SECRETORY DISORDERS

Abstract

Hyperhidrosis is an increasingly recognized disorder of excess sweating that may affect focal sites such as the axillae, the palms of the hands, the soles of the feet, or the face, or that may present more generally. Hyperhidrosis leads to substantial embarrassment and disability. Medical treatments such as systemic and topical pharmacologic agents as well as surgery, including sympathectomy, have been employed. More recently, botulinum neurotoxin (BoNT), which blocks the autonomic innervation of the sweat glands, has emerged as an effective and well-tolerated approach. Approved by the FDA for the treatment of severe primary axillary hyperhidrosis, onabotulinumtoxinA and other BoNT formulations are also being investigated in the management of palmar hypersecretion, gustatory sweating, and hypersecretory disorders such as excess drooling (sialorrhea), chronic rhinitis, and hyperlacrimation. Duration of relief of symptoms with BoNT varies with diagnosis but may last up to several months. BoNT injection is less invasive than surgery and shows promise for a range of hyperhidrosis and other secretory disorders beyond axillary hyperhidrosis.

Introduction

Hyperhidrosis is a disorder characterized by spontaneous, excessive sweating beyond that required to return the body temperature to normal.^{1, 2} This disorder is generally classified into either primary (essential) hyperhidrosis or secondary hyperhidrosis. Primary hyperhidrosis is typically idiopathic in nature and can affect a range of focal anatomic locations, including the axillae, the palms of the hands, the soles of the feet, or the face, or it can present in a more generalized pattern. Secondary hypherhidrosis is associated with an underlying medical condition and is typically generalized and less focal in presentation.^{3, 4} Gustatory sweating results in response to anticipation of food or salivation.⁵ Hyperhidrosis often lead to both social and professional embarrassment, causing sufferers to avoid handshakes and touching. Severe forms of palmar hyperhidrosis can lead to foul-swelling sweat, infection, and skin maceration.³ Overall, hyperhidrosis can lead to substantial distress, and an inability to function socially and professionally.⁶ Beyond these sweating disorders, other secretory disorders will be discussed, including sialorrhea (drooling), chronic rhinitis, and hyperlacrimation.

Epidemiology

Hyperhidrosis occurs in from 0.6% to 1% of the Western population, and is more prevalent in certain groups, including Southeast Asians, for whom up to 3% of the population can be affected.^{1, 3, 7} Primary focal hyperhidrosis is often associated with a family history of the disorder.^{3, 5} Primary focal hyperhidrosis most commonly affects the axillae (40%-50%) and the palms/soles of the feet (40%-50%), followed by the face (10%) ⁵ Secondary generalized hyperhidrosis often affects the entire body surface. Risk factors include chronic infection, malignancies, endocrinologic disturbances, spinal cord injury, and menopause.³

Clinical Features

Primary hyperhidrosis usually appears within the second or third decade of life, with some patients reporting excessive sweating during childhood or adolescence.^{3, 5} Patients report a requirement to change clothing frequently as well as an inability to control their sweating with over-the-counter antiperspirants. Although often self-limiting, severe cases of palmar hyperhidrosis can be associated with infection and skin maceration.³ Beyond embarrassment, patients may report feeling physical discomfort because of sodden shoes and clothing, and may experience difficulty handling paper or ink or gripping work tools.⁴ Gustatory sweating occurs on the cheek in response to food anticipation or salivation.⁵

Pathophysiology

Eccrine glands secrete a thick secretion hypotonic to plasma, which can lead to hyperhidrosis when secreted in excess. Note that apocrine glands, localized to the axillae and urogenital regions, produce a viscid secretion that can produce unpleasant odor, but these secretions generally do not contribute to hyperhidrosis, except in some cases of isolated axillary hyperhidrosis.⁴ The regulation of the rate and volume of sweat production is typically controlled at the level of the hypothalamus, which alters the secreted amount as part of the control of thermoregulation but also in response to emotional or physical stress.⁴ Primary hyperhidrosis (1) is most likely caused by a hyperfunctioning central sudomotor output; (2) has a predominantly emotional component; and (3) is associated with more tonic activity in the sympathetic innervations of vasomotor downstream effectors as well as more labile innervations of sudomotor effectors.³ Axillary hyperhidrosis, which reflects an abnormality of both the apocrine and eccrine glands, is believed to be driven by both thermoregulatory and emotional factors.³ Gustatory sweating occurs because of the missprouting of cholinergic secretomotor fibers subsequent to lesions of the parotid gland.⁵

Diagnosis

Collecting a patient history is very important for the diagnosis of hyperhidrosis—patients can provide information about age of onset and will likely report behavioral modifications related to anticipated social problems (ie, changing clothes frequently, avoidance of handshakes and touching, etc). Clinical laboratory tests that are used to diagnose the disease and document its extent include the Minor's starch-iodine test, which helps delineate areas of sweating.⁸ The test also allows the clinician to determine the rate of sweat production. The thermoregulatory sweat test is used to delineate the distribution of primary hyperhidrosis. Patients are exposed to a heat challenge and the pattern of sweating is measured. This test can also be used to determine response to therapy.^{3, 9}

Therapeutic Approaches

Treatments for hyperhidrosis include systemic and topical pharmacologic agents as well as surgery.^{5, 10, 11} Topical treatments include aluminum chloride salts in antiperspirants, which, although often effective, are impractical for hyperhidrosis and irritating.¹² Systemic medications (anticholinergics, alpha blockers) have limited efficacy and substantial side effects.^{1, 2}

Surgical treatment for axillary or palmar hyperhidrosis consists of excision of the sweat glands, subcutaneous curettage and liposuction, or sympathectomy, usually performed endoscopically. Excisional surgery can be complicated by side effects such as significant scarring, infection, and bleeding.^{2, 11} Palmar hyperhidrosis may be treated topically, with iontophoresis (topical introduction of ionized particles in the skin using direct current), or by endoscopic transthoracic sympathectomy.¹¹ Although the latter procedure is associated with frequent complications, including hemothorax and compensatory hyperhidrosis in other parts of the body,¹¹ it has been reported to have a high success rate of 98%.¹³ Subcutaneous curettage has been reported to result in satisfactory improvement. Liposuction offers permanent efficacy and has fewer side effects and less scarring than traditional excisional procedures.¹¹

The Role of Neurotoxins

The recognized ability of botulinum neurotoxin (BoNT) to block cholinergic transmission at the neuromuscular junction and the release of acetylcholine from cholinergic postganglionic sympathetic neurons¹⁴ has revolutionized the treatment of autonomic hypersecretory disorders. Since eccrine sweat glands are innervated by sympathetic nerve fibers and stimulated via cholinergic neurotransmission, BoNT blockade of cholinergic autonomic nerve endings that innervate the eccrine sweat glands reduces hypersecretion of sweat.^{5, 11} Table I shows studies of BoNT formulations used in the management of secretory disorders.

BoNT-A (onabotulinumtoxinA, BOTOX®) was approved by the FDA in 2004 for the treatment of primary axillary hyperhidrosis. Clinical efficacy and safety was demonstrated in large-scale clinical trials. In one 16-week study,¹⁵ 320 patients with bilateral primary axillary hyperhidrosis were treated with 50 units(U) of onabotulinumtoxinA per axilla or placebo delivered by 10 to 15 intradermal injections evenly distributed within the hyperhidrotic area. Compared with placebo, onabotulinumtoxinA reduced sweating at all time points after administration, with response documented in 95% of BoNT recipients versus 32% of placebo-treated patients at 1 week, 94% versus 36% at 4 weeks, and 82% versus 21% at 16 weeks, respectively. At the end of the study, 77% of onabotulinumtoxinA-treated patients were persistent responders compared with only 18% of placebo patients. In a quality-of-life follow-up,¹⁰ statistically significant improvements were reported in all clinical parameters for the onabotulinumtoxinA-treated group compared with placebo. Improvements were rapid (within 1 week) and sustained throughout the 16-week follow-up. Patients reported a greater level of treatment satisfaction with onabotulinumtoxinA than with other hyperhidrosis treatments, with few adverse events reported. In a 12-month extension of this study, 28% of patients did not require retreatment.¹⁶ Long-term onabotulinumtoxinA efficacy was also demonstrated in an 18-month, open-label, follow-up study, in which 5 of 12 patients required two active injections in 18 months, three required three injections, and four had four injections. Mean injection interval was approximately 6 months. No significant side effects were observed.¹⁷

Flanagin and colleagues¹⁸ conducted a single-center, randomized, parallel-group, 12-week study that randomized patients (N=25) with moderate-to-severe primary focal axillary hyperhidrosis to either onabotulinumtoxinA (50 U injected in each axilla bilaterally) or 20% aluminum chloride applied nightly (unless there was irritation, which warranted application every other night). Based on scores on the Hyperhidrosis Disease Severity Scale, 92% of subjects in the onabotulinumtoxinA-treated arm versus 33% in the aluminum chloride arm achieved treatment response at 4 weeks. In a large, randomized, double-blind, placebo-controlled trial.¹⁹

One hundred forty-five patients whose rate of sweat production exceeded 50 mg/min and who had hyperhidrosis unresponsive to topical treatment were injected with 200 U of abobotulinumtoxinA (Dysport®) in one axilla and placebo in the other. Two weeks later, axillae originally receiving placebo were injected with 100 U of abobotulinumtoxinA. Two weeks after the initial injections, mean rates of sweat production in the abobotulinumtoxinA-treated axillae dropped from 165 to 24 mg/min compared with 174 to 144 mg/min in the placebo-treated axillae. Two weeks after abobotulinumtoxinA injection into axillae originally treated with placebo, the rate was 32 mg/min. At 24 weeks, sweat-production rates remained lower than baseline in all BoNT-treated axillae.

A small (N =19) study found that rimabotulinumtoxinB (Myobloc®) dosed at 2000 U was comparable to onabotulinumtoxinA dosed at 100 U in abolishing axillary hyperhidrosis.²⁰ In a study of 20 patients, rimabotulinumtoxinB reduced sweating but was associated with a number of side effects, including bruising, dry eyes, dry mouth, and flu-like symptoms.²¹ Large-scale, randomized, controlled studies will be required to evaluate the safety and efficacy of rimabotulinumtoxinB for the treatment of axillary hyperhidrosis.

Clinicians should have practical expectations for therapy. In a review of the use of BoNT-A treatments for hyperhidrosis, Eisenach et al³ stated that after approximately 20 BoNT-A injections distributed evenly into the hyperhidrotic area, sweat reduction should be noticeable within 2 to 4 days and should be substantial within 2 weeks of the first injection. Follow-up injections may be necessary approximately every 4 to 17 months. A recent study²² showed BoNT injections can be given safely in patients with axillary hyperhydrosis undergoing concomitant diode laser hair removal.

Palmar Hyperhidrosis

Studies of BoNT-A in palmar hyperhidrosis have been more limited and less consistent than those in axillary hyperhidrosis because of the difficulty in maintaining a consistent injection technique and a wider range of individual susceptibility to treatment. Moreover, palmar injections are frequently painful and may require use of a nerve block of the median and ulnar nerves.^{2, 11}

In a prospective, single-blind, parallel-group trial in 24 patients with severe palmar hyperhidrosis,¹ 50 U or 100 U of onabotulinumtoxinA was injected intradermally in 20 sites in each palm. In the first month, there was a significant decrease in sweating that was still evident after 6 months in two-thirds of the patients. Although no effect on grip strength was noted, finger pinch strength decreased 2 weeks after the injection. In a double-blind, randomized, placebo-controlled trial,19 patients received placebo injections in one hand and onabotulinumtoxinA in the other.²³ There was a steady decline in sweat production during 28 days following treatment, and 100% of patients assessed for patient satisfaction rated treatment as successful compared with 12% for placebo. No concomitant decrease in grip strength or finger dexterity was reported. There were no serious adverse events.

Another double-blind, placebo-controlled study in 11 patients with palmar hyperhidrosis also showed a significant reduction of palmar sweating with abobotulinumtoxinA dosed at 120 mU in 6 different sites on the palm compared with placebo (p <.001) using a digitized ninhydrin test.²⁴ A double-blind, randomized study to compare onabotulinumtoxinA and abobotulinumtoxinA concluded that the efficacy of the two preparations was similar, with a trend toward greater improvement with abobotulinumtoxinA, albeit with a higher incidence of adverse events, thumb-index pinch weakness and one case of right upper limb heaviness that lasted for 8 days.²⁵

In a recent study comparing bilateral T2/T3 thoracoscopic sympathectomy versus onabotulinumtoxinA injection for palmar hyperhydrosis, the Minor’s iodine starch test showed a significant reduction in sweat parameters in the surgical group versus the BoNT-A group (94% versus 63% at 6 months and 94% versus 30% at 12 months reporting reduction, respectively). While patients reported greater satisfaction with onabotulinumtoxinA than surgery at 24 hours, the effect was reversed at 6 months.²⁶

Other BoNT-A products are also available and have been studied in a range of secretory conditions. A recent study reported on the use of incobotulinumtoxinA (Xeomin®) for patients previously treated with onabotulinumtoxinA.²⁷ The study included 64 patients with hyperhidrosis and seven with hypersalivation. Therapeutic outcomes with incobotulinumtoxinA were similar to those for onabotulinumtoxinA in terms of onset latencies, maximal extents, and duration of effects. Adverse effects were not significantly different between the two products. Clinicians should familiarize themselves with the different BoNT products and their potencies and side effects.

In terms of adverse-event management, Patel and colleagues recently reported a case of the use of topical anesthetic cream and forced hot air prior to BoNT injection in patients with palmar hyperhidrosis, in which the intensity of pain was decreased by 75%.²⁸ A prospective study attempted to treat palmar hyperhidrosis in 16 patients with unassisted transdermal delivery of onabotulinumtoxinA, but both subjective and objective measures showed the treatment to be ineffective, possibly because BoNT may be too large as a molecule and has to travel a relatively long way (2-5 mm) from the skin to reach the sweat glands through the sweat ducts, and may require an additional driving force.²⁹ Additional investigations of ways to alleviate or manage the pain of BoNT injection are warranted.

Gustatory Sweating

Several open-label studies demonstrated the efficacy of BoNT-A for gustatory sweating.^{30, 31} When onabotulinumtoxinA was injected intracutaneously in 45 patients with gustatory sweating, the result was a significant reduction in the area of local facial sweating (17.6 cm to 1.3 cm) (p <.0001). Gustatory sweating was completely abolished in approximately half of the patients, and hyperhidrosis did not recur in any patients during a 6-month follow-up.³² In 14 patients with diabetes and gustatory sweating, abobotulinumtoxinA injected into the affected areas was followed by cessation of sweating within 4 days. The response in all patients lasted up to 6 months.³⁰

Sialorrhea (Drooling)

Sialorrhea is a significant disability in neurologically impaired patients, including those with cerebral palsy (CP), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease.^{5, 31, 33, 34} By blocking acetylcholine release at the neurosecretory junction of the salivary glands, BoNT effectively reduces saliva production.³¹

A controlled, open-label, clinical trial compared onabotulinumtoxinA therapy and scopolamine across two episodes of drooling in children with CP. The first episode utilized scopolamine applied as a patch behind the ear and the second utilized a single-dose submandibular onabotulinumtoxinA injection that was adjusted per weight (scopolamine was applied before BoNT because the washout period of scopolamine is known). Patient response to scopolamine was assessed on the tenth day after the initial treatment. After a washout period of 2 to 4 weeks, BoNT was injected. Treatment with scopolamine and BoNT were each associated with an approximately 50% response rate and a significant reduction in drooling. Maximal effect of BoNT treatment was seen 2 to 8 weeks after injection. BoNT injections were associated with fewer and less serious side effects than applications of scopolamine.³⁵

Intraglandular (parotid and submandibular) onabotulinumtoxinA injections (10 units to 40 units) produced improvement in 22 children with CP and significant sialorrhea in an open-label, dose-escalation study. The improvement was found without local or systemic complications or impaired swallowing.³³ Small, open-label studies of onabotulinumtoxinA therapy in adults with Parkinson’s disease and ALS demonstrated improvement in drooling.^{31, 36} A pilot study of rimabotulinumtoxinB in Parkinson’s disease patients with sialorrhea showed that injections into the parotid and submandibular glands reduced sialorrhea without compromising swallowing.³⁷ AbobotulinumtoxinA has also been studied in the setting of CP: in 24 children who received a series of two injections (100 U and 140 U 4 months later), the agent improved drooling parameters, with only two patients experiencing a transient increase in drooling after treatment.³⁸ RimabotulinumtoxinB (at 2500 U injected into the parotid and submandibular glands under electromyographic guidance) was studied in a double-blind, randomized study among 20 ALS patients with sialorrhea refractory to medical therapy. Patients treated with rimabotulinumtoxinB reported a global impression of improvement of 82% at 2 weeks versus 38% for placebo-treated patients (p <.05) at 4 weeks and 50% versus 14% at 12 weeks. There were no significant adverse events associated with rimabotulinumtoxinB, including dysphagia or decline of vital capacity.³⁴

Other Secretory Disorders

Other possible uses for BoNT therapy include treating rhinorrhoea in intrinsic rhinitis patients and hyperlacrimation (crocodile tears).^39-41 The pathological basis for chronic rhinitis is thought to be overactive stimulation of the parasympathetic nerves on the nasal mucosa. Injection of BoNT into the nasal cavity significantly reduced rhinorrhea in a double-blind, placebo-controlled study.³⁹ In a randomized, placebo-controlled study, patients with allergic rhinitis received intranasal onabotulinumtoxinA (at either 20 U or 30 U in each nasal cavity) or placebo (isotonic saline) and were monitored for 8 weeks. Rhinorrhea, sneezing, and nasal blockage were significantly better in patients who received onabotulinumtoxinA at all time points than in those who received placebo. The effect of the 20 U dose was deemed similar to the 30 U injection.⁴²

Hyperlacrimation, or crocodile tear syndrome, is characterized by inappropriate and sometimes excessive tearing. Because the lacrimal glands are innervated by cholinergic fibers, hyperlacrimation can be effectively treated by intraglandular injections of BoNT.^{40, 41} In an open-label study, patients with hyperlacrimation secondary to idiopathic facial paralysis or ear infection were administered abobotulinumtoxinA in the lacrimal gland. Patients were then measured for lacrimation by the Schirmer’s test, before and after gustatory stimulation. All four patients reported partial or complete disappearance of reflex hyerlacrimation following treatment with abobotulinumtoxinA. The relief of symptoms persisted for 4 to 5 months.⁴¹ All patients experienced some minor side effects, which included ptosis, mild stinging, and eye dryness.⁴¹

Table 1. Studies of BoNT Formulations Used in the Management of Secretory Disorders

AEs, adverse events; ALS, amyotrophic lateral sclerosis; BoNT, botulinum neurotoxin; QoL, quality of life.

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