Coverage Policy Manual
Policy #: 2000034
Category: Surgery
Initiated: May 2000
Last Review: May 2017
  Hyperhidrosis Treatment

Description:
Hyperhidrosis may be defined as excessive sweating, beyond a level required to maintain normal body temperature in response to heat exposure or exercise.  Hyperhidrosis can be classified as either primary or secondary.  Primary hyperhidrosis is idiopathic in nature, typically involving the hands, feet or axillae.  Secondary hyperhidrosis can result from a variety of drugs, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, or underlying disease/conditions, such as febrile diseases, diabetes mellitus, or menopause.  Gustatory hyperhidrosis is an unusual iatrogenic cause of facial hyperhidrosis in response to hot or spicy foods, resulting from surgery to the parotid gland and subsequent aberrant regenerating parasympathetic fibers.  
 
The consequences of hyperhidrosis are primarily psychosocial in nature.  Excessive sweating may be socially embarrassing (i.e.., limiting the ability to shake hands) or interfere with certain professions.  In addition, hyperhidrosis may require several changes of clothing a day; excessive sweating may also result in staining of clothing or shoes.
 
Treatment of secondary hyperhidrosis focuses on treatment of the underlying cause.  A variety of therapies have been investigated for primary hyperhidrosis, including topical therapy with aluminum chloride or tanning agents, iontophoresis, botulinum toxin, liposuction, and endoscopic transthoracic sympathectomy.  Botulinum toxin has also been investigated as a treatment of secondary gustatory hyperhidrosis.
 
In 2004 the FDA approved botulinum toxin type A (Botox) to treat primary axillary hyperhidrosis (severe underarm sweating) that cannot be managed by topical agents. In 2009, this product was renamed to OnabotulinumtoxinA. Other FDA-approved botulinum toxin products include:
 
2000: RimabotulinumtoxinB, marketed as Myobloc (Solstice Neurosciences)
2009: AbobotulinumtoxinA, marketed as Dysport (Medicis Pharmaceutical Corporation, Scottsdale, AZ)
2010: IncobotulinumtoxinA, marketed as Xeomin (Merz Pharmaceuticals)
None of these other botulinum toxin products have an FDA approved indication for treatment of hyperhidrosis.
 
On July 31, 2009, the FDA approved the following revisions to the prescribing information of botulinum toxin products:
 
    • “A Boxed Warning highlighting the possibility of experiencing potentially life-threatening distant spread of toxin effect from injection site after local injection.
    •  A Risk Evaluation and Mitigation Strategy (REMS) that includes a Medication Guide to help patients understand the risk and benefits of botulinum toxin products.
    • Changes to the established drug names to reinforce individual potencies and prevent medication errors. The potency units are specific to each botulinum toxin product, and the doses or units of biological activity cannot be compared or converted from one product to any other botulinum toxin product. The new established names reinforce these differences and the lack of interchangeability among products.”
 

Policy/
Coverage:
Effective May 2013
The following treatments of primary hyperhidrosis meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the small subset of patients with medical complications such as skin maceration with secondary infections or patients with significant functional impairments that interfere with their employment:
 
    • Treatment with onabotulinumtoxin A for primary hyperhidrosis, in patients 18 years and older who have failed a trial of aluminum chloride.
    • Surgical treatment with thoracic sympathectomy for the endoscopic approach for patients who have failed treatment with aluminum chloride.
 
The following treatments for primary hyperhidrosis do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
    • Iontophoresis
    • Surgical treatment of axillary hyperhidrosis with liposuction
    • Any other circumstance not listed above as meeting primary coverage criteria
    • Lumbar sympathectomy
    • Radiofrequency ablation
 
For contracts without primary coverage criteria, the following treatments are considered investigational:
    • Iontophoresis
    • Surgical treatment of axillary hyperhidrosis with liposuction
    • Any other circumstance not listed above as meeting primary coverage criteria
    • Lumbar sympathectomy
    • Radiofrequency ablation
 
Investigational services are specific contract exclusions in the member benefit certificate of coverage.
 
Effective April 2011- April 2013
The following treatments of primary hyperhidrosis meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the small subset of patients with medical complications such as skin maceration with secondary infections or patients with significant functional impairments that interfere with their employment:
 
    • Treatment with onabotulinumtoxin A for primary hyperhidrosis, in patients 18 years and older who have failed a trial of aluminum chloride.
    • Surgical treatment with thoracic sympathectomy for the endoscopic approach for patients who have failed treatment with aluminum chloride.
 
The following treatments for primary hyperhidrosis do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
    • Iontophoresis
    • Surgical treatment of axillary hyperhidrosis with liposuction
    • Any other circumstance not listed above as meeting primary coverage criteria
    • Lumbar sympathectomy
 
For contracts without primary coverage criteria, the following treatments are considered investigational:
 
    • Iontophoresis
    • Surgical treatment of axillary hyperhidrosis with liposuction
    • Any other circumstance not listed above as meeting primary coverage criteria
    • Lumbar sympathectomy
 
Investigational services are specific contract exclusions in the member benefit certificate of coverage.
 
Effective Prior to April 2011
Treatment of primary hyperhidrosis is a covered benefit only for the small subset of patients with medical complications such as skin maceration with secondary infections, or patients with significant functional impairments that interfere with their employment.
 
Treatment with botulinum toxin A (Botox) is a covered benefit if the patient meets the above criteria and has failed a trial of aluminum chloride.
 
Surgical treatment with thoracic sympathectomy meets primary coverage criteria for effectiveness and is covered only for the endoscopic approach, and only if the patient has failed treatment with aluminum chloride.
 
Iontophoresis as a method of treatment for primary hyperhidrosis, surgical treatment of axillary hyperhidrosis with liposuction or any other circumstance not listed as covered above is not covered based on benefit certificate primary coverage criteria of effectiveness.
 
For contracts without primary coverage criteria, iontophoresis as a method of treatment for primary hyperhidrosis, surgical treatment of axillary hyperhidrosis with liposuction or any other circumstance not listed as covered above is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.

Rationale:
Aluminum chloride
Aluminum chloride is a common component of over-the-counter antiperspirants, although a prescription product is available (Drysol). Although the mechanism is unclear, aluminum chloride is associated with atrophy of the secretory cells seen in eccrine sweat glands.
 
Iontophoresis
Iontophoresis is a technique that involves the use of an electric current to introduce various ions through the skin.  The mechanism of action is not precisely known, but is thought to be related to plugging of the sweat gland pores. The typical device consists of trays containing electrodes. Prior to using, the trays are filled with tap water, the patient inserts the hands or feet or positions the device in the axilla, and the current is turned on. Patients are treated for approximately 20 minutes, with treatments every 2 to 3 days for 5 to 10 sessions before an effect is observed. Maintenance therapy may be applied every 2 weeks after initial therapy.
 
Iontophoresis in conjunction with tap water or anticholinergic agents is a long-standing treatment of palmar or plantar and more recently axillary idiopathic hyperhidrosis, with a reported success rate of up to 85%.  However, the published literature regarding iontophoresis as a treatment of hyperhidrosis is sparse. A 2003 Blue Cross Blue Shield Association Technology Evaluation Center Assessment on iontophoresis concluded that evidence was insufficient to determine whether the effects of iontophoresis for the treatment of hyperhidrosis exceed those of placebo.  The 2003 Blue Cross Blue Shield Association Technology Evaluation Center Assessment also concluded that, in the treatment of hyperhidrosis, there is insufficient evidence to show that tap water iontophoresis is as beneficial as topical drug administration. The conclusions of the Blue Cross Blue Shield Association Technology Evaluation Center Assessment form the rationale for the change in the policy statement, which in the original suggested that iontophoresis could be considered medically necessary.
 
Botulinum toxin
Botulinum toxin is a potent neurotoxin that blocks cholinergic nerve terminals; symptoms of botulism include cessation of sweating. Therefore, intracutaneous injections have been investigated at a treatment of gustatory hyperhidrosis and primary hyperhidrosis. Lasaki and colleagues reported on the outcomes of 19 patients with gustatory hyperhidrosis treated with botulinum toxin injected into every 4 cm2 of involved skin.  In all cases, gustatory sweating ceased within 2 days, with a mean duration of effect of 17 months. Schnider and colleagues reported on a double-blind trial of patients with palmar hyperhidrosis in which 1 palm was treated with 6 injections of botulinum toxin into different sites, while the other was treated with injections of sterile saline.  While there was no reduction in sweating in the placebo-treated palms, the treated palms were associated with a 26% reduction in sweating as measured by ninhydrin sweat tests. Shelley and colleagues reported on a case series in which 4 patients with palmar hyperhidrosis were successfully treated with 50 injections of subepidermal botulinum toxin.  The subepidermal vs. subcutaneous approach is more painful, requiring nerve blocks of the ulnar and median nerves. Positive results lasted up to 1 year. Nauman and colleagues reported on the use of botulinum toxin to treat axillary hyperhidrosis in a case series of 8 patients (16 axillae).  Similar to Lawaski’s approach, botulinum toxin was injected subcutaneously into every 4 cm2 of involved skin. In all patients, the toxin completely abolished sweating within 3 days, with no recurrences noted within the 5-month follow-up period. However, despite the reduction in sweating, treatment did not affect the unpleasant odor, perhaps due to the lack of effect of botulinum toxin on the apocrine sweat glands compared to the eccrine sweat glands.
 
Endoscopic Transthoracic Sympathectomy
Thoracic sympathectomy has been investigated as a treatment of palmar hyperhidrosis with reported success rates of up to 98% in large case series.   A variety of approaches have been reported but endoscopic techniques have emerged as a minimally invasive alternative to either transaxillary, supraclavicular, or anterior thoracic approaches. While accepted as an effective treatment, sympathectomy is not without complications. In addition to the immediate surgical complications of pneumothorax or temporary Horner’s syndrome, compensatory sweating on the trunk can occur in up to 55% of patients, reducing patient satisfaction with the procedure.  Gustatory sweating may also occur. Sympathectomy also results in cardiac sympathetic denervation, which in turn can lead to a 10% reduction in the heart rate.
 
2008 Update
A search of the MEDLINE database for studies published from 2005 through January 2008 indicates continued interest in the use of botulinum toxin to treat hyperhidrosis. Allergan funded a multicenter double-blind, randomized, placebo-controlled efficacy and safety study of botulinum toxin type A (BTX-A, 0, 50, or 75 U) in 322 subjects with persistent bilateral primary axillary hyperhidrosis (e.g., exhibiting at least 2 of the following: bilateral sweating, impairment of daily activities, frequency of at least once per week, younger than 25 years of age at onset, positive family history, and cessation of focal sweating during sleep). (29) Enrollment criteria included a resting sweat production of at least 50 mg/axilla in 5 minutes and a rating of 3 or 4 (underarm sweating barely tolerable or intolerable, and frequently or always interferes with daily activities) on the Hyperhidrosis Disease Severity Scale (HDSS). Retreatment after 4 weeks was allowed in subjects with at least 50 mg of sweat (per axilla) over 5 minutes and an HDSS score of 3 or 4. Following the first injection, 75% of subjects in the BTX-A groups showed at least a 2 point improvement in the HDSS, compared with 25% of subjects in the placebo group. Sweat production decreased by 87% (75 U), 82% (50 U), and 33% (vehicle). (Similar results were obtained in patients requiring a second treatment). The median duration of effect was 197, 205, and 96 days (75 U, 50 U, and vehicle, respectively). Seventy-eight percent of subjects (252) completed the 52-week study; 96/110 (87%) in the 75-U group, 83/104 (80%) in the 50-U group, and 73/108 (68%) in the control group. Intent-to-treat analysis at 52 weeks showed a responder rate (greater than 2 point improvement on the HDSS) for 54 (49%) subjects in the 75-U group, 57 (55%) in the 50-U group, and 6 (6%) in the placebo group. Injection-site pain was reported in about 10% of all groups, with a mean duration of 2.4 days (10 day maximum). A topical preparation of botulinum toxin A was studied in a small (12 patient) vehicle-controlled split-side trial.  At 4 weeks, sweat production was reduced by 65% with topical application of BTX-A vs. 25% on the vehicle-treated side. Additional studies with a larger number of subjects and longer follow-up are needed to assess this new formulation.
 
2011 Update
In 2008, an industry-sponsored single-center, randomized, open-label, study was conducted to compare the efficacy and safety of intradermal injections of botulinum toxin type A (Botox®) and 20% aluminum chloride (AC, Drysol™) topical for the treatment of primary focal axillary hyperhidrosis from baseline to week 4 (Flanagan, 2008). Subjects (n=50) were men and women 18 years of age and older who were randomized to either Botox or AC treatment. Prior to enrollment, more than 90% of the subjects in the study had used over-the-counter antiperspirants and described them as “poor” or “ineffective.” There was no significant difference in Hyperhidrosis Disease Severity Scale (HDSS) score at baseline. The primary endpoint was to determine the incidence of treatment response, as measured by an improvement of 2 or more grades on the HDSS. Participants returned for outpatient follow-up visits at weeks 4, 8, and 12 for an assessment of adverse events, changes in concomitant medications, and to complete two validated questionnaires HDSS, Hyperhidrosis Impact Questionnaire (HHIQ), and questions about irritation (QI), a third questionnaire. Given the very high dropout rate after week 4, the results are summarized here only for week 4 of treatment. Of the 50 subjects enrolled, 45 completed 4 weeks of the study, 22 from the Botox group and 23 from the AC group. The subjects in the Botox group had a mean change in their HDSS score of -2.42 versus -1.33 in the AC group. The difference in treatment response between the Botox and AC groups was not significant. On satisfaction with treatment at week 4, 21 subjects (87.5%) in the Botox group described themselves as “very satisfied” as compared with 8(33.3%) in the AC group. To date, this is the only study directly comparing botulinum type A with 20% AC for the treatment of moderate to severe axillary hyperhidrosis. However, the conclusions the authors draw, which state that botulinum type A is superior to aluminum chloride treatment in patients, will need further investigation with larger, longer term, randomized, blinded studies to determine if botulinum toxin A would be appropriate as a first-line therapy.
 
No randomized controlled trials were identified comparing the safety and efficacy of the newest formulation of botulinum toxin A, Xeomin to placebo or aluminum chloride. In 2010, Dressler published a double-blind RCT from Germany comparing Xeomin to Botox for treating primary axillary hyperhidrosis (Dressler, 2010).  Forty-six patients with bilateral axillary hyperhidrosis and a previously stable Botox treatment for at least 2 years received 50 MU of Botox in one axilla and 50 MU Xeomin in the other axilla. All patients completed the study. A total of 41 of 46 (89%) patients reported the therapeutic effect as excellent and 5 (11%) as good. The mean reported duration of therapeutic effect was 3.2 months. According to patient self-report in structured interviews, there were no side-to-side differences in therapeutic effect including onset latency, extent and duration, and no differences in injection site pain. Moreover, clinical examination did not identify any side-to-side differences in the diffuse sweating pattern.
 
There is less evidence in support of botulinum toxin type A for treating plantar hyperhidrosis. No randomized controlled trials or large uncontrolled studies were identified; most published studies are case reports or small case series.
 
The evidence evaluating botulinum toxin type A use for gustatory hyperhidrosis as a result of Frey’s syndrome includes non-controlled or non-randomized studies, all showing favorable treatment outcomes. The patient inclusion criteria were variable across the studies and case reports; ages varied (16 to 87 years); patients had undergone varied types of parotid surgery (i.e., bilateral, partial); not all studies documented gustatory sweating with Minor’s starch test as part of the patient screening; one case report and a cohort study included patients who were refractory to topical agents and surgery. In spite of what appears to be promising clinical efficacy and safety, there are no randomized controlled trials or head-to-head comparisons with other treatment options and numerous limitations in the current evidence. These limitations include small study group size and variability in patient inclusion and exclusion criteria, dose (which makes it difficult to assess the optimal one), outcomes measures for determining clinical efficacy, and follow-up time periods to evaluate long-term efficacy. Therefore, the evidence is insufficient to draw conclusions on the short- and long-term clinical effectiveness of botulinum type A for gustatory hyperhidrosis as a result of Frey’s syndrome.
 
Botulinum toxin type B
There was one placebo-controlled randomized trial on botulinum toxin B (Myobloc) for treating primary axillary hyperhidrosis and one on palmar hyperhidrosis. Both studies were by Baumann and colleagues and were published in 2005; neither discussed whether patients had failed previous treatments for hyperhidrosis. The study on axillary hyperhidrosis included 20 participants; they received subcutaneous injections of Myobloc (2500 U or 0.5 mL per axilla) (n=15) or placebo (n=5) (Baumann, 2005). Patients who received placebo were offered Myobloc at subsequent injections. One patient in the placebo group did not return for follow-up and another responded to placebo and did not return for a subsequent Myobloc injection. Data were available on Myobloc efficacy for the remaining 18 participants (15 in the initial Myobloc group and 3 crossovers). There was a statistically significant improvement in axillary hyperhidrosis according to patient and physician subjective assessment from baseline (before receiving an active injection) to Day 30. Details on the efficacy outcomes were not reported. The mean length of time to return to baseline levels of sweating in these 18 patients was 151 days (range 66 to 243 days). Sixteen participants reported 61 adverse events over the course of the study. Five of 61 adverse events (8.2%) were determined to be definitely related to the study; 4 axillary bruising events and 1 instance of pain at the injection site. Eleven adverse events (18%) were determined to be probably related to study treatment; dry eyes (n=3), dry mouth (n=5) and indigestion (n=3). Flu-like symptoms were reported by 6 of 20 patients (30%); however, the study period coincided with flu season. Note that the authors did not compare the active treatment and placebo groups in their analysis.
 
The RCT on Myobloc for treatment of palmar hyperhidrosis included 20 participants with excessive palmar sweating. Fifteen participants received injections of Myobloc (50000 U per palm) and 5 received placebo (Baumann, 2005). Non-responders were offered an injection of Myobloc at day 30. At day 30, the two quality of life measures were significantly higher in the Myobloc group compared to the control group. However, there was not a statistically significant difference in efficacy in the physician analysis of the palmar iodine starch test at day 30 (p=0.56). No further details were provided on the efficacy outcome measures described above. The mean duration of action according to self-report in 17 patients (15 in the initial treatment group and 2 who crossed-over from the placebo group) was 3.8 months (range=2.3 to 4.9 months). Participants were asked about specific adverse events. Eighteen of 20 (90%) reported dry mouth/throat, 12 (60%) reported indigestion, 12 (60%) reported excessively dry hands, 12 (60%) reported muscle weakness and 10 (50%) reported decreased grip strength. Both studies by Baumann and colleagues were limited by a small sample size.
 
A small randomized trial by Frasson and colleagues in Italy comparing botulinum toxin type A and type B for treating axillary hyperhidrosis was published in 2011 (Frasson, 2011). This study included 10 patients with idiopathic focal axillary hyperhidrosis that was unresponsive to other non-surgical treatments. Patients received 50U Botulinum toxin A in one axilla and 2500U botulinum toxin B in the contralateral axial. Gravimetry was performed at baseline and follow-up as an objective measurement of sweat production. In addition, the sweat area was photographed. At each follow-up point, the decrease in sweat weight from baseline was significantly lower on the botulinum toxin B side compared to the botulinum toxin A side. For example, after one month, the sweat weight in 5 minutes was 13% of the baseline value on the botulinum toxin A side and 4% of the baseline value on the botulinum toxin B side (p=0.049). By 6 months, the sweat weight at returned to 91% of baseline on the botulinum toxin A side and 56% of baseline weight on the botulinum toxin B side (p=0.02). Findings were similar for sweating area. The article stated that all patients tolerated injections of botulinum toxin types A and B well and that none reported systemic adverse effects. The authors commented that this study used a higher dosage of botulinum toxin B than previous studies.
 
Surgical interventions
 
Transthoracic sympathectomy for primary focal hyperhidrosis
No randomized controlled trials were identified that compared transthoracic sympathectomy to sham surgery. Several RCTs and one meta-analysis have compared different approaches to surgery. In 2010, Deng and colleagues published a meta-analysis of data from randomized controlled trials and observational studies evaluating thorascopic sympathectomy; they only included studies on patients with palmar hyperhidrosis (Deng, 2010). The authors pooled outcome data from different approaches to sympathectomy, i.e., single-ganglia blockage (T2, T3 or T4), and multi-ganglia blockage (T2-3, T2-4 or T3-4). Based on these analyses, they concluded that T3 (11 studies) and T3-4 (2 studies) had the “best” clinical efficacy i.e., postoperative resolution of symptoms. The T3 approach resulted in a 97.9% pooled efficacy rate and the T3-4 approach resulted in a 100% pooled efficacy rate. In the studies for which data were available, the pooled rate of postoperative compensatory sweating was 40% after T3 surgery. Data on compensatory sweating after T3-4 surgery was only available from one study with 60 patients; a pooled analysis could not be performed.
 
A randomized, controlled trial, published in 2008 by Inan and colleagues, included 80 male patients undergoing bilateral thoracoscopic sympathectomy or sympathetic blockage to treat primary hyperhidrosis (Inan, 2008). The subjects were divided into four groups depending on the technique used for sympathetic blockage; techniques included resection (n = 20), transection (n = 20), ablation (n = 20), and clipping (n = 20). The primary success rate was 96.3% for isolated palmar hyperhidrosis, 95.7% for palmar and axillary hyperhidrosis, and 66.7% for palmar and face/scalp hyperhidrosis. No recurrence was observed. The overall success rate of the operation was 95%, and the differences among the four groups were not statistically significant. In the clipping group, the duration of the surgical procedure was significantly shorter than in the other groups. Complication rates were similar among the groups. The postoperative chest roentgenogram revealed pneumothorax in 9 patients, but none of them required intervention. The authors concluded that thoracic endoscopic sympathetic blockage yields similar results irrespective of the surgical technique adopted, conclusions need to be tempered by the size of the study groups.
 
Liu and colleagues in China published a randomized trial in 2009 comparing T3 and T4 sympathectomy in 141 patients with primary palmar hyperhidrosis (Liu, 2009). The patients’ prior use of nonsurgical treatments was not reported. Only 43 patients (30%) had severe palmar hyperhidrosis; 86 (61%) and 12 (9%) reported moderate and minor hyperhidrosis, respectfully. After surgery, 46 of 62 (74.2%) of patients in the T3 group and 28 of 69 (40.5%) in the T4 group reported dry hands. This difference was statistically significant favoring the T3 group, p<0.001. However, 48 of 62 (77.4%) of patients in the T3 group and 39 of 69 (56.5%) of patients in the T4 group reported compensatory sweating. The rate of compensatory sweating was significantly higher in the T3 group, p=0.01. A moderate or embarrassing level of compensatory sweating was reported by 9 patients (14.5%) in the T3 group and 2 (2.9%) in the T4 group; no patients reporting disabling compensatory sweating.
 
There is also a large amount of data from case series on transthoracic sympathectomy for treating primary focal hyperhidrosis. Through 2003, large case series reported success rates of up to 98% (24-30) Recent case series also report high success rates, although there are potential adverse effects. For example, in 2010, Wait and colleagues published a retrospective analysis of prospectively collected data on patients who underwent bilateral thoracoscopic sympathectomy for hyperhidrosis (Wait, 2010).  Additional follow-up data were obtained from the patients. A total of 348 patients underwent surgery; data were available on 322 (93%) of patients. Patients’ previous use of non-surgical hyperhidrosis treatments was not reported. Procedures for the first 100 patients were sympathetic chain resections (sympathectomy) which involved completely excising the sympathetic chain using sharp dissection. In the remaining patients, focal in situ transaction of the upper sympathetic chain (sympathotomy) was performed. The extent of the sympathology varied according to the patient’s symptoms. The procedure was generally limited to T2 or T3 for isolated palmar or craniofacial hydrohidrosis, and extended from T2 to T4 for axillary hyperhidrosis. Patients had hyperhidrosis of one or more areas; 81.5% had more than one affected region. Complete resolution of symptoms was experienced by 300 of 301 (99.7%) with palmar hyperhidrosis, 136 of 186 (73%) with axillary hyperhidrosis, 27 of 30 (90%) with craniofacial hyperhidrosis and 19 of 197 (9.6%) with plantar hyperhidrosis. There was a low rate of complications, and most occurred in the first half of the series. Nine patients (2.8%) required chest tube evacuation of a pneumothorax. Seven patients (2.2%) had unilateral Horner’s syndrome; 5 of these were among the first 100 patients. Compensatory sweating was reported by a total of 201 of 322 (62%) patients. The compensatory sweating was severe in 20 (6.2%) of patients and mild or moderate in 181 (56.2%) of patients. It is worth noting that thoracoscopic sympathectomy was performed in some cases of plantar  hyperhidrosis and that there was a low rate of success. In addition, when reporting rates of compensatory sweating, the authors did not distinguish between mild and moderate levels of symptoms although these could have different clinical implications for the patient.
 
A prospective series from India by Prasad and colleagues reported on 322 patients with primary palmar hyperhidrosis who underwent endoscopic thoracic sympathectomy at the T3-T4 level and were followed for a minimum of 24 months (Prasad, 2010). The authors did not discuss patients’ previous use of other treatments. All patients reported cessation of palmar hyperhidrosis immediately following the procedure. Three patients (<1%) experienced recurrence, but reported that their symptoms were less severe than before. Eleven patients had symptoms requiring a post-operative x-ray; one patient had a minor pneumothorax. Sixty-four percent of patients reported compensatory sweating; symptoms were mild in 35%, moderate in 25% and severe in 4%; the remaining 37% of patients reported no compensatory sweating.
 
Endoscopic lumbar sympathectomy for primary plantar hyperhidrosis
No randomized controlled trials were identified. Several case series have been published recently. A 2009 series by Rieger and colleagues from Austria evaluated surgery results in 90 patients (59 men, 31 women with severe plantar hyperhidrosis (Rieger, 2009). Thirty-seven patients (41%) had only plantar hyperhidrosis and 53 (59%) had plantar and palmar hyperhidrosis. All patients had previously used topical aluminum chloride therapy, 47 (47%) had used iontophoresis, 16 (18%) had used botulinum toxin and 24 (27%) patients previously had bilateral endoscopic thoracic sympathectomy for palmar hyperhidrosis. There were a total of 178 procedures--90 on the right-side and 88 on the left side. The technique involved resecting a segment of the sympathetic trunk between the third and fourth lumbar bodies together with the ganglia (L3 and/or L4). Three patients (3%) had a postoperative complication; these were a muscle hematoma at the trocar insertion site, one case of pneumonia and one peripheral pulmonary embolism. Five of the 8 patients who had bilateral surgery experienced general physical weakness for 3-6 weeks. Most patients experienced mild pain immediately after surgery. After a mean follow-up of 24 months (range 3 to 45), hyperhidrosis was eliminated in 87 of 90 patients (97%). Post-operative neuralgia occurred in 38 (42%) patients between the 7th and 8th day. The pain lasted less than 4 weeks in 11 patients, 1-3 months in 19 patients, 4-12 months in 5 patients and more than 12 months in 3 patients. No patient in the series experienced permanent sexual dysfunction, although the sample size was too small to draw definitive conclusions about the safety of the surgery. Three men reported temporary sexual symptoms; one was incapable of ejaculation for 2 months. None of the women reported postoperative sexual dysfunction.
 
In 2010, Reisfeld reported on results of a U.S-based study from a specialized hyperhidrosis clinic in which bilateral endoscopic lumbar sympathectomy was performed in 63 patients with focal plantar hyperhidrosis (Reisfeld, 2009). There were 13 (21%) male patients and 50 (79%) female patients. A clamping method was used in which clamps were placed at L3 (46.6%), L4 (52.4%) and L2 in one case. There was a learning curve with this procedure and 5 early cases had to be converted to an open procedure. Fifty-six (89%) of the patients had previously undergone some form of thoracic sympathectomy and all had tried conservative measures. After a mean follow-up of 7 months, all patients considered their plantar hyperhidrosis symptoms to be “cured” or “improved”; 97% reported “cure”. All of the patients with previous thoracic sympathectomy had some degree of compensatory sweating. After lumbar sympathectomy, 51 of the 56 patients (91%) reported that their compensatory sweating was unchanged. In the 7 patients who did not have a previous thoracic sympathectomy, 1 reported mild and 6 reported moderate compensatory sweating. The authors stated that no sexual problems were reported by the male patients and they did not discuss possible sexual problems among the female patients.
 
It is worth noting, that in contrast to earlier concerns about this procedure being associated with risks of permanent sexual dysfunction in men and women, the recent case series did not find any instances of permanent sexual dysfunction. A 2004 review from a multi-specialty working group on hyperhidrosis stated that lumbar sympathectomy is not recommended for plantar hyperhidrosis because of associated sexual dysfunction; this article did not cite any data documenting sexual dysfunction (Hornberger, 2004). The authors of one of the recent series (Reisfeld, 2010) mentioned that the concern about sexual dysfunction may have come from studies in which lumbar sympathectomy was done in older men for peripheral vascular problems in patients who may have already had some degree of sexual dysfunction. Still, there are very few studies on endoscopic lumbar sympathectomy for focal plantar hyperhidrosis and no comparative studies.
 
Technology Assessments, Guidelines and Position Statements
In May 2008, the American Academy of Neurology (AAN) created guidelines for use of botulinum neurotoxin for the treatment of autonomic disorders and pain (Naumann, 2008). These guidelines include the following recommendations for hyperhidrosis:
Botulinum neurotoxin injection (BoNT) should be offered as a treatment option to patients with axillary hyperhidrosis (Level A).
BoNT should be considered as a treatment option for palmar hyperhidrosis and drooling (Level B).
BoNT may be considered for gustatory sweating (Level C).
 
2013 Update
This policy is updated with a literature review through April 2013.  The following is a summary of the key identified literature.
 
Radiofrequency ablation
A 2013 study evaluated radiofrequency ablation as a treatment option for patients with severe bilateral palmar hyperhidrosis resistant to conservative treatment (Purtuloglu, 2013). The study was conducted in Turkey and retrospectively reviewed outcomes after radiofrequency ablation (n=48) or transthoracic sympathectomy (n=46). Patients were not randomized to treatment group. After the mean of 15-month follow-up, palmar hydrosis was absent in 36 patients (75%) in the radiofrequency ablation group and 44 patients (96%) in the surgery group. The difference in outcomes was statistically significant between groups, favoring the surgical intervention (p<0.01). Six patients in each group reported moderate or severe compensatory sweating (p=0.78).
 
This nonrandomized comparative study represents insufficient evidence on radiofrequency ablation as a treatment of hyperhidrosis. The coverage statement has been revised to include radiofrequency ablation as not meeting primary coverage criteria for the treatment of hyperhidrosis.
 
Microwave treatment
A 2012 industry-sponsored case series reported on 31 patients with primary axillary hyperhidrosis who were treated with microwave therapy using the miraDry system (Hong, 2012). All patients had an HDSS score of 3 or 4 at baseline. The primary efficacy outcome, the proportion of patients whose HDSS decreased to 1 or 2 was 28 (90%) at 6 months and 12 months after treatment. Longer-term skin-related adverse effects (that all resolved over time) were altered sensation in the skin of the axillae (65% of patients, median duration, 37 days) and palpable bumps under the skin of the axillae (71% of patients, median duration, 41 days).
 
Transthoracic sympathectomy
In 2011, Smidfelt and Drott in Sweden reported on long-term outcomes after transthoracic sympathectomy (Smidfelt, 2011). Of 3,015 patients who had been treated with endoscopic thoracic sympathectomy for hyperhidrosis and/or facial blushing, 1,700 (56%) responded to a written survey after a mean of 14.6 (SD=2.4) years. A total of 85.1% of respondents reported that they had a satisfactory and lasting effect of the surgery. Sweating and/or blushing recurred and was considered a problem in 8.1%, and 6.9% reported no initial effect or a poor effect. Compensatory sweating was considered troublesome by 299 (17.6%), annoying by 409 (24.1%), severe by 367 (21.6%), and incapacitating by 190 (11.2%). Nearly half of the patients who underwent surgery did not respond to the survey; their outcomes may have been different from those of study respondents.
  
2014 Update
A literature search conducted through April 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Since the 2003 TEC Assessment, no randomized controlled trials (RCTs) evaluating tap water iontophoresis for treating hyperhidrosis have been published. Subsequent case series include a 2013 study from Ireland with 28 patients (McAleer, 2013) Patients received a minimum of 9 treatments over 21 days in a clinical setting. Twenty of the 25 patients (80%) for whom data were available after hospital administration of tap water iontophoresis reported a moderate or great amount of improvement in symptoms and a moderate or great improvement in quality of life (according to a Disease Life Quality Index). In addition, a 2014 retrospective case series from Turkey included 21 pediatric patients under age 18 (Dogruk, 2014). Most of the patients (n=16) had palmoplantar hyperhidrosis. Nineteen patients completed the course of 21 tap water iontophoresis sessions. Among study completers, the mean self-report treatment effectiveness score rated on a 0 to 10 visual analogue scale (VAS) was 6.36 at the end of treatment. Seventeen of 19 patients (89.5%) reported a 50% or more decrease in sweating at the end of treatment.
 
Two double-blind randomized trials have compared Xeomin to Botox. In 2014, Campanati and colleagues included 25 patients with moderate to severe primary palmar hyperhidrosis resistant to aluminum chloride or iontophoresis (Campanati, 2014). Patients received injections of Xeomin in a randomly selected hand and Botox in the other hand. The botulinum toxin was given at a fixed dosage per cm2 of the hand. There were no statistically significant differences in outcomes between groups. This included changes in the HDSS and the extent of sweating assessed using the Minor’s test.
 
A 2013 RCT by Ibrahim and colleagues compared botulinum toxin B and suction-curettage in 20 patients with primary axillary hyperhidrosis (Ibraham, 2013). Patients received 1 treatment in 1 axilla and the other treatment in the contralateral axilla. The primary outcomes were reduction in the sweat rate in resting and exerciseinduced states at 3 months. The mean percent reduction in the resting sweat rate at 3 months was 72.1% in the botulinum toxin group and 60.4% in the suction-curettage group; the difference between groups was not statistically significant, p=0.29). Similarly, the exercise-induced sweat rate did not differ between groups at 3 months. The mean percent reduction was 73.8% in the botulinum toxin group and 58.8% in the suction-curettage group, p=0.10. Scores on the validated 4-point HDSS, however, did differ significantly between groups at 3 months and favored botulinum toxin B treatment. The difference in the decrease in HDSS scores between the botulinum toxin and suction-curettage groups at 3 months was
0.80 points, p=0.0002. Although findings of this single small trial are not conclusive, study findings suggest that botulinum toxin B may be at least as effective as suction-curettage for treatment of primary axillary hyperhidrosis.
 
There are few RCTs evaluating botulinum toxin type B for treating hyperhidrosis. One small placebo-controlled RCT did not clearly demonstrate the efficacy of botulinum toxin type B in patients with palmar hyperhidrosis. Two RCTs support the efficacy of this treatment for patients with axillary hyperhidrosis. An additional RCT in patients with axillary hyperhidrosis compared botulinum toxin type B to suction and curettage, and found that botulinum toxin type B resulted in outcomes that did not differ significantly from suction and curettage.
 
A trial by Ishy et al in Brazil compared surgery at the T3 and T4 levels and one by Yuncu et al in Turkey compared surgery at the T3 and T3-T4 levels. Ishy et al included 20 patients with palmar hyperhidrosis (Ishy, 2011) All patients experienced complete bilateral remission of palmary sweating after 1 year of follow-up. The level of compensatory sweating did not differ significantly between groups at 1 week, 1 month, or 6 months, but at 1 year, there was a significantly higher rate in the T3 compared to the T4 group (20/20, 100% in the T3 group and 15/20, 75% in the T4 group, p=0.47). Yuncu et al included 60 patients with axillary hyperhidrosis; 17 were assigned to T3-4 surgery and 43 to T3 surgery (Yuncu, 2013). There were no significant differences between groups in post-operative satisfaction. At the 1-year follow-up, the incidence of compensatory sweating was lower in the T3 group (79%) than the T3-T4 group (100%).
 
There are insufficient data to conclude that any particular approach to surgery results in lower rates of compensatory sweating.
 
The National Institute for Health and Care Excellence (NICE, 2014) issued guidance in 2014 stating that there is sufficient evidence of the efficacy and safety of endoscopic thoracic sympathectomy (ETS) for primary facial blushing to support the use of the procedure (NICE, 2014).
 
2015 Update
A literature search conducted through April 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Several case series and 1 randomized controlled trial (RCT) were identified in subsequent literature searches. The RCT compared iontophoresis to an alternative intervention and does not provide data on the efficacy of this therapy compared with placebo.  In 2014, Rajagopal and colleagues compared iontophoresis with botulinum toxin in patients with palmar hyperhidrosis (Rajagopal, 2014).  . The trial included 60 patients who had a baseline score on the Hyperhidrosis Disease Severity Scale (HDSS) of 3 or 4 (ie sweating barely tolerable or intolerable, and frequently or always interferes with daily activities). Patients were randomized to receive treatment with iontophoresis 3 times weekly or 1 botulinum toxin injection in each hand, with 2 weeks between treatments. HDSS scores were recorded at 4 weeks; nonresponders were permitted to cross over to the other treatment arm. At the end of the initial 4 weeks, improvement (defined as decrease of at least 1 point in the HDSS score) was identified in 24 (80%) of 30 patients in the botulinum toxin group and 14 (47%) of 30 patients in the iontophoresis group (p=0.007). Sixteen patients in the iontophoresis arm crossed over to the botulinum toxin arm, and 12 of these showed excellent improvement after an additional 4 weeks. In contrast, only 1 of the 6 patients who crossed over from the botulinum toxin arm to the iontophoresis arm showed improvement after a second 4-week treatment period. In this relatively small sample with a relatively short intervention period, iontophoresis was found to be less effective than botulinum toxin.
 
The single RCT found that iontophoresis was less effective than botulinum toxin in the short-term treatment of palmar hyperhidrosis. RCTs are needed to show that iontophoresis is more effective than placebo treatment and/or appropriately designed trials to demonstrate that iontophoresis is at least as effective as alternative therapies.
 
Transthoracic Sympathectomy for Primary Focal Hyperhidrosis
Karamustafouglu and colleagues reported on 80 patients with primary hyperhidrosis (axillary and/or palmar)  (Karamustafouglu, 2014). All 80 patients responded to a questionnaire a mean of 35 months after surgery. Seventy-one (89%) of the 80 patients were very satisfied with the surgical outcome, and the other 11% were dissatisfied. Compensatory sweating was reported by 62 patients (78%).
 
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement. Two publications were identified addressing treatment of hyperhidrosis with botulinum toxin.
 
A 2015 RCT by An et al randomly assigned 24 patients with symmetrical axillary hyperhidrosis to receive injections of onabotulinumtoxinA 50 U in 1 axilla and rimabotulinumtoxinB 1500 U in the other (ie, a conversion rate of 1:30 was used) (An, 2015). Baseline HDSS scores were 2 (n=9), 3 (n=14), and 4 (n=1); those who scored 3 or 4 were categorized as having severe axillary hyperhidrosis. The primary efficacy outcome (the proportion of patients with an HDSS score of 1 or 2 at the 2-week follow-up) was 100% in each group (p=1.00). At 12 weeks, all patients still had a score of 1 or 2 on the HDSS (p=1.00) and at 20 weeks, 80% in each group had an HDSS score of 1 or 2 (p=1.00). A decrease of 2 points or more from baseline on the HDSS was reported at week 2 in 86.7% in each group (p=1.00); at week 12, the same decrease was reported in 80.0% in the botulinum toxin type A group and 86.7% in the botulinum toxin type B group (p=0.64); and at week 20, the same decrease was only reported in 13.3% of the botulinum toxin type A group and in 6.7% of the botulinum toxin type B group (p=0.56). No major systemic adverse effects were reported in any patients.
 
A 2015 Cochrane review did not identify any RCTs or quasi-randomized RCTs evaluating the efficacy of botulinum toxin injections for the treatment of gustatory hyperhidrosis as a result of Frey syndrome (Li, 2015). No RCTs were identified in literature searches.
 
2017 Update
A literature search conducted through March 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A RCT by An and colleagues randomly assigned 24 patients with symmetrical axillary hyperhidrosis to receiveinjections of onabotulinumtoxinA 50 U in 1 axilla and rimabotulinumtoxinB 1500 U in the other (ie, a conversion rate of 1:30 was used) (An, 2015). Baseline HDSS scores were 2 (n=9), 3 (n=14), and 4 (n=1); those who scored 3 or 4 were categorized as having severe axillary hyperhidrosis. The primary efficacy outcome (the proportion of patients with an HDSS score of 1 or 2 at the 2-week follow-up) was 100% in each group (p=1.00). At 12 weeks, all patients still had a score of 1 or 2 on the HDSS (p=1.00) and at 20 weeks, 80% in each group had an HDSS score of 1 or 2 (p=1.00). A decrease of 2 points or more from baseline on the HDSS was reported at week 2 in 86.7% in each group (p=1.00); at week 12, the same decrease was reported in 80.0% in the botulinum toxin type A group and 86.7% in the botulinum toxin type B group (p=0.64); and at week 20, the same decrease was only reported in 13.3% of the botulinum toxin type A group and in 6.7% of the botulinum toxin type B group (p=0.56). No major systemic adverse effects were reported in any patients.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
 
Ongoing:
(NCT01930604) Botulinum Toxin Treatment in Craniofacial, Inguinal, Palmar, Plantar and Truncal Hyperhidrosis; planned enrollment 274; projected completion date October 2017.
 

CPT/HCPCS:
32664Thoracoscopy, surgical; with thoracic sympathectomy
64650Chemodenervation of eccrine glands; both axillae
64653Chemodenervation of eccrine glands; other area(s) (eg, scalp, face, neck), per day
64818Sympathectomy, lumbar
97033Application of a modality to 1 or more areas; iontophoresis, each 15 minutes
J0585Injection, onabotulinumtoxinA, 1 unit

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