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Stimulated skin wrinkling as an indicator of limb sympathetic function
Clinical Neurophysiology 126 (2015) 10–16
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Review
Stimulated skin wrinkling as an indicator of limb sympathetic function Einar P.V. Wilder-Smith ⇑ Division of Neurology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Article history: Accepted 24 August 2014 Available online 2 September 2014 Keywords: Water-immersion skin wrinkling Stimulated skin wrinkling Aquagenic wrinkling Vasoconstriction Small nerve fiber test Sympathetic function
h i g h l i g h t s Stimulated skin wrinkling is a measure of limb sympathetic function. The underlying vasoconstriction causing stimulated skin wrinkling has been used to standardize and
improve testing. Studies show evidence of diagnostic usefulness for small fiber neuropathy and cystic fibrosis.
a b s t r a c t Skin wrinkling upon water immersion has been used as an indicator of limb nerve function for more than 80 years. Until recently, routine use of the test has been hampered by a poor understanding of the physiology and lack of standardization. The process underlying stimulated skin wrinkling has been recently identified as dependent on digital vasoconstriction mediated via sympathetic nerve fibers. Vasoconstriction is postulated to drive wrinkling through loss of digit volume, which induces a negative pressure in the digit pulp and exerts a downward pull on the overlying skin and ultimately results in wrinkles. Improved test standardization has been achieved through substituting water with EMLA for inducing skin wrinkling. This has made testing much easier and has helped implement stimulated skin wrinkling as a practical routine clinical bedside test. A literature search identified 10 studies of sufficient quality for evaluating stimulated skin wrinkling as a diagnostic test of sympathetic under or over function. Seven studies provide level 1 or 2 evidence as a diagnostic test of small fiber neuropathy and three provide level 1 or 2 evidence for cystic fibrosis. There is reasonable evidence allowing the test to be employed as a simple and effective marker for small fiber neuropathy and cystic fibrosis. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology of stimulated skin wrinkling. . . . . . . . . . . . . . . . . . . . . . . . . Stimulated skin wrinkling as a test parameter. . . . . . . . . . . . . . . . . . . . Correlation of stimulated skin wrinkling with small fiber neuropathy Correlation of stimulated skin wrinkling with cystic fibrosis . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix Addendum? 1. Stimulated skin wrinkling test procedure . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⇑ Address: Division of Neurology, National University of Singapore, 10E Kent Ridge Road, 119228 Singapore, Singapore. Tel.: +65 67724717; fax: +65 67794112. E-mail address: [email protected] http://dx.doi.org/10.1016/j.clinph.2014.08.007 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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E.P.V. Wilder-Smith / Clinical Neurophysiology 126 (2015) 10–16
1. Introduction Stimulated skin wrinkling is a curious phenomenon of reversible undulations of the skin of the palms and soles that occur 5–30 min after water immersion or exposure to vasoconstrictor substances such as EMLA (Wilder-Smith, 2004). Clinico-pathological correlations over the past 80 years have shown this phenomenon to be a useful bedside test of limb sympathetic nerve function (Lewis, 1936; Buncke, 1972; Braham et al., 1979; Clark et al., 1984; Vasudevan et al., 2000; Wilder-Smith and Chow, 2003a; Teoh et al., 2008). Reduced stimulated skin wrinkling (SSW) has been used as a diagnostic test of limb sympathetic nerve function in leprosy (Sheskin et al., 1983; Mende, 1985), diabetic neuropathy (Clark et al., 1984; Vasudevan et al., 2000; Ping Ng et al., 2013) autonomic dysfunction occurring with head-up tilt table testing (van Barneveld et al., 2010) and idiopathic small fiber neuropathy (Teoh et al., 2008; Wilder-Smith et al., 2009). Exaggerated stimulated skin wrinkling (in this context often referred to as aquagenic wrinkling) has been used as a diagnostic test for cystic fibrosis with test abnormality expressed in terms of time taken till wrinkles are formed (Berk et al., 2009; Gild et al., 2010; Arkin et al., 2012; Gild, 2012; Chinazzo et al., 2014). In the following we will first consider what is known about the physiology of stimulated skin wrinkling and then review the literature on the usefulness as a diagnostic test for limb sympathetic function and cystic fibrosis.
2. Physiology of stimulated skin wrinkling Stimulated skin wrinkling, has been proposed to represent a five step process, driven by digital vasoconstriction (WilderSmith and Chow, 2003b). The restriction of wrinkling to the most permeable sites of skin in the body (Scheuplein and Blank, 1971), the glabrous skin of palms and soles, highlights the first step involved, passive diffusion of stimulant substances to the digital pulp vasculature via the sweat glands. Two stimulant substances are in use: water and EMLA. Water requires 30 min of complete hand immersion; EMLA cream applied to cover the distal fingertip also requires 30 min. In the case of water, steps two and three represent dyselectrolytemia within digit pulp tissues leading to increased firing rates of the dense networks of sympathetic nerve fibers. For EMLA, it is more likely that there is direct stimulation of digital pulp sympathetic nerve fibers (Bjerring et al., 1989). In a fourth step, vasoconstriction of the digital pulp results in loss of pulp volume which, results in the final fifth step of the skin overlying the digital pulp being pulled down by the negative pressure force inside the digit pulp (Wilder-Smith, 2004; Hsieh et al., 2006, 2007). The physiological process of stimulated skin wrinkling is depicted in Fig. 1. The dependency of SSW on limb sympathetic function was first established when patients with either central (Djaldetti et al., 2001) or peripheral lesions of the sympathetic pathways were shown to lose the ability to wrinkle on exposure to water (Braham et al., 1979). Although all individuals with an intact sympathetic nervous system display stimulated skin wrinkling, it is important to realize that several factors affect the degree and latency of wrinkling onset (Wilder-Smith, 2004). Since SSW is driven by vasoconstriction of the vessels within the palms and soles, any process interfering with vasoconstriction and the resultant loss of digital pulp volume will have an effect on SSW. The change in volume is small and we have identified a change in volume of one digit tip accompanying SSW to be about 30 lL (Fig. 2). Increasing age, affects the degree of wrinkling through reduced skin elasticity, extensibility (Batisse et al., 2002) and loss of subcutaneous tissue (Wysong et al., 2013). Since the degree of skin aging is
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known to vary among different ethnic groups, it is important for laboratories to establish their own normal results for SSW (Tsukahara et al., 2004). In our Asian population, the wrinkling response to EMLA and water in healthy subjects (n = 25, mean age 35 years; range 24–52) was consistently normal (grade 3 and 4) (Wilder-Smith and Chow, 2003a) and based on our own laboratory experience, the normal wrinkling response (to grade 3) is maintained up to age 80. Care has to be taken in particular to avoid interference of antihypertensive medication with SSW, since some may interfere with the vasoconstrictive process (Wilder-Smith, 2004). One study has suggested that peripheral vascular disease does not interfere with stimulated wrinkling, indicating that the distal segment where vasoconstriction occurs is not adversely involved in the peripheral artery disease process (Clark et al., 1984). This further supports the proposition that volume changes of the digit pulp and not hemodynamics are the primary prerequisite for wrinkling. Barrier creams reduce or even eliminate the wrinkling response by inhibiting the access of the stimulant to its site of action in the dermis (Pueschel, 1985). Furthermore, since the sympathetic nervous system is the major determinant of hand and foot temperature regulation, it is important that the temperature of the hands are monitored and kept constant. In our laboratory we maintain palm temperature above 32 °C when applying EMLA as a stimulant. Decreased water temperature reduces the speed and degree of wrinkling onset, probably due to diminished water diffusion. If water immersion is used to stimulate, the onset of skin wrinkling is fastest at a water temperature of 40 °C (Cales and Weber, 1997). The tonicity of the water used for immersion has been found to affect the speed of wrinkling onset and its degree necessitating standardization (Tsai and Kirkham, 2005). The phenomena of increased skin wrinkling frequently alluded to as ‘‘aquagenic wrinkling’’ in subjects with cystic fibrosis is best interpreted as exaggerated SSW and is probably a result of the abnormal skin sweat electrolyte constitution resulting in a greater electrolyte change in the tissue surrounding the sweat glands which induces more pronounced and rapid skin sympathetic neuronal activity and thus more wrinkling (Wilder-Smith, 2013).
3. Stimulated skin wrinkling as a test parameter Wrinkling is tested on the hand since foot testing has proven technically difficult in reading wrinkling. Since EMLA application and water immersion show similar wrinkling scores as well as reduction in hand digit blood, we have opted to perform SSW using EMLA for a number of reasons (Wilder-Smith and Chow, 2003a). EMLA induced wrinkling allows for easier visual detection of wrinkling; it gives the patient mobility (there is no need to keep the hand continuously submerged in water for 30 min) and there is no need for cumbersome meddling with water temperature and water immersion electrolyte concentrations. The standardized procedures for performing SSW are given in the Addendum 1. Since environmental stimuli affect sympathetic nerve testing, it is important to maintain a standardized, quiet, temperature controlled environment for testing (Wilder-Smith et al., 2005). Test quantification for reduced wrinkling, which is used for detection of small fiber neuropathy on the basis of reduced limb sympathetic function, consists of visual assessment of the degree of skin wrinkling after 30 min of stimulation. It needs careful training. With training, inter- and intra-observer reliability is good (Wilder-Smith et al., 2009; Datema et al., 2012). The five level grading scale we employ (Teoh et al., 2008), is based on the original Clark scale (Clark et al., 1984). Greatest wrinkling (grade 4) is defined as completely distorting the pulp of the fingertip, grade 3 as 3 or more lines of wrinkling. Abnormal wrinkling is indicated by all grades of wrinkling below 3. Grade 2 wrinkling is 2 or less
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Fig. 1. Physiology of stimulated skin wrinkling. (A) Distal fingertip with magnified sweat glands adjacent to Glomus bodies. (B) Magnified digit skin/pulp. Sweat pores provide access to stimulant substances (water/EMLA) allowing these to reach the dense sympathetic nerve plexus supplying the digit vasculature, in particular the Glomus bodies. (C) Stimulants increase sympathetic nerve firing resulting in vasoconstriction with subsequent shrinking of Glomus bodies. This loss of dermal pulp volume results in skin retraction and manifests as skin wrinkling.
lines of wrinkling on the fingertip, grade 1 as just recognizable wrinkling (fingertip not completely smooth) and grade 0 is scored when wrinkling is completely absent (Fig. 3). In order to negate the effects of natural wrinkling present in fingertips we routinely photograph and examine the digit tips for natural wrinkling before stimulated wrinkling in order to be able to confidently assign the degree of new onset wrinkling.
Test quantification for increased wrinkling, which is used for the detection of cystic fibrosis and is frequently termed ‘‘aquagenic wrinkling’’, is the time taken to onset of wrinkling, occasionally the greater area of skin wrinkling (Wilder-Smith, 2013). This testing has received considerable attention recently due to its sensitivity and specificity for detecting cystic fibrosis (Weibel and Spinas, 2012; Grasemann et al., 2013; Chinazzo et al., 2014).
E.P.V. Wilder-Smith / Clinical Neurophysiology 126 (2015) 10–16
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Fig. 2. Volume changes over the third digit tip after 10 min application of EMLA. At time 0, the third digit is wrinkled and at 1800, wrinkling has disappeared.
Fig. 3. Wrinkling assessment (Ping Ng et al., 2013).
4. Correlation of stimulated skin wrinkling with small fiber neuropathy To assess the use of stimulated skin wrinkling for the detection of small fiber neuropathy a systematic review following PRISMA guidelines was performed (http://www.prisma-statement.org/) and involved searching the MEDLINE database (source PubMed, January 1, 1966 to November 1, 2013) for the search terms: [water immersion skin wrinkling], [stimulated skin wrinkling], [aquagenic skin wrinkling], [EMLA skin wrinkling], [neuropathy]. The automatic search was complemented by a manual check of the reference lists of the papers and relevant review articles identified by
the computerized literature search. We also searched articles published in any language and scrutinized references from these studies to identify other relevant studies. There was no language restriction, although the extracted articles were ultimately all in English. To be included for analysis, the article had to fulfill the following criteria: (1) represent original research on the topic of stimulated skin wrinkling (2) be designed to address the diagnostic use of stimulated skin wrinkling (3) include a gold standard or clearly defined comparator test (4) describe the tests evaluated in enough details as to allow reproduction of testing. Original research articles were then classified according to the five levels of evidence provided by the Oxford Centre for Evidence Based Medicine criteria (http://www.cebm.net/index.aspx?o=1025). With the search strategy, 47 unique publications were initially retrieved. Of these, 20 articles were considered of interest and full text was retrieved for detailed evaluation. 13 of these 20 articles were subsequently excluded as they did not meet the inclusion criteria). Finally, seven studies comprising a total of 503 subjects tested were included. All studies, demographic characteristics of the samples and results are summarized in Table 1. The best evidence for use of SSW as an indicator of sympathetic limb dysfunction is when used in a population of diabetics for the detection of diabetic neuropathy. One large sized (n = 210) level 1b study showed SSW to diagnose diabetic neuropathy, as identified by nerve conduction study, with a sensitivity of 81.3% and specificity of 67.0% (Ping Ng et al., 2013). The strength of the study was its prospective nature, the large sample size and the use of multiple standardized validated comparators of nerve function. These included nerve conduction studies, vibratory perception threshold, Semmes–Weinstein monofilaments and the diabetic neuropathy symptom score. Stimulated skin wrinkling showed good correlation with all tested parameters of diabetic neuropathy. The fact that sympathetic nerve dysfunction is one of the first nerve modalities to be damaged in diabetes, may render SSW especially useful for the detection of diabetic neuropathy (Vink, 2014). Two level 1b studies report good sensitivity and specificity for confirming a clinical diagnosis of idiopathic small nerve fiber disease (Teoh et al., 2008; Datema et al., 2012). The finding of close correlation of SSW to intraepidermal nerve fiber density in one study (Teoh et al., 2008) was confirmed in another level 1b study investigating the use of SSW in sensory neuropathies (WilderSmith et al., 2009). When SSW was compared with Neuropads (a simple sweat test) in picking up small fiber neuropathy, SSW showed better sensitivity but lower specificity (Datema et al., 2012). The authors reported that with both tests abnormal, a diagnosis of SFN was highly likely. Compared with another commonly used indicator of small fiber neuropathy, the sympathetic skin response (SSR), SSW showed far superior results (Teoh et al., 2008).
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Table 1 Studies investigating the use of stimulated wrinkling as a diagnostic test for small fiber neuropathy. Publication
Test purpose
Methodology
Result/conclusion
van Barneveld S, van der Palen J, van Putten MJAM. Clin Auton Res 2010;20:249–53
To predict an abnormal response to tilt table testing through water immersion skin wrinkling
No difference between tilt table and stimulated skin wrinkling. Stimulated wrinkling is able to predict abnormal tilt table test
Datema M, van Dijk G, Hoitsma E. Clin Neurophys 2012;123:2074–79
24 recent complete and 9 partial median/ulnar nerve lesions * Level 2b evidence 21 SFN * Level 1b
All complete median/ulnar nerve lesions had absent wrinkling. Varying responses to partial nerve lesions
Teoh HL, Chow A, Wilder-Smith EP. J Neurol Neurosurg Psychiatry 2008;79:835–7
To investigate the diagnostic yield of two simple tests (Neuropads – simple sweat test – and water immersion skin wrinkling) for SFN Comparison of multiple tests including water immersion skin wrinkling to detect complete and partial median/ ulnar nerve lesions Comparison of stimulated skin wrinkling (water and EMLA), IENFD and SSR in diagnosing SFN
20 healthy subjects, 15 patients referred for tilt table and compared with stimulated skin wrinkling * Level 2b evidence 35 patients with SFN, 61 controls * Level 1b evidence
Ping Ng KW, Ong JJ, Nyein Nyein TD, Liang S, Chan YC, Lee KO, WilderSmith EP. EMLA-Induced Skin Front Neurol. 2013;126:1–7
To detect diabetic neuropathy using stimulated skin wrinkling as compared to nerve conduction and diabetic neuropathy scores
210 diabetics with and without neuropathy * Level 1b evidence
Wilder-Smith EP, Guo Y, Chow A. Clin Neurophys 2009;120:953–8
Correlation of stimulated skin wrinkling (EMLA and water stimulated) with IENFD in sensory neuropathy Feasibility study to test SSW, cold face test and heart rate variability in critically ill patients
56 sensory neuropathy, 40 controls * Level 1b evidence 12 critically ill patients * Level 4 evidence
Phelps PE, Walker E. The Am J Occup Ther 1977;31:565–72
Wieske L, Kiszer ER, Schultz MJ, Verhamme C, van Schaik IN, Horn J. J Neurol. 2013;260:1511–7
Neuropads sensitivity 29%, specificity 93%. WISW sensitivity 66%, specificity 70%. When both tests abnormal, a diagnosis of SFN is highly likely
76% low IENFD, 71% impaired water-induced wrinkling, 67% impaired EMLA-induced wrinkling, 43% abnormal SSR. Stimulated skin wrinkling, shows good agreement with IENFD in diagnosing SFN Stimulated skin wrinkling able to distinguish between normal and abnormal nerve conduction and diabetic neuropathy scores. Sensitivity SSW, for diagnosing diabetic neuropathy 81.3%, specificity 67.0% EMLA wrinkling 81.6% sensitivity, 74.7% specificity; water wrinkling 71.4% sensitivity 73% specificity in detecting abnormal IENFD Cold face test and SSW correlated with each other but not with heart rate variability
SSR, sympathetic skin response; IENFD, intraepidermal nerve fiber density; SSW, stimulated skin wrinkling; EMLA, eutectic mixture of local anesthetic; SFN, small fiber neuropathy. * Levels of evidence according to the Oxford Centre for Evidence Based Medicine (CEBM at http://www.cebm.net/index.aspx?o=1025).
One level 2a study showed that water immersion skin wrinkling was consistently absent with complete median and ulnar nerve lesions but showed inconsistent results in partial lesions (Phelps and Walker, 1977). An interesting approach for the use of SSW was a 2b level study investigating whether SSW can be used to predict an abnormal response to tilt table testing (van Barneveld et al., 2010). The authors found that SSW was equivalent to head-up tilt table testing when applied to subjects being referred for investigation of neural syncope. A recent study addressed the feasibility of performing SSW as compared to the cold face test and heart rate variability in critically ill patients (Wieske et al., 2013). Although the study found SSW to be feasible in the critically ill, further conclusions with regard to correlation of a neuropathic process were not made in a detailed fashion.
5. Correlation of stimulated skin wrinkling with cystic fibrosis To assess the use of stimulated skin wrinkling for the detection of cystic fibrosis, we searched the databases MEDLINE (source PubMed, January 1, 1966 to November 1, 2013) as previously detailed, for the search terms: [water immersion skin wrinkling], [stimulated skin wrinkling], [aquagenic skin wrinkling], [EMLA skin wrinkling], [cystic fibrosis]. We found three studies comprising a total of 148 subjects (of which 78 were patients) tested (Table 2). It is important to emphasize that the end point assessment for diagnosing cystic fibrosis (CF) is different to that used for the assessment of neuropathy. It consists of the time to onset of wrinkling (Elliott, 1974; Gild et al., 2010; Arkin et al., 2012). One group defined test positivity as >30% wrinkling area over the palm with short (5 min) water immersion (Arkin et al., 2012).
Table 2 Studies investigating the use of stimulated wrinkling as a diagnostic test for cystic fibrosis. Publication
Test compared with
Methodology
Result/conclusion
Arkin LM, Flory JH, Shin DB, Gelfand JM, Treat JR, Allen J, Rubenstein RC, Yan AC. Pediatr Dermatol 2012:5;560–6
Genetic, clinical and sweat test
43 of CF subjects (84%) demonstrated aquagenic wrinkling, none (0%) in controls
Gild, Clay CD, Morey S. Brit J Dermatol 2010:163;1082–4
Genetic
51 CF children and 25 control children treated for asthma underwent a 5-min hand immersion in lukewarm water. Test for AWP was positive if subjects demonstrated >30% wrinkling over the palm. * Level 2b evidence 21 CF patients, 13 carriers and 15 controls. Time to wrinkling of <3 min was defined as AWP. * Level 2b evidence
Elliott RB. The Lancet 1974 December 7:1383
Clinical and sweat test
6 CF, 17 other diseases, all children * Level 1b evidence
AWP not seen in controls, occurred in 80% of CF and 25% of carriers Time to wrinkling decreases with decreased CFTR protein function 100% sensitivity and specificity for diagnosing CF using time to onset of wrinkling
CF, cystic fibrosis; AWP, Aquagenic skin wrinkling; CFTR, Cystic fibrosis transmembrane conductance regulator. * Levels of evidence according to the Oxford Centre for Evidence Based Medicine (CEBM at http://www.cebm.net/index.aspx?o=1025).
E.P.V. Wilder-Smith / Clinical Neurophysiology 126 (2015) 10–16
The original publication suggesting that SSW is a good test for CF (level 1b evidence) involved 6 cases with 100% sensitivity and specificity. However, the study provides little detail on how subjects were recruited. Two moderate sized level 2a studies show excellent sensitivity (84 and 80%) and specificity (100 and 100%). Subjects with genetically confirmed CF consistently demonstrated accelerated wrinkling and controls consistently an absence of accelerated wrinkling. When comparing the use of SSW in neuropathies with those for cystic fibrosis, sensitivity and specificity is better for cystic fibrosis. This may in part be due to a positive feature i.e. the appearance of wrinkling being more accurately identifiable as an outcome measure than a negative feature i.e. the disappearance of wrinkling. The effect of a limb sympathetic defect in cystic fibrosis has not been described although one may assume that this would result in amelioration or absence of SSW depending on severity of the sympathetic defect.
6. Conclusion SSW can be used at its two ends of spectrum, and used for the determination of limb sympathetic under-activity and over-activity. From the evidence presented, we can conclude that there is good support for the use of SSW for the detection of small fiber neuropathy as well as for the detection of cystic fibrosis. The main issue of SSW lies with the determination and alteration of an abnormal threshold for skin wrinkling. To improve test usefulness, standardized test conditions (constant temperature, quiet testing conditions, no use of prior skin creams, no intake of caffeine or smoking 2 h prior to testing) must be routinely implemented and similar to other neurophysiological tests, each laboratory should determine own age matched cut-off values for normal and abnormal wrinkling. Methods using photographic methods to improve wrinkling assessment have so far failed (Datema et al., 2012). Since volume changes are the main determinant of SSW, it would appear that sensitive estimation of digit volume changes may represent a future alternative to improve upon visual analysis. Acknowledgements Work presented was in part supported by Singapore NMRC Grant 466/2000 and Grant P00664/143, The Enterprise Challenge, The Prime Minister’s office, Singapore. Conflict of interest: None. Appendix Addendum 1. Stimulated skin wrinkling test procedure (1) Ensure patient has not consumed coffee/tea or products containing caffeine 2 h prior to the test. (2) Take temperature of patient’s hands. Use a thermal warming lamp if hands are <32 °C. (3) Apply approximately 1 g of EMLA creamÒ (lidocaine 2.5% and prilocaine 2.5%, AstraZeneca) evenly onto the distal digit pulp and ensure the digit pulp is completely covered. (4) EMLA is applied to the 2nd, 3rd, 4th and 5th digit pulps. (5) Cover the EMLA cream with a Tegaderm plaster and leave it on for 30 min. (6) Remove Tegaderm plasters after 30 min, clean off the EMLA cream with a tissue and assess grade of wrinkling. Grading of skin wrinkles ranging from 0 to 4: Abnormal grade 0 to 2 Grade 0: No wrinkling seen.
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Grade 1: Skin is no longer smooth. Grade 2: Center of the digit pulp remains wrinkle free with mild wrinkling at the sides. Normal grade 3 to 4 Grade 3: Distinct wrinkling seen in the pulp. Grade 4: Marked wrinkling with distortion of the digit pulp.
References Arkin LM, Flory JH, Shin DB, Gelfand JM, Treat JR, Allen J, et al. High prevalence of aquagenic wrinkling of the palms in patients with cystic fibrosis and association with measurable increases in transepidermal water loss. Pediatr Dermatol 2012;29:560–6. Batisse D, Bazin R, Baldeweck T, Querleux B, Leveque JL. Influence of age on the wrinkling capacities of skin. Skin Res Technol 2002;8:148–54. Berk DR, Ciliberto HM, Sweet SC, Ferkol TW, Bayliss SJ. Aquagenic wrinkling of the palms in cystic fibrosis: comparison with controls and genotype–phenotype correlations. Arch Dermatol 2009;145:1296–9. Bjerring P, Andersen PH, Arendt-Nielsen L. Vascular response of human skin after analgesia with EMLA cream. Br J Anesth 1989;63:655–60. Braham J, Sadeh M, Sarova-Pinhas I. Skin wrinkling on immersion of hands: a test of sympathetic function. Arch Neurol 1979;36:113–4. Buncke Jr HJ. Digital nerve repairs. Surg Clin North Am 1972;52:1267–85. Cales L, Weber RA. Effect of water temperature on skin wrinkling. J Hand Surg Am 1997;22:747–9. Chinazzo C, De Alessandri A, Menoni S, Romanisio G, Rebora A, Rongioletti F. Aquagenic wrinkling of the palms and cystic fibrosis: an Italian study with controls and genotype–phenotype correlations. Dermatology 2014;228:60–5. Clark CV, Pentland B, Ewing DJ, Clarke BF. Decreased skin wrinkling in diabetes mellitus. Diabetes Care 1984;7:224–7. Datema M, Gert van Dijk J, Hoitsma E. The diagnostic value of water immersion skin wrinkling and Neuropads in small fiber neuropathy. Clin Neurophysiol 2012;123:2074–9. Djaldetti R, Melamed E, Gadoth N. Abnormal skin wrinkling in the less affected side in hemiparkinsonism – a possible test for sympathetic dysfunction in Parkinson’s disease. Biomed Pharmacother 2001;55:475–8. Elliott RB. Letter: skin wrinkling in cystic fibrosis. Lancet 1974;2:1383. Gild R. Aquagenic wrinkling of the palms. Skinmed 2012;10:203–4. Gild R, Clay CD, Morey S. Aquagenic wrinkling of the palms in cystic fibrosis and the cystic fibrosis carrier state: a case–control study. Br J Dermatol 2010;163:1082–4. Grasemann H, Ratjen F, Solomon M. Aquagenic wrinkling of the palms in a patient with cystic fibrosis. N Engl J Med 2013;369:2362–3. Hsieh CH, Huang KF, Liliang PC, Huang PC, Shih HM, Rau CS. EMLA and water immersion cause similar vasodilatation in replanted fingers. J Surg Res 2007;143:265–9. Hsieh CH, Huang KF, LiLiang PC, Jeng SF, Tsai HH. Paradoxical response to water immersion in replanted fingers. Clin Auton Res 2006;16:223–7. Lewis TPG. Circulatory changes in fingers in some diseases of nervous system with special reference to digital atrophy of peripheral nerve lesions. Clin Sci 1936;2:149–75. Mende B. Fehlende Faltenbildung der Fingerkuppen im Warmwassertest bei lepromatoeser Nervenschaedigung [Loss of wrinkling of the finger-tips in soaking test with leprosy patients]. Z Hautkr 1985;60:1961–4. Phelps PE, Walker E. Comparison of the finger wrinkling test results to established sensory tests in peripheral nerve injury. Am J Occup Ther 1977;31:565–72. Ping Ng KW, Ong JJ, Nyein Nyein TD, Liang S, Chan YC, Lee KO, et al. EMLA-induced skin wrinkling for the detection of diabetic neuropathy. Front Neurol 2013;4:126. Pueschel KSA. Skin wrinkling in fresh and salt water at various temperatures. Z Rechtsmed 1985;95:1–18. Scheuplein RJ, Blank IH. Permeability of the skin. Physiol Rev 1971;51:702–47. Sheskin J, Sabatto S, Yosipovitz Z, Ilukevich A. Lack of wrinkle formation in the fingertips of patients with Hansen’s disease. Confirmation of previous observations. Hansenol Int 1983;8:54–60. Teoh HL, Chow A, Wilder-Smith EP. Skin wrinkling for diagnosing small fiber neuropathy: comparison with epidermal nerve density and sympathetic skin response. J Neurol Neurosurg Psychiatry 2008;79:835–7. Tsai N, Kirkham S. Fingertip skin wrinkling–the effect of varying tonicity. J Hand Surg Br 2005;30:273–5. Tsukahara K, Fujimura T, Yoshida Y, Kitahara T, Hotta M, Moriwaki S, et al. Comparison of age-related changes in wrinkling and sagging of the skin in Caucasian females and in Japanese females. J Cosmet Sci 2004;55:351–71. van Barneveld S, van der Palen J, van Putten MJ. Evaluation of the finger wrinkling test: a pilot study. Clin Auton Res 2010;20:249–53. Vasudevan TM, van Rij AM, Nukada H, Taylor PK. Skin wrinkling for the assessment of sympathetic function in the limbs. Aust N Z J Surg 2000;70:57–9. Vink AI. Diabetic neuropathy: a small fiber disease. Medscape 2014. www.medscape.org/viewarticle/418568. Weibel L, Spinas R. Images in clinical medicine. Aquagenic wrinkling of palms in cystic fibrosis. N Engl J Med 2012;366:e32.
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Wieske L, Kiszer ER, Schultz MJ, Verhamme C, van Schaik IN, Horn J. Examination of cardiovascular and peripheral autonomic function in the ICU: a pilot study. J Neurol 2013;260:1511–7. Wilder-Smith E, Chow A. Water immersion and EMLA cause similar digit skin wrinkling and vasoconstriction. Microvasc Res 2003a;66:68–72. Wilder-Smith EP. Water immersion wrinkling – physiology and use as an indicator of sympathetic function. Clin Auton Res 2004;14:125–31. Wilder-Smith EP. Aquagenic wrinkling of the palms is due to vasoconstriction of palmar skin vasculature. Med Hypotheses 2013;81:963–5. Wilder-Smith EP, Chow A. Water-immersion wrinkling is due to vasoconstriction. Muscle Nerve 2003b;27:307–11.
Wilder-Smith EP, Fook-Chong S, Liurong L. Reflex vasoconstrictor responses of the healthy human fingertip skin. Normal range, repeatability, and influencing factors. Microvasc Res 2005;69:101–5. Wilder-Smith EP, Guo Y, Chow A. Stimulated skin wrinkling for predicting intraepidermal nerve fiber density. Clin Neurophysiol 2009;120:953–8. Wysong A, Joseph T, Kim D, Tang JY, Gladstone HB. Quantifying soft tissue loss in facial aging: a study in women using magnetic resonance imaging. Dermatol Surg 2013;39:1895–902.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Review
Stimulated skin wrinkling as an indicator of limb sympathetic function Einar P.V. Wilder-Smith ⇑ Division of Neurology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
a r t i c l e
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Article history: Accepted 24 August 2014 Available online 2 September 2014 Keywords: Water-immersion skin wrinkling Stimulated skin wrinkling Aquagenic wrinkling Vasoconstriction Small nerve fiber test Sympathetic function
h i g h l i g h t s Stimulated skin wrinkling is a measure of limb sympathetic function. The underlying vasoconstriction causing stimulated skin wrinkling has been used to standardize and
improve testing. Studies show evidence of diagnostic usefulness for small fiber neuropathy and cystic fibrosis.
a b s t r a c t Skin wrinkling upon water immersion has been used as an indicator of limb nerve function for more than 80 years. Until recently, routine use of the test has been hampered by a poor understanding of the physiology and lack of standardization. The process underlying stimulated skin wrinkling has been recently identified as dependent on digital vasoconstriction mediated via sympathetic nerve fibers. Vasoconstriction is postulated to drive wrinkling through loss of digit volume, which induces a negative pressure in the digit pulp and exerts a downward pull on the overlying skin and ultimately results in wrinkles. Improved test standardization has been achieved through substituting water with EMLA for inducing skin wrinkling. This has made testing much easier and has helped implement stimulated skin wrinkling as a practical routine clinical bedside test. A literature search identified 10 studies of sufficient quality for evaluating stimulated skin wrinkling as a diagnostic test of sympathetic under or over function. Seven studies provide level 1 or 2 evidence as a diagnostic test of small fiber neuropathy and three provide level 1 or 2 evidence for cystic fibrosis. There is reasonable evidence allowing the test to be employed as a simple and effective marker for small fiber neuropathy and cystic fibrosis. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiology of stimulated skin wrinkling. . . . . . . . . . . . . . . . . . . . . . . . . Stimulated skin wrinkling as a test parameter. . . . . . . . . . . . . . . . . . . . Correlation of stimulated skin wrinkling with small fiber neuropathy Correlation of stimulated skin wrinkling with cystic fibrosis . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix Addendum? 1. Stimulated skin wrinkling test procedure . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⇑ Address: Division of Neurology, National University of Singapore, 10E Kent Ridge Road, 119228 Singapore, Singapore. Tel.: +65 67724717; fax: +65 67794112. E-mail address: [email protected] http://dx.doi.org/10.1016/j.clinph.2014.08.007 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
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1. Introduction Stimulated skin wrinkling is a curious phenomenon of reversible undulations of the skin of the palms and soles that occur 5–30 min after water immersion or exposure to vasoconstrictor substances such as EMLA (Wilder-Smith, 2004). Clinico-pathological correlations over the past 80 years have shown this phenomenon to be a useful bedside test of limb sympathetic nerve function (Lewis, 1936; Buncke, 1972; Braham et al., 1979; Clark et al., 1984; Vasudevan et al., 2000; Wilder-Smith and Chow, 2003a; Teoh et al., 2008). Reduced stimulated skin wrinkling (SSW) has been used as a diagnostic test of limb sympathetic nerve function in leprosy (Sheskin et al., 1983; Mende, 1985), diabetic neuropathy (Clark et al., 1984; Vasudevan et al., 2000; Ping Ng et al., 2013) autonomic dysfunction occurring with head-up tilt table testing (van Barneveld et al., 2010) and idiopathic small fiber neuropathy (Teoh et al., 2008; Wilder-Smith et al., 2009). Exaggerated stimulated skin wrinkling (in this context often referred to as aquagenic wrinkling) has been used as a diagnostic test for cystic fibrosis with test abnormality expressed in terms of time taken till wrinkles are formed (Berk et al., 2009; Gild et al., 2010; Arkin et al., 2012; Gild, 2012; Chinazzo et al., 2014). In the following we will first consider what is known about the physiology of stimulated skin wrinkling and then review the literature on the usefulness as a diagnostic test for limb sympathetic function and cystic fibrosis.
2. Physiology of stimulated skin wrinkling Stimulated skin wrinkling, has been proposed to represent a five step process, driven by digital vasoconstriction (WilderSmith and Chow, 2003b). The restriction of wrinkling to the most permeable sites of skin in the body (Scheuplein and Blank, 1971), the glabrous skin of palms and soles, highlights the first step involved, passive diffusion of stimulant substances to the digital pulp vasculature via the sweat glands. Two stimulant substances are in use: water and EMLA. Water requires 30 min of complete hand immersion; EMLA cream applied to cover the distal fingertip also requires 30 min. In the case of water, steps two and three represent dyselectrolytemia within digit pulp tissues leading to increased firing rates of the dense networks of sympathetic nerve fibers. For EMLA, it is more likely that there is direct stimulation of digital pulp sympathetic nerve fibers (Bjerring et al., 1989). In a fourth step, vasoconstriction of the digital pulp results in loss of pulp volume which, results in the final fifth step of the skin overlying the digital pulp being pulled down by the negative pressure force inside the digit pulp (Wilder-Smith, 2004; Hsieh et al., 2006, 2007). The physiological process of stimulated skin wrinkling is depicted in Fig. 1. The dependency of SSW on limb sympathetic function was first established when patients with either central (Djaldetti et al., 2001) or peripheral lesions of the sympathetic pathways were shown to lose the ability to wrinkle on exposure to water (Braham et al., 1979). Although all individuals with an intact sympathetic nervous system display stimulated skin wrinkling, it is important to realize that several factors affect the degree and latency of wrinkling onset (Wilder-Smith, 2004). Since SSW is driven by vasoconstriction of the vessels within the palms and soles, any process interfering with vasoconstriction and the resultant loss of digital pulp volume will have an effect on SSW. The change in volume is small and we have identified a change in volume of one digit tip accompanying SSW to be about 30 lL (Fig. 2). Increasing age, affects the degree of wrinkling through reduced skin elasticity, extensibility (Batisse et al., 2002) and loss of subcutaneous tissue (Wysong et al., 2013). Since the degree of skin aging is
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known to vary among different ethnic groups, it is important for laboratories to establish their own normal results for SSW (Tsukahara et al., 2004). In our Asian population, the wrinkling response to EMLA and water in healthy subjects (n = 25, mean age 35 years; range 24–52) was consistently normal (grade 3 and 4) (Wilder-Smith and Chow, 2003a) and based on our own laboratory experience, the normal wrinkling response (to grade 3) is maintained up to age 80. Care has to be taken in particular to avoid interference of antihypertensive medication with SSW, since some may interfere with the vasoconstrictive process (Wilder-Smith, 2004). One study has suggested that peripheral vascular disease does not interfere with stimulated wrinkling, indicating that the distal segment where vasoconstriction occurs is not adversely involved in the peripheral artery disease process (Clark et al., 1984). This further supports the proposition that volume changes of the digit pulp and not hemodynamics are the primary prerequisite for wrinkling. Barrier creams reduce or even eliminate the wrinkling response by inhibiting the access of the stimulant to its site of action in the dermis (Pueschel, 1985). Furthermore, since the sympathetic nervous system is the major determinant of hand and foot temperature regulation, it is important that the temperature of the hands are monitored and kept constant. In our laboratory we maintain palm temperature above 32 °C when applying EMLA as a stimulant. Decreased water temperature reduces the speed and degree of wrinkling onset, probably due to diminished water diffusion. If water immersion is used to stimulate, the onset of skin wrinkling is fastest at a water temperature of 40 °C (Cales and Weber, 1997). The tonicity of the water used for immersion has been found to affect the speed of wrinkling onset and its degree necessitating standardization (Tsai and Kirkham, 2005). The phenomena of increased skin wrinkling frequently alluded to as ‘‘aquagenic wrinkling’’ in subjects with cystic fibrosis is best interpreted as exaggerated SSW and is probably a result of the abnormal skin sweat electrolyte constitution resulting in a greater electrolyte change in the tissue surrounding the sweat glands which induces more pronounced and rapid skin sympathetic neuronal activity and thus more wrinkling (Wilder-Smith, 2013).
3. Stimulated skin wrinkling as a test parameter Wrinkling is tested on the hand since foot testing has proven technically difficult in reading wrinkling. Since EMLA application and water immersion show similar wrinkling scores as well as reduction in hand digit blood, we have opted to perform SSW using EMLA for a number of reasons (Wilder-Smith and Chow, 2003a). EMLA induced wrinkling allows for easier visual detection of wrinkling; it gives the patient mobility (there is no need to keep the hand continuously submerged in water for 30 min) and there is no need for cumbersome meddling with water temperature and water immersion electrolyte concentrations. The standardized procedures for performing SSW are given in the Addendum 1. Since environmental stimuli affect sympathetic nerve testing, it is important to maintain a standardized, quiet, temperature controlled environment for testing (Wilder-Smith et al., 2005). Test quantification for reduced wrinkling, which is used for detection of small fiber neuropathy on the basis of reduced limb sympathetic function, consists of visual assessment of the degree of skin wrinkling after 30 min of stimulation. It needs careful training. With training, inter- and intra-observer reliability is good (Wilder-Smith et al., 2009; Datema et al., 2012). The five level grading scale we employ (Teoh et al., 2008), is based on the original Clark scale (Clark et al., 1984). Greatest wrinkling (grade 4) is defined as completely distorting the pulp of the fingertip, grade 3 as 3 or more lines of wrinkling. Abnormal wrinkling is indicated by all grades of wrinkling below 3. Grade 2 wrinkling is 2 or less
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Fig. 1. Physiology of stimulated skin wrinkling. (A) Distal fingertip with magnified sweat glands adjacent to Glomus bodies. (B) Magnified digit skin/pulp. Sweat pores provide access to stimulant substances (water/EMLA) allowing these to reach the dense sympathetic nerve plexus supplying the digit vasculature, in particular the Glomus bodies. (C) Stimulants increase sympathetic nerve firing resulting in vasoconstriction with subsequent shrinking of Glomus bodies. This loss of dermal pulp volume results in skin retraction and manifests as skin wrinkling.
lines of wrinkling on the fingertip, grade 1 as just recognizable wrinkling (fingertip not completely smooth) and grade 0 is scored when wrinkling is completely absent (Fig. 3). In order to negate the effects of natural wrinkling present in fingertips we routinely photograph and examine the digit tips for natural wrinkling before stimulated wrinkling in order to be able to confidently assign the degree of new onset wrinkling.
Test quantification for increased wrinkling, which is used for the detection of cystic fibrosis and is frequently termed ‘‘aquagenic wrinkling’’, is the time taken to onset of wrinkling, occasionally the greater area of skin wrinkling (Wilder-Smith, 2013). This testing has received considerable attention recently due to its sensitivity and specificity for detecting cystic fibrosis (Weibel and Spinas, 2012; Grasemann et al., 2013; Chinazzo et al., 2014).
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Fig. 2. Volume changes over the third digit tip after 10 min application of EMLA. At time 0, the third digit is wrinkled and at 1800, wrinkling has disappeared.
Fig. 3. Wrinkling assessment (Ping Ng et al., 2013).
4. Correlation of stimulated skin wrinkling with small fiber neuropathy To assess the use of stimulated skin wrinkling for the detection of small fiber neuropathy a systematic review following PRISMA guidelines was performed (http://www.prisma-statement.org/) and involved searching the MEDLINE database (source PubMed, January 1, 1966 to November 1, 2013) for the search terms: [water immersion skin wrinkling], [stimulated skin wrinkling], [aquagenic skin wrinkling], [EMLA skin wrinkling], [neuropathy]. The automatic search was complemented by a manual check of the reference lists of the papers and relevant review articles identified by
the computerized literature search. We also searched articles published in any language and scrutinized references from these studies to identify other relevant studies. There was no language restriction, although the extracted articles were ultimately all in English. To be included for analysis, the article had to fulfill the following criteria: (1) represent original research on the topic of stimulated skin wrinkling (2) be designed to address the diagnostic use of stimulated skin wrinkling (3) include a gold standard or clearly defined comparator test (4) describe the tests evaluated in enough details as to allow reproduction of testing. Original research articles were then classified according to the five levels of evidence provided by the Oxford Centre for Evidence Based Medicine criteria (http://www.cebm.net/index.aspx?o=1025). With the search strategy, 47 unique publications were initially retrieved. Of these, 20 articles were considered of interest and full text was retrieved for detailed evaluation. 13 of these 20 articles were subsequently excluded as they did not meet the inclusion criteria). Finally, seven studies comprising a total of 503 subjects tested were included. All studies, demographic characteristics of the samples and results are summarized in Table 1. The best evidence for use of SSW as an indicator of sympathetic limb dysfunction is when used in a population of diabetics for the detection of diabetic neuropathy. One large sized (n = 210) level 1b study showed SSW to diagnose diabetic neuropathy, as identified by nerve conduction study, with a sensitivity of 81.3% and specificity of 67.0% (Ping Ng et al., 2013). The strength of the study was its prospective nature, the large sample size and the use of multiple standardized validated comparators of nerve function. These included nerve conduction studies, vibratory perception threshold, Semmes–Weinstein monofilaments and the diabetic neuropathy symptom score. Stimulated skin wrinkling showed good correlation with all tested parameters of diabetic neuropathy. The fact that sympathetic nerve dysfunction is one of the first nerve modalities to be damaged in diabetes, may render SSW especially useful for the detection of diabetic neuropathy (Vink, 2014). Two level 1b studies report good sensitivity and specificity for confirming a clinical diagnosis of idiopathic small nerve fiber disease (Teoh et al., 2008; Datema et al., 2012). The finding of close correlation of SSW to intraepidermal nerve fiber density in one study (Teoh et al., 2008) was confirmed in another level 1b study investigating the use of SSW in sensory neuropathies (WilderSmith et al., 2009). When SSW was compared with Neuropads (a simple sweat test) in picking up small fiber neuropathy, SSW showed better sensitivity but lower specificity (Datema et al., 2012). The authors reported that with both tests abnormal, a diagnosis of SFN was highly likely. Compared with another commonly used indicator of small fiber neuropathy, the sympathetic skin response (SSR), SSW showed far superior results (Teoh et al., 2008).
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Table 1 Studies investigating the use of stimulated wrinkling as a diagnostic test for small fiber neuropathy. Publication
Test purpose
Methodology
Result/conclusion
van Barneveld S, van der Palen J, van Putten MJAM. Clin Auton Res 2010;20:249–53
To predict an abnormal response to tilt table testing through water immersion skin wrinkling
No difference between tilt table and stimulated skin wrinkling. Stimulated wrinkling is able to predict abnormal tilt table test
Datema M, van Dijk G, Hoitsma E. Clin Neurophys 2012;123:2074–79
24 recent complete and 9 partial median/ulnar nerve lesions * Level 2b evidence 21 SFN * Level 1b
All complete median/ulnar nerve lesions had absent wrinkling. Varying responses to partial nerve lesions
Teoh HL, Chow A, Wilder-Smith EP. J Neurol Neurosurg Psychiatry 2008;79:835–7
To investigate the diagnostic yield of two simple tests (Neuropads – simple sweat test – and water immersion skin wrinkling) for SFN Comparison of multiple tests including water immersion skin wrinkling to detect complete and partial median/ ulnar nerve lesions Comparison of stimulated skin wrinkling (water and EMLA), IENFD and SSR in diagnosing SFN
20 healthy subjects, 15 patients referred for tilt table and compared with stimulated skin wrinkling * Level 2b evidence 35 patients with SFN, 61 controls * Level 1b evidence
Ping Ng KW, Ong JJ, Nyein Nyein TD, Liang S, Chan YC, Lee KO, WilderSmith EP. EMLA-Induced Skin Front Neurol. 2013;126:1–7
To detect diabetic neuropathy using stimulated skin wrinkling as compared to nerve conduction and diabetic neuropathy scores
210 diabetics with and without neuropathy * Level 1b evidence
Wilder-Smith EP, Guo Y, Chow A. Clin Neurophys 2009;120:953–8
Correlation of stimulated skin wrinkling (EMLA and water stimulated) with IENFD in sensory neuropathy Feasibility study to test SSW, cold face test and heart rate variability in critically ill patients
56 sensory neuropathy, 40 controls * Level 1b evidence 12 critically ill patients * Level 4 evidence
Phelps PE, Walker E. The Am J Occup Ther 1977;31:565–72
Wieske L, Kiszer ER, Schultz MJ, Verhamme C, van Schaik IN, Horn J. J Neurol. 2013;260:1511–7
Neuropads sensitivity 29%, specificity 93%. WISW sensitivity 66%, specificity 70%. When both tests abnormal, a diagnosis of SFN is highly likely
76% low IENFD, 71% impaired water-induced wrinkling, 67% impaired EMLA-induced wrinkling, 43% abnormal SSR. Stimulated skin wrinkling, shows good agreement with IENFD in diagnosing SFN Stimulated skin wrinkling able to distinguish between normal and abnormal nerve conduction and diabetic neuropathy scores. Sensitivity SSW, for diagnosing diabetic neuropathy 81.3%, specificity 67.0% EMLA wrinkling 81.6% sensitivity, 74.7% specificity; water wrinkling 71.4% sensitivity 73% specificity in detecting abnormal IENFD Cold face test and SSW correlated with each other but not with heart rate variability
SSR, sympathetic skin response; IENFD, intraepidermal nerve fiber density; SSW, stimulated skin wrinkling; EMLA, eutectic mixture of local anesthetic; SFN, small fiber neuropathy. * Levels of evidence according to the Oxford Centre for Evidence Based Medicine (CEBM at http://www.cebm.net/index.aspx?o=1025).
One level 2a study showed that water immersion skin wrinkling was consistently absent with complete median and ulnar nerve lesions but showed inconsistent results in partial lesions (Phelps and Walker, 1977). An interesting approach for the use of SSW was a 2b level study investigating whether SSW can be used to predict an abnormal response to tilt table testing (van Barneveld et al., 2010). The authors found that SSW was equivalent to head-up tilt table testing when applied to subjects being referred for investigation of neural syncope. A recent study addressed the feasibility of performing SSW as compared to the cold face test and heart rate variability in critically ill patients (Wieske et al., 2013). Although the study found SSW to be feasible in the critically ill, further conclusions with regard to correlation of a neuropathic process were not made in a detailed fashion.
5. Correlation of stimulated skin wrinkling with cystic fibrosis To assess the use of stimulated skin wrinkling for the detection of cystic fibrosis, we searched the databases MEDLINE (source PubMed, January 1, 1966 to November 1, 2013) as previously detailed, for the search terms: [water immersion skin wrinkling], [stimulated skin wrinkling], [aquagenic skin wrinkling], [EMLA skin wrinkling], [cystic fibrosis]. We found three studies comprising a total of 148 subjects (of which 78 were patients) tested (Table 2). It is important to emphasize that the end point assessment for diagnosing cystic fibrosis (CF) is different to that used for the assessment of neuropathy. It consists of the time to onset of wrinkling (Elliott, 1974; Gild et al., 2010; Arkin et al., 2012). One group defined test positivity as >30% wrinkling area over the palm with short (5 min) water immersion (Arkin et al., 2012).
Table 2 Studies investigating the use of stimulated wrinkling as a diagnostic test for cystic fibrosis. Publication
Test compared with
Methodology
Result/conclusion
Arkin LM, Flory JH, Shin DB, Gelfand JM, Treat JR, Allen J, Rubenstein RC, Yan AC. Pediatr Dermatol 2012:5;560–6
Genetic, clinical and sweat test
43 of CF subjects (84%) demonstrated aquagenic wrinkling, none (0%) in controls
Gild, Clay CD, Morey S. Brit J Dermatol 2010:163;1082–4
Genetic
51 CF children and 25 control children treated for asthma underwent a 5-min hand immersion in lukewarm water. Test for AWP was positive if subjects demonstrated >30% wrinkling over the palm. * Level 2b evidence 21 CF patients, 13 carriers and 15 controls. Time to wrinkling of <3 min was defined as AWP. * Level 2b evidence
Elliott RB. The Lancet 1974 December 7:1383
Clinical and sweat test
6 CF, 17 other diseases, all children * Level 1b evidence
AWP not seen in controls, occurred in 80% of CF and 25% of carriers Time to wrinkling decreases with decreased CFTR protein function 100% sensitivity and specificity for diagnosing CF using time to onset of wrinkling
CF, cystic fibrosis; AWP, Aquagenic skin wrinkling; CFTR, Cystic fibrosis transmembrane conductance regulator. * Levels of evidence according to the Oxford Centre for Evidence Based Medicine (CEBM at http://www.cebm.net/index.aspx?o=1025).
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The original publication suggesting that SSW is a good test for CF (level 1b evidence) involved 6 cases with 100% sensitivity and specificity. However, the study provides little detail on how subjects were recruited. Two moderate sized level 2a studies show excellent sensitivity (84 and 80%) and specificity (100 and 100%). Subjects with genetically confirmed CF consistently demonstrated accelerated wrinkling and controls consistently an absence of accelerated wrinkling. When comparing the use of SSW in neuropathies with those for cystic fibrosis, sensitivity and specificity is better for cystic fibrosis. This may in part be due to a positive feature i.e. the appearance of wrinkling being more accurately identifiable as an outcome measure than a negative feature i.e. the disappearance of wrinkling. The effect of a limb sympathetic defect in cystic fibrosis has not been described although one may assume that this would result in amelioration or absence of SSW depending on severity of the sympathetic defect.
6. Conclusion SSW can be used at its two ends of spectrum, and used for the determination of limb sympathetic under-activity and over-activity. From the evidence presented, we can conclude that there is good support for the use of SSW for the detection of small fiber neuropathy as well as for the detection of cystic fibrosis. The main issue of SSW lies with the determination and alteration of an abnormal threshold for skin wrinkling. To improve test usefulness, standardized test conditions (constant temperature, quiet testing conditions, no use of prior skin creams, no intake of caffeine or smoking 2 h prior to testing) must be routinely implemented and similar to other neurophysiological tests, each laboratory should determine own age matched cut-off values for normal and abnormal wrinkling. Methods using photographic methods to improve wrinkling assessment have so far failed (Datema et al., 2012). Since volume changes are the main determinant of SSW, it would appear that sensitive estimation of digit volume changes may represent a future alternative to improve upon visual analysis. Acknowledgements Work presented was in part supported by Singapore NMRC Grant 466/2000 and Grant P00664/143, The Enterprise Challenge, The Prime Minister’s office, Singapore. Conflict of interest: None. Appendix Addendum 1. Stimulated skin wrinkling test procedure (1) Ensure patient has not consumed coffee/tea or products containing caffeine 2 h prior to the test. (2) Take temperature of patient’s hands. Use a thermal warming lamp if hands are <32 °C. (3) Apply approximately 1 g of EMLA creamÒ (lidocaine 2.5% and prilocaine 2.5%, AstraZeneca) evenly onto the distal digit pulp and ensure the digit pulp is completely covered. (4) EMLA is applied to the 2nd, 3rd, 4th and 5th digit pulps. (5) Cover the EMLA cream with a Tegaderm plaster and leave it on for 30 min. (6) Remove Tegaderm plasters after 30 min, clean off the EMLA cream with a tissue and assess grade of wrinkling. Grading of skin wrinkles ranging from 0 to 4: Abnormal grade 0 to 2 Grade 0: No wrinkling seen.
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Grade 1: Skin is no longer smooth. Grade 2: Center of the digit pulp remains wrinkle free with mild wrinkling at the sides. Normal grade 3 to 4 Grade 3: Distinct wrinkling seen in the pulp. Grade 4: Marked wrinkling with distortion of the digit pulp.
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