Treatment of Primary Craniofacial Hyperhidrosis: A Systematic Review

Transcription

1 Am J Clin Dermatol (2015) 16: DOI /s SYSTEMATIC REVIEW Treatment of Primary Craniofacial Hyperhidrosis: A Systematic Review Rebecca Nicholas 1 Ayyaz Quddus 1 Daryll M. Baker 1 Published online: 9 June 2015 Springer International Publishing Switzerland 2015 Abstract Background Primary craniofacial hyperhidrosis (CH) can have a profoundly negative impact on quality of life. No comprehensive review of its management exists. Objective The objective of this review is to present the best clinical evidence to guide CH management. Methods A systematic review was performed using PRISMA guidelines. MEDLINE and EMBASE were searched from 1966 to 2014 for articles using the MeSH terms Hyperhidrosis, Head, Neck and synonymous text words. Inclusion criteria were experimental and observational studies addressing CH treatment. Two reviewers independently assessed study quality and analysed data. Results Of 833 references yielded, 27 met inclusion criteria and were analysed. Twenty-two studies evaluated T2 sympathetic ablation (Level III evidence). Outcome measures were subjective and mean follow-up was 29 months. Reported efficacy was high ( %), recurrence rates were generally low (0 8 %) and complications largely transient (e.g. pneumothorax 0 1 %). However, % experienced troubling compensatory sweating. One randomised controlled trial and one observational study evaluated botulinum toxin A (Level Ib and III, respectively). Both employed objective outcome measures and demonstrated similar findings. Presented at the SARS (society of academic and research surgery annual meeting) conference held on 7 january & Ayyaz Quddus ayyazquddus@googl .com Rebecca Nicholas rebeccanicholas@ymail.com Daryll M. Baker Daryll.baker@nhs.net 1 Department of Surgery, Royal Free Hospital, Pond St, London NW3 2QG, UK Efficacy was 100 %, lasted a median of 5 6 months and frontalis muscle inhibition was the main adverse effect ( %). Three studies evaluated anticholinergic therapy: topical glycopyrrolate demonstrated high efficacy (96 %) with minimal adverse effects (Level Ib) and oral oxybutynin demonstrated relatively high efficacy ( %) but with noticeable adverse effects ( %) (Level III). Conclusion There are few quality studies evaluating CH treatment. Based on available evidence, we recommend topical glycopyrrolate, oral oxybutynin and intradermal botulinum toxin A as first-line therapies due to their efficacy and safety. T2 sympathectomy should be considered for patients refractory to first-line therapy. Key Points Craniofacial hyperhidrosis (CH) is a facial form of focal hyperhidrosis referring to excess sweating beyond normal physiological function, which can have a profoundly negative impact upon quality of life. Clinical evidence supporting the effective treatment of CH is weak due to a lack of published randomised controlled trials. Based on the findings from our systematic review, we recommend topical glycopyrrolate, oral oxybutynin and intradermal botulinum toxin A as first-line therapies due to their high efficacy and favourable safety profiles. T2 sympathectomy should be reserved for patients who are refractory to firstline therapy due to the high incidence of postoperative compensatory sweating and rare yet significant postoperative complications.

2 362 R. Nicholas et al. 1 Introduction Craniofacial hyperhidrosis (CH) is a facial form of focal hyperhidrosis referring to excess sweating beyond normal physiological function. The condition usually affects the forehead bilaterally but can also involve other regions of the face such as the scalp, nose, chin and cheeks less frequently [1]. It is predominantly a primary condition characterised by sudomotor dysregulation stimulated by triggers such as heat and stress [2]. Skin biopsies from patients with primary focal hyperhidrosis have shown that the eccrine glands are not morphologically abnormal but purely hyperactive [3]. Primary CH, if severe enough, can have debilitating effects on an individual s quality of life [4] and, hence, it is of utmost importance to treat it successfully. 1.1 Incidence and Aetiology The incidence of primary hyperhidrosis is 2.9 %, with the greatest prevalence rate between the ages of 18 and 54 years [5]. Focal CH, however, only accounts for 22.8 % of this population, with the majority being axillary, palmar and plantar hyperhidrosis. Focal CH differs from other forms of focal hyperhidrosis in that it is more common in men and presents more frequently in an older subset of patients [6]. A genetic predisposition has been identified to developing focal palmar hyperhidrosis with evidence of variable penetrance, although no such genetic studies specific to CH have been conducted [7]. 1.2 Diagnosis Before a diagnosis of primary CH can be made, it is essential to rule out secondary conditions such as the onset of menopause, diabetes mellitus, endocrine disorders and certain medications such as nortriptyline hydrochloride and pilocarpine [1]. Subjective assessment of sweating plays an important role in the diagnosis of focal CH; however, objective evaluation of the intensity of sweating is essential in determining qualification for surgery and for the assessment of the results of the intervention [8]. Gravimetry has been shown to be an effective and reproducible means of objectively assessing sweating in facial hyperhidrosis [9]. The Minor iodine starch test is a useful clinical tool to evaluate distribution of CH but does not provide accurate objective measurement of the degree of sweating [10]. 1.3 Objective Current treatment modalities for CH include topical application of aluminium chloride, oral anticholinergic medication and invasive therapies such as intradermal injections of botulinum toxin A and endoscopic thoracic sympathectomy (ETS) in severe cases. However, to the best of our knowledge, no comprehensive review of its management exists. Our aim is to systematically review and evaluate the strength of available evidence from the last 48 years in order to propose evidence-based guidelines for the management of CH. 2 Methods A systematic literature review was performed according to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) guidelines. MEDLINE and EMBASE databases were searched for articles indexed with the MeSH (Medical section Heading) terms Hyperhidrosis, Head and Neck, alongside text words craniofacial, sweating, scalp, face, forehead, fore-head, facial and neck from 1966 to The following inclusion criteria were established to choose the studies: 1. Experimental, observational and comparative studies published in scientific journals with five or more patients specific to primary focal CH; 2. Written in English; 3. Addressing the efficacy of treatment modalities for primary CH; and 4. Clear statistical evidence of differentiating outcomes of treatment modalities of primary CH from gustatory sweating, Frey s syndrome and facial blushing, where relevant. 2.1 Data Extraction Numerical and qualitative data were extracted from the original publications and collated in a table of substantive characteristics (number of patients, treatment, outcome measure, immediate success rate, recurrence, rate of adverse effects, mean follow-up) and methodology (type of study). We graded each type of study according to the Centre of Evidence-Based Medicine, Oxford (CEBM) scale (Ia V) and subsequently assigned the treatment modality a grade of recommendation (A D) according to guidance from CEBM [11]. 3 Results The literature search identified 1552 articles. After eliminating duplicates and publications in foreign languages, 833 papers remained for detailed analysis. All titles and abstract were examined independently by two reviewers

3 Treatment of Primary Craniofacial Hyperhidrosis 363 against the inclusion criteria, leading to 754 articles being excluded and 79 potential relevant studies left. The full text of all 79 publications was fully accessed and assessed, and 52 papers were excluded due to non-compliance with the aforementioned criteria. This led to final inclusion of 27 original articles in the present review. The reasons for article exclusion were animal studies, expert opinions, case reports, review articles, studies involving less than five patients specific to focal CH, an unclear differentiation of the population of patients with CH from other forms of focal hyperhidrosis, and lack of quantitative data on the efficacy of the treatment modality in question (Fig. 1). The 27 articles that met all of the inclusion criteria involved a total of 10,237 patients, of which 1140 (11.1 %; mean n = 42.2, range 5 190) patients were specified to have primary focal CH (Tables 1, 2, 3). Three main modalities of treatment for focal CH were identified, including ETS, anticholinergics and intradermal botulinum toxin A injections. Of these studies, 22 (81.5 %) evaluated the surgical ablation of the upper thoracic sympathetic ganglions, specifically at T2 level, either by clipping or cauterisation (Table 3). Three (11.1 %) studies [12 14] looked at anticholinergic therapy, of which one was topical glycopyrrolate 2 % [12] and the other two were oral oxybutynin [13, 14]. The remaining two (7.4 %) studies looked at the use of botulinum toxin A injections [15, 16]. Of the 27 studies, only nine (33.3 %) were specific to focal CH (two botulinum toxin A, two anticholinergic and five ETS studies) and the remaining articles incorporated different forms of focal hyperhidrosis including axillary, palmar and plantar forms as well as facial hyperhidrosis. Each study was graded using the CEBM scale (Tables 1, 2, 3). Only two (7.4 %) [12, 15] studies employed randomised, case-controlled study designs (Level 1b evidence) and the remaining 25 (92.6 %) studies were nonrandomised, retrospective/prospective observational studies (Level III evidence). Outcome measures were variable, with 20 (74.1 %) studies reporting treatment outcome subjectively on either written or telephone questionnaire alone. One study [17] (3.7 %) used a visual analogue scale and three studies (11.1 %) [14, 18, 19] used clinical followup in addition to using questionnaires. Only four studies incorporated objective quantification of the degree of sweating pre- and post-intervention. These included gravimetry with patient questionnaire [12], starch iodine photography in isolation [15], sympathetic skin response with clinical follow-up and interview in a study [20], and gravimetry with starch iodine photography [16]. The mean immediate success rate reported for ETS and its variants over 22 studies was 93.3 % (range %), for topical or oral anticholinergic medication was 92 % (range %) and for intradermal botulinum toxin A injection was 100 %. Only 14 (51.9 %) of the total studies documented recurrence rates. For ETS and its modifications this was reported to be between 0 and 8 %; however, one study described a recurrence rate of 27.3 % [21]. Although this was documented as late recurrence, no objective demarcation specifying the time difference between late and immediate recurrence rates was defined. One study of topical anticholinergic medication [12] using 2 % glycopyrrolate cited 28 % recurrence of symptoms in 1 day, and one study using intradermal botulinum toxin A injections [15] reported a 0 % recurrence rate. The follow-up periods for the two intradermal botulinum toxin A injection studies [15, 16] were 5 and 6 months, respectively. The follow-up time was lower in two of the anticholinergic studies, ranging between 1 and 12 weeks for oral oxybutynin. However, one study [14] looking at the long-term efficacy of oral oxybutynin had a mean follow-up period of 17 months (range 6 61 months). Only 19 (86.4 %) ETS studies reported an objective follow-up period. Two studies [22, 23] did not cite any follow-up period, whereas one study [24] documented no long term follow up. The remaining studies displayed a wide variation in follow-up (range 1 month to 14.6 years, mean 29 months). 4 Discussion 4.1 Anticholinergic Therapy Eccrine glands that are responsible for focal hyperhidrosis are innervated by cholinergic fibres, part of the autonomic nervous system. Anticholinergic medication aims to block receptor sites at parasympathetic nerve endings and therefore disrupts normal sympathetic neurotransmission [25]. Evidence regarding the efficacy of oral anticholinergic medication in the treatment of focal CH is limited to two studies. One study was a prospective, randomised study (Level III evidence) involving five patients [13] and the second study [14] was a prospective, nonrandomised study (Level III evidence) involving 61 patients. In the study conducted by Wolosker et al. [13] with five CH patients, four (80 %) reported some benefit, subjectively measured using questionnaires. No objective analysis was employed. Systemic anticholinergic medication, such as oxybutynin, causes non-specific blockade of the muscarinic acetylcholine receptors leading to adverse effects such as urinary retention, headache and dry mouth. Wolosker et al. [13] reported a 66.6 % rate of dry mouth on oxybutynin 5 mg, which increased to 76.6 % on

4 364 R. Nicholas et al. Fig. 1 Flowchart of the study selection process for the management of primary craniofacial hyperhidrosis (CH) Articles initially identified through EMBASE and MEDLINE (n = 1552) Duplicates and foreign publications excluded Titles and abstracts of studies selected for further evaluation (n = 833) Studies selected for full text evaluation (n = 79) Excluded articles (n = 754) Animal studies Expert opinions Case reports Review articles Studies with <5 patients specific to focal CH Unclear differentiation of CH Studies included in the review (n = 27) Excluded articles following full text review (n = 52) Inclusion criteria: Experimental, observational and comparative studies published in scientific journals with 5 or more patients specific to primary focal CH Written in English Addressing the efficacy of treatment modalities for primary CH Clear statistical evidence differentiating outcomes of treatment modalities of primary CH from gustatory sweating, Frey s syndrome and facial blushing where relevant oxybutynin 10 mg. The higher dose also caused a 6.7 % rate of urinary retention. The rate of adverse effects in this study were difficult to interpret as different forms of focal hyperhidrosis were included and the follow-up period was limited to 12 weeks. The second study conducted by Wolosker et al. [14] looked at the management of oral oxybutynin in focal CH over a longer period of time. The study included 61 patients who had been followed up for an average duration of 17 months (range 6 61 months). Wolosker et al. [14] reported a 100 % immediate improvement in quality of life and symptoms of patients subjectively and 91.8 % of these patients remained in the same improvement category for the remainder of their follow-up. Dry mouth was a symptom experienced by 51 (83.6 %) patients initially, but only 26.1 % documented worsening of their dry mouth during the course of treatment. No serious adverse effects such as urinary retention or intestinal obstruction occurred, which is most likely due to the smaller starting dose of oxybutynin (2.5 mg) being used initially. The dose was subsequently titrated to a maximum of 5 mg as tolerated. In addition, more than 90 % of patients reported moderate to great improvements at all other hyperhidrosis sites, which is another benefit of oral oxybutynin for patients with

5 Treatment of Primary Craniofacial Hyperhidrosis 365 Table 1 Evidence for medical treatments of focal craniofacial hyperhidrosis: anticholinergics References Study type Level of evidence Total patients Patients with CH Intervention Outcome measure Immediate success rate (%) Main adverse effects Mean follow-up Kim et al. [12] Randomised clinical trial Ib % topical glycopyrrolate Gravimetry, patient QOLQ 96 4 % transient headache Wolosker et al. [13] Prospective, III 30 5 Oral oxybutynin Patient QOLQ % dry mouth 12 weeks Wolosker et al. [14] Prospective, non-randomised, III Oral oxybutynin QOLQ, clinical assessment on follow-up % mild dry mouth 1 week 17 months CH craniofacial hyperhidrosis, QOLQ Quality of Life Questionnaire Table 2 Evidence for medical treatments of focal craniofacial hyperhidrosis: intradermal injection of botulinum toxin A References Study type Level of evidence Total patients Patients with CH Intervention Outcome measure Immediate success rate (%) Main adverse effects Mean followup (months) Trindade de Almeida et al. [15] Double-blind, randomised Kinkelin et al. [16] Prospective, Ib Botulinum toxin A injection III Botulinum toxin A injection Iodine starch photography, patient QOLQ Iodine starch photography, patient QOLQ, gravimetry % frontalis muscle inhibition (transient) % frontalis muscle inhibition (transient) 6 5 CH craniofacial hyperhidrosis, QOLQ Quality of Life Questionnaire

6 366 R. Nicholas et al. Table 3 Evidence for surgical treatments of focal craniofacial hyperhidrosis: endoscopic thoracic sympathectomy and its variations References Study type Level of evidence Total patients Patients with CH Intervention Outcome measure Immediate success rate (%) Main adverse effects Mean follow-up Bell et al. [36] Retrospective, Chen et al. [20] Retrospective, Chou et al. [19] Prospective, Chuang and Liu [37] Retrospective, Doolabh et al. [38] Retrospective, Drott and Claes [17] Retrospective, Kao et al. [39] Prospective, Kim et al. [40] Retrospective, controlled Kwong et al. [41] Retrospective, Leao et al. [42] Retrospective, Lee et al. [22] Retrospective, Licht and Pilegaard [34] Retrospective, Lin and Chou [43] Retrospective, Lin and Fang [44] Prospective, Murphy et al. [21] Retrospective, casecontrolled Neumayer et al. [45] Prospective, casecontrolled III ETS Written then telephone QOLQ % CHH 1 month III ETS Sympathetic skin response, Clinic follow-up, Telephone QOLQ III ESB with clipping Clinic follow-up then telephone QOLQ III Thermoregulation of upper thoracic ganglion % CHH 3 months to 2 years % CHH 17 months Patient QOLQ 100 CH not assessed % Horner s syndrome 39 months III VATS Written plus telephone QOLQ % CHH 17 months III Upper thorascopic sympathectomy Patient QOLD plus visual analogue scale % CHH 31 months III ETS Telephone QOLQ % mild, transient ptosis III VAT ramicotomy vs. VAT T2 clipping III Upper thorascopic sympathectomy 3 months Telephone QOLQ % CHH 15 months Written QOLQ % CHH 6 months III VATS Written plus telephone QOLQ % CHH 3 months to 3 years III Upper thorascopic sympathectomy Written QOLQ % CHH, 8 % Horner s III VATS Written QOLQ % CHH 26 months III ESB with clipping Written QOLQ % CHH 25 months III ETS Written QOLQ % CHH 32 months III ETS Written QOLQ % CHH 25 months III ESB Written QOLQ % CHH 21 months

7 Treatment of Primary Craniofacial Hyperhidrosis 367 Table 3 continued Main adverse effects Mean follow-up Intervention Outcome measure Immediate success rate (%) Patients with CH Total patients References Study type Level of evidence % CHH 5.5 months III ESB Written QOLQ, clinic followup with examination Neumayer et al. [18] Prospective, casecontrolled III ETS Written QOLQ % CHH III ESB with clipping Written QOLQ % CHH 17 months Reisfeld et al. [24] Retrospective, Sciuchetti et al. [46] Prospective, III ETS Written QOLQ % CHH 14.6 years Retrospective, Smidfelt and Drott [33] III ETS with clipping Telephone plus written QOLQ % CHH 10 months III ETS Written QOLQ % postoperative complications, 3.6 % pneumothorax Sugimura et al. [35] Prospective, Sung et al. [23] Retrospective, CH craniofacial hyperhidrosis, CHH compensatory hyperhidrosis, ESB endoscopic sympathetic block, ETS endoscopic thoracic sympathectomy, QOLQ Quality of Life Questionnaire, VATS video-assisted thorascopic sympathectomy multifocal hyperhidrosis and in patients unsuitable for surgical intervention. Topical anticholinergic therapy such as 2 % glycopyrrolate penetrates the skin slowly and subsequently has been associated with fewer adverse effects than oral regimens [12]. A randomised clinical trial (Level Ib evidence) performed by Kim et al. [12] involving 25 patients with focal CH showed a 96 % immediate success rate of treatment evaluated subjectively and objectively using 5-min gravimetric assessment. One patient experienced a mild headache, but no serious complaints such as blurred vision, dry mouth or skin irritation were expressed. Although topical 2 % glycopyrrolate has been demonstrated to be a safe and effective treatment for focal CH, the follow-up was limited to 1 week and a single application reported a beneficial effect for 1 2 days. No clear application regimen was defined and long-term follow-up studies are essential to assess the long-term efficacy of topical glycopyrrolate. Based on the current available data, topical 2 % glycopyrrolate appears to be effective in the treatment of focal CH; however, long-term data are awaited. Oral oxybutynin has an important role in the management of facial hyperhidrosis, especially in patients with multifocal hyperhidrosis Evidence Levels 2 % Topical glycopyrrolate: strength of recommendation B, level of evidence Ib). Oxybutynin 5 mg: Strength of recommendation B, level of evidence III. 4.2 Intradermal Botulinum Toxin A Botulinum toxin A is the most potent neurotoxin of seven serotypes produced by the anaerobic bacterium Clostridium botulinum [25]. Injected intradermally, botulinum toxin inhibits the release of acetylcholine at the neuromuscular junction from cholinergic fibres, reducing sweat production from eccrine glands [26]. Trindade de Almeida et al. [15] conducted a doubleblind, randomised controlled trial involving 20 patients (Level Ib evidence) and showed 100 % efficacy in the treatment of focal CH measured objectively using starch iodine photography and subjectively using patient questionnaires. Kinkelin et al. [16] reported a smaller prospective, non-randomised study (Level III evidence) which recruited ten patients and showed an 100 % immediate success rate in the management of focal CH, measured objectively using gravimetry in addition to starch iodine photography. Subjective measurement using questionnaires was also undertaken.

8 368 R. Nicholas et al. Fig. 2 Suggested treatment algorithm for aiding clinicians in the management of primary focal craniofacial hyperhidrosis in view of the limited published clinical evidence currently available Primary craniofacial hyperhidrosis Oral oxybutynin ± topical 2% glycopyrrolate Intradermal botulinum toxin A No Good response? Yes Continue Good response? Yes Repeat as required No Make adjustments to technique, dose and/or areas covered Good response? Yes Repeat as required No Endoscopic thoracic sympathectomy Contraindication to surgery or unwilling to proceed after fully educated of benefits and risks of the procedure? Oral oxybutynin / other systemic treatment, e.g. propanolol Both studies documented transient frontalis muscle inhibition as their main adverse effect, lasting for up to a maximum of 8 weeks in one patient [16]. Follow-up was between 5 and 6 months in both studies, representing the average time the effects of a single intradermal injection of botulinum toxin A lasts on the forehead. The results of these two studies mirror randomised controlled studies evaluating the efficacy and safety of intradermal botulinum toxin A in the treatment of other forms of focal hyperhidrosis such as axillary [27, 28] and palmar [29, 30] hyperhidrosis. Although only a small number of patients have been studied using intradermal botulinum toxin A for focal CH, current data show that this treatment has an important role in the management of focal CH Evidence Levels Intradermal injection of botulinum toxin A: Strength of recommendation B, Level of evidence Ib. 4.3 Surgical Management The principle behind surgical management for treating focal CH is disruption of nerve impulses from the thoracic sympathetic ganglia (predominantly T2 T3) [31] to the eccrine sweat glands. ETS can achieve this through clamping, transection, ablation and clipping of ganglia [32]. While 22 studies from 1996 to 2014 have evaluated the role of ETS in

9 Treatment of Primary Craniofacial Hyperhidrosis 369 focal hyperhidrosis, only five studies have analysed its role specific to focal CH only. ETS has a high efficacy profile, with the average immediate success rate being reported as 93.3 % (range %), and has been associated with a small risk of pneumothorax, haemothorax, peripheral nerve injury and Horner s syndrome (0 1 %). In all studies, these adverse effects have been cited as transient and self-limiting, with a 0 % documented mortality rate. Recurrence rates have been low (0 8 %) and average follow-up has been 29 months (range 1 month to 14.6 years). Although the studies assessing ETS in the treatment for focal CH have included a large patient database, all of the studies have incorporated prospective or retrospective nonrandomised study designs (Level III evidence) with limited control groups and subjective outcome measurements using patient questionnaires or visual analogue scales. Another limitation of the use of ETS is the high rates of compensatory sweating observed postoperatively (range %, mean 57.8 %). Compensatory sweating refers to increased sweating in non-denervated parts of the body [33]. With T2 sympathectomy, this commonly occurs on the back, trunk and lower limbs but can also manifest on other parts of the body. This can be severely debilitating for some patients, leading them to regret the procedure in severe cases [34]. Reversal of the procedure can be performed in such cases if clipping or clamping sympathectomy techniques have been used [35]. Current data regarding reversal efficacy are limited with respect to focal CH. ETS has a good efficacy profile but requires higher-level evidence in the form of prospective randomised controlled studies to further evaluate its safety and efficacy. It is associated with significant adverse effects and thus its use in the management of focal CH should be reserved for more severe cases refractory to common first-line agents Evidence Levels Endoscopic thoracic sympathectomy and its variations: Strength of recommendation B, Level of evidence III. 4.4 Other Treatments Although other treatments are in clinical use, including topical antiperspirant therapy (e.g. aluminium salts) and other systemic medications such as propranolol, we identified no experimental or observational studies to support their use for the specific treatment of CH. 5 Conclusion Clinical evidence supporting the effective treatment of CH is weak due to a lack of randomised controlled trials. Based on our findings, we recommend topical glycopyrrolate, oral oxybutynin and intradermal botulinum toxin A as first-line therapies due to their high efficacy and favourable safety profiles reported in the available evidence. 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