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Journal of Drugs in Dermatology, Oct, 2003 by Lewis P Stolman
Hyperhidrosis, or excessive sweating, is a disorder that may cause social isolation or occupational disability. It may be generalized or localized, and although frequently idiopathic it may be a manifestation of a number of important systemic diseases. Drugs, surgical procedures, and electrical devices may all be employed by the physician as therapeutic weapons to treat hyperhidrosis.
The primary function of the eccrine sweat glands is to assist in the maintenance of body temperature in response to heat exposure or exercise. Hyperhidrosis may be defined as sweating beyond what is necessary to maintain thermal regulation. It may be primary (idiopathic, essential) or secondary to a number of diseases and prescribed drugs. It may be localized, regionalized, or generalized (1). Regardless of the type or the cause of the hyperhidrosis, it is frequently socially embarrassing and occupationally disabling. Excess sweat on the hands may soil paper and art work and make it virtually impossible to play many musical instruments. Careers in fields that require contact with paper, metal, or electrical components become unrealizable. Axillary and plantar hyperhidrosis may result in stains and damage to clothing and shoes. Generalized or regionalized hyperhidrosis may leave affected individuals with wet clothing that may have to be changed a number of times each day.
Physiologically, sweating is a function of the sympathetic nervous system. A sweat control center located in the preoptic area and anterior hypothalamus contains neurons that are sensitive to changes in internal temperature and also cerebral cortical events. Sweat glands are innervated by sympathetic postganglionic fibers but, unlike ordinary sympathetic innervation, the chemical mediator is acetylcholine. Sweating in response to thermal stimuli is generally acceptable and rarely a cause for complaint. Emotionally-induced sweating tends to be localized to the palms, soles, and sometimes the forehead. Axillary sweating may be the result of both emotional and thermal stimuli.
The causes for generalized hyperhidrosis (Table 1) include a number of febrile illnesses, neoplastic and neurologic diseases, metabolic disorders, and drugs. The causes and conditions associated with localized hyperhidrosis (Table 2) include primary or focal hyperhidrosis, unilateral circumscribed hyperhidrosis, hyperhidrosis associated with intrathoracic neoplasms, olfactory hyperhidrosis, gustatory hyperhidrosis, spinal cord injuries, and Frey’s syndrome. Although primary or focal hyperhidrosis is the most common cause of palmoplantar hyperhidrosis, it may also occur in some patients with Raynaud’s disease, rheumatoid arthritis, erythromelalgia, nail patella syndrome, keratosis palmaris et plantaris with clinodactyly, atrioventricular fistula, and cold injury. Whenever possible the cause for hyperhidrosis should be identified and if possible treated.
Primary or focal hyperhidrosis is a disorder in which there is excess sweating of the hands, feet, face, and axillae. A recent national survey estimated that 1.4% of the U.S. population (4.0 million individuals) suffers from axillary hyperhidrosis (2). One-third of these sufferers (1.3 million individuals) describe their sweating as barely tolerable or intolerable, and that it frequently or always interferes with their daily life. Primary hyperhidrosis may be inherited and in contrast to generalized hyperhidrosis usually has its time of onset in childhood or adolescence (3). Palmar hyperhidrosis usually commences in childhood and axillary hyperhidrosis in adolescence. Characteristically, focal hyperhidrosis does not occur while sleeping. Primary hyperhidrosis is aggravated by heat and emotional stimuli; however, it is important to note that although emotional stimuli are necessary for primary hyperhidrosis to occur in affected individuals, it is not a psychological disease but rather a physiological disorder. It seems that in patients with primary hyperhidrosis, the hypothalamic sweat centers are more sensitive to emotional stimuli of cerebral origin than those in ordinary people. The occasional onset of primary hyperhidrosis in the neonatal period is evidence that this is far more than an emotional disorder!
A number of medical and surgical remedies are available for the treatment of hyperhidrosis (Table 3).
Aluminum chloride and tanning agents are sometimes effective in the control of localized hyperhidrosis (4). Aluminum chloride may decrease sweating by mechanically obstructing eccrine sweat gland pores, although this mechanism has been disputed. The atrophy of the secretory cells seen in eccrine sweat glands exposed to aluminum chloride may account for the reduced sweating that most people enjoy with the use of products containing aluminum chloride. For most people with axillary hyperhidrosis, over-the-counter products are sufficient. For more severe sweating, Drysol[R] (20% aluminum chloride hexahydrate dissolved in anhydrous ethyl alcohol; Person & Covey, Inc., Glendale, CA) is frequently useful. The skin should be dry before application, since if moisture is present then irritating hydrochloric acid may form. Washing just before application should be avoided. The optimum way to use the product seems to be to apply it at bedtime to take advantage of the relative inactivity of sweat glands through the night and wash the product off first thing in the morning. Minor irritation can be relieved with the use of hydrocortisone creams. The product should be used nightly until an effect occurs and then the interval between applications can be lengthened. Although occlusion with plastic wrap can be attempted if direct application is not effective, this method is not only inconvenient but often results in increased irritation.
Glutaraldehyde, tannic acid, and formaldehyde may be useful to treat palmar and plantar hyperhidrosis, but their tendency to stain the skin (and the sensitizing potential of formaldehyde solution) limit their usefulness (5).
Systemic Treatments For those patients whose hyperhidrosis is related to specific anxiety-producing events such as a speaking engagement, school dance etc., the use of a drug such as Valium[R] (diazepam) may have an ameliorating affect. If hyperhidrosis is a part of a social anxiety disorder, Prozac[R] (flouxatine) may be a very useful therapeutic agent along with appropriate psychiatric care. Systemic anticholinergics may be helpful, but unfortunately the dosages required to achieve reduced sweating also result in side effects including xerostomia, mydriasis, cycloplegia, and bowel and bladder dysfunction. Most patients with localized or generalized hyperhidrosis can not tolerate them for long. However, the anticholinergic Ditropan[R] (oxybutynin) has been found to be useful in the relatively rare syndrome of episodic hyperhidrosis with hypothermia (6). A second anticholinergic, Cogentin[R] (benztropine) was successfully used to treat hyperhidrosis in a patient with venlafaxine-induced excess sweating (7). Effexor[R] (venlafaxine) is an antidepressant that inhibits the reuptake of serotonin and norepinephrine. Sweating is said to occur in as many as 12% of all patients exposed to venlafaxine and other serotonin selective reuptake inhibitors (SSRIs). The non-steroidal anti-inflammatory agent indomethacin in a dose of 25 mg t.i.d, was prescribed for a patient with arthritis who coincidentally had lifelong idiopathic generalized hyperhidrosis (8). Quite unexpectedly, she enjoyed a resolution of her lifelong hyperhidrosis. Although the mechanism for this beneficial effect is not clear, the fact that prostaglandin E is found in increased amounts in the sweat of some patients with hyperhidrosis may offer an explanation (9). Influx of calcium from the extracellular to the intracellular space is necessary for the active secretion of sweat by eccrine sweat glands. This likely accounted for the improvement in palmar and plantar hyperhidrosis observed when a calcium channel blocker, diltiazem, was used to treat a family with palmar and plantar hyperhidrosis (10). Tricyclic antidepressants may cause excess sweating, and yet one would expect the anticholinergic action of tricyclics should block sweating, not induce it. Catapres[R] (clonidine), a centrally active [alpha.sub.2]-adrenergic autoreceptor stimulant, has been found to be useful in the treatment of hyperhidrosis due to tricyclics as well as menopausen (11). Darvon[R] (propoxyphene hydrochloride), a narcotic and weak ganglionic blocking agent, may have an ameliorating effect on hyperhidrosis in patients with autonomic dysreflexia (12). Autonomic dysreflexia is a syndrome of sympathetic hyperactivity due to bladder or bowel distension seen in some patients with spinal cord lesions at or above the sixth thoracic level (T6). Fludrocortisone acetate 0.3 mg daily may control sweating in quadriplegics in whom orthostatic hypotension precipitates a sympathetic discharge (13). The reader is cautioned that many of these reports of therapeutic efficacy are anecdotal, and all of these systemic agents carry with them the risk of side effects.
Of all the types of hyperhidrosis, focal hyperhidrosis, which may involve the axillae, palms, sole and face, is the most common. Two therapeutic interventions, one old (iontophoresis) and one relatively new (botulinum toxin), are particularly valuable in the treatment of primary or focal hyperhidrosis.
One of the simplest, safest, and most cost-effective treatments for palmar and/or plantar hyperhidrosis is that of iontophoresis, which is defined as the introduction of an ionized substance through intact skin by the application of a direct current. In 1936, Ichihashi used various solutions of atropine, histamine, and formaldehyde and demonstrated that sweating of the palms could be reduced by iontophoresis (14). His work went relatively unnoticed until 1952, when Bouman and Gruenwald Lentzer published a report clearly demonstrating the efficacy of iontophoresis for the treatment of palmar and plantar hyperhidrosis in 113 patients (15). They demonstrated that the addition of an ionizable substance to the water was not necessary to obtain a therapeutic effect. Levit demonstrated a simple galvanic device that could be employed to relieve hyperhidrosis in 85% of affected patients (16,17).
Although the exact mechanism by which iontophoresis relieves palmar or plantar hyperhidrosis is not known it is thought to be due to poral plugging, since the effect is reversed by cellophane tapestripping of the skin overlying eccrine sweat glands rendered euhidrotic by iontophoresis (18,19). For those patients who fail to respond to simple tap-water iontophoresis, the addition of an anticholinergic directly to the tap water-filled treatment trays is frequently helpful.
Although a number of devices are available for the administration of iontophoresis, this author prefers the Fischer MD1a Galvanic unit, and the technique employed is described in Tables 4 and 5. Side effects from iontophoresis are few. Occasionally the palms become too dry and may become cracked or fissured. This may be relieved with the use of moisturizers and/or a reduction in the frequency of treatments. Erythema–and less frequently vesiculation of the skin–may follow treatments and can be treated if necessary with simple 1% hydrocortisone cream. Compensatory hyperhidrosis does not occur. Iontophoresis is difficult to administer to the axillae and seems to cause more irritation than when administered to the palms and soles; thus it not as useful for the treatment of axillary hyperhidrosis.
Justinus Kerner, a German physician and poet, published the first comprehensive description of the symptoms of botulism between 1817 and 1822. He also proposed the possible therapeutic use of botulinum toxin, which he called “sausage poison.” Kerner’s monograph (20) describes the following illness from ingesting inadequately cooked smoked bloodsausages: The tear fluid disappears, the gullet becomes a dead and motionless tube: in all mucous cavities of the human machine the secretion of the normal mucus stands still, from the biggest, the stomach, towards the tear canal and the excretory ducts of the lingual glands. No saliva is secreted. No drop of wetness is felt in the mouth, no tear is secreted any more[….] Urination can only be performed by standing, and with difficulty. Extreme drying out of the palms, the soles, and the eyelids occurs. Kerner went on to describe further effects in humans and animals: vomiting, intestinal spasms, mydriasis, ptosis, dysphagia, and in the end, respiratory failure. His reputation as an expert on “sausage poisoning” earned him the nickname “Sausage Kerner.” Subsequently sausage poisoning was named botulism from the Latin word for sausage, botulus. Years later, in 1895, the bacterium responsible for botulism was identified by Emil-Pierre van Ermengem.
Today botulinum toxin is a useful therapeutic agent for the treatment of a number of diseases related to muscular dystonia. This potent toxin has proven to be a highly effective remedy for the treatment of conditions previously recalcitrant in the fields of ophthalmology, otorhinolaryngology, pediatrics, gastroenterology, and urology. The cosmetic denervation of muscles of facial expression using botulinum toxin have given dermatologists and plastic surgeons a new weapon against facial expression-induced wrinkles and lines. In recent years certain types of hyperhidrosis have been successfully treated with botulinum toxin. Side effects reported following the local injection of botulinum toxin have been few and are usually related to undesired weakness in muscles adjacent to the treatment sites.
Treatment of Axillary Hyperhidrosis
Patients with quality-of-life-impairing axillary hyperhidrosis should be offered treatment with either botulinum toxin or surgical ablation of the axillary sweat glands. Since botulinum toxin not only inhibits the release of acetylcholine at neuromuscular junctions but also in postganglionic sympathetic fibers to sweat glands, it has been found to be useful to treat axillary hyperhidrosis (21-27). In the treatment of axillary hyperhidrosis as little as 50 units injected and distributed intradermally to each axilla can produce euhidrosis lasting as long as 6 months. With larger doses responses have been as long as 15 months. Many clinicians perform a starch iodine test prior to treatment to document the extent of the hyperhidrosis and to identify any so called “hot spots,” which are areas that produce greater amounts of sweat. This author uses a simple facial tissue and a gentian violet marker to identify such areas. The hyperhidrosis generally occurs in the hair-bearing part of the axillae and so it is in these areas that the toxin should be placed. Discomfort is minimal and simple ice-packs applied to the axillae prior to injection are sufficient for anesthesia.
Patients with axillary hyperhidrosis who are unresponsive to topical therapy do not want botulinum toxin or in whom it is contraindicated or simply want a more long-lasting remedy may be offered a variety of surgical techniques designed to ablate the axillary sweat glands. The areas of greatest sweat production may be identified by draping a piece of facial tissue paper over the axilla or a starch iodine test. Sometimes this area is quite small and a simple excision with closure is sufficient to remedy the problem (28). Patients with moderate to severe hyperhidrosis may require a more extensive procedure with undermining and resection of all exposed sweat glands (29). In order to obtain good closure and avoid limitation of movement due to cicatricial contracture, Z-plasty and bat-shaped excisions and repairs can be employed (30). Alternative treatments for axillary hyperhidrosis include subcutaneous liposuction and subcutaneous curettage (31,32).
Treatment of Palmar/Plantar Hyperhidrosis
Patients with palmar or plantar hyperhidrosis should be given a trial of a prescription-strength antiperspirant such as Drysol[R] prior to botulinum toxin or iontophoresis treatments(32). Botulinum injections are very effective for the treatment of palmar hyperhidrosis (33-35). The doses used are generally higher than those used for axillary hyperhidrosis, ranging from 100 to 200 units of Botox[R] per hand. Euhidrosis following such treatment may last for as long as a year. Although effective, the clinical usefulness of this treatment is limited by the need for repetitive relatively painful injections, the cost of the botulinum toxin, and reports of weakness of the small muscles of the hands (33). Anesthesia is mandatory for the administration of botulinum toxin to the hand or feet. Although topical anesthesia in the form of Elamax[R] under occlusion for an hour followed by ice packs seems satisfactory for some, most practitioners have found the need for a either a Bier block or a block of the median, ulnar, and radial nerves (36). The Bier block, once learned, is not only safe and effective but also carries with it the advantage over nerve blocks of not affecting motor function. As a result, patients can still use their hands immediately after the treatment.
Iontophoresis still remains a useful therapy since botulinum toxin injections for the treatment of palmar and plantar hyperhidrosis are not suitable for all patients (32). Specifically, musicians, surgeons, and others who depend on fine motor dexterity in their hands may not be able to accept the risks of diminished strength of their thumbs that may accompany botulinum toxin injections. Young children may not accept the discomfort involved in either regional nerve blocks or a Bier block for the anesthesia for botulinum injections into the hands. Finally, iontophoresis is far less costly than botulinum treatments for palmar and plantar hyperhidrosis, keeping in mind that from 100 to 200 units of botulinum toxin are used per hand and that anesthetic/administration fees would be involved.
Treatment of Craniofacial Hyperhidrosis
Craniofacial hyperhidrosis may respond to topical antiperspirants such as Drysol[R] or topical glycopyrrolate. Topical glycopyrrolate has been found to be useful to treat gustatory craniofacial hyperhidrosis in diabetics (37). Botulinum toxin is very effective for craniofacial hyperhidrosis and is considered the treatment of choice for patients with Frey’s syndrome. Frey’s syndrome is characterized by unilateral gustatory hyperhidrosis that occurs in as many as 50% of patients who have a parotidectomy (38). The most likely explanation is recurrence of parasympathetic nerve fibers that have lost their “target organ.” When botulinum toxin is used to treat craniofacial hyperhidrosis the technique differs from that to treat the facial musculature in that the injections are more superficial (i.e., intradermal) and evenly distributed over the hyperhidrotic area. The area may be identified by either the starch iodine technique or a facial tissue held against the skin. The botulinum toxin, 50 to 100 units of Botox[R], should be administered at least one and half centimeters above the supraorbital bridge in order to avoid a brow drop.
Sympathectomy or upper thoracic (T2) ganglionectomy is often offered to patients with severe palmar hyperhidrosis. Lumbar sympathectomy is not usually employed for plantar hyperhidrosis because of the risk of sexual dysfunction. Although the efficacy of this procedure in the treatment of palmar hyperhidrosis is not in doubt, with success rates of 9299%, the potential complications ate significant. Among the likely complications related (24% to 100% depending on the study) are compensatory hyperhidrosis (increased sweating in some other area of the body), gustatory sweating (sweating, usually of the face, related to the eating of foods), permanent Homers syndrome, wound infection, hemothorax, intercostal neuralgia, and recurrence of hyperhidrosis (39-48). The advent of endoscopic sympathectomy has reduced the incidence of many complications.
Compensatory hyperhidrosis is the most common complication and the major reason for patient dissatisfaction with the procedure. Compensatory hyperhidrosis following sympathectomy can be far more life-disrupting than palmar hyperhidrosis in that afflicted individuals may have to change sweat-soaked clothing two or three times per day. In a recent systematic literature review of sympathectomy for the treatment of hyperhidrosis the question was asked, “Are we paying a high price for surgical sympathectomy?” 135 articles are reviewed, reporting on 22,458 patients and 42,061 procedures. 84.3% of the reported patients had the surgery for hyperhidrosis. Compensatory hyperhidrosis occurred in 52.3% of the patients, gustatory sweating in 32.3%, phantom sweating in 38.6%, and Horner’s syndrome in 2.4%. In all, neuropathic complications occurred in 11.9% but were less common in patients who had the procedure for hyperhidrosis (48).
Moran (45) states it quite succinctly: “Complications related to the surgical approach, such as Homer’s syndrome, brachial plexus injuries, pneumothorax, and painful scars may occur, while following sympathectomy compensatory hyperhidrosis is usual and hyperhidrosis may recur.”
The patient who complains of hyperhidrosis presents the physician with a diagnostic and therapeutic challenge. Patients who present with generalized hyperhidrosis are in general adults whose sweating occurs both during the waking and sleeping hours. Such patients require a search for a cause which may sometimes be as simple as a drug that they are taking for some medical disorder. Occasionally a systemic illness may account for the onset of hyperhidrosis and a thorough exam and appropriate testing may be necessary to identify the cause. Most patients with primary or focal hyperhidrosis present in childhood or adolescence and have a problem localized to their axillae, hands, and/or feet. They have a physiologic disorder, not a psychiatric or endocrinologic disease. A number of systemic, topical, surgical, and electrical remedies are available for the treatment of hyperhidrosis. Patients with hyperhidrosis of the palm or soles who fail to respond to topical agents deserve a trial of conservative therapy, botulinum toxin, or iontophoresis before aggressive surgical techniques that carry with them the risk of lifelong troublesome side effects are offered.
LEWIS P STOLMAN MD FACP FRCP (C) ASSOCIATE PROFESSOR OF PEDIATRICS, UMDNJ NEWARK, NEW JERSEY
ADDRESS FOR CORRESPONDENCE: Lewis P Stolman MD FACP FRCP(C) Dermatology and Laser Center of Northern New Jersey 290 South Livingston Ave Livingston, NJ 07039 T: (973) 740-0101 F: (973) 740-0103
COPYRIGHT 2003 Journal of Drugs in Dermatology
Lewis P Stolman