Skin, Veins and Legs* H.A.M. Neumann Department of Dermatology, Erasmus MC, Rotterdam, the Netherlands

344 © Schattauer 2011 Review Skin, Veins and Legs* H.A.M. Neumann Department of Dermatology, Erasmus MC, Rotterdam, the Netherlands Keywords Schl...
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Review

Skin, Veins and Legs* H.A.M. Neumann Department of Dermatology, Erasmus MC, Rotterdam, the Netherlands

Keywords

Schlüsselwörter

Chronic venous insufficiency, Microcirculation, Skin alterations

Chronisch-venöse Insuffizienz, Mikrozirkulation, Hautveränderungen

Summary

Zusammenfassung

Skin, veins and legs are the three ingredients which compose together the symptom complex know as chronic venous insufficiency (CVI). High ambulatory venous pressure is transferred by simple physical laws to the skin microcirculation. The capillaries are not resistant to this high pressure and will leak water, erythrocytes and plasma proteins into the interstitium. The result is oedema, pigmentation, sclerosis, inflammation and ulceration. Although many forms of intervention for incompetent veins are available, compression therapy is still the cornerstone in the treatment of CVI. Beside the interface pressure, the stiffness of the compression material is essential. By increasing the stiffness the difference in pressure during walking increases and with this the massage effect of the therapy. Thermo-ablation is the treatment for varicose veins today. Knowledge about the development and transfer of the intravascular heat is essential to understand this treatment. New experiments, specially about steam development from the heat source in the blood are of great importance for the success rate. Fine tuning in those physical parameters is needed to optimally this treatment.

Haut, Venen und Beine sind die drei unterschiedlichen Faktoren, welche zusammen den Symptomenkomplex der chronisch-venösen Insuffizienz (CVI) formen. Hoher Venendruck überträgt sich beim Gehen durch einfache physikalische Gesetze auf die Mikrozirkulation der Haut. Die Kapillaren sind diesem hohen Druck nicht gewachsen, wodurch es zu einem Austritt von Wasser, Erythrozyten und PlasmaProteinen in das Interstitium kommt. Dies resultiert in Ödemen, Pigmentierung, Entzündungen und Sklerose und letztendlich in Geschwüren. Obwohl es verschiedene Behandlungmöglichkeiten inkompetenter Venen gibt, bleibt die Kompressionstherapie nach wie vor der Grundstein in der Behandlung der CVI. Neben dem Druck der Berührungsfläche ist die Steifigkeit des elastischen Materials entscheidend. Bei einer Erhöhung der Steifigkeit wird der Druckunterschied beim Gehen gesteigert und erhöht den Massage-Effekt der Therapie. Die endoluminale thermische Ablation der varikösen Gefäße ist heutzutage die Therapie der Wahl. Die Kenntnis über das Entstehen und die Weiterleitung der intravaskulären Wärme ist wichtig, um diese Behandlung besser zu verstehen. Neueren Untersuchungen, speziell über die Dampfentwicklung von Wärmequellen im Blut wird große Bedeutung beigemessen. Eine Feinabstimmung dieser physikalischen Parameter ist zur Verbesserung der Behandlungsresultate notwendig.

Korrespondenzadresse Prof. Dr. H.A. Martino Neumann, M.D., PhD Erasmus MC, Department of Dermatology Burg. s’ Jacobsplein 51, NL-3015 CA Rotterdam The Netherlands Phone +31 (0)10/703–4580, Fax –3822 E-Mail: [email protected]

Haut, Venen und Beine Phlebologie 2011; 40: 344–355 received and accepted: September 14, 2011

* Vortrag anlässlich der Verleihung der Max-Ratschow-Medaille 2011 in Berlin

For many years phlebology was based more on experience than on evidence. At the same time, this unacknowledged medical specialty was mainly practiced outside the university clinics, often in private practice. Phlebology is still not a UEMS-recognized medical specialty during the last three decades, even though evidence-based research is pursued at present by many researchers within a university clinic. Nevertheless, the total number of academic phlebological centers is low, especially considering the scale of the problem. Since varicose veins are one of the most numerous of all diseases in the western world, many phlebologists will still continue to work in private practice. Venous diseases are a true medical, social and financial burden. For example, 1–2 % of the inhabitants will develop a leg ulcer during their life in the Netherlands. Roughly half of such ulcers are based on deep and the other half on superficial venous incompetence. The costs are also 1–2 % of the total health care budget. We have to remember, that nearly all ulcers based on superficial and many after a deep venous thrombosis can be avoided by simple treatment of the varicose veins and/or adequate compression therapy. The fact that even today not all serious superficial incompetencies are treated, reflects that preventive medicine is not popular in health care decision makers. Lower-extremity venous insufficiency is a common medical condition and occurs in about 15 % of men and 35 % of women (1–3). The effect of venous insufficiency on patient’s health-related quality of life is substantial and comparable with other common chronic diseases such as arthritis, diabetes, and cardiovascular disease (4). In 1995 the overall cost associated with deep or superficial venous insufficiency, or both, was about 2.5 % of the total health care budget in France and Belgium (5). These data underline the need for good evidence based guidelines indicating how physicians should deal with early signs of venous insufficiency.

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H.A.M. Neumann: Skin, Veins and Legs

Although epidemiological studies have proven the progression from small varicous veins to the full blown venous decompensation, including the feared venous leg ulcer, up to now there are no predictive values which would indicate the severity of the progression in an individual. More research into this field is necessary. In the absence of evidence, we use the routine phlebological care criteria for establishing the required treatment described in 씰Tab. 1. In order to understand the etiology and the mechanisms of therapy of venous diseases, one has to be familiar with the human circulatory system, the role of gravitation, the walking mechanisms of the human leg and especially the function of the gaiter area (6). It is the complex interaction of all these systems combined with a lot of physics, which leads to our understanding of this common, but complicated disease. Very often phlebology is reduced to simple problems limited to varicose veins. However, phlebology is much broader than the simple problem of varicosity. A broad and thorough knowledge of the anatomy, the physiology and the pathology of the lower leg, the circulatory system, the dermatology, the clotting system and the wound healing is mandatory for every phlebologist. In this article I will unravel all these interactions based on the developments in the last three decades of our research with the aim, to provide an in-depth phlebological relationships between the skin, the veins and the legs.

The Skin Aulus Cornelius Celsus (±25BC–50 AD) already wrote in his „De Medicina“ on the relationship between varicose veins and leg ulcers. In other words, on the relationship between the appearance of skin changes and the preexisting venous incompetence. Classical signs of chronic venous insufficiency (CVI) are pigmentations, corona phlebectastica (ankle flare), eczema, atrophie blanche and dermato- et liposclerosis. With the introduction of the CEAP-classification, published in 1994 and revised in 2004 (7), clinicians and researchers can classify their patients in such a manner that one

Tab. 1 Practical criteria for medical treatment of varicosity. Complaints

Yes/No

1/0 point

Greater saphenous vein diameter

3–5/>5 mm

1/2 points

Edema

Yes/No

1/0 point

Minor skin changes matching with CVI

Yes/No

1/0 point

Major skin changes

Yes/No

(Atophie blanche and / dermatoet liposclerosis)

Yes/No

2/0 points

Treatment is advised in case of 2 points or more.

Tab. 2

The “C” of the CEAP Classification (7,

8).

Classifi- Symptom cation Co

No visible varicose veins

C1

Spider or reticular veins

C2

Varicose veins

C3

Edema

C4a

Pigmentation or eczema

C4b

Lipodermatoclerosis or Atrophie blanche

C5

Skin changes with healed ulceration

C6

Skin changes with active ulceration

S

Symptomatic, including aches, pain, tightness, skin irritation, heaviness, muscle cramps and other complaints attributable to venous disfunction

A

Asymptomatic

can compare one group with another. This is not only used as clinical but also as etiological, anatomical, and pathophysiological parameters to describe CVI (씰Tab. 2; 7, 8). However, in daily practice only the clinical part (C) of this classification is used. A separation is given between just varicosity (C0,1 and 2) and skin changes (C3–6). This is somewhat confusing because it is just the relationship between dysfunctioning of the veins and the skin microcirculation, which leads to complaints and signs. For example, an incompetent greater saphenous vein can be clinically invisible, especially in fat people, and consequently classified as C0 or C1, even

when edema is present. The same is true as C4–6 describes the skin changes, but the varicose veins are not included (by name), which is confusing when only the C of the CEAP-classification is used. Since the Duplex ultrasound investigation has become the gold standard today, the C of clinical should always be combined with the results of the Duplex-investigations. In addition, it is also mandatory to indicate, whether the patient is symptomatic (S) or not (A). In case the CEAP-classification is used in the right manner, namely to define all parameters (clinical, etiological, anatomical and pathophysiological), it is really useful, not only for research but also in general phlebological practice. Clinical symptoms of CVI may vary considerably and range from scarcely visible skin changes to serious changes in pigmentation, veinectasia, edema and ulceration, often associated with complaints of pain and discomfort. One has to consider that clinical signs of CVI, especially in the early stages, will not always correlate with the severity of the disturbed venous hemodynamics. Skin changes seen in CVI gradually develop over time, but the venous hypertension will exist (long) before. Next to varicose veins, a specific sign of early forms of venous incompetence is the socalled Corona phlebectatica para plantaris, also known as ankle flare (씰Fig. 1a): there are telangiectasias surrounding the malleoli of the ankle. This corona was first described by Dr. Hendrik van der Molen in the 1950s. It plays an important role in the classical Widmer classification for CVI (9). Our research has proven that the Widmer classification, though predating the CEAP classification, still has a good correlation with the Prandoni and CEAP-scores, and a fair correlation with the ambulatory pressure measurements (10). Other early signs are edema, hyperpigmentation of which the yellowish/brown pigmentation is specifically named dermatite jaune d’ocre, and eczema, signs of more advanced disease are dermato- and liposclerosis (씰Fig. 1b), a localized induration of the skin and sometimes of the underlying tissues, with fibrosis and inflammation. Through microthrombi an area of whitened skin with reddish spots may occur, called Atrophie blanche or white atrophy (씰Fig. 1c). In this

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a

b

c

d

Fig. 1 a. Ankle flare. b. Signs of dermato- et liposclerosis. c. Atrophie blanche. d. Venous leg ulcer.

sign, skin atrophy is accompanied by capillary dilatation and elongation. Finally, the most severe sign is the venous leg ulcer (씰Fig. 1d), a chronic wound that fails to heal spontaneously or within the time range of normal healing of the skin. When recanalization of the proximal vein (e.g., Vena iliaca) after an episode of deep venous thrombosis fails, collaterals in the venous circulation across the lower abdomen may form, connecting the venous system of the obstructed leg to that of the healthy leg, which are known as de Palma (씰Fig. 2), named after the surgical procedure aiming to achieve the same effect (11). Other, less frequent signs of CVI may include disorders of keratinization, nail deformities, and subcutaneous metaplasia (e.g., calcifications in the subcutis).

Unfortunately, there are hardly any data in literature on the incidence/prevalence of all these clinical signs. We studied a group of 151 legs presenting with an ulcer. In 31 % of the male and 44 % of the female patients Atrophie blanche was present (12). Atrophie blanche is known, just as dermato- et liposclerosis, as a serious risk factor for developing a leg ulcer. This underlines the importance of the clinical signs as indicators for the future development of more serious diseases such as a venous leg ulcer. Venous hypertension plays a key role in the pathophysiology of CVI. This venous hypertension in turn is caused by a combination of several factors, among which are valve incompetence, outflow obstruction and dysfunction of the calf muscle pump.

Both the deep and the superficial venous system contribute to the development of CVI. A special form of CVI is the postthrombotic syndrome (PTS) (13). In this case, CVI is caused by a deep venous thrombosis leading to valve destruction and or persistent obstruction. After initial thrombosis, lysis of the thrombus may start. Propagation of the thrombus also occurs. The two processes occur simultaneously, whereby recanalization and the formation of a new thrombus are competing processes. Haenen et al. (14) found that these processes may continue for as long as 24 months or longer. The consequence of this finding is to evaluate deep vein thrombosis patients at least for the next two years after their thrombosis. They may be discharged in case no reflux is present and by

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the absence of obstruction. In case the Duplex-investigations show abnormalities, further investigations such as phlebography, venous pressure measurements and venous resistance measurements may be necessary to make the final evaluation. However, especially in case of deep venous reflux many patients will need life-time compression (15). During the process of recanalization venous valves are destroyed and residual obstruction of the vein may follow. Reflux leads to uncomplicated venous hypertension, but obstruction may lead to venous claudication (complicated venous hypertension). The physiological return of venous blood from the legs is based on the visa-fronte, the vis-a-tergo, the venous capacity (tonus), the arterio-venous pulse pump and muscle pumps. The human heart is a pressure pump instead of a suction pump and therefore contributes very little to the venous return. Among all these mechanisms the most important is the action of the muscle pumps in the leg. The transport of blood is facilitated mainly by the calf muscle pump, but the muscle groups of the upper leg and the thigh also contribute to this transportation. There is a specific place for the foot pump, also known as Lejar’s sponge (16). This pump mechanism is based on the presence of valves in the veins, which allows a one-way blood flow when the muscles surrounding it are contracting. Loss of valve function in patients causes venous reflux and leads to overloading of the venous system, which in turn leads to widening of the veins and finally to an increase in venous volume. If the venous volume surpasses the capacity of the calf muscle pump, ambulatory venous hypertension results, which in turn causes further distension of the vein, leading to more valve incompetence and the development of secondary varicose veins. If there is residual obstruction in a vein, venous resistance and pressure increases, which also leads to a higher venous volume and the above described cascade is repeated. However, if venous resistance is high due to serious obstruction and the collaterals fails to take over the function of the deep veins, the venous return during walking will fail and pain will occur: venous

Fig. 2 Palma vein: Collateral vein of the lower abdomen following DVT.

claudication; we call this complicated venous hypertension. In general, reflux causes more de-compensation if it occurs in the distal part of the venous system (e.g. Vena poplitea) and obstruction causes more de-compensation if it occurs proximally (e.g. Vena iliaca).

CVI is highly influenced by gravity. In the standing position, venous pressure at the ankle is ±90 mmHg; during walking, this pressure should decrease to ±20 mmHg. Serious venous hypertension occur from 40 mmHg onwards. At the microcirculatory level, many theories have been put forward to explain the symptoms of CVI. By using transcutaneous oxygen tension measurement techniques we observed a significant reduction of the skin oxygen content in CVI-legs (17). Bollinger et al. (18) described microthrombi caused by the slowed passage of blood through the capillaries in patients with CVI. These microthrombi cause a decrease in the density of capillaries in the affected tissue, leading to a lowering of the transcutaneous oxygen pressure (tcPO2), which in turn causes the symptoms of CVI. In Atrophie blanche and Klinefeler’s syndrome we found an increased plasminogen-activator inhibitor-1 activity (19). This disturbance may also play a role in summer ulcerations and CVI (20). In the same year, Burnand et al. (21) postulated that the leakage of high molecular weight proteins because of increased ve-

nous pressure builds up a fibrin cuff around the capillaries, which also causes lowering of the tcPO2. Later we proved that fibrin did not form a barrier for oxygen (22). We studied the changes in microcirculation in patients with Atrophie blanche visualized by laser Doppler-perfusion imaging and tcPO2-measurements. The resting flux in Atrophie blanche is increased compared with clinically normal skin. The decrease of flux on venous occlusion is lower in Atrophie blanche than in healthy controls. A significant decrease in tcPO2-values occurred in Atrophie blanche lesions with 40 mmHg, in CVI-skin with 60 mmHg and in healthy controls with 80 mmHg by artificially induced venous hypertension (23). In dermato- et liposclerosis capillary leakage of water and plasma proteins is present, which results in a higher capillary filtration rate. In skin biopsies the result of this process can be seen as a peri-capillary halo, which contains fibrinogen. We studied the capillaries and their surrounding tissue to determine the thickness of the collagen IV layer. In lipodermatosclerosis a significant increase of the collagen-IV-layer was observed. Collagen-IV-thickness was measured by an index method. The collagen-IV-thickness for this purpose refers to the capillary diameter. It can be suggested that the increase of the venous pressure in the capillaries leads to leakage of several proteins, mostly fibrinogen. As a result of the increase of fibrinogen the collagen-

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of the muscle pumps. This pumps and especially the calf muscle pump is the major power, which returns the blood to the heart. Formation of sclerotic plaques in the skin (dermato-, lipo and fascio-sclerosis) counteracts the normal movements of the ankle joint, resulting in a partial secondary failure of the calf muscle pump and leads to CVI with a chronic compartment syndrome. We have to realize that patent veins and valves in relation to paralyzed muscles or any other form of dependency will lead to the clinic of CVI, often accompanied with a lot of edema. It is the cooperation of veins, valves and the musculoskeletal apparatus of the legs which makes a healthy venous return possible. In this case too, it is also true that the chain is as weak as its weakest link. Fig. 3

The Rotterdam model.

IV-layer becomes thicker, which leads to a decreasing function of the capillaries. In this manner, an auto-amplification mechanism maintains CVI (24). In combination with the found low tcPO2, we were able to start to design a model for the relationship between venous hypertension and the skin changes. The adherence of leukocytes to the capillary wall, caused by low flow and leading to an inflammatory reaction, was postulated by Coleridge Smith et al. (25) in 1988 as another possible cause for venous ulceration. In 1992, Edwards et al. suggested that increased venous pressure led to the damage of the skin through hyper-perfusion and release of free radicals, causing additional tissue damage (26). Falanga et al. (27) reported on growth factor trapping in 1993, but later studies in which growth factors were applied to venous ulcers, did not increase healing rates. This is possibly due to the fact that several growth factors, which work together synergistically, promote ulcer healing and treatments were performed with just a single growth factor. Most likely, all of the above factors participate more or less in the pathogenesis of CVI, where increased venous pressure leads to leakage of fluid and proteins and thus to an acute inflammatory process known as hypodermitis. This multi-causal model, first described by us as the Maastricht

model has now been updated and known as the Rotterdam model (씰Fig. 3) (28–31). Disturbances of the clotting system are not only important in the development of a deep venous thrombosis, but also for the development and the progression of CVI. The possible role of plasminogen-activator inhibitor-1 is already mentioned. We found that Factor-V-Leiden mutation was significantly more frequent in patients with CVI and venous leg ulcers than in the control group (23 % vs 7.5 %; p=0.03), and the patients with Factor-V-Leiden mutation were more likely to have a history of venous thromboembolism (91 % vs 48 %, p=0.002). Recurrent deep venous thrombosis (38 % vs 14 %) and recurrent leg ulcerations (9 episodes or more) also occurred more frequently in the patients with Factor-V-Leiden mutation (43 % vs 19 %, p=0.01). No difference was observed in the venous refill time or in the presence of dermato- et liposclerosis and Atrophie blanche (32). All of the clinical signs and symptoms of CVI are based on the dysfunction of the venous microcirculation that, in turn, is influenced by the changes in the macrocirculation. This goes for all venous problems with the exception of thrombophlebitis and varicose vein bleedings. In addition, the musculoskeletal apparatus is extremely important in the function

The veins Varicose veins have been present ever since human beings started to walk upright. Since that moment the heart became ±90 cm above floor level and gravitation became an important enemy of the venous return mechanism. Ancient Greek and Roman physicians already recognized the implications of varicose veins and were able to treat them with techniques not much unlike our modern ambulatory phlebectomy. In more recent times, the surgical treatment of saphenous varicose veins is one of the very few treatments that have barely changed since its invention more than a hundred years ago. In 1905, the American surgeon William Keller introduced the stripping technique using a wire and multiple incisions (33). An important disadvantage of surgery for varicose veins is the well-known high recurrence rate which is up to 30–60 % at longterm follow-up (34, 35). The main causes for recurrence of varicose veins after surgery are an insufficient understanding of venous hemodynamics, inadequate preoperative assessment, incorrect or incomplete surgery, progression of underlying venous disease and neovascularization at and around the ligated junction (36). Improving the quality of preoperative assessment routinely performing Duplex-ultrasound seems to be very important to reduce recur-

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rence. According to a randomized controlled trial, systematical use of Duplexultrasound significantly lowered the incidence of Duplex-detected recurrence at the sapheno-femoral junction or sapheno-poplitial junction and reduced the number of re-interventions within two years after surgery (37). Duplex-investigation is justly mandatory according to the Dutch guideline varicose veins (38). In the last years, new attention has been drawn to the surgical treatment of tributaries. Ambulatory conservative hemodynamic management of varicose veins (CHIVA), mainly performed in Italy and France, proved to give better results than stripping when considering the recurrence rate (39, 40). The newest idea, which is more or less related to the principles of CHIVA, is that tributaries have a high impact on the problem of varicose veins. Looking at the outcome of treating only varicose tributaries helps to distinguish between the ascending and the descending varicose veins. The idea is that treating superficial varicose veins can be divided into two different strategies based on two pathophysiologic concepts. First, treating the insufficient tributaries of the insufficient saphenous vein may lead to the abolition of the saphenous reflux, so that the saphenous vein need not be treated any further. This underlines the concept of ascending varicose veins (41). Treatment of the saphenous vein alone or in combination with tributaries is based on the descending theory. Promising results after performing phlebectomies without treating greater saphenous vein trunk incompetence have already been reported by Pittaluga (42). This interesting concept should be explored more in the near future. We have proved that the treatment of tributaries is much more effective by phlebectomy and sclerotherapy (43). Sclerotherapy, widely used in the daily practice, was known even before stripping. Chassaignac was the first to inject varicose veins with ferrochloride (1855). Since 1911, teleangiectasias and reticular veins have been injected with sodium carbonate and sodium salicylate. Later also quinine, sodium chloride and urethane were used as sclerosants. Fegan added compression to sclerotherapy in 1965 and since then sclero-

therapy has been combined by most physicians with compression to obtain better results (44, 45). Nowadays liquid and foam sclerotherapy are both commonly used with detergent sclerosant solutions such as polidocanol and sodium tetradecyl sulfate. Ultrasound-guided foam sclerotherapy is a variant in which liquid detergent sclerosant solution is mixed with air or a physiological neutral gas to create foam. The sclerosant reacts with the endothelial cells of the vascular wall and induces contraction, thrombus (‘sclerus’) formation and eventually fibrosis of the vein (46, 47). Foam is four times more effective than liquid sclerotherapy because of increased contact time with the venous wall, increased contact surface area with the venous wall, and ability to induce a venous spasm (48). Recently, a new technique has been marketed, which combines mechanical damage to the endothelium of veins with the application of polidocanol foam, the Clarivein®. The latest treatment option is the group of endovenous thermal ablation techniques (EVTA). The demand by our patients for cosmetically superior, less invasive and more successful treatment modalities has led to the introduction of minimally invasive techniques. These techniques were introduced only a decade ago and radically changed the treatment of varicose veins, which had remained unchanged for the last hundred years. The EVTA-techniques are endovenous laser ablation (EVLA), radiofrequency ablation (RFA) and endovenous steam ablation (EVSA). The advantage of EVTA is, that it is minimally invasive and can easily be performed under local tumescent anesthesia without need for spinal or general anesthesia and that the recurrence rate of the thermal techniques is lower than surgery (49). The first EVTA-procedures were performed with RFA with the VNUS Closure Plus system (50). Immediately thereafter, EVLA was developed and this soon became the most frequently used EVTA-method around the world. The laser light wavelength for EVLA varied from 800 to 1500 nm. In the last years two new RFA-systems have been introduced: VNUS Closure Fast (segmental RFA) and RFITT (radiofrequency induced thermotherapy). The newest invention of

thermal ablation is using steam at 120°C. Ongoing studies will show, whether this technique is as effective as EVLA and whether it is better appreciated by patients in terms of pain and discomfort. Looking ahead, the best invention would probably be a minimal invasive endovenous treatment, that is effective, painless, quick and does not need application of tumescent anesthesia. We recently reviewed all these minimal invasive techniques (51). In a meta-analysis, we concluded that of the 119 retrieved studies, 64 (53.8 %) were eligible and assessed with a total of 12,320 limbs. The average follow-up time was 32.2 months. After 3 years, the estimated pooled success rates (with 95 % confidence intervals [CI]) for stripping, foam sclerotherapy, radiofrequency ablation, and laser therapy were about 78 % (70–-84 %), 77 % (69–84 %), 84 % (75–90 %), and 94 % (87–98 %), respectively. After adjusting for follow-up, foam therapy and radiofrequency ablation were as effective as surgical stripping (adjusted odds ratio [AOR]: 0.12 [95 % CI: –0.61 to 0.85] and 0.43 [95 % CI: –0.19 to 1.04], respectively). Endovenous laser therapy was significantly more effective compared with stripping (AOR: 1.13; 95 % CI: 0.40–1.87), foam therapy (AOR: 1.02; 95 % CI: 0.28–1.75), and radiofrequency ablation (AOR: 0.71; 95% CI: 0.15–1.27) (49). It is logical from this data that most phlebologists have given up the stripping and changed to endovascular techniques, especially lasers. There is still an ongoing debate on the optimal laser wavelength. We did some experiments to evaluate this. Very high temperatures at the laser fiber tip have been reported during EVLA. We hypothesized that the laser irradiation deposits a layer of strongly absorbing carbonized blood of very high temperature on the fiber tip. We sought to prove the existence of these layers and study their properties by optical transmission, optical coherence tomography (OCT) and microscopy. We analyzed 23 EVLA-fibers, 8 used at 810 nm, 7 at 940 nm and 8 at 1,470 nm and we measured the transmission of these fibers at two wavelength bands (450–950 nm; 950–1,650 nm). We used 1,310 nm OCT to assess the thickness of the layers and the attenuation as a function of the depth to de-

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termine the absorption coefficient. Microscopy was used to view the tip surface. All fibers showed a slightly increasing transmission with wavelength in the 450–950 nm band, and a virtually wavelength-independent transmission in the 950–1,650 nm band. OCT-scans showed a thin layer deposited on all the 13 investigated fibers, 6 used at 810 nm, 4 at 940 nm and 3 at 1,470 nm, some with non-homogeneities over the tip area. The average absorption coefficient of the 13 layers was 72±16 mm-1. The average layer thickness estimated from the transmission and absorption measurements was 8.0±2.7 μm. From the OCT data, the average maximal thickness was 26±6 μm. Microscopy of three fiber tips, one for each EVLA wavelength, showed rough, cracked and sometimes seriously damaged tip surfaces. There was no clear correlation between the properties of the layers and the EVLA-parameters such as wavelength, except for a positive correlation between layer thickness and total delivered energy. We found strong evidence that all EVLA-procedures in blood filled veins deposit a heavily absorbing hot layer of carbonized blood on the fiber tip, with concomitant tip damage. This major EVLA-mechanism is unlikely to have much wavelength dependence at similar delivered energies per centimeter of vein. Optical–thermal interaction between the vein wall and the transmitted laser light depends on wavelength (52). The difference in pain by using a low wavelength laser (e.g., 810 nm) and a high (1470 nm) can be explained that in the latter the fluence is lower and less vein wall burns will occur. This is supported by another experiment in which temperature measurements were performed using thermocouples. The experimental set-up consisted of a transparent box in which a glass tube was fixed. Different laser parameters (wavelength and power) and 2 different pullback speeds (2 and 5 mm/s) were used. Thermocouples were placed at different distances from the fiber tip. Validity of the experimental setting was assessed by performing the same temperature measurements using a stripped varicose vein. The maximum temperature rise and the time span that the temperature was

above collagen denaturation temperature were measured. The results showed that decreasing the pullback speed (2 mm/s) and increasing the power (up to 14 W) both caused higher maximal temperatures. The use of different laser wavelengths (940 or 1470 nm) did not influence the temperature profile (53). The results of our experiments indicated that the heat induction, which is responsible for vein occlusion in EVLA, is independent of laser wavelength. A clinical trial should prove this concept in humans. Duplex investigations showed steam bubbles arising from the tip during EVLA. We investigated this steam formation in vitro. This steam bubbles are important for the intravascular heat conduction. EVLAproduces boiling bubbles emerging from pores within the hot fiber tip and traveling over a distal length of about 20 mm before condensing. Just a small portion of the laser energy is transferred by direct heat transmission; most is used to create superheated steam which releases its energy upon condensation. This evaporation-condensation mechanism makes the vein act like a heat pipe, where very efficient heat transport maintains a constant temperature, the saturation temperature of 100oC, over the volume where these non-condensing bubbles exist. During EVLA the abovementioned observations indicate that a venous cylindrical volume with a length of about 20 mm is kept at 100oC. Pullback velocities of a few mm/s then cause at least the upper part of the treated vein wall to remain close to 100oC for a time sufficient to cause irreversible injury. The mechanism of action of boiling bubbles during EVLA is an efficient heat-pipe resembling way of heating of the vein wall (54). The newest method of thermal ablation is pulsated steam, which works by heating the vein with steam at 120°C. We did in vitro animal and human studies with the aim to bring steam ablation to an alternative treatment for varicose vein (55, 56). A study assessed the effectiveness of steam ablation of varicose veins in sheep and in humans. We used ultrasound imaging to examine occlusion of the veins. Changes in treated veins were examined microscopically, no cardiovascular changes occurred during treatment. Histologic

examination of treated veins showed typical changes, such as disappearance of the endothelial layer, fibrotic thrombosis, and major alterations in collagen fibers in the media of the vein wall. In a pilot study, 20 veins in 19 patients with insufficiency of the great or the small saphenous vein were treated with pulsated steam ablation. Anatomic success, patient satisfaction, and complications were investigated for 6 months after the procedure. Steam ablation was effective in the 19 patients: 13 of the 20 veins were completely closed, and 7 showed a very small segment of recanalization after 6 months of followup that did not seem to be clinically relevant. Nine patients had some ecchymoses at the puncture site, and one patient had a transient superficial phlebitis. A median maximal pain score of 1 (range 0–10; 55) was reported. No serious side effects such as deep vein thrombosis, nerve injury, skin burns or infections were reported. Patients were very satisfied with the treatment, with a median satisfaction score of 9.25 (range 0–10) (55). In this proof-of-principle study, pulsated steam ablation was an effective treatment for saphenous varicose veins. These studies are good examples of translational medical research. Animal and laboratory models are the basis for the development of these endovascular techniques. The final place of these modalities in treatment should be based on multiple prospective randomized clinical trials.

The legs The patient with a leg problem consults the phlebologist. Varicose veins and all the skin changes belonging to CVI are visible. However, venous anatomy of the deep system, perforators and other alterations such as a Baker’s cyst are invisible to the human eye. The phlebologist has new eyes since the introduction of the Duplex ultrasound. The Duplex ultrasound as a diagnostic tool in phlebology represents the major progress in the last two decades. The leg contains the musculoskeletal apparatus necessary for walking, which activatesthe muscle pumps. The treatment of CVI is based on severity of the disease and guided by the ana-

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tomy and pathophysiological considerations (57). The main target of any effective treatment of CVI is to lower the abnormal high ambulatory venous pressure. This can be achieved by eliminating reflux with all known techniques as EVTA, sclerosis, compression and surgery. One of the main aims of compression therapy is to counteract gravity. Compression therapy is able to affect the venous hemodynamics, if the interface pressure is high enough to overcome the intravenous pressure, always adjusted to the body position and thus gravity. In the upright position this means that an interface pressure of more than 40 mmHg is needed for an intermittent occlusion of the incompetent veins and for the reduction of the ambulatory venous hypertension during walking (58). The leg is also the place where compression, still the cornerstone in phlebological treatment, is effective. In the last decades we did also a lot of research into the action of compression therapy on the human leg. We noted that nearly all work on compression was done under static conditions although compression therapy is widely known only to be effective under dynamic, e.g. walking condition. Phlebologists speak of ambulatory compression therapy to stress the importance of this combination. Compression is characterized by the pressure compression material exerts on the leg. In the European Committee of Normalization (CEN) prenorm, medical compression hosiery are classified in compression classes according to the pressure exerted on the smallest diameter of the lower leg, at the ankle (the so-called ‘‘B pressure’’) (59). To date this is the only way of distinguishing one type of medical compression hosiery from another. Nevertheless, in daily practice, it is well known that the behavior of a compression class II medical compression hosiery can significantly differ from another compression class II medical compression hosiery, for instance, for the prevention of edema. Stiffness of the material seems to play a major role in this difference. We found a large variation between the static stiffness of different medical compression hosieries, all CEN class II (60). For this reasons it is unjustified to categorize medical compression therapy only by the interface pressure.

According to the CEN, stiffness is defined as the increase of pressure at the B level if the circumference increases by 1 cm (59). Stiffness is also known as elasticity coefficient and slope. This is an important characteristic of elastic material. The increase in stiffness is correlated with higher effectiveness (61). Moreover, it is known from studies on compression bandages that the so-called massaging effect, which is directly related to the elasticity and the stiffness, is important for optimizing venous return (62, 63). The massaging effect will increase and the effectiveness of medical elastic compression hosiery will improve by increasing the pressure and the stiffness. For that reason we were interested in what stiffness does during walking. In other words, is there also a dynamic stiffness? The determination of pressure values of medical compression hosiery at textile laboratories is calculated from semi static tension values (59). Although these values provide a good indication of the passive pressure that the hosiery exerts on the relevant leg of the patient, unfortunately, they do not provide information on the behavior of the hosiery during walking. Such information is very essential for effective compression therapy that has been proven to be especially effective in an ambulant patient (64–66). Therefore, medical compression hosiery should be investigated under ambulatory conditions to establish their real biologic effect. To date, the direct measurement of this dynamic behavior of the medical compression hosiery is physically impossible. The pressure that is exerted depends on the shape of the leg. This shape is irregular and changes during walking. In an effort to overcome the technical problems, we developed a simple artificial leg segment model with a more uniform circular leg shape to investigate the dynamic behavior of the medical compression hosiery. Using this model, it was hoped to establish a new parameter that may explain the differences in medical compression hosiery behavior in one and the same compression class during walking. The pressure changes of the medical compression hosiery during walking are more important than was realized. For instance, from simulation we deduced that the dynamic pressure at the cB1

level (at the insertion of the tendon of the gastrocnemius muscles) varied from 10.8 to 51.2 mmHg with a static pressure of 27 mmHg (67). In this study, a new parameter, based on the CEN definition of stiffness, the dynamic stiffness index (DSI), was introduced. It expressed the change in pressure as a result of the change in the circumference of the lower leg during walking. A high DSI implies that the medical compression hosiery generates relatively high-pressure pulses during walking (67). We did a study in which we calculated the DSI of 18 different brands of medical elastic compression hosieries. All the 18 different brands were divided into five categories (class II round-knitted, class II flatknitted, class III round-knitted, class III flat-knitted and class IV flat-knitted hosieries) and were tested for the static pressure and the dynamic pressure pulsations at the B1 level. The DSI was calculated according to the stiffness definition of CEN. We found that the DSI of all 18 brands of hosieries showed higher values compared with the static stiffness. A wide range of dynamic stiffness indices was observed not only between all brands of hosieries, but also within the five categories. So the DSI of hosieries is independent of the compression class and the type of knit (68). The variation in the DSIs between different medical compression hosieries is an important characteristic of the compression device and would indicate that different therapeutic effectiveness may be expected within one compression class in case the DSI differs. Therefore, a refinement in the current classification system for medical elastic compression hosiery is advised. We also proved a good correlation between static stiffness, DSI and the density of the material used (69, 70). The next question was how hosieries will behave in relation to the DSI during a day of walking. It was the objective of this study (71), to assess the change(s) in the characteristics of medical compression hosiery and not to determine the wear-andtear of hosieries after been worn for eight hours. Elastic material of the compression devices may return to the baseline (as is the case before wearing hosiery) after relaxation of the knit. The results of our pilot study showed that the pressure of all tested

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Fig. 4 Example of a stocking that shows a decrease in pressure and continuous pressure pulsations (dynamic stiffness index) during the day (71).

Fig. 5 Distribution of DSI of 18 different brands of class II and class III medical elastic compression hosieries. Each dot represents one hosiery (68).

medical elastic compression hosiery had dropped significantly after having been worn for eight hours. Moreover, it has to be remarked, that only one stocking per brand was measured. This was based on the results of our previous studies in which the same brands of hosieries were investigated (68). However, it is noticeable, that eight of the 12 brands of hosieries do not fulfill the criteria of a class II stocking at a certain point during the day. What does this mean in daily practice? It is not the pressure, but the pressure pulsations created by the stiffness of the medical elastic compression hosiery that is important. In contrast to the pressure alterations, the changes in DSI are not significant and are likely to be due to the variation in the measurement. This was also confirmed by the observation, that the changes in DSI were noted to be either

positive or negative. Interestingly, there were no differences between the roundknitted and the flat-knitted hosieries as far as the change in DSI was concerned. We can explain the pressure drop on the basis of fatigue of the elastic materials. Since stiffness is a characteristic of all the materials and particularly of elastic materials, its role can best be explained as the result of internal friction between the threads, stitches and the resistance against deformation. Since neither friction nor resistance is related to elasticity, stiffness will not alter during the eight hours of wear (day). The information on the stiffness of medical elastic compression hosieries is essential in daily practice. A correct combination of interface pressure, as indicated by the CEN compression classes and the DSI is essential for prescribing optimal am-

bulatory compression therapy with hosieries. On the one hand, hosieries with low DSI will not only lose the pressure they exert during daytime, but will also have a low walking pressure-amplitude. Patients who wear such hosieries have a risk of developing edema during the day. Formation of edema is related to the severity of venous insufficiency. One can speak of a decompensated venous incompetence. On the other hand, hosieries with a medium pressure and high stiffness are perfectly able to prevent edema because of the high pressure amplitudes during walking. It is now clear that the DSI is highly important for sufficient compression during daytime. The natural decrease during day time in interface pressure can be compensated with an appropriate DSI. An example of this is shown in 씰Fig. 4 (71). Although at the end of the day the pressure drops below the minimum pressure allowed at the B1 level of a class II stocking, under ambulatory conditions the pressure pulsations provide adequate pressures during most part of the day. Therefore, we recommend prescribing hosieries with a high DSI and high pressure to all patients with a strong tendency towards the formation of edema and in whom a constant high pressure is necessary, for instance in patients suffering from a postthrombotic syndrome. In patients with mild venous problems, such as patients suffering from mild venous symptoms (C0–C1), prescription of hosieries with a lower DSI and lower pressure will be sufficient.

Thus, a physician can choose an appropriate hosiery by choosing a higher stiffness for treating severe chronic venous insufficiency, without increasing the pressure. Looking at stiffness and dynamic stiffness, it is also possible to tailor the stocking to the needs of the patient. Active people benefit from stockings with a high DSI, having better pressure when walking and a low resting pressure, whereas immobile patients benefit from stockings with higher elasticity and lower DSI, with a high resting pressure. Partsch recently introduced a simple in vivo method to assess the static stiffness index, which is defined as the pressure dif-

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ference between active standing and lying (72). However, pressure differences were divided by 1 cm for reasons of simplicity, assuming that the increase in the circumference was 1 cm. Unlike the calculation reported by Partsch, we conducted our measurements with an actual increase in circumference of 1 cm. In our opinion the change in circumference is very important because a small increase in circumference results in higher pressure due to higher stiffness (씰Fig. 5; 68). Our measurements were in vitro. However, it would be desirable also to conduct such measurements in vivo in order to be able to compare them with those reported in other studies. Mosti and Mattaliano studied simultaneous changes of leg circumference and interface pressure under compression bandages in vivo (73). They used the modified SSI as the pressure difference between the standing and the lying condition corrected for the actual increase of leg circumference. In a recent study by Partsch et al. it was clearly shown, that in vivo measurements of the interface pressure and the SSI correlated well with in vitro laboratory measurements of the static stiffness (74). Benigni et al. proposed to define a DSI as the difference between the high and the low pressures recorded during walking (75). Measurements were performed on a treadmill using a pressure transducer with two sensors. The measured interface pressures were the mean pressures of both sensors. However, they did not take the change in circumference during walking into consideration, and measurements were not conducted at the B1 level. This meant, that the results of their study could not be compared with those reported in other studies. There is little or no evidencebased literature for evaluating the role of stiffness of medical elastic compression hosiery in patients with chronic venous insufficiency. The reported clinical trials were of poor design and confusing. The compression that was used was often not clearly defined, which made the comparison of results difficult, if not impossible. As a direct result, considerable interest has arisen in the physical properties of medical elastic compression hosiery and their relationship with the therapeutic effectiveness. In our opinion, it is essential to pursue well-de-

signed clinical trials and investigations concerning medical elastic compression hosiery and compression therapy in general. Insight into the differences between the different types of medical elastic compression hosiery that are commercially available is required, in order to develop or refine a more accurate classification that would clearly reflect the therapeutic effectiveness of medical elastic compression hosiery for treating chronic venous insufficiency.

Acknowledgements I thank all those who cooperated from the beginning in our research in phlebology. It started in the late seventies of the last century with a first publication on leg ulcers and skin grafting (76). Until today they include Paul Berretty, Marie-José van den Broek, Leon Therry, Joep Veraart, Birgitte Maessen-Visch, Michael Kockaert, KeesPeter de Roos, Dinanda Kolbach, Pierre van Neer, Tamar Nijsten, Renate van den Bos, Rob Stolk, Karin van der Wegen-Franken, Anja Sommer, Tim Wentel, Sterre Langendoen, Suzan Reeder and Marianne de Maesseneer.

Conclusion Skin, veins and legs are the ingredients, composing the palette with which the phlebologist have to deal. The disease we have named CVI is a complex of clinical signs and symptoms based on a deficient return of the venous blood from the (lower) legs, and starts with alterations within the vein, mostly the vein wall, sometimes in the cups of the valves or caused by a thrombotic process within veins and/or capillaries. The battle field is the skin microcirculation and the surrounding extra cellular matrix. Here we find the origin of all clinical signs of CVI. However, only just correcting the microcirculation, for example with veinoactive drugs (e.g. rutosides), will not be useful if we ignore the underlining disturbed macrocirculation. New endovascular ablative techniques, especially laser, have taken the place of the classical stripping. The new parameter in compression therapy is the DSI. This has provided us with new background information to understand which compression therapy is effective. Although pressure diminishes during the day, the DSI remains constant, which is the safeguard for the patient, because the interface pressure can easily drop below the required threshold. The interaction between macro circulation, gravitation on one side and the continuous pressure waves during ambulant walking, which can be amplified with different compression devices, makes a healthy venous return possible even under pathological conditions of veins and microcirculation. Nevertheless, compression therapy still remains mandatory.

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13. Wentel TD, Neumann HAM. Management of the Postthrombotic Syndrome: The Rotterdam Approach. Semin Thromb Hemost 2006; 32(8): 814–821. 14. Haenen JH, Wollersheim H, Janssen MCH et al. Evolution of deep venous thrombosis: a 2-year follow-up using duplex ultrasound scan and straingauge plethysmography. J Vasc Surg 2001; 34: 649–655. 15. Kolbach DN, Sandbrink MW et al. Compression therapy for treating stage I and II (Widmer) postthrombotic syndrome. Cochrane Database Syst Rev 2003; 4: CD004177. 16. Thiery L, Neumann M, Uytterhaegen P. Insightful Phlebology. Belvedére-Overveen:The Netherlands. 2009. Ch 1.0 17. Neumann HA, van Leeuwen M et al. Transcutaneous oxygen tension in chronic venous insufficiency syndrome. VASA 1984; 13: 213–219. 18. Bollinger A, Jäger K, Geser A, Spier F, Seglias J. Transcapillary and interstitial diffusion of Na-fluorescein in chronic venous insufficiency with atrophy. Int J Microcirc Clin Exp 1982; 1: 5–17. 19. Veraart JC, Hamulyak K et al. Increased plasma activity of plasminogen activator inhibitor 1 (PAI-1) in two patients with Klinefelter’s syndrome complicated by leg ulcers. Br J Dermatol 1994; 130(5): 641–644. 20. Maessen-Visch MB, Neumann HAM et al. Répercussion de l’atrophie blanche chez les patients atteints d’un ulcus cruris venosum. Phlébologie 1996; 50: 367–370. 21. Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary fibrin in the ulcer-bearing skin of the leg: the cause of lipodermatosclerosis and venous ulceration. BMJ 1982; 285: 1071–1077. 22. Neumann HAM, van den Broek MJTB, Boersma IH, Veraart JCJM. Transcutaneous oxygen tension in patients with and without pericapillary fibrin cuffs in chronic venous insufficiency, porphyria cutanea tarda and non-venous leg ulcers. VASA 1996; 25 127–133. 23. Maessen-Visch MB, Sommer A, et al. Changes in microcirculation in patients with atrophie blanche visualized by laser Doppler perfusion imaging and transcutaneous oxygen measurements. Phlebology 1998; 13: 45–49. 24. Neumann HA, Van den Broek MJ. Increased collagen IV layer in the basal membrane area of the capillaries in severe chronic venous insufficiency. VASA 1991; 20: 26–29. 25. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new hypothesis. BMJ 1988; 296: 1726–1727. 26. Edwards AT, Herrick SE, Suarez-Mendez VJ, McCollum CN. Oxidants, antioxidants and venous ulceration. Br J Surg 1992; 79: 443–444. 27. Falanga V, Eaglestein WH. The ‘‘trap’’ hypothesis of venous ulceration. Lancet 1993; 341: 1006–1008. 28. Blaauw GHM, Neumann HAM, Berretty PJM. La lipodermatosclérose et l’ épaisseur dermale. Phlébologie 1993; 46: 2531. 29. Neumann HAM. Measurement of microcirculation. In: Altmeyer P, El-Gammal S, Hoffmann K, eds. Wound Healing and Skin Physiology. Berlin: Springer 1995; 115–126. 30. Veraart JCM, Neumann HAM. Morphological and functional skin changes in chronic venous insufficiency. Scripta Phlebologica 1995; 3: 25–29.

31. Maessen-Visch MB, Koedam MI, et al. Atrophie blanche, a review. Int J Dermatol 1999; 38: 161–172. 32. Maessen-Visch MB, Hamulyak K et al. The prevalence of factor V Leiden mutation in patients with leg ulcers and venous insufficiency. Arch Dermatol 1999; 135(1): 41–44. 33. Keller W. A new method of extirpating the internal saphenous and similar veins in varicose conditions: a preliminary report. N Y Med J 1905; 82: 385–386. 34. Hartmann K, Klode J, Pfister R et al. Recurrent varicose veins: sonography-based re-examination of 210 patients 14 years after ligation and saphenous vein stripping. Vasa 2006; 35: 21–26. 35. Darke SG. The morphology of recurrent varicose veins. Eur J Vasc Surg 1992; 6: 512–517. 36. De Maeseneer MG, Van Schil PE, Philippe MM, Vanmaele RG, Eyskens EJ. Is recurrence of varicose veins after surgery unavoidable? Acta Chir Belg 1995; 95: 21–26. 37. Blomgren L, Johansson G, Bergqvist D. Randomized clinical trial of routine preoperative duplex imaging before varicose vein surgery. Br J Surg 2005; 92: 688–694. 38. CBO richtlijn Varices, www.huidarts.info/rich tlijnen/varices 39. Carandina S, Mari C, De Palma M et al. Varicose vein stripping vs haemodynamic correction (CHIVA): a long term randomised trial. Eur J Vasc Endovasc Surg 2008; 35: 230–237. 40. Pares JO, Juan J, Tellez R et al. Varicose vein surgery: stripping versus the CHIVA method: a randomized controlled trial. Ann Surg 2010; 251: 624–631. 41. Thiery L. Le probleme des perforantes. Phlébologie – Anales vasculaires 1998; 41: 215–228. 42. Pittaluga P, Chastanet S, Locret T, Barbe R. The effect of isolated phlebectomy on reflux and diameter of the great saphenous vein: a prospective study. Eur J Vasc Endovasc Surg 2010; 40: 122–128. 43. De Roos KP, Nieman FH, Neumann HA. Ambulatory phlebectomy versus compression sclerotherapy: results of a randomized controlled trial. Dermatol Surg 2003; 29: 221–226. 44. Fegan WG. Continuous compression technique of injecting varicose veins. Lancet 1963; 2: 109–112. 45. Fegan WG. Injection with compression as a treatment for varicose veins. Proc R Soc Med 1965; 58: 874–6 46. Parsi K, Exner T, Connor DE, Ma DD, Joseph JE. In vitro effects of detergent sclerosants on coagulation, platelets and microparticles. Eur J Vasc Endovasc Surg 2007; 34: 731–740. 47. Helenius A, Simons K. Solubilization of membranes by detergents. Biochim Biophys Acta 1975; 415: 29–79. 48. Yamaki T, Nozaki M, Iwasaka S. Comparative study of duplex-guided foam sclerotherapy and duplexguided liquid sclerotherapy for the treatment of superficial venous insufficiency. Dermatol Surg 2004; 30: 718–722; discussion 22 49. van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous therapies of lower extremity varicosities: a meta-analysis. J Vasc Surg 2009; 49: 230–239. 50. Goldman MP. Closure of the greater saphenous vein with endoluminal radiofrequency thermal heating of the vein wall in combination with ambulatory phlebectomy: preliminary 6-month followup. Dermatol Surg 2000; 26: 452–456.

51. Nijsten T, van den Bos RR, Goldman MP, .Kockaert MA, Proebstle TM, Rabe E, Sadick NS, Weiss R, Neumann HAM. Minimal invasive techniques in the treatment of truncal varicose veins: a review. J Am Acad Dermatol 2009; 60(1): 110–119. 52. Amzayyb M, van den Bos RR, Kodach VM, de Bruin DM, Nijsten T, Neumann HA, van Gemert MJ. Carbonized blood deposited on fibres during 810, 940 and 1,470 nm endovenous laser ablation: thickness and absorption by optical coherence tomography. Lasers Med Sci 2010; 25(3): 439–447. 53. Van den Bos RR, van Ruijven PWM, van der Geld CWM, van Gemert MJC, Neumann HAM, Nijsten T. Endovenous simulated laser experiments at 940 nm and 1470 nm suggest wavelength independent temperature profiles. Submitted. 54. Van der Geld CW, van den Bos RR, van Ruijven PW, Nijsten T, Neumann HA, van Gemert MJ. The heatpipe resembling action of boiling bubbles in endovenous laser ablation. Lasers Med Sci 2010; 25(6): 907–909. 55. Van den Bos RR, Milleret R, Neumann M, Nijsten T. Proof-of-principle study of steam ablation as novel thermal therapy for saphenous varicose veins. J Vasc Surg 2010; 53(1): 181–186. 56. van Ruijven PW, van den Bos RR, Alazard LM, van der Geld CW, Nijsten T. Temperature measurements for dose-finding in steam ablation. J Vasc Surg 2011; 53(5): 1454–1456. 57. Eberhardt RT, Raffetrto JD. Chronic venous insufficiency. Circulation 2005; 111: 2398–2409. 58. Partsch H. Effects of compression therapy of leg veins dependent upon pressure and material properties. Vasomed 2006; 18: 46–50. 59. European Committee for Standardization (CEN). Non-active Medical Devices. Working Group 2 ENV 12718: European Prestandard „Medical Compression Hosiery.“ CEN TC 205. Brussels: CEN 2001. 60. Van der Wegen-Franken K, Roest W, Tank B, Neumann M. Calculating the pressure and the stiffness in three different categories of class II medical elastic compression stockings. Dermatol Surg 2006; 32: 216–223. 61. Van Geest AJ, Veraart JCJM, Nelemans P, Neumann HAM. The effect of medical elastic compression stockings with different slope values on edema. Dermatol Surg 2000; 26: 244–247. 62. Veraart JCJM, Daamen E, Neumann HAM. Short stretch versus elastic bandages: effect of time andwalking. Phlebol 1997; 26: 19–24. 63. Partsch H, Menzinger G, Mostbeck A. Inelastic leg compression is more effective to reduce deep venous refluxes than elastic bandages. Dermatol Surg 1999; 25: 695–700. 64. Neumann HAM, Tazelaar DJ. Compression therapy. In: Goldman MP, Weiss RA, Bergan JJ, eds. Varicose Veins and Telangiectasias. St. Louis: Quality Medical Publishing 1999; 127–149. 65. Neumann HAM. Compression therapy with medical elastic stockings for venous diseases. Dermatol Surg 1998; 24: 765–770. 66. Lentner A, Wienert V. Influence of medical compression stockings on venolymphatic drainage in phlebologically healthy test persons and patients with chronic venous insufficiency. Int J Microcirc Clin Exp 1996; 16: 320–324. 67. Stolk R, van der Wegen-Franken CPM, Neumann HAM. A method for measuring the dynamic beha-

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H.A.M. Neumann: Skin, Veins and Legs

vior of medical compression hosiery during walking. Dermatol Surg 2004; 30: 729–736. 68. Van der Wegen-Franken CPM, Mulder P, Tank B, Neumann HAM. Variation in the dynamic stiffness index of different types of medical elastic compression stockings. Phlebology 2008; 23: 77–84. 69. Van der Wegen-Franken CPM, Tank B et al. correlation the static and dynamic stiffness indices of medical elastic compression stockings. Dermatol Surg 2008; 34: 1477–1485. 70. C.P.M. van der Wegen-Franken. Medical elastic compression stockings. Chapter VII. Maastricht: Datawyse Universitaire Pers 2009; 101–113.

71. Van der Wegen CPM, Tank B et al. Changes in the pressure and the dynamic stiffness index of medical elastic compression stockings after having been worn for eight hours: a pilot study. Phlebology 2009; 24: 31–37. 72. Partsch H. The static stiffness index: a simple method to assess the elastic property of compression material in vivo. Dermatol Surg 2005; 31: 625–630. 73. Mosti GB, Mattaliano V. Simultaneous changes of leg circumference and interface pressure under different compression bandages. Eur J Vasc Endovasc Surg 2007; 33: 476–482.

74. Partsch H, Partsch B, Braun W. Interface pressure and stiffness of readymade compression stockings: comparison of in vivo and in vitro measurements. J Vasc Surg 2006; 44: 809–814. 75. Benigni JP, CornuThe´nard A, Uhl JF, Schadeck M. Compression stockings. Walking pressure and proposal of a dynamic stiffness index. (abstract) Int Angiol 2005; 24: 21. 76. Berretty PJ, Neumann HA et al. Treatment of ulcers on legs from venous Hypertension by Split-Thickness skin grafts. J Dermatol Surg Oncol 1979; 5(12): 966–970.

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