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Current Concepts In Diagnosing And Treating Hyperhidrosis

Excessive sweat on the plantar surface of the foot can be embarrassing for patients and potentially lead to complications such as fungal infection. Accordingly, this author offers keys to differentiating between primary and secondary hyperhidrosis, discusses the reported social stigma associated with the condition, and provides a thorough review of the literature on current and emerging therapies.

For many patients, the thought of spring and summer means breaking out their sandals. However, for those who suffer with plantar hyperhidrosis, it means the possibility of walking right out of a sandal due to excessive sweat not allowing a shoe to remain on the foot. This excessive sweating is not due to an increased number of sweat glands. It is caused by hyperactivity of the eccrine sweat glands despite a normal body temperature.1 Hyperhidrosis is excessive sweating disproportionate to the environmental conditions or what is needed for thermoregulation.2

Hyperhidrosis affects about 3 percent of the population, not including unreported cases, many of which may be due to patient embarrassment.1 Hyperhidrosis can be a generalized condition with various etiologies but when it is focal, such as when it affects the plantar surface of feet, the condition is usually idiopathic.1 Some other causes of focal hyperhidrosis include malignancy or congenital/genetic causes such as epidermolysis bullosa syndromes, pachyonychia congenita, palmoplantar keratoderma syndromes or eccrine gland autonomic pathologies.2

Hyperhidrosis occurs at locations with a high density of eccrine glands, such as plantar, palmar and craniofacial surfaces, and locations with apocrine glands, such as the axilla.3 Other than women having a slightly higher likelihood of having axillary hyperhidrosis, researchers have not found significant gender differences in prevalence at any other anatomic site.3,4 In one study, almost 47 percent had primary hyperhidrosis of multiple sites and plantar hyperhidrosis was present in just over 50 percent of cases, making the plantar surface the most frequently involved anatomic site.3 The age of onset for plantar hyperhidrosis tends to be between infancy and 19 years of age with almost 56 percent occurring between infancy and 11 years of age although authors have suggested that hyperhidrosis may regress spontaneously due to the low prevalence among the elderly.5 In an epidemiological study by Lear and colleagues, the plantar surface of the foot was affected in almost 46 percent of patients with hyperhidrosis.5

A Guide To Diagnosing Plantar Hyperhidrosis

Plantar hyperhidrosis is typically primary and idiopathic, but there are primary and secondary variations of hyperhidrosis.2

Primary hyperhidrosis tends to be an idiopathic increase in sympathetic nervous system activity while secondary hyperhidrosis is usually caused by either a medication or an underlying disease.2 Primary hyperhidrosis tends to be typically distributed in the axilla, palms, soles and craniofacial area in a bilateral and symmetric pattern with an increase in cutaneous infections.

While secondary hyperhidrosis does affect the feet, it has different etiologies and typical patterns of distribution.2 Secondary hyperhidrosis tends to be caused by generalized medical conditions or medications. The generalized medical conditions can include endocrine, neurologic, cardiovascular, neoplastic and infectious diseases. One study found 57 percent of secondary hyperhidrosis was caused by endocrine pathology, including diabetes mellitus, hyperthyroidism and hyperpituitarism; and 32 percent was caused by neurologic diseases including peripheral nerve injury, Parkinson’s disease, reflex sympathetic dystrophy, spinal cord injury and Arnold-Chiari malformation.2

If a patient has not had lab work recently, I will order a thyroid panel to rule out hyperthyroidism prior to initiating hyperhidrosis therapy. Secondary hyperhidrosis is more likely to have unilateral and/or asymmetrical distribution, to be more generalized than focal, to be present at night during sleep, to have an onset older than age 25, and these patients are more likely to lack a family history of the condition.2 The medications to be aware of that may cause secondary hyperhidrosis include adrenergics, anticholinesterases/cholinergics, antidepressants, anti-diabetes agents, antiemetics, antineoplastics, antipsychotics, antipyretics, anxiolytics, alcohol, and opiates.2  

The diagnosis of primary focal hyperhidrosis is not simply excessive sweating.6 The criteria for diagnosis generally is excessive sweating that lasts for at least six months and has at least two of the following symptoms: a bilateral and symmetric pattern of sweating that occurs at least once per week; impairment of daily activities; initial presentation before the age of 25; focal sweating ceases during sleep at night; and a family history.7

Walling described a more specific diagnostic criteria with a higher positive predictive value in determining the presence of primary hyperhidrosis.2 The author defined this criteria as excessive sweating for six months or more with four of the following: presence in eccrine-dense areas such as the axilla, palms, soles, and craniofacial areas; bilateral and symmetrical distribution; absence of excessive sweating nocturnally; episodes at least weekly; onset at 25 years or younger; family history; and the impairment of daily activities.2

There is some evidence that primary hyperhidrosis is an autosomal dominant trait with variable penetrance.8,9 In a study of 410 patients in Japan, 36 percent had positive family histories of palmoplantar hyperhidrosis.9 The most common pattern was parent-child (58 percent) incidence and 13 percent of patients had three generations affected by palmoplantar hyperhidrosis.9  

A Closer Look At The Social Effects Of Hyperhidrosis

Plantar hyperhidrosis doesn’t just affect the patient’s feet. It can be an extremely embarrassing condition for which many patients tend to delay seeking treatment from a health care provider. In some cases, this delay has been up to almost nine years from the onset of symptoms.3 Mood changes such as anxiety and embarrassment are commonly associated with hyperhidrosis.10 Activities such as playing sports, working out at a gym and dealing with professional and interpersonal relationships can all be affected as patients may need to change their shoes and socks several times per day.4,10,11

Braganca and coworkers found the prevalence of anxiety, more so than depression, is significantly higher in people with hyperhidrosis in comparison to the general population.10 Of the patients studied, 72 percent had the plantar surfaces affected and 68 percent of those also had anxiety. Not only can hyperhidrosis cause emotional stress, Walling’s case control study in 2009 found that 56.7 percent of the patients with primary hyperhidrosis reported that it was exacerbated by stress, emotion, anxiety or social situations.3 In addition, 22 percent of people reported that heat and humidity also exacerbated their hyperhidrosis.

Besides having to change socks and shoes multiple times daily, another cause for anxiety for these patients is bromhidrosis, which is an unpleasant odor caused by the decomposition of sweat by bacteria.12 Beyond the odor that bacteria can cause, Walling noted the overall risk of any cutaneous infection was increased in sites with hyperhidrosis.3 There is an increased risk of fungal infections with a particularly increased risk of dermatophyte infections of cutaneous surfaces, such as tinea pedis, tinea manuum, tinea corporis and tinea cruris.3 In patients with onychomycosis and hyperhidrosis, maceration of the skin decreases the defense against fungal infection, and the damp environment facilitates the growth and proliferation of fungi.13

In a study by Zheng and colleagues, out of 40 patients with both onychomycosis and hyperhidrosis, 20 were treated for onychomycosis, and the other 20 were treated for both onychomycosis and hyperhidrosis. Sixteen out of 20 just treated for onychomycosis had positive nail clearing but 20 out of 20 treated for both onychomycosis and hyperhidrosis had a positive resolution for their nail infection.13 Besides fungal infections, plantar hyperhidrosis also carries an increased risk of bacterial infection, particularly pitted keratolysis, commonly caused by Corynebacterium and Micrococcus species.3 Hyperhidrosis and maceration may be present in 70 to 90 percent of cases of pitted keratolysis.14 Although one can treat pitted keratolysis successfully with topical antibiotics like clindamycin, it can also be resistant to treatment and chronically recur in the presence of hyperhidrosis.14 Researchers believe the presence of hyperhidrosis in pitted keratolysis may either create a supportive environment for bacterial growth and proliferation, or it may lessen the effect of topical medications.14  

What The Literature Reveals About Aluminum Chloride, Iontophoresis And Botox

The first line of treatment is the topical application of an antiperspirant, such as aluminum chloride.1 When an antiperspirant mixes with sweat, this chemical reaction creates a precipitate salt, which physically blocks the duct around 24 hours.15 Patients should apply an antiperspirant at bedtime that will not wash off if bathing occurs the next morning due to this physical block. They can apply a deodorant in the morning after bathing if necessary.

In 2011, Streker and colleagues conducted a study on the effectiveness of two different concentrations of aluminum chloride, 12.5 percent and 30 percent, and found that both significantly reduced sweat production in plantar hyperhidrosis in six weeks.16 Since both were effective, they recommend using aluminum chloride 12.5 percent. Ultimately, it is recommended to begin with the lowest dose over the counter and progress to the prescription antiperspirants to have the least irritation.  

Either as a primary treatment or when antiperspirants have been ineffective or have caused skin irritation, tap water iontophoresis (Hidrex USA) is another option for plantar hyperhidrosis treatment.17 Iontophoresis allows an ionized substance to pass through intact skin via a direct electrical current. Patients can use iontophoresis with just tap water or by adding the anticholinergic glycopyrrolate.17 Patients can do this treatment about three times per week.

It is not fully understood why iontophoresis is effective for plantar hyperhidrosis but different theories suggest ion deposition plugging sweat glands, blocking the transmission of sympathetic nerves, or the accumulation of hydrogen ions causing a decrease in pH.17 There can be mild adverse effects associated with this treatment such as erythema, vesiculation, burning sensation, pins and needles, and dry skin, but patients can manage these with moisturizers, petroleum jelly, and reducing the frequency of treatments.17 Iontophoresis treatment, however, is contraindicated in women who are pregnant, in people who have pacemakers or metal implants, and those with cardiac conditions or epilepsy.17

Injectable botulinum toxin A is another method that researchers have explored for the treatment of plantar hyperhidrosis although its use on the plantar surface of feet is still considered off-label use.11 It is a purified neurotoxin that may be an effective treatment when conservative therapy such as antiperspirants or iontophoresis are ineffective.18 OnabotulinumtoxinA (Botox, Allergan) is a protein that inhibits presynaptic release of acetylcholine, thereby limiting the sympathetic stimulation of the eccrine sweat glands that cause the excess sweating.18 Since the eccrine sweat glands are normal in size, number and density in primary focal hyperhidrosis, botulinum toxin works by inhibiting the overactive postganglionic sympathetic cholinergic fibers innervating them.11

A case series by Vlahovic and colleagues showed Botox to be an effective treatment of recalcitrant plantar hyperhidrosis with patients reporting decreased sweating up to six months after injection and a 75 percent improvement in symptoms.18 I recommend giving the patient a local anesthetic with an ankle block and/or topical application of ice/ethyl chloride as these plantar injections can be painful.18 One can perform a Minor’s iodine starch test (application of betadine followed by corn starch) to determine the focal areas of hyperhidrosis and then inject the non-cosmetic version of Botox intradermally into spots 2 cm apart in a grid pattern. This treatment is a pregnancy Category C drug and one should avoid using it in nursing mothers.11

In a study by Vadoud-Seyedi of 10 patients (five men, five women), eight out of 10 patients were satisfied and had a significant decrease in sweating with the maximum duration of benefits occurring between three and six months after treatment.19 In a study by Tamura and colleagues, two patients with both plantar hyperhidrosis and pitted keratolysis had injections of botulinum toxin, had resolution of symptoms within 14 days and continued without symptoms six months after treatment.14  

Assessing The Study Findings On Glycopyrrolate, Glycopyrronium Tosylate And Oxybutynin

In addition, oral glycopyrrolate is reportedly an effective treatment for hyperhidrosis.20 An anticholinergic drug, glycopyrrolate acts on the nerves innervating sweat glands to decrease sympathetic stimulation and thus decrease sweat production.20

In a study in which feet were the second most common area to be affected, Lee and colleagues assessed glycopyrrolate and found that 75 percent of patients with primary hyperhidrosis had an actual decrease in the amount of sweating, and patients also reported a decrease in discomfort in their everyday lives.20 Thirty-six percent of patients experienced some side effects, such as oral dryness, palpitations and headache.

This medication is effective in decreasing sweat production without causing a plethora of central side effects since it is a highly polar molecule that does not pass through lipid membranes to the central nervous system.20 In regard to dosing, clinicians can prescribe 1 mg twice per day and potentially increase this to 8 mg per day.20  

The most recent addition to the anticholinergic-based therapies is Qbrexza (Dermira), which is glycopyrronium tosylate as a medicated single-use towelette. It is FDA approved for axillary sweating and one can apply it as a premedicated wipe to both axillae once daily. In studies,  Qbrexza was well tolerated in children as young as 9 years old.21,22

Oxybutynin is another oral medication that researchers have explored for the treatment of hyperhidrosis due to its antimuscarinic effects.23 In a study of children under the age of 14 with palmar and plantar hyperhidrosis, 91 percent reported moderate or great improvement in their level of sweating, and almost 95 percent reported an improvement in their quality of life.23 Ninety-one percent of these patients reported plantar hyperhidrosis.2

In this study, patients received 2.5 mg twice of oxybutynin a day for the first seven days, 2.5 mg twice a day the next seven days and then 5 mg twice a day from day 22 to six months.23 The most common side effect was dry mouth but at six weeks, all patients reported moderate or great improvement in sweating levels, and 91 percent reported the same at six months.23 Of those who had plantar sweating, 90.6 percent reported moderate or great improvement at six months.23  

In another study of the long-term effects of oxybutynin on plantar hyperhidrosis by Wolosker and coworkers of a sample of patients ranging in age from 9 to 71, of the patients who continued to follow-up for six months, 84.7 reported moderate or great improvement in self-perceived plantar sweating.24

The main contraindication for using this medication is glaucoma.24 Also, one should advise patients that with an oral medication such as oxybutynin, it can take up to three weeks from the start of the medication for the patient to see improvement in symptoms.24

Can Thermal Energy Or The Endoscopic Lumbar Sympathectomy Have An Impact?

Researchers have also explored thermal energy for treatment of hyperhidrosis but it is not approved for plantar hyperhidrosis. The miraDry device (Miramar Labs) has been tested and approved for the treatment of axillary hyperhidrosis. It uses microwave energy at 5,800 MHz, which is between infrared (CO2 lasers) and radiowaves on the electromagnetic spectrum.25 Using an antenna, the microwave energy penetrates the skin to the eccrine sweat glands, preferentially targeting the skin-adipose junction where most eccrine glands are located.25 The device causes simultaneous cooling as this treatment causes thermolysis of the sweat glands.25

In a study by Hong and Lupin, miraDry was 90 percent effective after 12 months with almost 90 percent patient satisfaction at 12 months.26 The authors found the amount of sweat produced decreased by an average of 82 percent at 12 months. Ninety percent of patients had at least a 50 percent reduction in axillary sweat production from baseline. The most common side effects were edema (90 percent), redness (87 percent), discomfort (84 percent) and altered sensation for up to four months (45 percent). Hopefully, this device will be studied on plantar hyperhidrosis in order to give our patients another non-invasive modality.  

Aside from the non-invasive therapies listed, surgical treatment for plantar hyperhidrosis is endoscopic lumbar sympathectomy.12 In a study by Rieger and coworkers, 52 patients with primary plantar hyperhidrosis had an endoscopic lumbar sympathectomy.12 Of these patients, 96 percent reported the elimination of plantar sweating. Sixty-five percent reported compensatory sweating, which is common after sympathectomies. Eighty-eight percent of study participants reported they would have the surgery again and 96 percent were satisfied with their postoperative results, reporting a decrease in plantar sweating and an increase in their quality of life. For the majority of our patients, we would use this treatment after all conservative therapies have failed.

In Conclusion

One should first properly diagnose plantar hyperhidrosis and initiate topical therapy, starting with gentle modalities and moving to treatments that may be more irritating in terms of potential pain and side effects. If topical therapies fail, consider other conservative therapies such as Qbrexza, iontophoresis, Botox injections, miraDry or an oral anticholinergic. Most of these are not FDA-approved for plantar hyperhidrosis and one may consult with dermatology or primary care in order to have the best patient outcome. One can also recommend that patients visit the website www.sweathelp.org, which lists various treatment possibilities, home care and community support to aid our patients in the day-to-day challenges of having hyperhidrosis.

Dr. Vlahovic is a Clinical Professor in the Department of Podiatric Medicine at the Temple University School of Podiatric Medicine.

References

1.    Streker M, Tilmann R, Hagen L, Kerscher M. Hyperhidrosis plantaris- a randomized, half-side trial for efficacy and safety of an antiperspirant containing different concentrations of aluminum chloride. J German Soc Dermatol. 2012; 10(2):115-119.
2.    Walling HW. Clinical differentiation of primary from secondary hyperhidrosis. J Am Acad Dermatol. 2011; 64(4):690-5.
3.    Walling HW. Primary hyperhidrosis increases the risk of cutaneous infection: A case-control study of 387 patients. J Am Acad Dermatol. 2009; 61(2):242-246.
4.    Lima SO, Aragão JF, Machado Neto J, Almeida KB, Menezes LM, Santana VR. Research of primary hyperhidrosis in students of medicine of the State of Sergipe, Brazil. An Bras Dermatol. 2015; 90(5):661-5.
5.    Lear W, Kessler E, Solish N, Glaser DA. An epidemiological study of hyperhidrosis. Dermatol Surg. 2007; 33(1):S69-S75.
6.    Ak M, Dincer D, Haciomeroglu B, Akarsu S, Cinar A, Lapsekili N. Temperament and character properties of primary focal hyperhidrosis patients. Health Qual Life Outcomes. 2013; 11: 1-5.
7.    Hornberger J, Grimes K, Naumann M, et al. Recognition, diagnosis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol. 2004; 51(2):274-86.
8.    Kaufmann H, Saadia D, Polin C, Hague S, Singleton A, Singleton A. Primary hyperhidrosis – evidence for autosomal dominant inheritance. Clin Auton Res. 2003; 13(2):96–98.
9.    Yamashita N, Tamada Y, Kawada M, Mizutani K, Watanabe D, Matsumoto Y. Analysis of family history of palmoplantar hyperhidrosis in Japan. J Dermatol. 2009; 36(12):628-31.
10.    Braganca GMG, Lima SO, Neto AFP, Marques LM, Melo EV, Reis, FP. Evaluation of anxiety and depression prevalence in patients with primary severe hyperhidrosis. An Bras Dermatol. 2014; 89(2):230-5.
11.    Weinberg T, Solish N, Murray C. Botulinum neurotoxin treatment of palmar and plantar hyperhidrosis. Dermatol Clin. 2014; 32(4):505-15.
12.    Rieger R, Pedevilla S, Lausecker J. Quality of life after endoscopic lumbar sympathectomy for primary plantar hyperhidrosis. World J Surg. 2015; 39(4):905–911.
13.    Zheng Y, Yanqing W, Chen H, Zhu Z, Liu L, Zeng J. Analysis of the factors influencing the therapeutic effects of onychomycosis. J Tongji Med Univ. 2001; 21(3):259-262.
14.    Tamura B, Cucé LC, Souza RL, Levtites J. Plantar hyperhidrosis and pitted keratolysis treated with botulinum toxin injection. Dermatol Surg. 2004;30(12):1510–1514.
15.    Antiperspirant basics. International Hyperhidrosis Society. Available at https://www.sweathelp.org/hyperhidrosis-treatments/antiperspirants/antiperspirant-basics .
16.    Streker M, Reuther T, Hagen L, Kerscher M. Hyperhidrosis plantaris – a randomized, half-side trial for efficacy and safety of an antiperspirant containing different concentrations of aluminum chloride. J Dtsch Dermatol Ges. 2012;10(2):115-9.
17.    Karakoc Y, Aydemir EH, Kalkan MT. Placebo-controlled evaluation of direct electrical current administration for palmoplantar hyperhidrosis. Int J Dermatol. 2004;43(7):503-5.
18.    Vlahovic TC, Dunn SP, Blau, JC, Gauthier C. Injectable botulinum toxin as a treatment for plantar hyperhidrosis: A case study. J Am Podiatr Med Assoc. 2008; 98(2):156-159.
19.    Vadoud-Seyedi J. Treatment of plantar hyperhidrosis with botulinum toxin type A. Int J Dermatol. 2004; 43(12):969-971.
20.    Hong HH, Kim DW, Kim DW, Kim C.  Efficacy of glycopyrrolate in primary hyperhidrosis patients. Korean J Pain. 2012; 25(1):28–32.
21.    QBREXZA™ (glycopyrronium) cloth prescribing information. Menlo Park, CA: Dermira; 2018.
22.    Glaser DA, Hebert AA, Nast A, et al. Topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: results from the ATMOS-1 and ATMOS-2 phase 3 randomized controlled trials. J Am Acad Dermatol. 2019;80(1):128-138.
23.    Wolosker N, Tievelis MP, Krutman M, et al. Long-term efficacy of oxybutynin for palmar and plantar hyperhidrosis in children younger than 14 years. Pediatr Dermatol. 2014; 32(5):663–667.
24.    Wolosker N, Tievelis MP, Krutman M, et al. Long-term results of the use of oxybutynin for the treatment of plantar hyperhidrosis. Int J Dermatol. 2015; 54(5):605–611.
25.    Jacob C. Treatment of hyperhidrosis with microwave technology. Semin Cutan Med Surg. 2013; 32(1):2-8.
26.    Chih-Ho Hong H, Lupin M, O’Shaughnessy KF. Clinical evaluation of a microwave device for treating axillary hyperhidrosis. Dermatol Surg. 2012; 38(5):728–735

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By Tracey C. Vlahovic, DPM
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