Diagnosis and qualitative identification of hyperhidrosis

Introduction

Hyperhidrosis (HH) is a chronic, autonomic disorder involving excessive sweat secretion beyond the physiological need for thermoregulation. HH can be classified as primary, resulting from an unknown cause (idiopathic), or secondary, resulting from an underlying medical condition or medication consumption (1,2), and may further be classified according to its distribution (1,3). Most often, secondary HH manifests as generalized exaggerated sweating, whereas primary focal idiopathic hyperhidrosis (PFHH) typically presents in a focal, bilateral, and symmetric distribution, commonly affecting the axillae (73%), hands (45.9%), feet (41.1%), and craniofacial regions (22.8%) (1,4-11). In the same patient, more than one area may be affected (8,12). PFHH accounts for 93% of all HH cases and can occur in otherwise healthy individuals without other medical problems (1,4,13). It mostly presents in a phasic manner and usually does not occur at night.

“Excessive sweating” is difficult to define. Instead of quantifying sweat secretion, it refers to the amount of perspiration perceived as limiting activities of daily living, causing physical, emotional, and social discomfort, and impacting quality of life (QoL) (14,15). PFHH may be provoked by thermal stimulations, emotional stress, and physical activity, or no stimuli at all (15,16). It is not considered a psychological disorder (1).

The reported prevalence of PFHH varies due to a lack of a precise definition (5). It is reported that at least 4.8% of the US population develops HH (11,17), but this may be an underestimation as HH is likely under-disclosed by patients and under-detected by healthcare professionals (8). It has previously been reported that only 38% of PFHH patients consult a healthcare provider (8), but with increasing awareness of the condition, the percentage of individuals seeking medical treatment has increased to 51% (11).

PFHH can occur at any age, but the usual onset occurs between 14 and 25 years of age, depending on the area affected (18). Palmar or plantar PFHH usually appears at a prepubertal age, whereas axillary disease emerges more commonly during adolescence (6,8,19,20). The incidence of PFHH in individuals aged 18–39 years has been reported as 8.8%, in contrast to 2.1% in adults aged >65 years and children. The uncommon occurrence of the condition in the elderly suggests its spontaneous regression (21). Both sexes are equally affected, with women seeking treatment more frequently than men (8,10,14).

There is likely a genetic factor involved in PFHH, since 30–65% of patients describe a family history (22-25). A definitive family history is more common with an earlier age of onset (<20 years) (6). PFHH may have a variable phenotype, partial penetrance, and an autosomal dominant form of transmission (6,22,24-27). Loci for the condition have been mapped on chromosomes 14q11.2-q13 and 2q31.1 (23,27,28).

Approximately 2–4 million sweat glands are found on the human body in varying gland densities: 700/cm² on the hands, 181/cm² over the forehead, 64/cm² on the back, and various other densities on other body surfaces (29,30). Three different recognizable sweat gland types, eccrine, apocrine, and apocrine glands, have been described in humans (31), with the eccrine gland being the most abundant overall and the most numerous in the hands, feet, and axillae (29). Eccrine glands can generate total sweat per day of up to 10 liters under intense physical activity, stress, or extremely hot temperatures (21,29). These glands are considered accountable for PFHH (29,32). However, there is no increase in number or size, or change in microscopic or macroscopic appearance, of these glands in affected patients (21,30,33). Instead, PFHH results from altered kinetics of sweat secretion, with changes in the control mechanism of sweating resulting in the disproportional sweat overproduction.

The cause of PFHH is unknown. The most reasonable etiology is a hyperexcitability or neurogenic overactivity of the normal eccrine glands’ reflex circuits, which is likely associated with a complex dysfunction of the parasympathetic and sympathetic elements of the autonomic nervous system (13). Additionally, the condition may result from a central control anomaly of emotional sweating, since the hands, feet, and axillae are affected in both PFHH and emotional sweating (34,35).

PFHH may have serious consequences on daily life, including emotional and psychological effects resulting in low self-confidence, diminished self-esteem, unhappiness, depression, and even suicidal ideation (14,35); impaired social and interpersonal relationships leading to social interaction avoidance and leisure activity restrictions; and impaired occupational performance and work productivity (5,35-40). One-third to one-half of PFHH individuals find their sweating to be meddling in their daily lives and hardly tolerable (11), and one-half to three-fourths of patients are emotionally affected by their sweating (24,41). The proportion of patients reporting reduced self-confidence is 69–74%, and 54–63% declare feeling unhappy or depressed (24). Moreover, 37–71% complain of feeling severely restrained in social circumstances, such as while socializing, being in public places, and developing personal relationships (8); 54–63% report spending less time for leisure; 63% are seriously restricted at work; and 22% minimize their working time (24). Coping capabilities for the condition do not appear to improve with time (8). In fact, PFHH patients have lower managing-abilities and more psychologic and emotional difficulties than healthy individuals or other dermatologic patients (38). The decline in QoL for PFHH patients is similar to that of other diseases, such as multiple sclerosis, end-stage renal disease, rheumatoid arthritis, and severe psoriasis (39,42-45); however, it exceeds that observed in patients with vitiligo, acne vulgaris, Hailey-Hailey disease, and Darier’s disease (42,46,47). The harmful effects of PFHH may be intensified by the lack of awareness of PFHH being a treatable medical disease (35).

PFHH diagnosis

Early diagnosis and proper treatment of PFHH are essential for minimizing its emotional, psychosocial, and physical effects (48). Secondary HH must be excluded prior to making a diagnosis of PFHH (1,13,14,20,30) (Table 1). A complete medical history and physical examination should be performed, which frequently presents all information necessary to differentiate secondary HH from PFHH (49). Laboratory tests are unnecessary in classic PFHH, but should be implemented in atypical PFHH and generalized HH cases (5,14).

PFHH has distinguishable characteristics, allowing its diagnosis to be made solely on the medical history and physical examination (1,5). These characteristics include: healthy young patients with a possible family history; focal, symmetric, and bilateral involvement of the hands, feet, and/or axillae; a possible history of aggravating stimuli (emotional, physical, and/or thermal); and cessation during sleep. The Multi-Specialty Working Group on Hyperhidrosis proposed the following diagnostic criteria for PFHH (5,48): at least 6 months of visible, detectable, focal, exaggerated sweating without any apparent explanation, and two or more of the following typical features: frequent occurrence of at least one incident/week; bilateral and somewhat symmetrical distribution; onset before 25 years of age; a positive family history; lack of focal sweating during sleep; and interference in daily activities. Medical history questions should focus on age of disease onset, family history, HH pattern, impact of HH on a patient’s daily life, other associated symptoms, and any medication consumption to exclude secondary causes. Questions assessing further classification of HH are as follows: symptoms, duration, areas affected, symmetry, frequency, amount, distinct triggers, and existence of sweating while asleep. Physical observation should include visible indication of disproportionate sweating in the typical focal areas or signs indicating secondary HH.

After establishing a diagnosis of PFHH, severity is determined (48). Some researchers consider the importance of observing actual perspiration during the physical examination, but since PFHH can be episodic and unpredictable, it may be impossible, and the diagnosis needs to rely on the patient’s own assessment of the impact the symptoms have on his or her life.

When sweating is visible during clinical examination, PFHH severity can be classified based on the extent of sweating. Sweat stains on clothing can be useful for axillary involvement: sweat stain diameter <5 cm is considered to be normal; stain diameter of 5–10 cm is considered mild HH; stain diameter of 10–20 cm is defined as moderate HH; and stain diameter >20 cm and approaching the waistline is considered severe HH (50). Regarding palmar HH, the following classifications have been devised: mild involvement—sweaty hands without visible droplets; moderate involvement—hand perspiration reaches the fingertips; severe involvement—sweat drips off the hand and extends to all fingertips (50).

Various quantitative and qualitative methods are available to establish a diagnosis of HH, its severity, and the effect the condition has on a patient’s QoL (13).

Quantitative sweat-production tests

Quantitative measurements for sweat production are not frequently performed in routine clinical practice but may assist in establishing the diagnosis or guiding therapeutic measures (5,13). Currently, a commonly accepted sweat quantity to define HH does not exist. One study characterized normal sweat quantities to be <1 mL/m²/min (29). A threshold for axillary HH was determined to be >100 mg/5 minutes and >50 mg/5 minutes of sweat per axillae for men and women, respectively, or >50 mg/1 minute in men (29,51,52). Additionally, palmar HH may be diagnosed when sweat production is >30–40 mg/min (13,53).

Various quantitative sweat-production measurement tools are available for clinical purposes, with the gravimetry test and starch-iodine (Minor’s) test being the most commonly used (5).

Gravimetry (gravimetric testing) is an easy to use and fast procedure for assessing the amount of sweat produced in a certain period of time (51,52,54). After the affected area is thoroughly dried, a pre-weighed filter paper is placed on the HH region for a predetermined period of time. The difference in paper weight before and after the test establishes the amount of sweat produced within that time period, expressed in milligrams/minute. The time required for quantitative measurements varies among authors from 1 (51), 5 (52,55), 10 (56), and 15 minutes (57). This technique has debatable reliability with inter- and intra-patient variability (5,42,51,52).

Gravimetry generates an absolute value, as it does not take into consideration the size of the sweat-secreting area. The Hyperhidrosis Area and Severity Index (HASI) aims to consider the amount of sweat produced in a specific time interval, as well as the size of the sweat-secreting area (56). After performing the gravimetric test, the sweat site is stained using the Minor’s starch iodine technique and the area’s size is estimated by ‘point counting’. After defining the sweat area’s size, the amount of sweat secreted can be expressed in mg/cm²/minute (56). HH presumably exists when HASI values are >1 mg/cm²/minute (56).

Another way to standardize gravimetry is to divide the gravimetric test results by the patient’s body area, which is calculated using the individual’s height [body area (m²) = 0.01667 × height (cm)^0.5 × mass (kg)^0.5] (58).

The Minor’s starch-iodine test is a simple and inexpensive method for recognizing the presence of perspiration, identifying the affected surface area, and assessing the severity of sweat-overproduction (1,59,60). The technique is mainly useful in mapping areas of focal perspiration before and after treatments (i.e., botulinum toxin injection or surgery) (48,53,55,61,62). The Minor’s test is not used to quantify HH severity, but it can identify different perspiration intensities.

Before the test, the skin area to be evaluated needs to be thoroughly cleaned and dried. A 1–5% iodine in alcohol solution is applied over the field. The Modified starch-iodine test utilizes BetadineTM solution. After the solution is thoroughly dried, a starch powder (e.g., cooking corn starch) is lightly dusted on the skin area using a cotton ball, brush, sifter, or loose gauze. Paper saturated with starch-iodine placed over the sweat area works similarly. The sweat moisture dissolves the iodine and starch, resulting in a polyiodide chain via a chemical reaction, which turns the light brown iodine color into a dark purple color (61). The purple area marks the sweat gland orifices, which appear as small dots. Alizarin or ponceau red dye and starch, instead of iodine solution, may be used for iodine-sensitive patients and result in the sweat area turning pink (63). False positives, appearing as streaks or smears of dark pigments, occur if the skin has not been thoroughly dried of sweat or if the iodine solution is not thoroughly dried prior to starch application. False negatives may occur if the starch is applied too heavily. Digital photography taken from the hyperhidrotic areas aids in documentation and comparison pre- and post-treatment.

Although the Minor’s test does not determine HH severity (48), it can categorize different perspiration intensities by using the Intensity Visual Scale. Applying a 6-grade visual scale, the final color from the Minor’s test is classified as follows: 0, no sweating; 1, initial; 2, mild; 3, moderate; 4, intense; and 5, excess sweating (64). Regions with great sweating will appear homogenous and highly pigmented (scores 3–5), whereas areas with less sweating will appear heterogeneous and speckled (scores 0–2) (64).

Other less frequently used objective quantitative tests for HH measurements are presented below.

The ninhydrin test is a quantification method that relies on the chemical reaction between ninhydrin and amino acids in the sweat. Ninhydrin is sprayed on a paper, which is placed over the sweat area (65). The image produced on the paper can assess the sweat production via a digital analysis.

Dynamic quantitative sudometry is a technique that quantifies the amount of moisture absorbed into a dried gas flowing through a chamber that is placed over the examined area (66,67).

Evaporimetry is a quantitative test that measures the amount of evaporated sweat produced using a vapor pressure gradient. It represents an indirect transepidermal water loss (TEWL) measurement through the skin (68). Different methods for measuring TEWL include the open-chamber, ventilated-chamber, and unventilated-chamber (closed) methods (69). In closed-chamber devices, TEWL is measured by calculating the evaporation rate (evaporimetry) based on the increased relative humidity in the closed chamber. The resultant calculation is expressed in weighed amount of water (g)/area of evaporation (m²)/time (hours) (70). Various evaporimetry measurement devices have been reported.

Qualitative sweat-production tests

HH is commonly determined in qualitative terms. Any amount that substantially interferes with an individual’s QoL and affects his/her daily life is determined to be abnormal sweating (13). In other words, the individual’s subjective perception of the impact his/her perspiration has on daily activities is the focus in diagnosing PFHH. As a result, it is imperative to qualitatively measure the effects of PFHH on a patient’s QoL, and any resultant daily life impairments (47). These data can be collected through history taking, specifically-designed questionnaires, or self-rated patient evaluations (47).

The scoring systems used in questionnaires are subjective, reflecting a bias in data collection (71). Patients from different cultures may place varying importance on the diverse aspects of impairment included in a questionnaire (71), which can explain the wide variability of PFHH prevalence rates obtained in various countries. Although 4.8% is the most widely cited population prevalence estimation of HH in the United States (11,17,72,73), prevalence rates of 12.3–17% for HH from other countries [12.3% in Vancouver, Canada (74); 12.8% in Japan (75); 14.5% in Shanghai, China (74); 16.3% in Germany (76); and 16.7% in Poland (77)] have also been reported.

Impact on QoL has evolved to be the most valuable and essential evaluation modality for PFHH (35). QoL has different interpretations and traits. It acknowledges various factors, such as medical health, emotional, mental, and physical welfare, cultural background, and education level. QoL involves the individual’s environment, including occupation, family, and friends. Furthermore, QoL must be interpreted in the context of the patient’s social and cultural environment, standards, and values.

Various QoL evaluation questionnaires are available for PFHH patients (35,36). They can be HH disease-specific [such as the Hyperhidrosis Disease Severity Scale (HDSS) or The Hyperhidrosis Impact Questionnaire (HHIQ)], dermatology-related (such as The Dermatology Life Quality Index (DLQI) or Skindex), or general [such as the Short Form questionnaire-36 items (SF-36)] health-related assessments of QoL. HDSS, DLQI, and Hyperhidrosis Quality of Life Questionnaire (HQLQ) are the most commonly used questionnaires in the literature for QoL evaluation in HH patients. It is common to find two or more questionnaires (such as DLQI and HDSS) being used concurrently. These tests have shown substantial QoL decline in various aspects of daily living in PFHH patients (42).

The Hyperhidrosis Disease Severity Scale (HDSS) is disease-specific, simple, and the most commonly used method for measuring QoL in HH patients. It consists of a single-item questionnaire for patients to grade their responses using a four-point scale (48,78). The tolerability and interference that perspiration causes in daily life is graded as follows: tolerable/never interferes =1 (lack of HH); tolerable/sometimes interferes =2 (moderate HH); hardly tolerable/repeatedly interferes =3 (severe HH); and intolerable/constantly interferes =4 (severe HH) (48,79). The greater the score, the more negative impact PFHH has on the patient’s QoL (39,48,80).

The Canadian Hyperhidrosis Advisory Committee used HDSS as an important tool in outlining treatment recommendations based on the severity of PFHH (48). HDSS scores show good correlation with gravimetric results (78). Treatment success is interpreted as HDSS score improvement from 4 or 3 to 2 or 1, or from 2 to 1, reflecting improvement in QoL. Failed therapy is defined as absence of a HDSS score change at 1-month post-treatment, or unbearable treatment (35). Two-point improvement in HDSS score was correlated with 80% decrease in sweat production, whereas one-point improvement was associated with a 50% reduction (13,78,81).

The Dermatology Life Quality Index (DLQI) is a validated, sensitive questionnaire that assesses the effects of chronic dermatologic diseases on QoL (71,82). It consists of ten questions related to activities of daily living, occupation, school, leisure, intimate contacts, disease manifestations, and treatment. Each question has the following four graded-responses: no impact or not relevant = ‘0’; little effect = ‘1’; a lot of influence = ‘2’; and very significant disturbance = ‘3’. All ten scores are added up, resulting in a sum ranging from 0 to 30, with higher scores indicating worse QoL. For PFHH patients, the average combined DLQI result was found to be 9.2, with the highest influence revealed in the daily life category (24). Since DLQI is a dermatology-related questionnaire, it is often considered too general for recognition of hyperhidrosis-specific concerns.

The Hyperhidrosis Quality of Life Questionnaire (HQLQ) is a questionnaire consisting of one comprehensive question regarding the general decline in a patient’s QoL, and 20 additional specific questions concerning the outcomes in four domains: social activities and function; limitations with partners; emotional damage; and restrictions in specific circumstances, such as hot environments, occupational activities or stressful situations (such as speaking in public or in an important meeting, or taking an examination) (36,38). Each question has five graded-responses from 1 (excellent) to 5 (very poor). Adding the scored responses results in a cumulative score between 20 and 100, which corresponds to one of five QoL categories: 20–35, excellent QoL; 36–51, very good; 52–67, good; 68–83, poor; and 84–100, very poor. HQLQ was constructed specifically for QoL evaluation following surgical intervention.

The 36-item Short Form Health Survey (SF-36), along with its alternative, abbreviated variant, the 12-item Short Form Health Survey (SF-12), is a reliable and widely utilized questionnaire designed to assess basic, daily functioning and emotional status, and is not a disease-specific QoL evaluation (83,84). The SF-36 includes questions comprising eight health categories, including energy, pain, sense of overall health, physical and mental well-being, and physical, emotional, and social performance conditions. Answers are expressed in 2 major measurements, namely the Mental Component Summary (MCS) and Physical Component Summary (PCS) scores. Summed scores range from 0 to 100, with higher scores indicating better QoL. The SF-36 questionnaire has revealed that PFHH patients have inferior MCS and PCS scores compared to healthy individuals (85) and improved SF-36 scores after endoscopic thoracic sympathectomy (ETS) (86-89). The SF-12 tool is a shorter version of the SF-36 form, reducing the time needed to complete the questionnaire to approximately two minutes but still preserving the certainty of the SF-36 survey results (90).

The Keller scale includes three blocks with five questions each, concerning social and physical limitations experienced from excessive axillary, palmar, and plantar sweating, respectively (91,92). This questionnaire scales the impact on QoL from mild to severe (0 to 10). This scale has revealed the benefits of ETS in treating palmar and plantar PFHH (93-95).

The Hyperhidrosis Impact Questionnaire (HHIQ) assesses the effect of PFHH on daily activities and monitors treatment response (13). It appraises typical disease features, various daily activities, work productivity, and emotional and psychological health (96). The test combines two related components: 41 questions for measuring the baseline impact of the disease and 10 items for follow-up assessment.

The Skindex test is a questionnaire used to evaluate the impact of a dermatologic disease on a patient’s QoL (97). It includes 61 components, which are divided into 8 domains (physical limitations and discomfort, embarrassment, fear, anger, depression, and cognitive and social effects), within three categories: symptoms, functioning, and emotions. The test utilizes five graded responses never, rarely, sometimes, often, all the time. The summed results are standardized to a scale of 0–100, with 100 indicating the maximum impact on a patient’s QoL. The original 61-item questionnaire has been shortened to sequential versions of 29-item (Skindex-29) (98), 17-item (Skindex-17) (99), and 16-item (Skindex-16) questionnaires to minimize the time required to complete the form (100), while still maintaining comparable tests.

The disease-specific health-related questionnaire for hyperhidrosis by Amir et al. is a 35-item questionnaire with a 7-point scale for each answer, divided into five domains (38). Score levels are as follows: 1–2 (high QoL); 3–5 (medium QoL); and 6–7 (significantly low QoL). The results for PFHH patients have shown that women’s QoL is more affected than men’s, various aspects of QoL are affected, and that lower QoL occurs when the disease begins in childhood (101). This questionnaire has also demonstrated the effectiveness of surgical interventions for PFHH patients (102).

The Hyperhidrosis Quality of Life Index (HidroQoL) is a newly developed disease-specific QoL measurement tool (103). Its final version contains 18 items, categorized into two domains: activities of daily living (6 questions) and psychosocial impact (12 questions). Patient responses are rated in a 6-point scale: not at all = ‘1’; little = ‘2’; somewhat = ‘3’; quite a bit = ‘4’; very much = ‘5’; and not relevant = ‘6’. The results are summed up to either a sub-score (Q1–Q6 activities of daily living score, or Q7–Q18 psychosocial impact score), or overall score.

The Hyperhidrosis Questionnaire is a disease-specific tool that includes 29 questions combining five domains: physical, functional, social, psychological, and affective (104).

The Illness Intrusive Rating Scale (IIRS) is a non-disease-specific questionnaire designed to appraise the intrusion impact of either a disease, its therapy, or both, on a patient’s daily activity (43,105). IIRS utilizes 13 QoL domains, which are scored using seven scaled responses from not very much to very much (1 to 7). The questionnaire may be used as one, 13-item scale, or may be separated into three individual subsets of personal, family or social relationship development; intimacy; and influential (such as work) applications. Even though IIRS is too general for QoL assessment of PFHH patients, patients have shown dramatically improved scores after surgery using this questionnaire (43).

Other less frequently used measurement tools for reviewing QoL of HH patients, which are mostly mentioned in single literature articles, include The Everyday Life Questionnaire (106), Patient Benefit Index (107), Hyperhidrosis Disease Severity Measure-Axillary (108), The State–Trait Anxiety Inventory (109), VQ-Dermato scale: a French-language scoring instrument validated for chronic skin diseases (110,111), Freiburg Life Quality Assessment (112), EuroQol-5 Dimensions (113), The Leibowitz Social Anxiety Scale (114), The University of California, Los Angeles, Loneliness Scale (115), The Nottingham Health Profile (116), and Quality of Life survey adaptation from the Caregiver Questionnaire (117).

Conclusions

HH is a debilitating disease affecting patients in almost every aspect of daily living. Early diagnosis and proper treatment may prevent devastating consequences on QoL. Although the diagnosis of HH is commonly based on subjective testimonies from HH patients, various quantitative and qualitative measurement tools are available to identify the disease, grade its severity, and provide appropriate and prompt treatment.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Federico Raveglia and Marco Scarci) for the series “Hyperhidrosis Management: from Diagnosis to Therapy” published in Shanghai Chest. The article has undergone external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/shc.2019.06.04). The series “Hyperhidrosis Management: from Diagnosis to Therapy” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Walling HW. Clinical differentiation of primary from secondary hyperhidrosis. J Am Acad Dermatol 2011;64:690-5. [Crossref] [PubMed]
2. Goh CL. Aluminum chloride hexahydrate versus palmar hyperhidrosis. Evaporimeter assessment. Int J Dermatol 1990;29:368-70. [Crossref] [PubMed]
3. Wörle B, Rapprich S, Heckmann M. Definition and treatment of primary hyperhidrosis. J Dtsch Dermatol Ges 2007;5:625-8. [Crossref] [PubMed]
4. Eisenach JH, Atkinson JL, Fealey RD. Hyperhidrosis: evolving therapies for a well-established phenomenon. Mayo Clin Proc 2005;80:657-66. [Crossref] [PubMed]
5. Hornberger J, Grimes K, Naumann M, et al. Recognition, diagnosis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol 2004;51:274-86. [Crossref] [PubMed]
6. Lear W, Kessler E, Solish N, et al. An epidemiological study of hyperhidrosis. Dermatol Surg 2007;33:S69-75. [Crossref] [PubMed]
7. Vorkamp T, Foo FJ, Khan S, et al. Hyperhidrosis: evolving concepts and a comprehensive review. Surgeon 2010;8:287-92. [Crossref] [PubMed]
8. Strutton DR, Kowalski JW, Glaser DA, et al. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol 2004;51:241-8. [Crossref] [PubMed]
9. Moran KT, Brady MP. Surgical management of primary hyperhidrosis. Br J Surg 1991;78:279-83. [Crossref] [PubMed]
10. Walling HW. Primary hyperhidrosis increases the risk of cutaneous infection: a case-control study of 387 patients. J Am Acad Dermatol 2009;61:242-6. [Crossref] [PubMed]
11. Doolittle J, Walker P, Mills T, et al. Hyperhidrosis: an update on prevalence and severity in the United States. Arch Dermatol Res 2016;308:743-9. [Crossref] [PubMed]
12. Baumgartner FJ, Bertin S, Konecny J. Superiority of thoracoscopic sympathectomy over medical management for the palmoplantar subset of severe hyperhidrosis. Ann Vasc Surg 2009;23:1-7. [Crossref] [PubMed]
13. Solish N, Wang R, Murray CA. Evaluating the patient presenting with hyperhidrosis. Thorac Surg Clin 2008;18:133-40. [Crossref] [PubMed]
14. Leung AK, Chan PY, Choi MC. Hyperhidrosis. Int J Dermatol 1999;38:561-7. [Crossref] [PubMed]
15. Schick CH. Pathophysiology of Hyperhidrosis. Thorac Surg Clin 2016;26:389-93. [Crossref] [PubMed]
16. 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;140:677-80. [Crossref] [PubMed]
17. Nawrocki S, Cha J. The Etiology, Diagnosis and Management of Hyperhidrosis: A Comprehensive Review. Part I. Etiology and Clinical Work-Up. J Am Acad Dermatol 2019; [Epub ahead of print]. [Crossref]
18. Stolman LP. Hyperhidrosis: medical and surgical treatment. Eplasty 2008;8:e22 [PubMed]
19. Drott C, Gothberg G, Claes G. Endoscopic transthoracic sympathectomy: an efficient and safe method for the treatment of hyperhidrosis. J Am Acad Dermatol 1995;33:78-81. [Crossref] [PubMed]
20. Altman RS, Schwartz RA. Emotionally induced hyperhidrosis. Cutis 2002;69:336-8. [PubMed]
21. Lonsdale-Eccles A, Leonard N, Lawrence C. Axillary hyperhidrosis: eccrine or apocrine? Clin Exp Dermatol 2003;28:2-7. [Crossref] [PubMed]
22. Ro KM, Cantor RM, Lange KL, et al. Palmar hyperhidrosis: Evidence of genetic transmission. J Vasc Surg 2002;35:382-6. [Crossref] [PubMed]
23. Higashimoto I, Yoshiura K, Hirakawa N, et al. Primary palmar hyperhidrosis locus maps to 14q11.2-q13. Am J Med Genet A 2006;140:567-72. [Crossref] [PubMed]
24. Hamm H, Naumann MK, Kowalski JW, et al. Primary focal hyperhidrosis: disease characteristics and functional impairment. Dermatology 2006;212:343-53. [Crossref] [PubMed]
25. Herbst F, Plas EG, Függer R, et al. Endoscopic thoracic sympathectomy for primary hyperhidrosis of the upper limbs. A critical analysis and long-term results of 480 operations. Ann Surg 1994;220:86-90. [Crossref] [PubMed]
26. Kaufmann H, Saadia D, Polin C, et al. Primary hyperhidrosis--evidence for autosomal dominant inheritance. Clin Auton Res 2003;13:96-8. [Crossref] [PubMed]
27. Chen J, Lin M, Chen X, et al. A novel locus for primary focal hyperhidrosis mapped on chromosome 2q31.1. Br J Dermatol 2015;172:1150-3. [Crossref] [PubMed]
28. Del Sorbo F, Brancati F, De Joanna G, et al. Primary focal hyperhidrosis in a new family not linked to known loci. Dermatology 2011;223:335-42. [Crossref] [PubMed]
29. Sato K, Kang WH, Saga K, et al. Biology of sweat glands and their disorders. I. Normal sweat gland function. J Am Acad Dermatol 1989;20:537-63. [Crossref] [PubMed]
30. Sato K, Kang WH, Saga K, et al. Biology of sweat glands and their disorders. II. Disorders of sweat gland function. J Am Acad Dermatol 1989;20:713-26. [Crossref] [PubMed]
31. Scrivener Y, Cribier B. Morphology of sweat glands. Morphologie 2002;86:5-17. [PubMed]
32. Kreyden OP, Scheidegger EP. Anatomy of the sweat glands, pharmacology of botulinum toxin, and distinctive syndromes associated with hyperhidrosis. Clin Dermatol 2004;22:40-4. [Crossref] [PubMed]
33. Bovell DL, Clunes MT, Elder HY, et al. Ultrastructure of the hyperhidrotic eccrine sweat gland. Br J Dermatol 2001;145:298-301. [Crossref] [PubMed]
34. Saadia D, Voustianiouk A, Wang AK, et al. Botulinum toxin type A in primary palmar hyperhidrosis: randomized, single-blind, two-dose study. Neurology 2001;57:2095-99. [Crossref] [PubMed]
35. Hamm H. Impact of hyperhidrosis on quality of life and its assessment. Dermatol Clin 2014;32:467-76. [Crossref] [PubMed]
36. de Campos JR, Kauffman P, Werebe Ede C, et al. Quality of life, before and after thoracic sympathectomy: report on 378 operated patients. Ann Thorac Surg 2003;76:886-91. [Crossref] [PubMed]
37. Atkins JL, Butler PE. Hyperhidrosis: a review of current management. Plast Reconstr Surg 2002;110:222-8. [Crossref] [PubMed]
38. Amir M, Arish A, Weinstein Y, et al. Impairment in quality of life among patients seeking surgery for hyperhidrosis (excessive sweating): preliminary results. Isr J Psychiatry Relat Sci 2000;37:25-31. [PubMed]
39. Solish N, Benohanian A, Kowalski JW. Prospective open-label study of botulinum toxin type A in patients with axillary hyperhidrosis: effects on functional impairment and quality of life. Dermatol Surg 2005;31:405-13. [Crossref] [PubMed]
40. Adar R, Kurchin A, Zweig A, et al. Palmar hyperhidrosis and its surgical treatment: a report of 100 cases. Ann Surg 1977;186:34-41. [Crossref] [PubMed]
41. Naumann MK, Hamm H, Lowe NJ. 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;147:1218-26. [Crossref] [PubMed]
42. Swartling C, Naver H, Lindberg M. Botulinum A toxin improves life quality in severe primary focal hyperhidrosis. Eur J Neurol 2001;8:247-52. [Crossref] [PubMed]
43. Cinà CS, Clase CM. The Illness Intrusiveness Rating Scale: a measure of severity in individuals with hyperhidrosis. Qual Life Res 1999;8:693-8. [Crossref] [PubMed]
44. Ellis CN, Mordin MM, Adler EY. Effects of alefacept on health-related quality of life in patients with psoriasis: results from a randomized, placebo-controlled phase II trial. Am J Clin Dermatol 2003;4:131-9. [Crossref] [PubMed]
45. Finlay AY, Salek MS, Haney J. Intramuscular alefacept improves health-related quality of life in patients with chronic plaque psoriasis. Dermatology 2003;206:307-15. [Crossref] [PubMed]
46. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 1998;134:454-8. [Crossref] [PubMed]
47. Higaki Y, Kawamoto K, Kamo T, et al. The Japanese version of Skindex-16: a brief quality-of-life measure for patients with skin diseases. J Dermatol 2002;29:693-8. [Crossref] [PubMed]
48. Solish N, Bertucci V, Dansereau A, et al. A comprehensive approach to the recognition, diagnosis, and severity-based treatment of focal hyperhidrosis: recommendations of the Canadian Hyperhidrosis Advisory Committee. Dermatol Surg 2007;33:908-23. [PubMed]
49. Vary JC Jr. Selected Disorders of Skin Appendages--Acne, Alopecia, Hyperhidrosis. Med Clin North Am 2015;99:1195-211. [Crossref] [PubMed]
50. Hölzle E. Pathophysiology of sweating. Curr Probl Dermatol 2002;30:10-22. [PubMed]
51. Heckmann M, Ceballos-Baumann AO, Plewig G. Botulinum toxin A for axillary hyperhidrosis (excessive sweating). N Engl J Med 2001;344:488-93. [Crossref] [PubMed]
52. Hund M, Kinkelin I, Naumann M, et al. Definition of axillary hyperhidrosis by gravimetric assessment. Arch Dermatol 2002;138:539-41. [Crossref] [PubMed]
53. Glogau RG. Treatment of palmar hyperhidrosis with botulinum toxin. Semin Cutan Med Surg 2001;20:101-8. [Crossref] [PubMed]
54. Stefaniak TJ, Proczko M. Gravimetry in sweating assessment in primary hyperhidrosis and healthy individuals. Clin Auton Res 2013;23:197-200. [Crossref] [PubMed]
55. Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. BMJ 2001;323:596-9. [Crossref] [PubMed]
56. Bahmer FA, Sachse MM. Hyperhidrosis area and severity index. Dermatol Surg 2008;34:1744-5. [PubMed]
57. Odderson IR. Long-term quantitative benefits of botulinum toxin type A in the treatment of axillary hyperhidrosis. Dermatol Surg 2002;28:480-3. [PubMed]
58. Verbraecken J, Van de Heyning P, De Backer W, et al. Body surface area in normal-weight, overweight, and obese adults. A comparison study. Metab Clin Exp 2006;55:515-24. [Crossref] [PubMed]
59. Cohen JL, Cohen G, Solish N, et al. Diagnosis, impact, and management of focal hyperhidrosis: treatment review including botulinum toxin therapy. Facial Plast Surg Clin North Am 2007;15:17-30. v-vi. [Crossref] [PubMed]
60. Sriraam LM, Sundaram R, Ramalingam R, et al. Minor's Test: Objective Demonstration of Horner's Syndrome. Indian J Otolaryngol Head Neck Surg 2015;67:190-2. [Crossref] [PubMed]
61. Swinehart JM. Treatment of axillary hyperhidrosis: combination of the starch-iodine test with the tumescent liposuction technique. Dermatol Surg 2000;26:392-6. [Crossref] [PubMed]
62. Rompel R, Scholz S. Subcutaneous curettage vs. injection of botulinum toxin A for treatment of axillary hyperhidrosis. J Eur Acad Dermatol Venereol 2001;15:207-11. [Crossref] [PubMed]
63. Bushara KO, Park DM. Botulinum toxin and sweating. J Neurol Neurosurg Psychiatry 1994;57:1437-8. [Crossref] [PubMed]
64. Hexsel D, Rodrigues TC, Soirefmann M, et al. Recommendations for performing and evaluating the results of the minor test according to a sweating intensity visual scale. Dermatol Surg 2010;36:120-2. [Crossref] [PubMed]
65. Friedman M. Applications of the ninhydrin reaction for analysis of amino acids, peptides, and proteins to agricultural and biomedical sciences. J Agric Food Chem 2004;52:385-406. [Crossref] [PubMed]
66. Low PA, Caskey PE, Tuck RR, et al. Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol 1983;14:573-80. [Crossref] [PubMed]
67. Lang E, Foerster A, Pfannmuller D, et al. Quantitative assessment of sudomotor activity by capacitance hygrometry. Clin Auton Res 1993;3:107-15. [Crossref] [PubMed]
68. Akdeniz M, Gabriel S, Lichterfeld-Kottner A, et al. Transepidermal water loss in healthy adults: a systematic review and meta-analysis update. Br J Dermatol 2018;179:1049-55. [Crossref] [PubMed]
69. De Paepe K, Houben E, Adam R, et al. Validation of the VapoMeter, a closed unventilated chamber system to assess transepidermal water loss vs. the open chamber Tewameter. Skin Res Technol 2005;11:61-9. [Crossref] [PubMed]
70. Sakiyama BY, Monteiro TV, Ishy A, et al. Quantitative assessment of the intensity of palmar and plantar sweating in patients with primary palmoplantar hyperhidrosis. J Bras Pneumol 2012;38:573-8. [Crossref] [PubMed]
71. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19:210-6. [Crossref] [PubMed]
72. Glaser DA, Hebert A, Pieretti L, et al. Understanding Patient Experience With Hyperhidrosis: A National Survey of 1,985 Patients. J Drugs Dermatol 2018;17:392-6. [PubMed]
73. Glaser DA, Hebert AA, Nast A, et al. Topical glycopyrronium tosylate for the treatment of primary axillary hyperhidrosis: Results from the ATMOS-1 and ATMOS-2 phase 3 randomized controlled trials. J Am Acad Dermatol 2019;80:128-38.e2. [Crossref] [PubMed]
74. Liu Y, Bahar R, Kalia S, et al. Hyperhidrosis Prevalence and Demographical Characteristics in Dermatology Outpatients in Shanghai and Vancouver. PLoS One 2016;11:e0153719 [Crossref] [PubMed]
75. Fujimoto T, Kawahara K, Yokozeki H. Epidemiological study and considerations of primary focal hyperhidrosis in Japan: from questionnaire analysis. J Dermatol. Nov 2013;40(:886-90.
76. Augustin M, Radtke MA, Herberger K, et al. Prevalence and disease burden of hyperhidrosis in the adult population. Dermatology 2013;227:10-3. [Crossref] [PubMed]
77. Stefaniak T, Tomaszewski KA, Proczko-Markuszewska M, et al. Is subjective hyperhidrosis assessment sufficient enough? Prevalence of hyperhidrosis among young Polish adults. J Dermatol 2013;40:819-23. [PubMed]
78. Kowalski JW, Eadie N, Dagget S, et al. Validity and reliability of the hyperhidrosis disease severity scale (HDSS). J Am Acad Dermatol 2004;50:51. [Crossref]
79. Haider A, Solish N. Focal hyperhidrosis: diagnosis and management. CMAJ 2005;172:69-75. [Crossref] [PubMed]
80. Cetindag IB, Boley TM, Webb KN, et al. Long-term results and quality-of-life measures in the management of hyperhidrosis. Thorac Surg Clin 2008;18:217-22. [Crossref] [PubMed]
81. Lowe NJ, Glaser DA, Eadie N, et al. Botulinum toxin type A in the treatment of primary axillary hyperhidrosis: a 52-week multicenter double-blind, randomized, placebo-controlled study of efficacy and safety. J Am Acad Dermatol 2007;56:604-11. [Crossref] [PubMed]
82. Basra MK, Fenech R, Gatt RM, et al. The Dermatology Life Quality Index 1994-2007: a comprehensive review of validation data and clinical results. Br J Dermatol 2008;159:997-1035. [PubMed]
83. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473-83. [Crossref] [PubMed]
84. Zhang Y, Qu B, Lun SS, et al. The 36-item short form health survey: reliability and validity in Chinese medical students. Int J Med Sci 2012;9:521-6. [Crossref] [PubMed]
85. Sayeed RA, Nyamekye I, Ghauri AS, et al. Quality of life after transthoracic endoscopic sympathectomy for upper limb hyperhidrosis. Eur J Surg Suppl 1998;39-42. [PubMed]
86. Young O, Neary P, Keaveny TV, et al. Evaluation of the Impact of Transthoracic Endoscopic Sympathectomy on Patients with Palmar Hyperhydrosis. Eur J Vasc Endovasc Surg 2003;26:673-6. [Crossref] [PubMed]
87. Kumagai K, Kawase H, Kawanishi M. Health-related quality of life after thoracoscopic sympathectomy for palmar hyperhidrosis. Ann Thorac Surg 2005;80:461-6. [Crossref] [PubMed]
88. Rodríguez PM, Freixinet JL, Hussein M, et al. Side effects, complications and outcome of thoracoscopic sympathectomy for palmar and axillary hyperhidrosis in 406 patients. Eur J Cardiothorac Surg 2008;34:514-9. [Crossref] [PubMed]
89. Ambrogi V, Campione E, Mineo D, et al. Bilateral Thoracoscopic T2 to T3 Sympathectomy Versus Botulinum Injection in Palmar Hyperhidrosis. Ann Thorac Surg 2009;88:238-45. [Crossref] [PubMed]
90. Ware J Jr, Kosinski M, Keller SD A. 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34:220-33. [Crossref] [PubMed]
91. Lee HH, Kim DW, Kim DW, et al. Efficacy of glycopyrrolate in primary hyperhidrosis patients. Korean J Pain 2012;25:28-32. [Crossref] [PubMed]
92. Neumayer C, Panhofer P, Zacherl J, et al. Effect of endoscopic thoracic sympathetic block on plantar hyperhidrosis. Arch Surg 2005;140:676-80; discussion 680. [Crossref] [PubMed]
93. Panhofer P, Ringhofer C, Gleiss A, et al. Quality of life after sympathetic surgery at the T4 ganglion for primary hyperhidrosis: clip application versus diathermic cut. Int J Surg 2014;12:1478-83. [Crossref] [PubMed]
94. Rieger R, Pedevilla S, Lausecker J. Quality of life after endoscopic lumbar sympathectomy for primary plantar hyperhidrosis. World J Surg 2015;39:905-11. [Crossref] [PubMed]
95. Panhofer P, Gleiss A, Eilenberg WH, et al. Long-term outcomes after endothoracic sympathetic block at the T4 ganglion for upper limb hyperhidrosis. Br J Surg 2013;100:1471-7. [Crossref] [PubMed]
96. Naumann M, Lowe NJ, Kumar CR, et al. Botulinum toxin type a is a safe and effective treatment for axillary hyperhidrosis over 16 months: a prospective study. Arch Dermatol 2003;139:731-6. [Crossref] [PubMed]
97. Chren MM, Lasek RJ, Quinn LM, et al. Skindex, a quality-of-life measure for patients with skin disease: reliability, validity, and responsiveness. J Invest Dermatol 1996;107:707-13. [Crossref] [PubMed]
98. Chren MM, Lasek RJ, Flocke SA, et al. Improved discriminative and evaluative capability of a refined version of Skindex, a quality-of-life instrument for patients with skin diseases. Arch Dermatol 1997;133:1433-40. [Crossref] [PubMed]
99. Nijsten TE, Sampogna F, Chren MM, et al. Testing and reducing skindex-29 using Rasch analysis: Skindex-17. J Invest Dermatol 2006;126:1244-50. [Crossref] [PubMed]
100. Chren MM, Lasek RJ, Sahay AP, et al. Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin diseases. J Cutan Med Surg 2001;5:105-10. [Crossref] [PubMed]
101. Wolosker N, Schvartsman C, Krutman M, et al. Efficacy and quality of life outcomes of oxybutynin for treating palmar hyperhidrosis in children younger than 14 years old. Pediatr Dermatol 2014;31:48-53. [Crossref] [PubMed]
102. Wolosker N, Yazbek G, de Campos JR, et al. Quality of life before surgery is a predictive factor for satisfaction among patients undergoing sympathectomy to treat hyperhidrosis. J Vasc Surg 2010;51:1190-4. [Crossref] [PubMed]
103. Kamudoni P, Mueller B, Salek MS. The development and validation of a disease-specific quality of life measure in hyperhidrosis: the Hyperhidrosis Quality of Life Index (HidroQOL(c)). Qual Life Res 2015;24:1017-27. [Crossref] [PubMed]
104. Kuo CH, Yen M, Lin PC. Developing an instrument to measure quality of life of patients with hyperhidrosis. J Nurs Res 2004;12:21-30. [Crossref] [PubMed]
105. Devins GM. Illness intrusiveness and the psychosocial impact of lifestyle disruptions in chronic life-threatening disease. Adv Ren Replace Ther 1994;1:251-63. [Crossref] [PubMed]
106. Koskinen LO, Blomstedt P, Sjoberg RL. Predicting improvement after surgery for palmar hyperhidrosis. Acta Neurol Scand 2012;126:324-8. [Crossref] [PubMed]
107. Augustin M, Radtke MA, Zschocke I, et al. The patient benefit index: a novel approach in patient-defined outcomes measurement for skin diseases. Arch Dermatol Res 2009;301:561-71. [Crossref] [PubMed]
108. Kirsch BM, Burke L, Hobart J, et al. The Hyperhidrosis Disease Severity Measure-Axillary: Conceptualization and Development of Item Content. J Drugs Dermatol 2018;17:707-14. [PubMed]
109. Vazquez LD, Staples NL, Sears SF, et al. Psychosocial functioning of patients after endoscopic thoracic sympathectomy. Eur J Cardiothorac Surg 2011;39:1018-21. [Crossref] [PubMed]
110. Delaplace M, Dumont P, Lorette G, et al. Factors associated with long-term outcome of endoscopic thoracic sympathectomy for palmar hyperhidrosis: a questionnaire survey in a cohort of French patients. Br J Dermatol 2015;172:805-7. [Crossref] [PubMed]
111. Grob JJ, Auquier P, Martin S, et al. Development and validation of a quality of life measurement for chronic skin disorders in french: VQ-Dermato. The ReseaudEpidemiolo gie en Dermatologie. Dermatology 1999;199:213-22. [Crossref] [PubMed]
112. Augustin M, Lange S, Wenninger K, et al. Validation of a comprehensive Freiburg Life Quality Assessment (FLQA) core questionnaire and development of a threshold system. Eur J Dermatol 2004;14:107-13. [PubMed]
113. Kamudoni P, Salek MS, Mueller B. The Burden of Primary Hyperhidrosis On The Patient: Eq-5d-5l Utilities, Willingness To Pay And Daily Time Spent In Managing The Condition. Value Health 2014;17:A611. [Crossref] [PubMed]
114. Rytwinski NK, Fresco DM, Heimberg RG, et al. Screening for social anxiety disorder with the self-report version of the Liebowitz Social Anxiety Scale. Depress Anxiety 2009;26:34-8. [Crossref] [PubMed]
115. Kouris A, Armyra K, Stefanaki C, et al. Quality of life and social isolation in Greek adolescents with primary focal hyperhidrosis treated with botulinum toxin type A: a case series. Pediatr Dermatol 2015;32:226-30. [Crossref] [PubMed]
116. Rzany B, Muller C, Hund M. Focal hyperhidrosis. Quality of life, socioeconomic importance and use of internal medicinal therapy. Hautarzt 2012;63:456-61. [Crossref] [PubMed]
117. Coutinho dos Santos LH, Gomes AM, Giraldi S, et al. Palmar hyperhidrosis: long-term follow-up of nine children and adolescents treated with botulinum toxin type A. Pediatr Dermatol 2009;26:439-44. [Crossref] [PubMed]