Evidence-based (S3) guidelines for diagnostics and treatment of venous leg ulcers

Journal of the European Academy of Dermatology and VenereologyVolume 30, Issue 11 p. 1843-1875 GuidelinesFree Access Evidence-based (S3) guidelines for diagnostics and treatment of venous leg ulcers First published: 25 August 2016 https://doi.org/10.1111/jdv.13848Citations: 33AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL S3-Guideline on Venous Leg Ulcer Developed by the Guideline Subcommittee ‘Diagnostics and Treatment of Venous Leg Ulcers’ of the European Dermatology Forum Subcommittee Members: Prof. Dr. H.A.M. Neumann, Rotterdam (The Netherlands) Dr. A. Cornu-Thénard, Paris (France) Prof. Dr. M. Jünger, Greifswald (Germany) Dr. G. Mosti, Luca (Italy) Dr. K. Munte, Rotterdam (The Netherlands) Prof. Dr. H. Partsch, Vienna (Austria) Prof. Dr. E. Rabe, Bonn (Germany) Dr. Dr. h.c. A. A. Ramelet, Bern and Lausanne (Switzerland) Dr. M. Streit, Aarau (Switzerland) Members of EDF Guideline Committee: Prof. Dr. Werner Aberer, Graz (Austria) Prof. Dr. Martine Bagot, Créteil (France) Prof. Dr. Lasse Braathen, Bern (Switzerland) Prof. Dr. Sergio Chimenti, Rome (Italy) Prof. Dr. José Luis Diaz-Perez, Bilbao (Spain) Prof. Dr. Vladimir Hegyi, Bratislava (Slovak Republic) Prof. Dr. Lajos Kemény, Szeged (Hungary) Prof. Dr. Hans Christian Korting, Munich (Germany) Prof. Dr. Gillian Murphy, Dublin (Ireland) Prof. Dr. Martino Neumann, Rotterdam (The Netherlands) Prof. Dr. Tony Ormerod, Aberdeen (UK) Prof. Dr. Annamari Ranki, Helsinki (Finland) Prof. Dr. Nikolai Tsankov, Sofia (Bulgaria) Prof. Dr. Fenella Wojnarowska, Oxford (UK) Chairman of EDF Guideline Committee: Dr. A. Nast, Berlin (Germany) Expiry date: 2019 EDF Guidelines Secretariat to Dr. Nast: Bettina Schulze, Klinik für Dermatologie, Venerologie und Allergologie, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Phone: ++49 30 450 518 062, Fax: ++49 30 450 518 911, E-mail: [email protected]é.de List of conflicts of interests: H.A.M. Neumann No conflict of interest M. Jünger No conflict of interest K. Munte No conflict of interest E. Rabe No conflict of interest M. Streit No conflict of interest A. Cornu-Thénard No conflict of interest G. Mosti No conflict of interest H. Partsch No conflict of interest A. A. Ramelet No conflict of interest EDF Guidelines Secretariat to Dr. Nast: Bettina Schulze, Klinik für Dermatologie, Venerologie und Allergologie, Campus Charité Mitte, Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Phone: ++49 30 450 518 062, Fax: ++49 30 450 518 911, E-mail: [email protected]é.de Evidence-based (S3) guidelines for diagnostics and treatment of venous leg ulcers H.A.M. Neumann,1 A. Cornu-Thénard,2 M. Jünger,3 G. Mosti,4 K. Munte,5 H. Partsch,6 E. Rabe,7 A.-A. Ramelet,8 M. Streit9 1Department of Dermatology, Erasmus University Hospital, Rotterdam, The Netherlands 2Department of Vascular Medicine, H^opital Saint-Antoine, Paris, France 3Klinik und Poliklinik für Hautkrankheiten, Universitätsmedizin Greifswald, Greifswald, Germany 4Department of Angiology, Barbantini Clinic, Lucca, Italy 5Department of Dermatology, Maasstad Hospital, Rotterdam, The Netherlands 6Department of Dermatology, University of Vienna, Vienna, Austria 7Department of Dermatology, Universitätsklinikum Bonn, Bonn, Germany 8Department of Dermatology and Angiology, University Hospital Bern, Bern, Switzerland 9Department of Dermatology, Kantonsspital Aarau, Aarau, Switzerland Received: 24 February 2016; Accepted: 17 June 2016 General The need for European guidelines in dermatology is indicated by the ongoing development in European dermatology. The EDF, the EADV and the ESDR headed by the UEMS, also officially approved by the European Community, form the structure of pan European dermatology. The European guidelines differ substantially from individual national guidelines. The main differences are: No restrictions by different national regulations for EDF Guidelines No restrictions imposed by local rules on drug distribution, reimbursement facilities, etc. The diagnosis and the treatment of venous leg ulcers is an important consideration within all European dermatological departments. Although, this is not exclusive for this particular specialism, phlebology, surgeons, physicians interested in vascular medicine and general practitioners also treat patients with venous leg ulcers. Nevertheless in general, the most difficult and complicated cases are treated by dermatologists. Therefore, the European Dermatological Forum has decided to compile a European guideline on this subject. The process was as follows: This EDF guideline replaces the EDF guideline on venous leg ulcers – 2006 Introduction This guideline on the management of venous leg ulcers was prepared by the guidelines committee of the European Dermatological Forum (EDF) and based on the already existing EDF guideline venous leg ulcers (2006). It presents evidence-based approach for treatment, identifying the strength of evidence available at the time of preparation of the guideline, and a brief overview of epidemiological aspects, diagnosis and investigation (level S3). Aim This guideline is a document with recommendations and management instructions supporting the daily practice in which the optimum treatment (particularly healing and prevention of recurrences) of the patient is central. The guideline is based on the results of scientific research and contiguous opinions aimed at explicating good medical practice. The document is intended as a guideline for the everyday diagnostics and treatment of venous leg ulcers by dermatologists or other medical specialists. Problem description and initial questions Questions regarding the diagnostics, the treatment, the follow-up treatment and the organization of care of venous leg ulcers were answered for the purpose of developing the guideline. Working group The Commission on guidelines of the European Dermatological Federation (EDF) inaugurated the Chairman of the working group on wound healing during its annual EDF meeting in January 2004. This guideline is part of the first on wound healing guidelines and covers the subject of venous leg ulcers Scientific basis This guideline is based on the earlier guideline on venous leg ulcer from 2006 and as much as possible on the proof provided in published scientific literature. Relevant publications were searched via systematic search in Medline, Cochrane and CINAHL databases from 1995 to 2012. Previously searched literature was used for the literature prior to 1995. Hereby, it must be remarked that evidence-based medicine started relatively late in Phlebology. This meant that much of the Anglo-Saxon literature was a repeat of the earlier efforts (at international meetings) in French, German, Swiss, Italian or Spanish literature. In addition to the publications found via literature search, articles were also extracted from requested list of references. Publications that remained after the selection by the members of the working group are cited as the basis for the various conclusions. The selected publications were then assessed on the quality of the research and were graded for the strength of proof by the members of the working group. The classification that was used hereby is shown in Table 1. Table 1. Classification of the literature according to the strength of proof For articles concerning: intervention (prevention or therapy) A1. Systematic reviews of at least several studies of A2-level, whereby the results of individual studies are consistent A2. Randomized comparative clinical study of good quality (randomized, double-blind controlled trials) of adequate size and consistency B. Randomized clinical trials of moderate quality or inadequate size or other comparative study (not randomized, comparative cohort study, patient–control study) C. Non-comparative study D. Opinions of experts, e.g. the members of the working group For articles concerning: diagnostics A1. Study into the effects of diagnostics on the clinical outcomes in a prospectively followed well-defined patient group with a previously defined policy on the grounds of the to be investigated test results, or a decision study into the effects of the diagnostics on the clinical outcomes, whereby results of studies of A2-level are used as a basis and adequate consideration has been given to the mutual dependence of the diagnostic tests A2. Study in light of a reference test, whereby criteria have been defined beforehand for the investigation test and for a reference test, with a good description of the test and the studied clinical population; it must concern an adequately large series of consecutive patients and must make use of the pre-defined cut-off values and the results of the test and the ‘golden standard’ must have been assessed independently. In situations in which multiple, diagnostic tests play a role, in principle, a mutual dependence and the analysis should be adjusted to this, e.g. with logical regression B. Comparison with a reference test, description of the investigated test and the population, but excluding the characteristics that are mentioned further in A C. Non-comparative study D. Opinions of the experts, e.g. members of the working group Level of the conclusions 1. One systematic review (A1) of at least two independently conducted studies of levels A1 or A2 2. At least two independently conducted studies of level B 3. One study of level A2 or B or a study of level C 4. Opinions of the experts, e.g. the members of the working group One may consider that European references, especially in German and French are underestimated as compared with those from North America due to the of lack of papers cited in PubMed/M/code in the field of phlebology. The assessment of the various publications may be found in the different texts under the heading ‘scientific basis’. The scientific proof is then briefly summarized in a conclusion. The most important literature including the strength of proof on which this conclusion was based is cited in the conclusion. Since evidence-based medical (EBM) publications are limited in medical journals in a field in which it is hard to recruit enough and comparable patients, no improvement in the treatment of leg ulcers could be achieved, especially with surgical techniques (think of paratibial fasciotomy, etc.). Therefore, the experience of experts is essential and the ‘recommendation’ is a good way to present it (Level D). For a recommendation, besides the scientific proof, often other aspects such as patients’ choices, costs, availability (in various echelons) of organizational aspects are important. These aspects are mentioned under the heading ‘other considerations’. The recommendation is the outcome of the available proof and other considerations. Following this procedure increases the transparency of the guideline. It offers an opportunity for an efficient discussion during the meetings of the working group and also increases the clarity for the user of the guideline. Legal significance of guidelines Guidelines are not legal regulations, but ‘evidence-based’ insights and recommendations, which should be satisfied by the care providers in order to provide good quality care. Considering that these recommendations are mainly based on the ‘average patient’, the care providers may, if required, deviate from the recommendations on the basis of their professional autonomy. Deviation from the guideline is necessary if the situation of the patient requires it. Any deviation from the guideline should be based on arguments and should be accurately documented. Revision The client/responsible authority will determine at the latest in 2019 whether this guideline is still valid. If required, a new working group is inaugurated for the purpose of revising and updating the guideline. The guideline will become redundant if new developments make revisions mandatory. Guideline development standard operating procedure of EDF Step Responsible Task 1 EDF Guidelines Committee (EDF-GC) Decision on topic of specific guideline 2 EDF Guidelines Committee Inauguration of subcommittee for specific guidelines, nomination of EDF members (50%) 3 EDF Guidelines Subcommittee (EDF-GSubC) Identification of all existing guidelines for the specific guideline (active process: literature survey plus contact with Dermatological Societies) 4 EDF Guidelines Subcommittee Selection of the guidelines with highest quality. Criteria for selection:Availability of strength of evidenceAvailability of strength of recommendationEvidence of mechanics of literature review 5 EDF Guidelines Subcommittee Identification/nomination of additional 50% EDF members for the EDF-GsubC from among the authors of the best guidelines 6 EDF Guidelines Subcommittee Nomination of chairperson for EDF-GSubC from the GSubC members 7 Chairperson Consideration of involvement of other disciplines and patients′ organizations 8 EDF Guidelines Subcommittee MeetingTo decide the author of the first draft and to discuss the present guidelines, their strengths and weaknessesSix months later, to discuss the draft (consensus conference) 9 Chairperson Circulation of the guideline draft to National Dermatological Societies for comments 10 Guidelines Subcommittee Circulation of final version for approval among members of the guideline subcommittee 11 Chairperson of Subcommittee Delivery of final version to EDF guideline chairperson 12 EDF Guidelines Committee Review and comment on guideline 13 EDF Guidelines Committee chairperson Sending of guideline for official approval to UEMS (formal approval) 14 EDF secretary Distribution of guideline for advance information to EDF members and National Dermatological Societies 15 EDF PublicationOn EDF homepageIn European Journal of Dermatology, British Journal of Dermatology and Journal of Deutsche Dermatologische Gesellschaft Chapter 1 – Epidemiology, Aetiology and Symptomatology Epidemiology A venous leg ulcer is a defect in pathologically altered tissue on the lower leg on the basis of chronic venous insufficiency (CVI). CVI is a complex disease of symptoms and signs based on an inadequate venous return, which leads to a decompensation of the venous and the microcirculatory function. Chronic venous ulceration is the severest manifestation of this disorder.1 A venous ulcer with no tendency to heal within 6 weeks to 3 months or that has not healed within a year after optimum phlebological therapy is designated as therapy resistant.2 About three-quarters of all leg ulcers are generally considered to be mainly of venous origin.3 Epidemiological data are more difficult to interpret than expected at first sight because of methodological differences. It makes a big difference whether a whole population, a particular group of individuals in a certain region or a patient population is investigated. The manner of registration also influences the outcome. Even filled-out polls, polls filled out by an investigator, special questionnaires on the presence of ulcers and whether or not a physical examination was conducted – all have a considerable influence on the results.4The most recent and convincing data came from the Bonn Vein Study5 and from the group of Fowkes.6 The prevalence of venous ulcers varies between 1.5 and 3% in the population,1 and in 4–5% of individuals older than 80 years.2, 7 This was in keeping with the findings that 1–2% of the adult population either has or had a venous ulcer.5, 8 In the Western countries, a prevalence of active venous ulcers in the general population older than 18 years was reliably estimated to be 0.1–0.3%.9-11 An ulcer is encountered 2–3 times as often in women of all age groups.12, 13 There is a clear increase with age. Chronic ulcers below the age of 60 years are unusual.1 Since venous leg ulcers in young patients are nearly always associated with severe CVI as congenital malformations/absence of the vena cava and/or non-recanalized deep venous thrombosis, they should not be included in clinical therapeutical studies. Leg ulcers in white atrophy in Klinefelter patients also occur due to plasminogen inhibitor 1 deficiency.14 The prevalence among the elderly may be quite high (12.6% of leg ulcers (C5-C6) in a Swedish rural population older than 70 years).15 However, up to 50% of leg ulcers are caused by superficial venous insufficiency.16-18 Early treatment of varicose veins with significant reflux19 may thus prevent 50% of all venous leg ulcers. Co-morbidity plays an important role at least in the developed world and there is a very high correlation between obesity and venous leg ulcers.20, 21 The prevalence of active and healed ulcers together is about 0.6–1%.1, 5, 22 The prognosis is not very good. The incidence of iliocaval venous obstruction is possibly a significant contributor for venous hypertension in advanced disease.23 About 50% of the treated ulcers had healed within 4 months,1 about 20% had still not healed after 2 years and about 8% had not healed after 5 years.1, 2, 10 The annual recurrence was 6–15%.10 The total risk of recurrence was about 3–15%1 and the risk of recurrence within the first year was 30–57%.2 The majority of the ulcers recurred at least once. Carpentier et al. reported no significant difference between the prevalence of varicose veins in different areas in France. No data were available on leg ulcers,24 but a consistent difference between sexes was noted; 50.5% of those affected were women and 30.1% were men. Key data are shown in Table 1. Table 1. Key statistics on venous leg ulcer Prevalence References All ages 1.5–3% 1 >80 years 4–5% 2,7 Active ulcers 1.1–0.3% 9,10,11 Prognosis Healed <9 month 50% 1 <2 years 80% 1,2,10 <5 years 92% 1,2,10 Recurrence <1 year 30–57% 2 Aetiology Venous insufficiency was noted to be the most important cause in a large number of venous ulcers. In addition, arterial insufficiency and arteriolosclerosis, diabetes mellitus, vasculitis, malignancy, infections and other less frequent causes for ulceration may accompany venous disease in up to almost 20% of the cases.25 In a large number of cases, long-term complications of deep venous thrombosis, the so-called post-thrombotic syndrome, may lead to venous ulcers.25 The post-thrombotic syndrome is a special part of CVI in which the underlining aetiological event is a venous thrombosis.26 Estimates vary (as do the used definitions), but on the average, one in three patients who suffers from a deep venous thrombosis develops post-thrombotic complications in the subsequent 5 years. The chance of developing CVI after a thrombotic leg, thus a post-thrombotic syndrome, is about 50% lower when medical elastic compression hosiery (MECH) is worn.27-29 There are different mechanisms for pumping the blood effectively against the pull of gravity. The cooperation between the venous valves and the calf muscle pump is the most important factor.26 The blood is pumped towards the heart while walking when the valves prevent the backflow. As a consequence, the venous pressure drops when the person is walking. A reflux of the blood occurs when this mechanism fails (in upright position) and an increased pressure develops in the veins of the lower legs (increased ambulatory venous pressure or venous hypertension). All the structures of the venous system may play a role in CVI and thus the venous leg ulcer (Fig. 1). Figure 1Open in figure viewerPowerPoint Pathways from vein to ulcer. Varices will develop initially because of the alterations in the vein wall. Incompetence will develop both in the descending and the ascending processes.30 Several of the previously mentioned studies reported that varicose veins were more common in women than in men. This difference may be explained by selection bias, since women consider varicose veins as a cosmetic problem more often than men and consult a physician more often, and therefore are more likely to participate in studies. Most general population studies failed to demonstrate a sex difference. However, more advanced chronic venous disease (CVD) occurs equally in both sexes. It may lead to leg ulceration as the end stage (Fig. 1). Venous leg ulceration has a lifetime prevalence of 1% and a prevalence of active ulceration of 0.3% in the adult Western population. The prevalence of venous leg ulceration increases with age. Chronic ulceration in those younger than 60 years is unusual and often related to severe deep venous insufficiency. The venous pressure will also increase in the venules and in the capillaries upon further decompensation. As a result of this increased intra-capillary pressure, the capillary filtration fraction will increase and oedema will develop because of the leakage of fluid. Besides the leakage of fluid, there is also a leakage of high molecular weight substances such as fibrin. This can be observed as a ‘cuff’ around the capillaries. Initially, it was thought that these fibrin cuffs formed a barrier for the diffusion of oxygen resulting in local anoxia and ulceration.31 However, this thought was discarded by the fact that fibrin cuffs around capillaries were demonstrated in other skin diseases without any disturbance in the transcutaneous oxygen tension.32 The trapping of leucocytes in the capillaries and the release of free radicals were also proposed as a possible explanation.33, 34 Furthermore, the transmission of high venous pressures to the dermal microcirculation results in the stimulation of an inflammatory process in which cytokine and growth factor release leads to leucocyte migration into the interstitium and the triggering of further inflammatory events.34, 35 This process is associated with the intense dermal fibrosis and tissue remodelling seen in CVI.36 Thrombus formation in the capillaries of the skin was not only observed in white atrophy lesions, but also in other cutaneous manifestations of CVI at microscopy. This was also proposed as an explanation for the ulceration. Finally, it was demonstrated that the fibrin cuffs around the venous leg ulcer do not capture oxygen, but probably growth factors do,37 so that these are less active in the wound. All these contributory factors in the development of a venous leg ulcer are combined in the Rotterdam model.19, 26 Some authors speculated that a biofilm may play an important role.38 All the structures of the venous system may contribute in CVI and thus the venous leg ulcer (Fig. 1). Obesity is certainly a risk factor for venous leg ulcers. Obesity may cause venous hypertension and later venous ulcers, even without valve incompetence or permanent obstruction of the venous system.21 Dependency is another negative co-factor. The muscle pumps will not function due to immobility and consequently venous hypertension will occur. In both cases, the venous valves can be patent. This is also one of the important reasons to combine the classical physical examination with the technical investigations, especially duplex ultrasound techniques. The duplex examination is for this reasons best performed by the physician and a technician. Symptomatology The venous leg ulcer arises either ‘spontaneously’ or often after a minor trauma. The complaints of the patient as a result of the ulcer may vary from less pronounced to very pronounced. Although many textbooks mention the opposite, venous leg ulcers can be painful. The complaints of pain are particularly prominent in the ulcerative phase of white atrophy or if accompanied by other factors such as an infection. Clinically, venous leg ulcer is a part of CVI. Patients with CVI develop various skin abnormalities like pigmentation, corona phlebectatica, white atrophy and dermato-et liposclerosis (Fig. 2) over a period of time. The percentage of patients who develop symptoms remains unknown because it has never been properly investigated. Figure 2Open in figure viewerPowerPoint The Rotterdam model explains the pathways from venous hypertension to venous leg ulcer (clinical symptoms are in purple). The venous ulcer is generally located on the medial and less frequently on the lateral side of the ankle. A particular form is the ulceration in acroangiodermatitis2, 39 of the forefoot in patients with a foot pump incompetence. If the ulcer is located on another part of the lower leg, then one must strongly suspect that causes other than venous insufficiency play a role. The clinical characteristics of CVI are generally known. For the sake of completeness, they are mentioned here once again: varicosity, oedema, corona phlebectatica, hyper-pigmentation, dermato- et liposclerosis, white atrophy, secondary lymphedema stasis dermatitis, which can be classified better as eczema cruris due to CVI and the ulcer.40 The changes in the skin in venous insufficiency are a result of changes in the macro- and microcirculation (Fig. 2). It is unclear why an extensive dermato- et liposclerosis is formed in one patient, whereas a white atrophy is prominent in another patient. Local factors possibly play a role in this and should be investigated further. Quality of life Venous ulcers have a substantial impact on patients’ lives and affect most issues of health-related quality of life (HRQOL) such as bodily pain, health transition, mental health, social functioning and vitality.41-43 Treatment and especially healing of venous ulcers results in a significant improvement in these areas. Nonetheless, a few specific HRQOL instruments have been developed. Studies indicated that these instruments were suboptimal and that generic instruments such as the SF-36, SF-12 and EuroQoL-5D were recommended for measuring the impact on patients’ lives, for time being.44, 45 Today, the society requires treatment evaluation, which includes patient-related outcome parameters. References 1 The Venous Forum of the Royal Society of Medicine and Societas Phlebologica Scandinavica. The management of chronic venous disorders of the leg: an evidence based report of an international task force. Phlebology 1999; 14(Suppl 1): 23– 25. 2Korting HC, Callies R, Reusch M, Schlaeger M, Schöpf E, Sterry W. Dermatologische Leitlinienarbeit 2007 in der Perspektive. J Dtsch Dermatol Ges 2007; 5: 1– 3. 3Chaby G, Viseux V, Ramelet AA, Ganry O, Billet A, Lok C. Refractory venous leg ulcers: a study of risk factors. Dermatol Surg 2006; 32: 512– 519. 4Krijnen RMA, de Boer EM, Bruynzeel DP. Epidemiology of venous disorders in the general and occupational populations. Epidemiol Rev 1997; 19(): 309. 5Rabe E, Pannier-Fischer F, Bromen K et al. Bonner Venenstudie der Deutschen Gesellschaft fur Phlebologie. Epidemiologische Untersuchung zur Frage der Haufigkeit und Ausspagung von chronischen Venenkrankheiten in der stadtischen und landlichen Wohnbevolkerung. Phlebologie 2003; 32: 1– 14. 6Robertson L, Lee AJ, Gallagher K et al. Risk factors for chronic ulceration in patients with varicose veins: a case control study. J Vasc Surg 2009; 49: 1490– 1498. 7Graham ID, Harrisson MB, Nelson EA et al. Prevalence of lower-limb ulceration: a systematic review of prevalence studies. Adv Skin Wound Care 2003; 16: 305– 316. 8Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg; extent of the problem and provision of care. Br Med J (Clin Res Ed) 1985; 290: 1855– 1856. 9Agus GB, Allegra C, Arpaia G et al. Guidelines for the diagnosis and therapy for diseases of the veins and lymphatic vessels: evidence-based report by the Italian College of Phlebology. Int Angiol 2001; 20(Suppl 2): 1– 73. 10Nicolaides AN. Investigation of chronic venous insufficiency: a consensus statement. Circulation 2000; 102(): 63. 11Pannier-Fischer F, Rabe E. Epidemiology of chronic venous diseases. Hautarzt 2003; 54: 1037– 1044. 12The Alexander House Group Consensus paper on venous leg ulcers. Phlebology 1992; 7: 48– 58. 13Heit JA, Rooke TW, Silverstein MD et al. Trends in the incidence of venous stasis syndrome and venous ulcer: a 25 year population-based study. J Vasc Surg 2001; 33: 1022– 1027. 14Veraart JC, Hamulyak K, Neumann HA. Leg ulcers and Klinefelter's syndrome. Arch Dermatol 1995; 131: 958– 959. 15Marklund B, Sulau T, Lindholm C. Prevalence of non- healed and healed chronic leg ulcers in an elderly rural population. Scand J Prim Health Care 2000; 18: 58– 60. 16Nelzén O, Bergquist D, Lindhagen A. Leg ulcer etiology: a cross-sectional population study. J Vas Surg 1991; 14: 557– 564. 17Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F; VCP Coordinators. Epidemiology of chronic venous disorders in geographically diverse populations: results from the Vein Consult Program. Int Angiol 2012; 31: 105– 115. 18Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med 2006; 355: 488– 498. 19Neu