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INTRODUCTION

Background: 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, the sites most commonly affected are the palms, soles, and axillae. This condition may be idiopathic or secondary to other diseases, metabolic disorders, febrile illnesses, or medication use. Hyperhidrosis exists in 3 forms: emotionally induced (in which it affects the palms, soles, and axillae), localized, or generalized. The condition often causes great emotional distress and occupational disability for the patient, regardless of the form.

Pathophysiology: 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 (Esen, 2005). It does not appear to be a generalized disorder involving vascular endothelium.

Frequency:

• In the US: In adolescents and young adults, an incidence of 0.6-1.0% is reported (Adar, 1977).

• Internationally: Palmoplantar hyperhidrosis occurs 20 times more frequently in the Japanese than in any other ethnic group (Cloward, 1957; Cloward, 1969).

Mortality/Morbidity:

• Hyperhidrosis is not associated with mortality.

• Severe cases of hyperhidrosis may adversely affect the patient's quality of life (see Complications).

Race: All races can be affected; however, Japanese are reportedly affected more than 20 times more frequently than other ethnic groups (Cloward, 1957; Cloward, 1969).

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 (Drott, 1995).
  

CLINICAL

History:

• 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 (Tugnoli, 1999).

• 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 (Moon, 2005). The sympathetic deficits are usually limited to the face.

Physical:

• Visible signs of hyperhidrosis are clearly evident.

• If direct visualization of the affected areas 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 will turn black.

Causes: 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

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

• Febrile illnesses

• Use of medications (eg, propranolol, physostigmine, pilocarpine, tricyclic antidepressants, venlafaxine)

• Chronic alcoholism

• Hodgkin disease or tuberculosis (in nocturnal hyperhidrosis)

• Localized hyperhidrosis may be emotionally induced and usually affects the palms, soles, and/or axillae. Unlike sweating on the remainder of the body, sweating on the palms and soles is controlled solely by the cerebral cortex and is responsive to emotional stimuli rather than to temperature stimuli (Sato, 1989). Both emotional and thermoregulatory stimuli control sweating in the axillae; therefore, palmoplantar hyperhidrosis, unlike generalized hyperhidrosis, does not occur during sleep or sedation.

• 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

• Eccrine angiomatous hamartoma

• 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

DIFFERENTIALS

Other Problems to be Considered:

Burning feet syndrome
Neoplastic diseases
Neurologic diseases
Thyrotoxicosis
Diabetes mellitus
Hypoglycemia
Gout
Pheochromocytoma
Menopause
Febrile illnesses
Use of medications (eg, propranolol, physostigmine, pilocarpine, tricyclic antidepressants, venlafaxine)
Chronic alcoholism
Hodgkin disease
Tuberculosis
Eccrine nevus
Eccrine angiomatous hamartoma
Riley-Day syndrome (familial dysautonomia)

WORKUP

Lab Studies:

• Search for primary causes if generalized hyperhidrosis is noted.

• Important laboratory studies 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.

Imaging Studies:

• Chest radiography may be used to rule out tuberculosis or a neoplastic cause.

Histologic Findings: 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.

TREATMENT

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

• Topical agents include topical anticholinergics, boric acid, 2-5% tannic acid solutions, resorcinol, potassium permanganate, formaldehyde (which may cause sensitization [Shelley, 1954]), glutaraldehyde, and methenamine. Drysol (20% aluminum chloride hexahydrate in absolute anhydrous ethyl alcohol is usually the most effective 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 (Sato, 1989).

• Systemic agents used to treat hyperhidrosis include anticholinergic medications. Anticholinergics such as propantheline bromide, glycopyrrolate, oxybutynin, and benztropine are effective because the preglandular neurotransmitter for sweat secretion is acetylcholine (although the sympathetic nervous system innervates the eccrine sweat glands). 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 (Bouman, 1952). 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 (Sato, 1991). 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 (Sato, 1991). 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 (Abell, 1974).

• 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.

• 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 (Shelley, 1998). 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.

• In a similar study the effects of sodium chloride solution injections in one palm were compared with botulinum toxin injections in the other palm (Schnider, 1997). 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.

Surgical Care: In addition to pharmacologic therapy, other treatments include surgical sympathectomy, surgical excision of the affected areas, and subcutaneous liposuction. Each modality has been used effectively.

Palmar hyperhidrosis is a benign functional disorder that is a psychological and social handicap (Kumagai, 2005). A survey showed thoracoscopic sympathectomy to be safe, 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 (Kotzareff, 1920). Sympathectomy involves the surgical destruction of the ganglia responsible for hyperhidrosis.

• 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. Recently, 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 (Drott, 1995). After a 31-month average follow-up, symptoms recurred in 17 patients.

• 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 (Drott, 1995). In a similar study 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% (Lai, 1997).
  • T4 ganglion interruption for palmar hyperhidrosis is an effective approach that can simultaneously minimize the rate of compensatory hyperhidrosis (Chou, 2005). 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 (Heckmann, 1998).

• 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.

• 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 (Lillis, 1990).

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

MEDICATION:

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Aldehydes -- These agents reduce perspiration by denaturing keratin and thereby occluding the pores of the sweat glands. They have a short-lasting effect. Contact sensitization is increased, especially with formalin. Aldehydes are used to treat the palms and soles; they are not as effective in the axillae.

Drug Name	Glutaraldehyde solution -- 2% as Cidex. Not as effective but less staining. 20-50% solution can be diluted to 10% (more effective, especially for feet, but still staining occurs).
Adult Dose	Apply to affected areas 3 times per wk for 2 wk, then every wk or prn
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Avoid contact with eyes or mucous membranes; produces a temporary brown discoloration; may cause local irritation; thermal decomposition may release harmful fumes according to MSDS

Drug Category: Aluminum compounds -- These agents are antiperspirants that are used in the management of hyperhidrosis.

Drug Name	Aluminum chloride (20% Drysol) -- Certin-Dri and Xerac are over-the-counter products at low concentrations. Work best if applied to a dry area and covered with plastic overnight. Should be washed off in the morning. Effect should be noted within 1 mo.
Adult Dose	Apply to affected area qhs for 2-7 consecutive days prn; to prevent irritation, completely dry area prior to application
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not for application on irritated, broken, or recently shaved skin

Drug Category: Anticholinergic agents -- The use of these agents is 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.

Drug Name	Propantheline (Pro-Banthine) -- Blocks action of acetylcholine at postganglionic parasympathetic receptor sites.
Adult Dose	15 mg PO bid/tid 30 min ac initially; gradually titrate to effect
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; ulcerative colitis; narrow-angle glaucoma; obstructive disease of GI tract or urinary tract
Interactions	Concurrent antacids decrease effects; concurrent disopyramide, tricyclic antidepressants, phenothiazides, corticosteroids, atenolol, digoxin, bretylium, or other drugs with anticholinergic activity increase toxicity; may decrease effectiveness of phenothiazides
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal, CNS, or hepatic disease; caution in geriatric patients and patients with Down syndrome; may cause urinary retention, arrhythmia, CNS dysfunction, visual changes, xerostomia, constipation, or heat intolerance

Drug Name	Glycopyrrolate (Robinul) -- Acts in smooth muscle, CNS, and secretory glands to blocks action of acetylcholine at parasympathetic sites.
Adult Dose	1-2 mg PO bid/tid initially, then titrate to effective dose
Pediatric Dose	<12 years: Not recommended >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; ulcerative colitis; narrow-angle glaucoma; obstructive disease of GI tract or urinary tract
Interactions	Levodopa decreases effects; concurrent antacids decrease effects; concurrent disopyramide, tricyclic antidepressants, phenothiazides, corticosteroids, atenolol, digoxin, bretylium, or other drugs with anticholinergic activity increase activity; may decrease effectiveness of phenothiazides; Slow-K enteric toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal, CNS, or hepatic disease; caution in geriatric patients and patients with Down syndrome; may cause urinary retention, arrhythmia, CNS dysfunction, visual changes, xerostomia, constipation, or heat intolerance

Drug Name	Benztropine (Cogentin) -- Blocks striatal cholinergic receptors; may help balance cholinergic and dopaminergic activity in striatum.
Adult Dose	1-2 mg/d PO; not to exceed 6 mg/d
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; ulcerative colitis; narrow-angle glaucoma; obstructive disease of GI tract or urinary tract
Interactions	Decreases effects of levodopa; concurrent antacids decrease effects; concurrent disopyramide, tricyclic antidepressants, phenothiazides, corticosteroids, atenolol, digoxin, bretylium, or other drugs with anticholinergic activity increase toxicity; may decrease effectiveness of phenothiazides
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal, CNS, or hepatic disease; caution in geriatric patients and patients with Down syndrome; may cause urinary retention, arrhythmia, CNS dysfunction, visual changes, xerostomia, constipation, or heat intolerance

Drug Name	Oxybutynin (Ditropan) -- Inhibits action of acetylcholine on smooth muscle and has direct antispasmodic effect on smooth muscles.
Adult Dose	5 mg PO bid/tid; not to exceed 5 mg qid
Pediatric Dose	<5 years: Not established >5 years: 5 mg bid/tid
Contraindications	Documented hypersensitivity; ulcerative colitis; narrow-angle glaucoma; obstructive disease of GI tract or urinary tract
Interactions	Effects decrease with concurrent antacids; concurrent disopyramide, tricyclic antidepressants, phenothiazides, corticosteroids, atenolol, digoxin, bretylium, or other drugs with anticholinergic activity increase toxicity; may decrease effectiveness of phenothiazides
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal, CNS, or hepatic disease; caution in geriatric patients and patients with Down syndrome; may cause urinary retention, arrhythmia, CNS dysfunction, visual changes, xerostomia, constipation, or heat intolerance

Drug Category: Neuromuscular blocking agents -- These agents inhibit the transmission of nerve impulses at the neuromuscular junction of skeletal muscle and/or autonomic ganglia.

Drug Name	Botulinum toxin A (BOTOX?) -- 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. Results in anhydrosis lasting 4-12 months (Shelley, 1998). Injections of botulinum toxin must be repeated at varying intervals to maintain long-term results.
Adult Dose	Palmar hyperhidrosis: 50 subepidermal injections of 2 U per palm (total 100 U per palm)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Aminoglycosides or drugs that interfere with neuromuscular transmission may potentiate effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not exceed recommended dosages and frequencies of administration; presence of antibodies to botulinum toxin type A may reduce effects of therapy; mild transient thumb weakness and muscle weakness at toxin-treated sites may occur but resolve within 2-5 wk

FOLLOW-UP

Further Inpatient Care:

• Sympathectomy requires an inpatient stay.

Further Outpatient Care:

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

Complications:

• 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).

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

• Axillary hyperhidrosis may be malodorous, causing social embarrassment.

Prognosis:

• Hyperhidrosis is difficult to treat effectively.

• With the newer treatment modalities now available, the patient has numerous options and is offered a better prognosis.

Patient Education:

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

• For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article BOTOX® Injections.

MISCELLANEOUS

Medical/Legal Pitfalls:

• The failure to search for systemic causes for hyperhidrosis with an onset later in life is a pitfall.

• The failure to search for systemic causes of generalized hyperhidrosis is a pitfall.

• The failure to recognize underlying conditions is a pitfall that may result in unnecessary patient discomfort and ineffective treatment. Correction of underlying conditions may resolve hyperhidrosis.

AUTHOR INFORMATION

Author: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School Coauthor(s): Rachel Altman, MD, Consulting Staff, Department of Dermatology, Rush University Medical Center; George Kihiczak, MD, Clinical Associate Professor, Department of Dermatology, New Jersey Medical School University Hospital

Robert A Schwartz, MD, MPH, is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Editor(s): C Lisa Kauffman, MD, Chief of Dermatology, Associate Professor, Departments of Internal Medicine and Pathology, Georgetown University Medical Center; Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center; Lester Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; and Dirk M Elston, MD, Teaching Faculty, Department of Dermatology, Geisinger Medical Center