Advisory Editor
Markus Naumann, MD
Professor of Neurology
Department of Neurology,
University of Wurzburg Germany
Normal sweating is controlled by circulating catecholamines and sympathetic innervation of the eccrine sweat glands (Lowe et al, 2004). Hyperhidrosis is an idiopathic disorder that affects approximately 1% of the population and is characterized by spontaneous excessive, uncontrollable sweating beyond that required to return body temperature to normal (Saadia et al, 2001; Adar, 1994; Lowe et al, 2004). In some patients with hyperhidrosis, sweat production can exceed 40 mL/m 2/min, or 40 times the normal rate (Cohen and Solish, 2003; Sato et al, 1989). The disorder is thought to be caused by overactivity of the eccrine sweat glands in the affected area in response to metabolic, environmental, neurologic, or gustatory stimuli and may be exacerbated under conditions of stress and anxiety (Lowe et al, 2004; Naumann and Jost, 2004). Primary (essential or idiopathic) hyperhidrosis is focal, typically affecting the axillae (40% to 50%), palms or soles of the feet (40% to 50%), or the face (10%). Primary focal hyperhidrosis, which usually appears in the second or third decade of life and is often associated with a family history of the disorder, is frequently made worse by emotional situations (Kreyden and Scheidegger, 2004; Naumann and Jost, 2004). Secondary or generalized hyperhidrosis affects the entire body surface and is usually caused by underlying disease (Kreyden and Scheidegger, 2004).
Although hyperhidrosis is not life-threatening, it causes significant social stigma and can be of considerable detriment to the patient’s daily functions, interpersonal relationships, and work activities, resulting in an overall reduced quality of life (Amir et al, 2000; Naumann et al, 2002). Moreover, severely affected patients may suffer from skin maceration, which may result in secondary microbial infections (Heckmann et al, 2001; Naumann and Jost, 2004).
The severity of hyperhidrosis and the efficacy of treatment can be assessed gravimetrically by measuring the rate of sweating over a period of time (measured by weighing filter paper before and after sweating) or by semiquantitative methods such as the Minor iodine starch test (Heckmann et al, 2001; Lowe et al, 2002). The Minor test involves wiping the skin with an antibacterial iodine solution that is allowed to dry and then dusting the skin with a cornstarch powder. As sweat reaches the skin surface, a reaction between the iodine and starch produces a colorimetric reaction as the cornstarch powder turns deep purple. The magnitude of the sweat area can then be photographed and measured (Glogau, 2004) (Figure 1).
Figure 1. Minor sweat test.
After application of iodine liquid followed by starch powder, the hyperhidrotic area becomes visible as a distinctive violet patch, enabling the clinician to precisely define the region of treatment as well as the intensity of hyperhidrosis. Reproduced with permission from Kreyden OP, Scheidegger EP. Anatomy of the sweat glands, pharmacology of botulinum toxin, and distinctive syndromes associated with hyperhidrosis. Clin Dermatol. 2004;22:40-44.
Conventional treatments for axillary hyperhidrosis have included systemic and topical pharmacologic agents and surgical procedures (Lowe et al, 2004; Atkins and Butler, 2002). Topical treatments include aluminum salts, which, although effective for many patients, are short acting and can cause irritation (Naumann et al, 2002). Systemic medications, including anticholinergic agents and beta blockers, have limited efficacy and substantial side effects, including orthostatic hypotension, dry mouth, and blurred vision (Saadia et al, 2001; Lowe et al, 2004; Cohen and Solish, 2003).
Axillary hyperhidrosis can be treated surgically by excision of the sweat glands, subcutaneous curettage and liposuction, or surgical sympathectomy, usually performed endoscopically. Until recently, surgical endoscopic transthoracic sympathectomy was considered to be the most effective treatment for this disorder, but it is associated with frequent complications, including pneumothorax and compensatory hyperhidrosis in other parts of the body (Saadia et al, 2001; Lai et al, 1997; Glogau, 2004; Gossot et al, 2001; Heckmann, 1998; Adar, 1998). Excisional surgery can be complicated by infection, bleeding, and significant scarring (Cohen and Solish, 2003; Wu, 1994). Subcutaneous curettage and liposuction offers permanent efficacy and is associated with fewer side effects and less scarring compared with excisional procedures (Cohen and Solish, 2003; Lowe et al, 2004; Rompel and Scholz, 2001).
Palmar hyperhidrosis is also treated topically or systemically, although sympathectomy surgery involving upper thoracic ganglionectomy or lumbar sympathectomy is usually not recommended for this condition (Lowe, 2004). Endoscopic transthoracic sympathectomy for excessive palmar sweating has a high success rate and was initially the preferred surgical treatment option. However, this procedure requires general anesthesia and may not be successful (Cohen and Solish, 2003; Kao et al, 1996; Lowe et al, 2004). Like other surgical approaches, endoscopic transthoracic sympathectomy is associated with increased compensatory sweating in other body areas, which has been reported in 26% to 90% of patients (Cohen and Solish, 2003; Ling and Fang, 1999; Lowe et al, 2004; Furlan et al, 2000). Iontophoresis is an effective treatment for palmar or plantar hyperhidrosis, but the necessary electrical introduction of ions through the skin may produce an uncomfortable stinging sensation and must be repeated frequently (Atkins and Butler, 2002).
Dr. Naumann discusses treatment options for hyperhidrosis. (Windows Media)
The discovery over half a century ago that botulinum neurotoxin (BoNT) blocked neuromuscular transmission (Burgen et al, 1949) paved the way for its development as an important pharmacologic tool for the treatment of overactive muscle conditions (Munchau and Bhatia, 2000). BoNT, produced by the anaerobic bacterium Clostridium botulinum, exists as 7 distinct neurotoxins designated as serotypes A-G. The bulk of clinical experience to date has been with serotype A. BoNT cleaves the synaptosomal-associated protein (SNAP) 25, a component of the SNARE protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. This action blocks the release of acetylcholine and subsequent synaptic transmission at the neuromuscular junction, causing muscles to become weak and atrophic (Munchau and Bhatia, 2000; Naumann and Jost, 2004) (Figure 2). This mechanism of action led to the use of botulinum toxin in conditions associated with increased muscle tone, including dystonia and spasticity.
The recognized ability of BoNT to block not only cholinergic transmission at the neuromuscular junction but also the release of acetylcholine from cholinergic postganglionic sympathetic neurons has revolutionized the treatment of autonomic hypersecretory disorders (Munchau and Bhatia, 2000). 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 (Kreyden and Scheidegger, 2004).
Figure 2. Mechanism of action of botulinum toxin.
NSF=N-ethylmaleimide-sensitive fusion protein.
SNAP-25=synaptosomal-associated protein of 25 kd.
SNARE=soluble NSF-attachement protein receptor.
A, Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex that allows the membrane of the synaptic vesicle containing acetylcholine to fuse with the neuronal cell membrane. The synaptic fusion complex is a set of SNARE proteins, which include synaptobrevin, SNAP-25, and syntaxin. After membrane fusion, acetylcholine is released into the synaptic cleft and then bound by receptors on the muscle cell.
B, Botulinum toxin binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis. The light chain of botulinum toxin cleaves specific sites on the SNARE proteins, preventing complete assembly of the synaptic fusion complex and thereby blocking acetylcholine release. Botulinum toxins types B, D, F, and G cleave synaptobrevin; types A, C, and E cleave SNAP-25; and type C cleaves syntaxin. Without acetylcholine release, the muscle is unable to contract.
Reproduced with permission from Arnon SS, Schechter R, Inglesby TV, et al; Working Group on Civilian Biodefense. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059-1070.
BoNT type A was approved by the Food and Drug Administration in July 2004 for the treatment of primary axillary hyperhidrosis (http://www.fda.gov/bbs/topics/answers/2004/ANS01301.html, online press release). The clinical efficacy and safety of BoNT type A was demonstrated in recent large, randomized, controlled, clinical trials. In one 16-week study, Naumann and Lowe treated 320 patients with bilateral primary axillary hyperhidrosis with a BoNT type A formulation (Botox®; Allergan, Inc., Irvine, CA) 50 U per axilla or placebo delivered by 10 to 15 intradermal injections evenly distributed within the hyperhidrotic area, as defined by Minor’s iodine starch test (Naumann and Lowe, 2001). The primary efficacy measure was the incidence of responders at week 4, with responders defined as patients with a ³50% reduction from baseline in spontaneous axillary sweat measured gravimetrically, and a 25% point difference in the number of responders between treatment groups was considered clinically significant. Secondary outcome measures included the patient’s global assessment of treatment satisfaction score and persistent responders at week 16 (patients who were nonresponders at 2 consecutive visits). A total of 307 patients completed the study. Efficacy analysis revealed that Botox® effectively reduced sweating at all time points after treatment compared with placebo: comparison of percentage of responders showed 95% responders in the Botox® treatment group vs 32% of placebo-treated subjects at 1 week, 94% vs 36% at 4 weeks, and 82% vs 21% at 16 weeks. At the end of the study, 77% of the Botox®-treated patients were persistent treatment responders as compared with 18% of the placebo-treated group. Moreover, reduction in sweating was accompanied by a high level of treatment satisfaction. Few adverse events were reported. This study demonstrated that a single Botox® treatment safely produced rapid, significant long-lasting reduction of sweating in axillary hyperhidrosis.
The major real-life impact of hyperhidrosis is its detrimental effect on the patients’ quality of life (Table 1). Therefore, as an adjunct to demonstration of its efficacy, the impact of BoNT type A treatment on quality of life in patients with axillary hyperhidrosis was evaluated in the 320 patients in the study discussed above (Naumann et al, 2002). A Hyperhidrosis Impact Questionnaire and Medical Outcomes Trust Short Form-12 Health Survey were administered at baseline and at 1, 4, 8, 12, and 16 weeks posttreatment and at baseline and 16 weeks posttreatment, respectively. At baseline, patients reported moderate limitations due to the negative impact of hyperhidrosis in many aspects of their daily lives, including relationships with family and friends, participation in sports, being in public places, and meeting new people. The majority of respondents reported that hyperhidrosis negatively impacted their emotional status and hindered their work performance and productivity. Following the treatment period, statistically significant improvements in all clinical parameters were observed for the Botox®-treated group compared with the placebo group (P <.01). These improvements were rapid (within 1 week of treatment) and sustained (throughout the 16-week follow-up period). Furthermore, patients reported a greater level of overall treatment satisfaction with BoNT type A than with other hyperhidrosis treatments. This study established that BoNT type A not only has clinical efficacy in treating axillary hyperhidrosis but also markedly improves quality of life.
Table 1. Effects of hyperhidrosis on daily life and activities (n=320).
| My hyperhidrosis has caused me to… | No. (%) of patients |
|---|---|
| Feel less confident than I would like | 227 (71.8) |
| Feel unhappy or depressed | 154 (48.7) |
| Change the types of leisure activities I pursue | 141 (44.6) |
| Become frustrated with many daily activities | 96 (30.4) |
| Miss outings or events with friends or family | 79 (25.0) |
| Decrease amount of time spent on leisure activities | 61 (19.3) |
Values are numbers (and percentage) of patients who indicated that the above statements were true. From Naumann M, Hamm H, Lowe NJ; Botox® Hyperhidrosis Clinical Study Group. Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: a randomized controlled trial. Br J Dermatol. 2002;147:1218-1226.
In an extension of the 2001 Naumann study, patients were followed for an additional 12 months, during which time 3 additional BoNT type A injections could be given if needed, with a 16-week interval between injections (Naumann et al, 2003). Among patients receiving multiple treatments, patient satisfaction remained high following subsequent treatment cycles. Moreover, 28% of patients did not require retreatment, suggesting a considerable effect duration.
The long-term efficacy of BoNT type A in the treatment of axillary hyperhidrosis was demonstrated in a small, 18-month, open-label, noncomparative, follow-up study of patients who had completed a previous randomized study (Lowe et al, 2003). Of 12 patients in this study, 5 required only 1 additional injection in 18 months of follow-up; 3 patients required 2 additional injections and 4 had 3 additional treatments. Overall, the mean time between injections was approximately 6 months. No significant side effects were observed.
The safety and efficacy of BoNT type A as treatment for axillary hyperhidrosis was further demonstrated in a second large, multicenter, randomized, double-blind, placebo-controlled trial (Heckmann et al, 2001). A total of 145 patients whose rate of sweat production exceeded 50 mg/min and had hyperhidrosis that was unresponsive to topical treatment were injected with BoNT type A (Dysport®; Ipsen-Pharma, Ettlingen, Germany) 200 U in 1 axilla and placebo in the other. Two weeks later, axillae that had originally received placebo were injected with 100 U of Dysport®. Changes in the rate of sweat production were measured gravimetrically.
At baseline, the mean rate of sweat production was 165 mg/min in the axillae assigned to treatment with Dysport® and 174 mg/min in the axillae assigned to placebo. Two weeks after the initial injections, mean rates of sweat production were 24 ± 27 mg/min in the Dysport®-treated axillae and 144 ± 113 mg/min in the axillae treated with placebo. Two weeks after injection of 100 U Dysport® into axillae originally treated with placebo, the rate of sweat production was reduced to 32 ± 39 mg/min. At 26-week follow-up, the rates of sweat production remained lower than baseline values in both the axillae that received placebo and 100 U Dysport® and the axillae that received 200 U Dysport® (Figure 3).
Figure 3. Mean (± SE) rates of sweat production after intradermal injection of botulinum toxin type A (Dysport®) or placebo.
At week 0, 200 U of Dysport® was injected into 1 axilla in each patient and placebo into the other. At week 2, 100 U of Dysport® was injected into the axilla that had received placebo. Data were available for 145 patients at week 14 and for 136 at week 26. For the axillae that received 200 U of Dysport®, the rate differed significantly (P<.001) from the baseline rate throughout follow-up. For the axillae that initially received placebo, the value differed significantly from baseline at week 2 (P<.004); the changes from baseline also were significant at weeks 4, 14, and 26, after the injection of 100 U of Dysport® (P<.001). Paired t-tests were used for all comparisons. Reproduced from Heckmann M, Ceballos-Baumann AO, Plewig G; Hyperhidrosis Study Group. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med. 2001;344:488-493.
The results of the 2 large, randomized, placebo-controlled trials that established the safety and efficacy of BoNT type A as a treatment for axillary hyperhidrosis are summarized in Table 2.
Table 2. Randomized controlled trials of BoNT in axillary hyperhidrosis.
| Study | Trial Design | Efficacy Results |
|---|---|---|
| Naumann and Lowe, 2001, 2003 |
|
|
| Heckmann et al, 2001 |
|
|
Dr. Naumann discusses clinical studies of BoNT in axillary hyperhidrosis. (Windows Media)
Dr. Naumann discusses data from a long-term study of BoNT in axillary hyperhidrosis in which it was shown that there was no antibody formation after long-term use. (Windows Media)
A recommended algorithm for the use of BoNT type A in the treatment of axillary hyperhidrosis is shown in Figure 4.
Figure 4. Algorithm for the use of BoNT type A in the treatment of axillary hyperhidrosis.
Reproduced with permission from Lowe N, Campanati A, Bodokh I, et al. The place of botulinum toxin type A in the treatment of focal hyperhidrosis. Br J Dermatol. 2004;151:1115-1122.
The overwhelming majority of studies with botulinum toxin for the treatment of hyperhidrosis have utilized serotype A (BoNT type A; Botox® in the United States, Dysport® in Europe). The recent approval of BoNT type B (known as Myobloc® in the United States and as Neurobloc® in Europe) for the treatment of cervical dystonia has prompted exploratory studies of its efficacy in hyperhidrosis (Baumann and Halem, 2004; Dressler et al, 2002). A recent small (N = 19) study that compared BoNT type B with BoNT type A found that BoNT type B was as efficacious as BoNT type A in abolishing axillary hyperhidrosis (Dressler et al, 2002). In another study of 20 patients, BoNT type B effectively reduced sweating but was associated with side effects (Baumann and Halem, 2004). Additional large-scale, randomized, controlled studies will be required to evaluate the safety and efficacy of BoNT type B for the treatment of axillary hyperhidrosis.
Studies of BoNT type 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. Additionally, palmar injections are frequently painful and may require use of a nerve block of the median and ulnar nerves (Naumann and Jost, 2004; Lowe et al, 2004; Cohen and Solish, 2003). Despite these considerations, a number of studies have demonstrated a positive effect of BoNT type A on palmar hyperhidrosis.
A prospective, single-blind, parallel-group trial examined the anhidrotic effects of a high and a low dose of BoNT type A (Botox®) in 24 patients with severe palmar hyperhidrosis (Saadia et al, 2001). Patients were injected intradermally in 20 sites in each palm with 50 U or 100 U of Botox®. In the first month, the iodine starch test revealed a significant decrease in sweating. After 6 months, the anhidrotic effect was still evident in two thirds of the patients in both groups, and 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 injections of placebo in 1 hand and BoNT type A in the other (Lowe et al, 2002). Efficacy measures were obtained at study visits 7, 14, and 28 days after injection and included gravimetric measurement, Minor iodine starch test, physician and patient assessments, and grip strength. Efficacy analysis revealed a steady decline in sweat production during 28 days following treatment, as assessed by gravimetric measurement and iodine starch test, and improvements in physician and patient assessments of sweat production. Moreover, 100% of patients assessed for patient satisfaction rated the treatment as successful. No concomitant decrease in grip strength or finger dexterity was reported. There were no serious adverse events. A recent double-blind, randomized study used a conversion factor of 1:4 to compare the efficacy of Botox® vs Dysport® (which are not bioequivalent) in palmar hyperhidrosis. The study concluded that the efficacy of the 2 preparations was similar, although there was a trend toward greater improvement with Dysport®, albeit with a higher incidence of adverse events (Simonetta Moreau et al, 2003).
The randomized controlled trials of BoNT type A in palmar hyperhidrosis are summarized in Table 3. Although each of these studies was small, the results suggest that BoNT type A can effectively treat palmar hyperhidrosis. However, BoNT type A is not yet approved for the treatment of palmar hyperhidrosis, and further studies are needed.
Table 3. Randomized controlled trials of BoNT in palmar hyperhidrosis.
| Study | Trial Design | Efficacy Results |
|---|---|---|
| Saadia et al, 2001 |
|
|
| Lowe et al, 2002 |
|
|
| Simonetta Moreau et al, 2003 |
|
|
Several open-label studies demonstrated the efficacy of BoNT type A in the treatment of gustatory sweating (Naumann, 2001; Naumann et al, 1997). A mean dose of 21 U BoNT type A (range, 5 U to 72 U) resulted in significant reduction of local facial sweating in an open-label study of 45 patients (Naumann et al, 1997). The area of sweating decreased from 17.6 cm 2 to 1.3 cm 2 after BoNT injection (P<.0001). Gustatory sweating was completely abolished in approximately half of the patients and hyperhidrosis did not recur in any of the patients during a 6-month follow-up.
Gustatory sweating can occur in diabetic patients with neuropathy and often involves sympathetic autonomic fibers (Restivo et al, 2002; Watkins, 1973). Restivo et al treated 14 patients with diabetes and gustatory sweating with BoNT type A injected into the affected facial areas. Within 4 days of treatment, sweating ceased, and all patients showed a positive response to BoNT treatment that lasted as long as 6 months (Restivo et al, 2002).
Sialorrhea (excessive drooling or salivation) commonly affects neurologically impaired patients including those with cerebral palsy (10% to 38%), amyotrophic lateral sclerosis (20%), Parkinson’s disease (PD) (70%), and other neurologic conditions (Jongerius et al, 2001; Van De Heyning et al, 1980; Naumann and Jost, 2004; Giess et al, 2000; Rose 1987). In most cases, hypersalivation combined with swallowing dysfunction causes the associated drooling. Sialorrhea is not only socially disabling but can also lead to choking, aspiration, and chest infection.
Medical treatment of sialorrhea has traditionally involved the use of anticholinergic medications. Although these medications effectively reduce drooling, their use is associated with considerable side effects. Recent studies suggest that BoNT type A, by blocking acetylcholine release at the neurosecretory junction of the salivary glands, effectively reduces saliva production (Giess et al, 2000; Jongerius et al, 2001).
A number of studies evaluated the clinical efficacy of BoNT in children with cerebral palsy. In a controlled clinical trial on the treatment of drooling in children with cerebral palsy, submandibular injections of BoNT type A were compared with scopolamine treatment (Jongerius et al, 2004). Treatment with either scopolamine or BoNT type A was associated with an approximately 50% response rate and a significant reduction in drooling, with a maximal effect 2 to 8 weeks after injection. BoNT injections were associated with fewer and less serious side effects than seen after injections of scopolamine. Intraglandular (parotid and submandibular) BoNT type A injections were given to 22 children with cerebral palsy and significant sialorrhea in an open-label, dose-escalation study (dose range, 10 U to 40 U) (Suskind and Tilton, 2002). A “drool rating scale” was used to quantify drooling and dental roll weights were used for objective measurement of drooling. BoNT type A produced improvement as reported in the drool rating questionnaire. No adverse events or impaired swallowing were noted.
Several small, open-label studies of BoNT type A therapy in adults with PD and amyotrophic lateral sclerosis demonstrated improvement in drooling with BoNT type A treatment (Bhatia et al, 1999; O'Sullivan et al, 2000; Pal et al, 2000; Giess et al, 2000). Friedman and Potulska assessed the effects of 5 U BoNT type A injected into each parotid salivary gland in 11 PD patients with sialorrhea and compared the patients with 14 control subjects (Friedman and Potulska, 2001). Salivation was measured by weighing dental rolls. Baseline saliva secretion was significantly higher in the PD patients compared with the controls (0.39 g/2 min and 0.19 g/2 min, respectively; P=.03). After treatment, saliva secretion in the PD patients decreased to 0.25 g/2 min, which was not significantly different from that of the control subjects. No side effects were observed in any of the patients. A double-blind, placebo-controlled trial compared the efficacy of 3 different doses of BoNT type A (Dysport®) (18.75, 37.5, and 75 MU per parotid gland) in 32 patients with amyotrophic lateral sclerosis, PD, multiple system atrophy, or corticobasal degeneration, all of whom suffered from sialorrhea (Lipp et al, 2003). A significant decrease in drooling was observed with the highest dose without adverse events, suggesting that BoNT type A was safe and effective in treating patients with sialorrhea. A recent pilot study of BoNT type B in PD patients with sialorrhea showed that injections of BoNT type B (Myobloc®, Elan Pharmaceuticals, New York, NY) into the parotid and submandibular glands effectively reduced sialorrhea without compromising swallowing (Ondo et al, 2004). The results of these studies suggest that further randomized, controlled clinical trials are warranted to evaluate the safety and efficacy of botulinum toxin in the treatment of sialorrhea.
Vasomotor rhinitis is characterized by excessive parasympathetic activity (Bentivoglio and Albanese, 1999). One double-blind, placebo-controlled study assessed the effect of BoNT therapy in chronic rhinitis patients (Kim et al, 1998). Each nasal cavity was injected with 4 U BoNT type A. Rhinorrhea was found to improve significantly by subjective rating and was associated with a 50% reduction in the number of paper tissues used.
Boroojerdi et al evaluated the effects of BoNT type A injection into the orbicularis oculi muscle and lacrimal gland in 10 patients with aberrant regeneration after peripheral facial nerve palsy (facial synkinesis and hyperlacrimation) (Boroojerdi et al, 1998). The dose used was slightly lower than the dose usually recommended for treatment of hemifacial spasm. BoNT produced good to excellent (grades 3 and 4 on a 0 to 4 scale) results over 6 months in 91% of injections and a moderate (grade 2) effect in the remaining 9%. Patients with hyperlacrimation showed a nearly complete recovery. Focal side effects attributable to a temporary weakness of the orbicularis oculi muscle occurred in some patients (Boroojerdi et al, 1998; Keegan et al, 2002; Montoya et al, 2002). In 2 case series of 4 patients each, Montoya et al and Keegan et al each noted that BoNT type A was effective in treating confirmed cases of hyperlacrimation (Keegan et al, 2002; Montoya et al, 2002).
The demonstrated safety and efficacy of botulinum toxin in treating axillary hyperhidrosis has revolutionized the clinical approach to this socially disabling condition. Further controlled trials of this drug class are needed in patients with focal hyperhidrosis disorders to refine the optimal dose and injection techniques. Randomized controlled trials of BoNT are warranted in the treatment of sialorrhea, rhinitis, and gustatory sweating to confirm the observations of open-label studies and limited controlled data.
Adar R. Surgical treatment of palmar hyperhidrosis before thoracoscopy: experience with 475 patients. Eur J Surg Suppl. 1994;(572):9-11.
Adar R. Compensatory hyperhidrosis after thoracic sympathectomy. Lancet.1998;351:231-232.
Amir M, Arish A, Weinstein Y, Pfeffer M, Levy Y. Impairment in quality of life among patients seeking surgery for hyperhidrosis (excessive sweating): preliminary results. Isr J Psychiatry Relat Sci. 2000;37:25-31.
Arnon SS, Schechter R, Inglesby TV, et al; Working Group on Civilian Biodefense. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059-1070.
Atkins JL, Butler PE. Hyperhidrosis: a review of current management. Plast Reconstr Surg. 2002;110:222-228.
Baumann LS, Halem ML. Botulinum toxin-B and the management of hyperhidrosis. Clin Dermatol. 2004;22:60-65.
Bentivoglio AR, Albanese A. Botulinum toxin in motor disorders. Curr Opin Neurol.
1999;12:447-456.
Bhatia KP, M unchau A, Brown P. Botulinum toxin is a useful treatment in excessive drooling in saliva. J Neurol Neurosurg Psychiatry. 1999;67:697.
Boroojerdi B, Ferbert A, Schwarz M, Herath H, Noth J. Botulinum toxin treatment of synkinesia and hyperlacrimation after facial palsy. J Neurol Neurosurg Psychiatry. 1998;65:111-114.
Burgen AS, Dickens F, Zatman LJ. The action of botulinum toxin on the neuro-muscular junction. J Physiol. 1949;109:10-24.
Cohen JL, Solish N. Treatment of hyperhidrosis with botulinum toxin. Facial Plast Surg Clin North Am. 2003;11:493-502.
Dressler D, Adib Saberi F, Benecke R. Botulinum toxin type B for treatment of axillar hyperhidrosis. J Neurol. 2002:249:1729-1732.
Food and Drug Administration. FDA approves Botox to treat severe underarm sweating. Talk paper T04-26, July 20, 2004. Available at: http://www.fda.gov/bbs/topics/answers/2004/ANS01301.html. Accessed March 20, 2005.
Friedman A, Potulska A. Botulinum toxin for treatment of parkinsonian sialorrhea. Neurol Neurochir Pol. 2001;35(suppl 3):23-27.
Furlan AD, Mailis A, Papagapiou M. Are we paying a high price for surgical sympathectomy? A systematic literature review of late complications. J Pain.2000;1:245-257.
Giess R, Naumann M, Werner E, et al. Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2000;69:121-123.
Glogau RG. Treatment of hyperhidrosis with botulinum toxin. Dermatol Clin. 2004;22:177-185.
Gossot D, Kabiri H, Caliandro R, et al. Early complications of thoracic endoscopic sympathectomy: a prospective study of 940 procedures. Ann Thorac Surg. 2001;71:1116-1119.
Heckmann M. Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. Neurosurgery. 1998;42:1403-1404.
Heckmann M, Ceballos-Baumann AO, Plewig G; Hyperhidrosis Study Group. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med. 2001;344:488-493.
Jongerius PH, Rotteveel JJ, van den Hoogen F, Joosten F, van Hulst K, Gabreels FJ. Botulinum toxin A: a new option for treatment of drooling in children with cerebral palsy. Presentation of a case series. Eur J Pediatr. 2001;160:509-512.
Jongerius PH, van den Hoogen FJ, van Limbeek J, Gabreels FJ, van Hulst K, Rotteveel JJ. Effect of botulinum toxin in the treatment of drooling: a controlled clinical trial. Pediatrics. 2004;114:620-627.
Kao MC, Lin JY, Chin YL, et al. Minimally invasive surgery: video endoscopic thoracic sympathectomy for palmar hyperhidrosis. Ann Acad Med Singapore.1996;25:673-678.
Keegan DJ, Geerling G, Lee JP, Blake G, Collin JR, Plant GT. Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation. Br J Ophthalmol. 2002;86:43-46.
Kim KS, Kim SS, Yoon JH, Han JW. The effect of botulinum toxin type A injection for intrinsic rhinitis. J Laryngol Otol. 1998;112:248-251.
Kreyden OP, Scheidegger EP. Anatomy of the sweat glands, pharmacology of botulinum toxin, and distinctive syndromes associated with hyperhidrosis. Clin Dermatol. 2004;22:40-44.
Lai YT, Yang LH, Chio CC, Chen HH. Complications in patients with palmar hyperhidrosis treated with transthoracic endoscopic sympathectomy. Neurosurgery.1997;41:110-113.
Ling TS, Fang HY. Thoracic endoscopic sympathectomy in the treatment of palmar hyperhidrosis-with emphasis on perioperative management. Surg Neurol.1999;52:453-457.
Lipp A, Trottenberg T, Schink T, Kupsch A, Arnold G. A randomized trial of botulinum toxin A for treatment of drooling. Neurology. 2003;61:1279-1281.
Lowe N, Campanati A, Bodokh I, et al. The place of botulinum toxin type A in the treatment of focal hyperhidrosis. Br J Dermatol. 2004;151:1115-1122.
Lowe PL, Cerdan-Sanz S, Lowe NJ. Botulinum toxin type A in the treatment of bilateral primary axillary hyperhidrosis: efficacy and duration with repeated treatments. Dermatol Surg. 2003;29:545-548.
Lowe NJ, Yamauchi PS, Lask GP, Patnaik R, Iyer S. Efficacy and safety of botulinum toxin type A in the treatment of palmar hyperhidrosis: a double-blind, randomized, placebo-controlled study. Dermatol Surg. 2002;28:822-827.
Montoya FJ, Riddell CE, Caesar R, Hague S. Treatment of gustatory hyperlacrimation (crocodile tears) with injection of botulinum toxin into the lacrimal gland. Eye. 2002;16:705-709.
Munchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ. 2000;320:161-165.
Naumann M. Evidence-based medicine: botulinum toxin in focal hyperhidrosis. J Neurol.
2001;248(suppl 1):I31-I33.
Naumann M, Hamm H, Lowe NJ; Botox Ò Hyperhidrosis Clinical Study Group. Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: a randomized controlled trial. Br J Dermatol. 2002;147:1218-1226.
Naumann M, Jost W. Botulinum toxin treatment of secretory disorders. Mov Disord. 2004;19(suppl 8):S137-S141.
Naumann M, Lowe NJ; Hyperhidrosis Clinical Study Group. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. BMJ. 2001;323:596-599.
Naumann M, Lowe NJ, Kumar CR, Hamm H; Hyperhidrosis Clinical Investigators Group. Botulinum toxin type A is a safe and effective treatment for axillary hyperhidrosis over 16 months: a prospective study. Arch Dermatol. 2003;139:731-736.
Naumann M, Zellner M, Toyka KV, Reiners K. Treatment of gustatory sweating with botulinum toxin. Ann Neurol. 1997;42:973-975.
Ondo WG, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson’s disease. Neurology. 2004;62:37-40.
O'Sullivan JD, Bhatia KP, Lees AJ. Botulinum toxin A as treatment for drooling saliva in PD. Neurology. 2000;55:606-607.
Pal PK, Calne DB, Calne S, Tsui JK. Botulinum toxin A as treatment for drooling saliva in PD. Neurology. 2000;54:244-247.
Restivo DA, Lanza S, Patti F, et al. Improvement of diabetic autonomic gustatory sweating by botulinum toxin type A. Neurology. 2002;59:1971-1973.
Rose FC. The management of motor neuron disease. Adv Exp Med Biol. 1987;209:167-174.
Saadia D, Voustianiouk A, Wang AK, Kaufmann H. Botulinum toxin type A in primary palmar hyperhidrosis: randomized, single-blind, two-dose study. Neurology. 2001;57:2095-2099.
Sato K, Kang WH, Saga K, Sato KT. Biology of sweat glands and their disorders. I. Normal sweat gland function. J Am Acad Dermatol. 1989;20:537-563.
Schnider P, Binder M, Kittler H, et al. A randomized, double-blind, placebo-controlled trial of botulinum A toxin for severe axillary hyperhidrosis. Br J Dermatol. 1999;140:677-680.
Simonetta Moreau A, Cauhepe C, Magues JP, Senard JM. A double-blind, randomized, comparative study of Dysport vs. Botox in primary palmar hyperhidrosis. Br J Dermatol. 2003;149:1041-1045.
Suskind DL, Tilton A. Clinical study of botulinum-A toxin in the treatment of sialorrhea in children with cerebral palsy. Laryngoscope. 2002;112:73-81.
Van De Heyning PH, Marquet JF, Creten WL. Drooling in children with cerebral palsy. Acta Otorhinolaryngol Belg. 1980;34:691-705.
Watkins PJ. Facial sweating after food: a new sign of diabetic autonomic neuropathy. Br Med J. 1973;1:583-587.
Wu WH. Surgical treatment of axillary osmidrosis. An analysis of 343 cases. Plast Reconstr Surg. 1994;94:288-294.