Hyperhidrosis

Hyperhidrosis, which is sweating in excess of that required for normal thermoregulation, is a condition that usually begins in either childhood or adolescence. Although any site on the body can be affected by hyperhidrosis, the sites most commonly affected are the palms, soles, and axillae. See the image below.

Hyperhidrosis of the palms. Courtesy of DermNet New Zealand (http://www.dermnetnz.org/assets/Uploads/hair-nails-sweat/hyperhidrosis.jpg).

Hyperhidrosis may be idiopathic or secondary to other diseases, metabolic disorders, febrile illnesses, or medication use. Hyperhidrosis exists in 3 forms: emotionally induced hyperhidrosis (in which it affects the palms, soles, and axillae),[1, 2] localized hyperhidrosis, and generalized hyperhidrosis. Hyperhidrosis often causes great emotional distress and occupational disability for the patient, regardless of the form.

Generalized hyperhidrosis may be the consequence of autonomic dysregulation, or it may develop secondary to a metabolic disorder, febrile illness, or malignancy. In its localized form, hyperhidrosis may result from a disruption followed by abnormal regeneration of sympathetic nerves or a localized abnormality in the number or distribution of the eccrine glands, or it may be associated with other (usually vascular) abnormalities.

Essential hyperhidrosis, a disorder of the eccrine sweat glands, is associated with sympathetic overactivity.[3] Essential hyperhidrosis does not appear to be a generalized disorder involving vascular endothelium.

Palmoplantar hyperhidrosis may be inherited in an autosomal dominant manner.[4]

Hyperhidrosis may be idiopathic or secondary to other diseases, metabolic disorders, febrile illnesses, or medication use.

Generalized hyperhidrosis may be secondary to numerous conditions including the following:

• Neurologic or neoplastic diseases: Contralateral hyperhidrosis in the left ophthalmic trigeminal division was documented on the forehead after a lateral medullary infarction.[5] Paroxysmal sympathetic hyperactivity after a spontaneous intracerebral hemorrhage may also produce hyperhidrosis.[6]

• Spontaneous periodic hypothermia and hyperhidrosis: This is postulated to be a rare cerebral neurotransmitter disorder.[7, 8]

• Metabolic disorders or processes (eg, thyrotoxicosis, diabetes mellitus, hypoglycemia, gout, pheochromocytoma, menopause)

• Febrile illnesses

• Medications: Use of medications may affect one or more components of human thermoregulation and induce hyperhidrosis. Agents such as propranolol, physostigmine, pilocarpine, tricyclic antidepressants, and serotonin reuptake inhibitors have been implicated. Efavirenz was recently described to induce excessive nocturnal sweating that resolved after dose reduction.[9]

• Chronic alcoholism

• Hodgkin disease or tuberculosis (in nocturnal hyperhidrosis)

Localized unilateral or segmental hyperhidrosis is rare and of unknown origin. The condition usually presents on the forearm or forehead in otherwise healthy individuals, without evidence of the typical triggering factors found in essential hyperhidrosis. Primary focal hyperhidrosis tends to arise on the palms, plantar feet, and axillae, as well as from the face and scalp of children and young adults; there seems to have a distinct subtype of craniofacial hyperhidrosis in postmenopausal women.[10]

Unilateral hyperhidrosis with accompanying contralateral anhidrosis is also rare.[11] Unilateral hyperhidrosis has been described on the right sides of the forehead, the nose, and the palmar surface of the right hand, with anhidrosis on the left hand.

Localized hyperhidrosis may also be associated with the following:

• Gustatory stimuli (associated with Frey syndrome, encephalitis, syringomyelia, diabetic neuropathies, herpes zoster parotitis, and parotid abscess)

• Eccrine nevus: This may be associated with severe localized hyperhidrosis.[12]

• Eccrine angiomatous hamartoma: This is a rare, benign malformation characterized by both eccrine and vascular components.[13, 14] It is usually first evident at birth or during early infancy and childhood as a nodule or a plaque, usually solitary, involving acral skin. Although often asymptomatic, it may be associated with focal hyperhidrosis, hypertrichosis, and pain.

• Blue rubber-bleb nevus

• Glomus tumor

• Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma-proliferative disorder, and skin changes (POEMS) syndrome

• Burning feet syndrome

• Pachydermoperiostosis

• Pretibial myxedema

• Spinal cord tumors: Rarely, hyperhidrosis may be an initial symptom. ^[15]

Frequency

United States

In the United States and the United Kingdom, 1-1.6% of people have records reflecting hyperhidrosis.[16]  About 60% in both databases were women.

In adolescents and young adults, an incidence rate of 0.6-1% is reported for hyperhidrosis.[17]

International

Palmoplantar hyperhidrosis occurs 20 times more frequently in the Japanese than in any other ethnic group.[18, 19]

Race

All races can be affected by hyperhidrosis; however, Japanese are reportedly affected more than 20 times more frequently than other ethnic groups.[18, 19]

Sex

Both sexes can be affected by hyperhidrosis.

Age

Persons of all ages can be affected by hyperhidrosis. Localized hyperhidrosis, unlike generalized hyperhidrosis, usually begins in childhood or adolescence. In a study of 850 patients with palmar, axillary, or facial hyperhidrosis, 62% of patients reported that sweating began since before they could remember; 33%, since puberty; and 5%, during adulthood.[20]

Hyperhidrosis is difficult to treat effectively. Hyperhidrosis is not associated with mortality. Severe cases of hyperhidrosis may adversely affect the patient's quality of life (see Complications). With the newer treatment modalities now available, the patient has numerous options and is offered a better prognosis.

Patients with hyperhidrosis should be educated regarding all of the treatment options, including their corresponding complications and costs.

For patient education resources, see Hyperhidrosis (Excessive Sweating) and BOTOX® Injections.

Essential hyperhidrosis is a dermatologic and neurologic disorder characterized by excessive sweating of the eccrine sweat glands.[21]

Patients note excessive sweating in affected areas, which ultimately prompts them to seek medical attention.

Palmoplantar hyperhidrosis (excessive sweating of the palms and soles) is observed in persons with chronic alcoholism.[22]

Localized hyperhidrosis, unlike generalized hyperhidrosis, usually begins in childhood or adolescence.

Hyperhidrosis beginning later in life should prompt a search for secondary causes such as systemic diseases, adverse effects of medication use, or metabolic disorders. Harlequin syndrome is characterized by unilateral hyperhidrosis and flushing, predominantly induced by heat or exercise.[23] The sympathetic deficits are usually limited to the face.

An echo-Doppler study found impaired left ventricular filling in patients with essential hyperhidrosis, which is associated with cardiac autonomic dysfunction because sympathetic fibers to eccrine glands of the palms of the hand arise from stellate and upper thoracic ganglia, which also innervate the heart.[21] This study indicated that hyperactivity of the sympathetic nervous system in patients with hyperhidrosis may alter cardiac function in the long term.

The temperament and character profile for patients with essential hyperhidrosis has stimulated interest,[24] but data suggest that hyperhidrosis is not related to social phobia or personality disorder.

Excessive sweating may be primary (idiopathic) or secondary to medication or disease. Secondary causes include endocrine diseases such as diabetes mellitus, hyperthyroidism, and hyperpituitarism. In one series, one third of cases were neurologic in origin, including peripheral nerve injury, Parkinson disease, reflex sympathetic dystrophy, spinal injury, and Arnold-Chiari malformation. Additional causes to consider include pheochromocytoma, respiratory disease, and psychiatric disease. Asymmetric hyperhidrosis may suggest neurologic disease.[25]

Diagnostic criteria favoring primary hyperhidrosis include excessive sweating of 6 months or more in duration, with 4 or more of the following: primarily involving eccrine-dense (axillae/palms/soles/craniofacial) sites; bilateral and symmetric; absent nocturnally; episodes at least weekly; onset at age 25 years or younger; positive family history; and impairment of daily activities.[25]

Visible signs of hyperhidrosis are clearly evident. If direct visualization of the affected areas by hyperhidrosis is desired, the iodine starch test may be used. This test requires spraying of the affected area with a mixture of 0.5-1 g of iodine crystals and 500 g of soluble starch. Areas that produce sweat turn black.

Severe cases of hyperhidrosis may adversely affect the patient's quality of life by causing great emotional distress, social embarrassment, and work-related disability (due to palmoplantar hyperhidrosis). It may also be linked with depressive symptoms.[26]

Palmoplantar sweating may result in irritation of the affected skin, ultimately leading to chafing.

Axillary hyperhidrosis may be malodorous, causing social embarrassment.

Search for primary causes if generalized hyperhidrosis is noted.

Important laboratory studies in the hyperhidrosis workup may include the following:

• Thyroid function tests may reveal underlying hyperthyroidism or thyrotoxicosis.

• Blood glucose levels may reveal diabetes mellitus or hypoglycemia.

• Urinary catecholamines may reveal a possible pheochromocytoma.

• Uric acid levels may reveal gout.

• A purified protein derivative (PPD) test can be performed to screen for tuberculosis.

Chest radiography may be used to rule out tuberculosis or a neoplastic cause of the hyperhidrosis.

Individuals with hyperhidrosis have morphologically and functionally normal eccrine glands. Localized hyperhidrosis may result from an abnormal number and/or distribution of otherwise normal eccrine glands. Examples of such conditions include eccrine nevus and eccrine angiomatous hamartoma.

Therapy for hyperhidrosis can be challenging for both the patient and the physician. Both topical and systemic medications have been used in the treatment of hyperhidrosis. Other treatment options for hyperhidrosis include iontophoresis and botulinum toxin injections.

Topical agents for hyperhidrosis therapy include topical anticholinergics, boric acid, 2-5% tannic acid solutions, resorcinol, potassium permanganate, formaldehyde (which may cause sensitization[27] ), glutaraldehyde, and methenamine. All of these agents are limited by staining, contact sensitization, irritancy, or limited effectiveness. These agents reduce perspiration by denaturing keratin and thereby occluding the pores of the sweat glands. They have a short-lasting effect.

The US Food and Drug Administration (FDA) approved glycopyrronium tosylate topical cloth in June 2018 for primary axillary hyperhidrosis in adults and children aged 9 years or older. It is an anticholinergic agent that inhibits the action of acetylcholine on sweat glands. Approval was based on results from two phase 3 clinical trials, ATMOS-1 and ATMOS-2 (n=697). Of these, 44 were pediatric patients aged 9-16 years. The proportions of patients experiencing a reduction of at least 50% in sweat production at 4 weeks for pediatric versus adult patients were 79.9% versus 74.3% of glycopyrronium tosylate–treated patients compared with 54.8% versus 53% of vehicle-treated patients, respectively.[28, 29]  Topical glycopyrronium tosylate has been judged as a cost-effective measure relative to prescription aluminum chloride.[30]

Contact sensitization is increased, especially with formalin. Aldehydes are used to treat the palms and soles; they are not as effective in the axillae. Glutaraldehyde solution 2% is sold as Cidex. It is not as effective but less staining. The 20-50% solution can be diluted to 10% (more effective, especially for feet, but still staining occurs).

Because of the limitations of other agents, Drysol (20% aluminum chloride hexahydrate in absolute anhydrous ethyl alcohol) is more commonly used as the first-line topical agent. Drysol should be applied nightly on dry skin with or without occlusion until a positive result is obtained, after which the intervals between applications may be lengthened. To minimize irritation, the remainder of the medication should be washed off when the patient awakes, and the area may be neutralized with the topical application of baking soda.[31]

Axillary hyperhidrosis may be treated with aluminium chloride gel, although the gel may cause mild cutaneous irritation.[32] Its antiperspirant action for treatment of palmar hyperhidrosis and its low risk of systemic adverse effects from absorption and accumulation of aluminium in visceral organs are noteworthy.[33]  Use of a novel microwave device has been suggested for axillary hyperhidrosis.[34]  A single high-energy microwave treatment may be efficacious for selected patients with primary axillary hyperhidrosis.[35]

Systemic agents used to treat hyperhidrosis include anticholinergic medications. Anticholinergics such as propantheline bromide, glycopyrrolate, oxybutynin,[36] and benztropine are effective because the preglandular neurotransmitter for sweat secretion is acetylcholine (although the sympathetic nervous system innervates the eccrine sweat glands).[37, 38] The use of anticholinergics may be unappealing because their adverse effect profile includes mydriasis, blurry vision, dry mouth and eyes, difficulty with micturition, and constipation. In addition, other systemic medications, such as sedatives and tranquilizers, indomethacin, and calcium channel blockers, may be beneficial in the treatment of palmoplantar hyperhidrosis.

Iontophoresis was introduced in 1952 and consists of passing a direct current across the skin.[39, 40, 41] The mechanism of action remains under debate. In palmoplantar hyperhidrosis, the daily treatment of each palm or sole for 30 minutes at 15-20 mA with tap water iontophoresis is effective.[42] Intact skin can endure 0.2-mA/cm2 galvanic current without negative consequences, and as much as 20-25 mA per palm may be tolerated.[42] Numerous agents have been used to induce hypohidrosis, including tap water and anticholinergics; however, treatment with anticholinergic iontophoresis is more effective than tap water iontophoresis.[43] However, the latter is safe and effective when used on Monday, Wednesday, and Friday for 4 weeks, with continued treatment maintaining the effect.[44] Noncompliance is common with tap water iontophoresis, as it can be time-consuming.[45] This technique merits consideration prior to systemicoraggressive surgical intervention.

Botulinum toxin injections are effective because of their anticholinergic effects at the neuromuscular junction and in the postganglionic sympathetic cholinergic nerves in the sweat glands.[46, 47, 48, 49, 50]

In palmar hyperhidrosis, 50 subepidermal injections of 2 mouse units per palm (total 100 mouse units per palm) results in anhydrosis lasting 4-12 months.[51] Each injection produces an area of anhydrosis approximately 1.2 cm in diameter. The only adverse effect is mild transient thumb weakness that resolves within 3 weeks. Adverse effects of intradermal injections of botulinum A toxin may result from diffusion into underlying muscles.[52] A substantial increase in the duration of efficacy may be produced by repetitive injections in those with primary palmar hyperhidrosis.[53]

In a similar study, the effects of sodium chloride solution injections in one palm were compared with botulinum toxin injections in the other palm.[54] Treatment with 120 mouse units of botulinum toxin (injected into 6 sites in the palm) resulted in a 26% reduction in sweat production after 3 and 8 weeks and a 31% reduction after 13 weeks. Noted adverse effects included minor muscle weakness at the toxin-treated sites, which resolved after 2-5 weeks. Injections of botulinum toxin must be repeated at varying intervals to maintain long-term results.

Treatment of axillary hyperhidrosis with botulinum toxin type A reconstituted in lidocaine or in normal saline was described in a randomized, side-by-side, double-blind study.[55] The results were the same; however, injections of botulinum toxin A reconstituted in lidocaine are associated with significantly reduced pain, thus, lidocaine-reconstituted botulinum toxin A may be preferable for treating axillary hyperhidrosis.

A 2008 study found botulinum toxin type A to be more effective than topical 20% aluminum chloride for the treatment of moderate-to-severe primary focal axillary hyperhidrosis.[56]

Woolery-Lloyd et al reported on successful treatment of inguinal hyperhidrosis with botulinum toxin A. The condition was initially misdiagnosis as urinary incontinence.[57]

Bromhidrosis may be treated with a glycine-soja sterocomplex topical agent, which has shown encouraging results on both the intensity and quality of odor in patients with bromhidrosis.[58]

In addition to pharmacologic therapy, other treatments include surgical sympathectomy, radiofrequency ablation,[59] surgical excision of the affected areas, and subcutaneous liposuction. Each modality has been used effectively. Use of microneedle radiofrequency therapy for axillary hyperhidrosis has been recommended.[60]

Palmar hyperhidrosis is a benign functional disorder that is a psychological and social handicap.[61] A survey showed thoracoscopic sympathectomy to be minimally invasive and to improve the patient's quality of life, even if compensatory hyperhidrosis occurs.

Sympathectomy has been used as a permanent effective treatment since 1920. Usually, it is reserved for the final treatment option.[62] Sympathectomy involves the surgical destruction of the ganglia responsible for hyperhidrosis.[63, 64, 65]  Sympathectomy for hyperhidrosis treatment requires an inpatient stay. Modified R5-R8 thoracic sympathectomy has been used for severe compensatory hyperhidrosis.[66]

The second (T2) and third (T3) thoracic ganglia are responsible for palmar hyperhidrosis, the fourth (T4) thoracic ganglia controls axillary hyperhidrosis, and the first (T1) thoracic ganglia controls facial hyperhidrosis.

Two surgical approaches are available: an open approach and a newer endoscopic approach. The endoscopic approach has become favored because of its improvements in terms of complications, surgical scars, and surgical times. Endoscopic thoracic sympathectomy is an effective treatment for hyperhidrosis; in one study, immediate positive results occurred in 832 (98%) of 850 patients.[20] After a 31-month average follow-up, symptoms recurred in 17 patients. Improved quality of life has been described for upper limb hyperhidrosis after treatment with limited endoscopic thoracic sympathetic block at T4.[67]

Numerous complications are associated with this endoscopic treatment option; these include compensatory sweating (induction of sweating in previously unaffected areas of the body), gustatory sweating, pneumothorax, intercostal neuralgia, Horner syndrome, recurrence of hyperhidrosis, and the sequelae of general anesthetic use.

Of 850 patients who underwent endoscopic transthoracic sympathectomy, 55% had compensatory sweating (mostly on the trunk), and 36% had gustatory sweating.[20] In a similar study[68] of 72 patients who underwent transthoracic endoscopic sympathectomy (T2 or T2 and T3) for palmar hyperhidrosis, the success rate was 93%; compensatory sweating occurred in an overwhelming 99% of patients within 1 month after surgery, and gustatory sweating occurred in 17%. The overall occurrence of severe compensatory hyperhidrosis was reduced after T3 ganglionectomy as opposed to ganglionectomies performed at all other levels.[69] .

T4 ganglion interruption for palmar hyperhidrosis is an effective approach that can simultaneously minimize the rate of compensatory hyperhidrosis.[70] Thus, T4 sympathectomy may be an effective cure. Its rate of compensatory hyperhidrosis appears to be remarkably low compared with T2 sympathetic ganglionic interruption. An effective treatment for such compensatory sweating is the intradermal injection of botulinum toxin.[71]

Li et al reported on minimizing endoscopic thoracic sympathectomy for hyperhidrosis of the palms using the skin temperature of the palms and Doppler-guided blood flow analysis as aids.[72]

Video-assisted thoracic sympathectomy may be preferable to no treatment for children with palmar hyperhidrosis and a poor quality of life.[73]

Topical glycopyrrolate application may be effective and safe for the treatment of excessive facial sweating in primary craniofacial and secondary gustatory hyperhidrosis following sympathectomy.[74]

Surgical excision of the affected area (identified with iodine starch testing) removes the appropriate sweat glands, thereby eliminating sweating. This technique is particularly useful in axillary hyperhidrosis.

The treatment of axillary hyperhidrosis using the 1064-nm Nd-YAG laser was found to be effective and safe in a pilot trial.[75] Fractional carbon dioxide laser–assisted botulinum toxin type A (onabotulinumtoxinA) delivery for the treatment of primary palmar hyperhidrosis has also been used.[76] Radiofrequency thermotherapy has also been recommended.[77]

Subcutaneous liposuction is another means of removing the eccrine sweat glands responsible for axillary hyperhidrosis. Compared with classic surgical excision, this modality results in less disruption to the overlying skin, resulting in smaller surgical scars and a diminished area of hair loss.[78]

Consult a neurosurgeon if sympathectomy is necessary in severe cases of hyperhidrosis that are refractory to all other treatments.

Many of the treatment options for hyperhidrosis require repeat visits to the dermatologist for continuing care (eg, repeated botulinum injections, refill prescriptions) and for evaluating therapeutic progress.

The goals of pharmacotherapy for hyperhidrosis are to reduce morbidity and prevent complications. Control of palmar hyperhidrosis with a new dry-type iontophoretic device has been described.[79] Dry-type iontophoresis may reduce palmar sweating more conveniently than other conventional methods.[80]  Although usually an oral preparation, oxybutynin transdermal may be beneficial in selected patients with hyperhidrosis.[81] Similarly, oxybutynin 3% gel has been used successfully for the primary focal hyperhidrosis in adolescents and young adults.[82]  Use of glycopyrronium tosylate topical for primary axillary hyperhidrosis in adults and children aged 9 years or older is also a consideration.[28, 29]

Class Summary

These agents are antiperspirants that are used in the management of hyperhidrosis.

Aluminum chloride topical (20% Drysol)

Certin-Dri and Xerac are over-the-counter products at low concentrations. These work best if applied to a dry area and covered with plastic overnight. Aluminum chloride should be washed off in the morning. Effects should be noted within 1 month.

Class Summary

Topical glycopyrronium tosylate for primary axillary hyperhidrosis is available, allowing for a more tolerable route of administration. Orally administered anticholinergics are usually avoided because they are poorly tolerated at the required doses when given systemically. Acetylcholine is the preglandular neurotransmitter for sweat secretion. These drugs inhibit the binding of acetylcholine to the cholinergic receptor. Clinical effects usually occur within days.

Glycopyrronium tosylate topical (Qbrexza)

This is a topically applied anticholinergic agent that inhibits the action of acetylcholine on sweat glands. It is indicated for primary axillary hyperhidrosis in adults and children aged 9 years or older. It is applied using single-use, premoistened cloth to clean, dry skin on the underarm areas only, no more frequently than once every 24 hours.

Propantheline (Pro-Banthine)

Propantheline blocks the action of acetylcholine at postganglionic parasympathetic receptor sites.

Glycopyrrolate (Robinul)

Glycopyrrolate acts in the smooth muscle, CNS, and secretory glands to block the action of acetylcholine at parasympathetic sites.

Benztropine (Cogentin)

Benztropine blocks striatal cholinergic receptors; it may help balance cholinergic and dopaminergic activity in the striatum.

Oxybutynin (Ditropan)

Oxybutynin inhibits the action of acetylcholine on smooth muscle and has direct antispasmodic effects on smooth muscles. Although usually an oral preparation, its transdermal use for hyperhidrosis may be beneficial in selected patients.

Class Summary

These agents inhibit the transmission of nerve impulses at the neuromuscular junction of skeletal muscle and/or autonomic ganglia.

OnabotulinumtoxinA (BOTOX®)

OnabotulinumtoxinA prevents calcium-dependent release of acetylcholine and produces a state of denervation at the neuromuscular junction and postganglionic sympathetic cholinergic nerves in the sweat glands.

Each injection produces an area of anhydrosis approximately 1.2 cm in diameter. Treatment reportedly results in anhydrosis lasting 4-12 monts.

Injections of botulinum toxin must be repeated at varying intervals to maintain long-term results.