therapy and focused ultrasound are emerging as safe and effective alternatives for refractory disease. Oral anticholinergics are generally well tolerated and can also be used for intractable disease. Last-line interventions include local surgical options and sympathectomy, though some patients may prefer permanent treatment. Further investigation of novel treatments as well as ways to optimize existing therapeutic options are needed.

Key Words:
antiperspirants, aluminum chloride, botulinum toxin, anticholinergics, focused ultrasound, hyperhidrosis, iontophoresis, microwave thermolysis

Introduction

Primary focal hyperhidrosis, characterized as sweating beyond what is needed for adequate thermoregulation, can have a dramatic effect on quality of life and has an estimated prevalence of 4.8% in the United States.1,2 Primary focal disease differs from secondary hyperhidrosis in that it is located in discrete areas of the body (e.g. palms, soles, axilla, face or scalp) and is not induced by medications or other medical conditions.3,4 While a complete understanding of the cause or causes of primary focal hyperhidrosis remains unknown, its pathogenesis is thought to be linked to the thermoregulatory center of the hypothalamus and the autonomic nervous system.5 Post-ganglionic sympathetic cholinergic neurons release the neurotransmitter acetylcholine, which acts on eccrine sweat glands leading to sweat secretion.6 Increased sympathetic activity on eccrine glands can be induced by either emotional or thermal stimuli.7 Thus, potential treatment targets include the neurotransmitter, nerves, eccrine glands, and eccrine ducts (Figure 1).

Proposed pathway of sweat production and sites of therapeutic intervention
Figure 1: Proposed pathway of sweat production and sites of therapeutic intervention. A. Sympathectomy interrupts thoracic sympathetic outflow from the sympathetic chain. B. Botulinum toxin (BTX-A) injection prevents the release of acetylcholine (ACh) into the synapse. C. Topical and systemic anticholinergics competitively inhibit binding of ACh to muscarinic receptors on the eccrine sweat gland. D. Microwave thermolysis, laser therapy, focused ultrasound and local surgical interventions all damage and/or remove the eccrine sweat glands. E. Aluminum chloride antiperspirants precipitate and block the sweat gland duct.

There are many treatment options that exist for primary focal hyperhidrosis, which can be local or systemic and range from topical therapies to surgical management.8 Disease severity, disease location, treatment cost, side effect profile and patient preference are all important considerations when deciding on therapeutic options.8 Here, we review current and emerging treatment options for primary focal hyperhidrosis. We summarize our findings in Table 1 and then provide our treatment recommendations in Table 2.

TypeTreatmentMechanism of ActionSummarySide Effects
Topical TherapiesAluminum chloride antiperspirantsPrecipitates and blocks sweat gland ductsAn effective initial option, although many patients require additional forms of treatment. Requires continued use.Local skin irritation.
Topical anticholinergicsCompetitive inhibition of acetylcholineCan be used as an alternative topical option. Studies of topical anticholinergic medications have been promising, although additional research is needed.General anticholinergic effects (i.e. dry mouth, vision changes, acute closed angle glaucoma, decreased intestinal motility, urinary retention). Possible cognitive impairment with long-term use.
Local Non-Surgical TherapiesIontophoresisUnknownA great treatment option for palmoplantar disease with minimal side effects. Can also be used to deliver other medications through the skin.Local skin irritation and burns.
Botulinum toxin APrevents acetylcholine release into the synapseAn extremely effective treatment option for all disease locations.

Requires multiple treatments, although symptomatic relief may be prolonged with repeated injection sessions. Less painful delivery methods are being investigated.

Pain at injection site, phantom sweating, reversible muscle weakness.
Emerging Procedural InterventionsMicrowave thermolysisDestroys sweat glandsProvides symptomatic relief and may have long-term efficacy. Is a noninvasive but expensive treatment option.Pain, swelling, local skin irritation, transient subcutaneous nodules, reversible neuropathy.
Laser therapyDestroys sweat glandsNd:YAG laser therapy is an effective, minimally invasive treatment option.

Diode laser therapy (800 nm) requires additional investigation.

Nd:YAG: Swelling, burns, transient neuropathy, transient axillary hair loss.

Diode laser (800 nm): Transient
axillary skin depigmentation.

Focused ultrasoundDestroys sweat glandsAn effective therapy that may provide long-term symptomatic relief. Additional research is needed.Pain, paresthesia, bruising, blistering, seroma formation, hyperpigmentation.
Surgical ManagementLocal surgical treatment (suction curettage, local excision)Destroys and/or removes sweat glandsGenerally effective, although very invasive treatment options.Pain, bruising, bleeding, swelling, scaring, infection.
SympathectomyInterrupts sympathetic outflow to sweat glandsAn effective but invasive surgical treatment that provides long-term symptomatic relief. More effective for palmar disease than axillary disease. Compensatory sweating is its major limitation.Pneumothorax, Horner’s syndrome, neuropathy, subcutaneous emphysema, bradycardia and other surgical risks.
Systemic TherapyOral anticholinergicsCompetitive inhibition of acetylcholineGenerally effective treatment options with reasonable side effect profiles.General anticholinergic effects (i.e. dry mouth, vision changes, acute closed angle glaucoma, decreased intestinal motility, urinary retention). Possible cognitive impairment with long-term use.
Table 1: Summary of literature review for hyperhydrosis treatments.

 

 

Disease LocationRecommendations
Mild to Moderate DiseaseSevere Disease
Axillary
  • 1st line: Topical antiperspirant
  • 2nd line: BTX-A injection
  • 3rd line: Topical or oral anticholinergics
  • 1st line: Topical antiperspirant
  • 2nd line: BTX-A injection
  • 3rd line: Topical or oral anticholinergics
  • 4th line: Microwave thermolysis, Nd:YAG laser or focused ultrasound
  • 5th line: Suction curettage
  • 6th line: Sympathectomy
Palmoplantar
  • 1st line: Topical antiperspirant
  • 2nd line: Iontophoresis
  • 3rd line: BTX-A injection
  • 4th line: Topical or oral anticholinergics
  • 1st line: Topical antiperspirant
  • 2nd line: Iontophoresis
  • 3rd line: BTX-A injection
  • 4th line: Topical or oral anticholinergics
  • 5th line: Sympathectomy (only if palmar involvement)
Craniofacial
  • 1st line: Topical antiperspirant
  • 2nd line: BTX-A injection
  • 3rd line: Topical or oral anticholinergics
  • 1st line: Topical antiperspirant
  • 2nd line: BTX-A injection
  • 3rd line: Topical or oral anticholinergics
  • 4th line: Sympathectomy
Table 2: Summary of our treatment recommendations based on disease location and severity.

Methods

A review of the literature was performed utilizing multiple databases, including PubMed, ClinicalTrials.gov and Google Scholar. Search criteria included general terms such as, “Hyperhidrosis therapy” and “Hyperhidrosis treatment”, as well as more specific terms relating to each respective therapy.

Local Non-Surgical Therapies

Topical Therapies

Topical antiperspirants are generally regarded as first-line options for primary focal hyperhidrosis and can be used as initial therapy for palmoplantar, axillary or craniofacial disease.3,4,8 They are considered effective with a reasonable side effect and cost profile.9 Typically, aluminum chloride based antiperspirants are used, which precipitate with mucopolysaccharides, damage ductal epithelial cells and block the duct, ultimately preventing sweat secretion (Figure 1E).3,10 In mild cases, over-the-counter aluminum chloride based medications may prove effective, although for more severe cases, prescription aluminum chloride hexahydrate at concentrations of 10% to 35% is recommended.3,4,8,11 Aluminum chloride based antiperspirants require continued administration, as the injured epithelium of the eccrine duct will eventually redevelop; although prolonged administration can result in persistent damage to eccrine glands and produce a more durable response.3,4,10

One study of 20 patients with plantar hyperhidrosis demonstrated that aluminum chloride hexahydrate at concentrations of both 12.5% and 30% produced an approximately 52% decrease in sweating after 6 weeks of treatment, as assessed by Minor’s iodine sweat test.12 Another study of 20% aluminum sesquichlorohydrate foam for palmar and axillary disease demonstrated a mean 61% reduction in Minor score after 4 weeks of treatment.13

Local skin irritation is the major side effect of topical aluminum based antiperspirant therapy, although non-alcohol containing formulations, such as aluminum chloride hexahydrate in salicylic gel, may be more tolerable.14 Application of white petroleum jelly prior to aluminum chloride antiperspirant application can also help to prevent skin irritation.15

Topical anticholinergic therapy is another emerging treatment option for hyperhidrosis that likely works through hindering cholinergic activation of eccrine glands (Figure 1C).3,16 In a prospective study of 40 patients with axillary hyperhidrosis, treatment with 2% glycopyrrolate spray decreased sweating similar to botulinum toxin type A injections.17 Another randomized, double-blind, split area study of patients with palmar, plantar or axillary disease found that 10% topical oxybutynin treatment resulted in a mean Dermatology Life Quality Index (DLQI) score reduction of 7.6 points when compared to pretreatment scores.18 Topical anticholinergic therapies such as umeclidinium and glycopyrronium are also being further studied in clinical trials.16,19,20 In particular, glycopyrronium tosylate topical wipes (DRM04, Qbrexza™), recently approved by the US FDA, have been shown to be well tolerated and efficacious for the treatment of axillary disease.20 In two recent phase 3 clinical trials, patients treated with once daily DRM04 topical wipes experienced significant improvement in Axillary Sweating Daily Diary scores (ASDD) and in sweat production as measured by gravimetry.20

Iontophoresis

Iontophoresis involves passing an electrical current through the skin and is an acceptable first-line treatment for palmoplantar hyperhidrosis after a trial of topical antiperspirants for more severe disease.8,21 Patients submerge their hands and/or feet in tap water and an electrical current is applied.21 Although its exact mechanism of action remains unknown, therapy does not alter the structure of the glands.22 Iontophoresis is effective with the added benefit of at-home treatment options.23

In a recent clinical trial examining patients treated with tap water iontophoresis for palmar disease, approximately 93% of patients had symptomatic improvement after 2 weeks of treatment, as measured by starch-iodine test, compared to 38.5% in the sham group.24 Gravimetric analysis revealed that iontophoresis treated patients had a mean reduction in sweat rate of 91.8% and 69% at 2 and 6 weeks post-treatment, respectively.24 Another study demonstrated that with tap water iontophoresis treatment 3 days per week for 4 weeks, patients experienced on average a 75% and 65% reduction of symptoms on their palms and soles, respectively, as measured by self-assessed disease severity scores.25

Iontophoresis can also be used as a mechanism to deliver other medications such as aluminum chloride and anticholinergics.26-28 For example, in a 2011 study of 22 patients with palmar hyperhidrosis, treatment with glycopyrronium bromide iontophoresis resulted in a 54% reduction of mean sweat production as measured by gravimetry.28

Side effects of iontophoresis are generally mild and their severity may depend on the voltage and current used, and can include local skin irritation, pain and burns.25,29

Botulinum Toxin

Botulinum toxin type A (BTX-A) is generally considered a second-line therapy for primary focal hyperhidrosis, although in severe or craniofacial disease it can be considered for first-line use.8 The treatment is effective, however, it is invasive and more expensive than topical options and typically requires repeated administration.30 The injected toxin acts by cleaving the SNARE protein complex, which is required for the pre-synaptic release of acetylcholine, thus halting its effect on the eccrine gland (Figure 1B).31

One randomized, double-blind, multi-institution, prospective study of 207 patients with axillary disease found that 4 weeks after their first BTX-A injection patients experienced a mean decrease in sweat production of 84.6% as measured by gravimetry.32 Furthermore, approximately 96% of patients reported higher satisfaction with BTX-A injection compared to previous treatments they had received.32 Another 2008 study demonstrated that axillary injection with BTX-A is more effective when compared to topical 20% aluminum chloridebased antiperspirants in patients with moderate to severe disease (mean Hyperhidrosis Disease Severity Scale [HDSS] reduction of 2.4 vs.1.33 at 4 weeks of therapy, respectively, p<0.0001).33 Long-term use of BTX-A is safe and effective, and repeated injections may increase the duration of symptomatic relief.34 In a retrospective study of patients receiving a mean of 4 axillary BTX-A injection sessions, the last injection resulted in a 3 month longer median duration of efficacy compared to the first injection.34

Side effects are typically minor and include pain and irritation at the injection site, subjective feeling of increased sweating and reversible muscle weakness.32-35 Pain from the injection is sometimes a limitation of the therapy, although studies of less painful administration methods such as diluting BTX-A in lidocaine or transdermal jet nebulization have been promising.36,37

Emerging Procedural Interventions

Microwave Thermolysis

Microwave thermolysis (miraDry®) is a relatively new secondline therapy for axillary hyperhidrosis that was FDA cleared in 2011.38 The treatment uses microwave energy focused on the dermal-hypodermal junction to heat and permanently destroy both eccrine and apocrine glands (Figure 1D).39

In one group’s report involving 50 patients, 80% experienced more than a 50% sweat reduction after two treatments.40 In a multiinstitution clinical trial limited to patients with HDSS scores of 3 or 4, 89% of patients had HDSS scores of 1 or 2, compared to 54% in the sham group 1 month after microwave therapy.41 At 6 month follow-up, 67% of treated patients had HDSS scores of 1 or 2, however, there was not a statistically significant difference in sweat production between the treatment and sham groups, as measured by gravimetry.41 Another 2012 study, also limited to patients with HDSS scores of 3 or 4, demonstrated more durable results for the therapy.42 Approximately 90% of treated patients reported an HDSS score of 1 or 2, at both 1 month and 1 year after treatment.42 This result was corroborated by gravimetry, with more than 90% of patients experiencing a 50% or greater reduction in sweat production at both 1 month and 1 year followups. 42

Microwave thermolysis is generally well tolerated by patients and the side effects of treatment include pain, local irritation, transient subcutaneous nodules, reversible neuropathy, and swelling.40,41 One limitation of the therapy is its potentially prohibitive cost, as the treatment is often considered to be cosmetic by insurance companies.38

Laser Therapy

Another treatment modality that destroys the sweat glands and yields longer lasting results for patients with axillary hyperhidrosis is laser therapy.38 There are two types of lasers utilized in the treatment of axillary hyperhidrosis: neodymium:yttrium aluminum garnet (Nd:YAG) and 800 nm diode lasers.43

Nd:YAG laser therapy is often used for hair removal, however, it also damages the surrounding eccrine glands through optomechanical and thermal mechanisms (Figure 1D).44,45 Histological examination after axillary Nd:YAG treatment shows a decrease in the density of eccrine glands, highlighting its ability to destroy the glands.44 In one 17 participant study, treatment with a 1064 nm Nd:YAG laser resulted in 70.6% of patients experiencing an excellent result as per patient’s global assessment and a decrease in mean area of sweating of 48 cm2.45 Side effects were minimal and included swelling, burns, transient neuropathy and transient axillary hair loss.45

While 800 nm diode lasers have been used in the treatment of axillary hyperhidrosis, there is comparatively less supporting literature available.46 In a 21 patient, randomized, half-side, comparison trial, five treatments with an 800 nm diode laser resulted in a median sweat rate reduction of 41 mg/minute (min) and 13 mg/min in the treated axilla and untreated axilla, respectively.46 Interestingly, there was no difference in gravimetric results between the treated and untreated axilla (p=0.10), which the authors credited to placebo effect.46 The 800 nm diode laser does not appear to decrease the density of axillary eccrine glands, as was seen after Nd:YAG laser therapy.44,46 The only side effect observed in the study was an isolated case of transient axillary skin depigmentation.46

Focused Ultrasound Therapy

Focused ultrasound is a relatively new treatment option for axillary hyperhidrosis.47 The ultrasound energy is targeted beneath the superficial dermis where eccrine sweat glands exist and acts through a thermal mechanism to damage the sweat glands (Figure 1D).47

A randomized, double-blinded, pilot study found that after two micro-focused ultrasound treatments, 83% of patients had a 50% or greater decrease in sweat secretion as measured by gravimetry.47 Patients were also pleased with the treatment, as approximately 92% reported that they would recommend the therapy and 83% noted decreased embarrassment from their disease.47 The most common side effect reported was local tenderness, with other common side effects including paresthesia and bruising.4

In another 2009 prospective study, patients treated with focused ultrasound therapy experienced a 62% mean improvement in sweating when comparing pre-treatment and post-treatment patient assessment scores.48 Side effects noted during this study were generally mild and included blistering, seroma formation and hyperpigmentation.48

Surgical Management

Local Surgical Options

Local surgical management is generally considered one of the last-line options for axillary hyperhidrosis.8 The principle behind local surgical techniques is to remove the sweat glands, thus theoretically permanently eliminating the source of the disease.49 Local surgical options typically include destruction and removal of the glands through curettage, suction, excision or a combination of these techniques (Figure 1D).49-53

A recent 2017 study of 20 patients with axillary disease found an approximately 80% mean reduction in sweat rate 3 months after treatment with suction curettage.50 Interestingly, there was no significant difference in mean sweat rate reduction between suction-curettage and BTX-A treated groups (mean sweat rate reduction of 68.22 mg/min vs. 71.17 mg/min, respectively, p=0.21).50 This finding was corroborated in another study that demonstrated similar efficacy between the two treatment options, with a mean sweat rate reduction of 60.4% and 72.1%, for suction curettage and BTX-A injection treated groups, respectively (p=0.29).51

Suction curettage has persistent results.52 In a prospective study of 28 patients treated with axillary suction curettage, the mean resting sweat rate of treated patients was reduced by 58% from baseline at 1 year follow-up.52 The study also noted that suction curettage was more effective in patients with higher baseline sweat rates, which led the authors to question the use of the procedure in patients with pre-operative sweat rates of less than 25 mg/min.52

Axillary skin excision is a less commonly used treatment method for hyperhidrosis, and there are multiple techniques available with varying amounts of tissue excision.49,53 In a 2006 prospective study of patients with axillary hyperhidrosis, treatment with local skin excision resulted in a mean sweat reduction of 65% as assessed by post-operative patient reporting.49 Another 56 patient retrospective study found that 88% of patients undergoing axillary skin resection were satisfied with the results 3 months after surgery.53

Although surgical methods carry more significant adverse effects than less invasive treatment options, they remain an alternative for patients with refractory axillary disease.49-53 Major side effects of local surgical options include pain, bruising, bleeding, swelling, scaring, and infection.49-53

Sympathectomy

Sympathectomy is the most invasive surgical procedure for primary focal hyperhidrosis and is reserved as a last-line treatment option for refractory palmar, axillary and craniofacial disease.8 By surgically damaging the thoracic sympathetic outlets, the upstream source of eccrine gland stimulation is disrupted, leading to symptomatic relief (Figure 1A).54 The surgery is often done endoscopically and there are multiple methods of sympathetic interruption, including cutting, clipping and electrocauterization.54-57 Although effective, a major limitation of sympathectomy is compensatory sweating.54,55,57

One study of 283 patients that had undergone bilateral T3- T4 endoscopic sympathectomy demonstrated a mean sweat rate reduction of 91.8% and 63.3%, in the palms and axilla, respectively.55 These results were persistent through 3 years of follow-up.55 Although most patients experienced compensatory sweating, approximately 76% considered it acceptable at 3 years follow-up.55

In a study of 352 patients undergoing thoracoscopic sympathectomy, 91.1% reported dry skin after an average of 16 years of follow-up.57 The surgery was more effective for palmar disease than axillary disease, and high rates of compensatory sweating were again noted.57

Additional research has examined less invasive surgical methods of disrupting sympathetic outflow.56,58-60 For example, singleport videoscopic surgery is a safe and effective method of minimally invasive sympathectomy.56,60 Smaller incisions with a needlescopic approach have also been successfully attempted.58,59

Surgical sympathectomy is an invasive procedure and carries typical surgical risks.54 Major side effects include pneumothorax, Horner’s syndrome, neuropathy, subcutaneous emphysema and bradycardia.54,55,57

Systemic Therapies

Systemic therapies are generally considered second- or thirdline options depending on disease severity and location.8 The main class of oral medication prescribed for hyperhidrosis is anticholinergics, although antihypertensives and psychiatric medications have also been utilized.61 Anticholinergic medications act through blocking sweat gland muscarinic receptor activation by acetylcholine (Figure 1C).61 Although many anticholinergic medications are effective, there is some reluctancy to use them as a result of their side effect profile.61-65

In a 2012 prospective study investigating the efficacy and safety of low dose oral oxybutynin, approximately 35% and 39% of treated patients reported their quality of life as “much better” or “a little better,” respectively.62 This was compared to just 13.6% of patients in the placebo group reporting “a little better” quality of life, and none reporting “much better” quality of life.62 Dry mouth was the only adverse effect noted during the study and was considered moderate to severe in 26.1% and 34.8% of patients receiving 5 mg and 10 mg oxybutynin therapy, respectively.62

Glycopyrrolate is another anticholinergic drug that has been studied in primary hyperhidrosis.64 In one retrospective study including 31 pediatric patients with recalcitrant disease, oral glycopyrrolate therapy resulted in “major improvement” in 71% of treated patients.64 The medication was generally well tolerated and the most common side effect was dry mouth.64

Methantheline bromide is additional systemic anticholinergic option.61,65 In a 2013 multicenter clinical trial involving 339 patients with axillary or palmar disease, axillary sweat secretion was reduced 41% after 1 month of oral methantheline bromide treatment; no significant difference in palmar sweat production was noted.65 Treated patients also experienced decreases in both HDSS and DLQI scores.65 Similar to other anticholinergic medication studies, dry mouth was the most frequently experienced side effect.65

Research into methods of reducing the side effects of anticholinergic medications has also yielded some promising results.63 For example, recent study of an oxybutynin/pilocarpine combination drug demonstrated both efficacy and a lower incidence of dry mouth.63

Side effects of anticholinergic medications generally include dry mouth, dry eyes, changes in vision, and decreased intestinal motility.61,64,65 Caution must be exercised when prescribing these drugs, especially in patients that may experience urinary retention or acute closed angle glaucoma.61 There is also literature suggesting that long-term anticholinergic use may be a risk factor for cognitive impairment.66,67

Conclusion

Primary focal hyperhidrosis afflicts a significant number of patients in the United States and greatly impacts their quality of life. Treatment decisions should take into consideration disease location, severity and patient preference. Topical antiperspirants remain a reasonable primary treatment option for all forms of disease. BTX-A is an effective second-line therapy, particularly for axillary disease. Iontophoresis is a superior option for palmoplantar disease and further investigation into the utilization of iontophoresis to deliver sweat reducing medications may yield additional treatment prospects. More recent procedural interventions such as microwave thermolysis, focused ultrasound and laser therapies have also demonstrated considerable promise in the treatment of refractory disease. Oral systemic therapies, specifically anticholinergic medications, appear to be a safe and effective alternative option for all forms of primary hyperhidrosis. More invasive options such as suction curettage and surgical sympathectomy, while effective, should be reserved for more severe refractory cases. Continued research into novel treatment options and methods of improving the efficacy and reducing the side effects of existing treatment options is needed.

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