Analysis of Lymphatic Drainage in Various Forms of Leg Edema Using Two Compartment Lymphoscintigraphy

Lymphology 31 (1998) 43-55

ANALYSIS OF LYMPHATIC DRAINAGE IN VARIOUS FORMS OF LEG EDEMA USING TWO COMPARTMENT LYMPHOSCINTIGRAPHY

P. Brautigam, E. FOldi, I. Schaiper, T. Krause, W. Vanscheidt, E. Moser

Abteilung Nuklearmedizin, Radiol. University Klinik Freiburg (PB,TK,EM), FOldiklinik, Fachklinik ftir lymphologische Erkrankungen, Hinterzarten (EF), Zentrum ftir Nuklearmedizin, Paracelsus- Klinik Osnabrtick (IS), and Universitats-Hautklinik, Freiburg (WV), Germany

ABSTRACT was reduced. Patients with lipedema (obesity) scintigraphically showed no alteration in The anatomical and functional status lymphatic transport. of the epifascial and subfascial lymphatic This study demonstrates that lymphatic compartments was analyzed using two drainage is notably affected (except in obesity compartment lymphoscintigraphy in five termed lipedema) in various edemas of the leg. groups of patients (total 55) with various Lymphatic drainage varied depending on the forms of edema of the lower extremities. specific compartment and the pathophysiologic Digital whole body scintigraphy enabled mechanism accounting for the edema. Two semiquantitative estimation of radio tracer compartment lymphoscintigraphy is a valuable transport with comparison of lymphatic diagnostic tool for accurate assessment of leg drainage between those individuals without edema of known and unknown origin. (normal) and those with leg edema by calculating the uptake of the radiopharma- The lymphatic system is deranged in ceutical transported to regional lymph nodes. various forms of leg edema of both lymphatic A visual assessment of the lymphatic drainage and non-lymphatic origin including venous- pathways of the legs was also performed. lymphedema, cyclic idiopathic edema, and In patients with cyclic idiopathic edema, lipedema (obesity) (1,2). As no discrete an accelerated rate of lymphatic transport differences exist on clinical grounds among was detected (high lymph volume overload or the various edema syndromes, differential dynamic insufficiency). In those with venous diagnosis and identification of the main (phlebo )edemas, high volume lymphatic pathophysiologic factors may be difficult or overload (dynamic insufficiency) of the impossible (1). epifascial compartment was scintigraphically Cyclic idiopathic edema of women entails detected by increased tracer uptake in regional much more than manifestations of the nodes. In patients with deep femoral venous premenstrual syndrome. Because of increased occlusion (post-thrombotic syndrome), permeability of the blood capillaries, both subfasciallymphatic transport was uniformly plasma proteins and great quantities of fluid markedly reduced (safety valve lymphatic (6-8 liters) may accumulate in the inter- insufficiency). On the other hand, in the stitium within a few days. As a result, the epifascial compartment, lymph transport was lymphatic system is overloaded (high volume accelerated. In those patients with recurrent insufficiency) with anasarca and in rare or extensive skin ulceration, lymph transport instances, even pulmonary edema (2).

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In phleboedema, the venous and capillary Group 1: Eighteen patients (10 female, hydrostatic pressure are increased and the 8 male; age 19-48 years) had localized demand for lymphatic drainage increases (2). malignant melanoma of the skin proximal to Over time, the lymphatic system becomes the umbilicus. Accordingly, involvement of functionally insufficient, the lymph transport the lymphatic drainage of the lower extremity capacity decreases, and edema ensues was deemed unlikely. Two compartment (termed safety valve lymphatic insufficiency) lymphoscintigraphy was carried out and the (2). In more chronic venous insufficiency, results were used to define normal values. lymph flow is also impaired (lymphedema). In lipedema or obesity, the pathophysiology Group 2: Ten women (age 21-41 years) of lymphatic drainage is less clear. Stallworth had cyclic idiopathic edema likely from et al (3) claims that the lymphatics, arteries, increased microvascular permeability (8). and veins are unaltered. Herpertz (4), on the Fluid retention consisted of swelling of the other hand, suggests a slight mechanical face, breast, abdomen, and legs which drainage blockage to lymph capillaries, worsened as the day advanced. A diurnal precollectors, and collectors secondary to weight variation of more than 1.4 kg daily increased pressure of the excess fatty tissue. was considered abnormal. A modified FOidi et al (2) emphasizes a combination of Streeten test (9) was also used and was contributions to leg enlargement including considered positive if the renal excretion of lipedema + lymphedema and lipedema + an oral fluid load (20 mllkg body weight) was cyclic idiopathic edema. In the clinical pre- less than 60% after 4 hours of orthostasis. sentation of patients with lipedema (pressure sensitive edema and a supramalleolar fat Group 3: Seven patients (4 male, 3 collar), both edema of the top of the foot and female; age 36-64 years) with primary venous a positive Stemmer's thickened skin fold sign varicosities of the greater saphenous vein (signs of lymphedema) are present as well. (phleboedema) (stage IV according to Hach) Two compartment lymphoscintigraphy (10) underwent lymphoscintigraphy to is a useful method to quantify lymphatic exclude occult lymphedema before excision drainage in the epifascial and subfascial and ligation of varicose veins. Functionally compartment of the legs (5-7). This study and morphologically, the femoral (deep) analyzed the lymphatic drainage in the venous system was intact according to previously mentioned forms of leg edema as Doppler sonography and phlebography. well as in deep venous occlusion (post- thrombotic syndrome) using two compart- Group 4: Eleven patients (6 male, 5 ment lymphoscintigraphy. Of special interest female; age 45-68 years) had deep vein was the contribution of this scintiscan thrombosis (from 1-19 years) (post- technique in the differential diagnosis in leg thrombotic syndrome) before lymphoscinti- edema of uncertain origin. graphy. Clinical complications included dermatoliposclerosis and recurrent skin ulcerations. MATERIAL AND METHODS Group 5: Five of 9 women (age 23-37 Patients years) showed considerable fat changes of the upper and lower legs (lipedema). In the other Between 1990 and 1996, 55 patients four patients, "edema" was seen only in the clinically separated into five groups were upper leg. Stemmer's skin fold sign was subjected to two compartment absent in all patients and lipedema had been lymphoscintigraphy. present for over 5 years.

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Fig. 1. Injection of the radio tracer into the lateral aspect of the side of the foot at a depth of 1.5 cm ensures drainage by the sUbfasciallymphatics.

Lymphoscintigraphy To examine the epifascial compartment, a second study using identical lymphatic Subjasciai compartment: 4x20 MBq 99m stimulation and acquisition was performed Tc of labeled human albumin nanocolloid was after disappearance of residual tracer activity injected into the dorsolateral muscles of the (at least 2 days later) but the radiopharma- sole of the foot (Fig. 1). Standardized stimu- ceutical was injected subcutaneously between lation of lymph flow followed using bicycle the first and third toes. ergometry at a low level of intensity (25 Watt) Lymphatic function was assessed by in 2 phases. After 20 minutes the first whole analyzing the uptake of the radiopharma- body scintigram was performed using a single ceutical into the lymph nodes. For this head gamma camera (Diacam®, Siemens purpose, regions of interest (ROI) were Company). After another 30 minutes of drawn, one over the inguinal and parailiac bicycle ergometry and a recovery phase, a lymph nodes (ROIl)' and a second over the second scintigram was obtained at 2 hours. injection site and the lymph vessels (R0I2).

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50 50 50 50 50

•• 40 40 40 40 40 ••• •• • 1i. • • • ...';30 30 • 30 • 30 30 :l Q. ::::I • • Gi .:-. .., • • • • • g 20 • 20 20 • 20 20 • 0 •••• • •• '6.. • • • •••••• a:: :• •• .-.... : ...... • 10 - -.::.- .. 10 10 10 10 - •••••.-. • • • .:.• 0 0 0 0 0 Cyclic Postthrombo- Lipedema Controls idiopathic Phlebedema tic Syndrome Edema

Fig. 2. Lymph node radiotracer uptake (%) for each patient in the epifascial compartment.

Percent uptake was calculated as RESULTS (R0I1)/{R0I1 + R0I2) x 100. Lymphatic transport was also visually The radiotracer uptake values for each evaluated. Reduced or absent radiotracer patient are shown in Fig. 2 (epifascial activity in regional lymph nodes represented compartment) and Fig. 3 (subfascial impaired lymphatic drainage. The compartment). In cyclic idiopathic edema appearance of 99m Tc nanocolloid in the and lipedema, the uptake values are shown proximal portion of the thoracic duct was for both legs. In phleboedema and deep interpreted as physiologic lymph pooling venous occlusion (post-thrombotic syndrome), before entry into the venous system and only the uptake values for the affected thought to represent accelerated lymphatic (edematous) side are shown. The median, the transport (high lymph volume overload or 5th and the 95th percentiles of each patient dynamic insufficiency). subgroup are shown in Table 1. A comparison The median, the 5th and the 95th of these results with those of patients with percentiles were determined for each set of lymphedema (11) are shown in Table 2. data. The data were also analyzed with one way ANOV A followed by multivariant Control Group analysis (Dunn's test). A significant difference was accepted at a p value of <0.05. Quantitative evaluation: The radiotracer

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35 5 • 35 35 35

30 30 • 30 30 30

_ 25 25 • • 25 25 25 • • • ...." • S,20 • 20 • 20 20 20 ::I a; • • • • u • • • 15 15 15 15 15 0 • • • :;;.. • • • a: - -.. • • 10 •- 10 • • 10 10 10 -.::-••• -:. • • 5 .:::: 5 • 5 • 5 5 • • • .. : ... -.: • • • •• • • • 0 0 0 0 ------ji_ .. 0 Cyclic Postthrombo- Lipedema Controls idiopathic Phlebedema tic Syndrome Edema

Fig. 3. Lymph nodal radiotracer uptake (%) for each patient in the subfascial compartment. uptake in the lymph nodes of patients with legs when compared with the control subjects. intact lymphatic systems varied widely with In one patient, tracer uptake of 43% was the range of uptake values in the subfascial approximately 3 times higher than that of the compartment greater than those of the average uptake of control patients. None epifascial compartment (see Table 1, Figs. 2,3). showed a reduced uptake. Subfascially, the uptake was also significantly increased Visual assessment: Each of 18 patients compared with the controls as well as those showed both epifascially and subfascially a with phleboedema (Table 1). Fig. 5 shows a substantial enhancement of the inguinal and characteristic pattern of a patient with cyclic parailiac lymph nodes (Fig. 4). The paraaortic idiopathic edema. lymph nodes were visualized in 6/18 patients. The popliteal lymph nodes were visible after Visual assessment: Lymphoscintigraphy subfascial injection in 16/18 patients and in typically showed unusually intense activity 2 patients also after epifascial injection. of regional lymph nodes involved in lymph Radioactive "bands" of the draining lymph drainage of the legs in the epifascial vessels were observed within 20 min. after compartment. In 4 of 10 patients, the labeled tracer injection. nanocolloid was detectable at the origin of the thoracic duct. Liver and spleen activity was Cyclic Idiopathic Edema also seen. Of interest, highly intense activity bands were seen in draining lymph vessels Quantitative evaluation: There was a 2 hours after injection in 5 of 10 patients significantly higher epifascial uptake in both suggestive of ongoing (increased) lymphatic

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TABLE 1 Median, 5th and 95th Percentile of the Radiotracer Uptake Values of Each Patient in Each Subgroup for Both the Epifascial and Subfascial Compartment. A Significant Statistical Difference Between a Given Group and Control Subjects is Marked with *, and with Cyclic Idiopathic Edema with ... , and Phleboedema with ••

Epifascial Subfascial

5th 95th 5th 95th Patients median percentile percentile median percentile percentile Controls ....13.0% 11.8% 13.5% 7.0%... 5.6% 9.0% Cyclic idiopathic edema 27.2% 23.0% 34.5% 19.2% 11.9% 23.9% * * • Phleboedema 20.4% 17.5% 33.5% 6.1% 2.1% 18.5% * ... Post-thrombotic syndrome 6.3% 1.8% 24.5% 0.4% 0.2% 0.7% ...... * Lipedema (obesity) ....12.7% 9.3% 16.8% ...5.9% 4.7% 8.1%

TABLE 2 Comparison of the Scintigraphic Results with the Functional State in Different Forms of Leg Edema. The Lymph Transport Rates, as Quantified by Two Compartment Lymphoscintigraphy.

Leg Edema Lymph Transport Pathophysiological comments

subfascial epifascial subfascial epifascial

Lymphedema* - N low volume (lymph) low volume (lymph) overload; - insufficiency in the first four months transport rates often are normal* Lipedema (obesity) N N unchanged but lymphatics may be involved with both low and high volume insufficiency

Cyclic idiopathic edema + + high volume (lymph) high volume (lymph) overload insufficiency Varicosities with N + no changes in high volume (lymph) overload patient deep veins N lymph transport Post-thrombotic syndrome - + safety valve high volume (lymph) overload (deep varicosities) N (lymphatic) early; safety lymphatic valve insufficiency insufficiency, superimposed late

N = Normal + = Increased, - = Decreased. *The data for lymphedema were taken from a previous report (25).

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Fig. 4. Normal scintigraphic findings (control). Epifascially, the inguinal and R L 'R L parailiac lymph nodes are well visualized with intact lymphatic drainage. sub fa-,'s cia epifas.ci'a Subfascially, the popliteal lymph nodes are also visible in most patients. The tracer uptake values are shown (% of injected dose).

transport of the radiopharmaceutical. Visual assessment: Epifascially, normal Subfascially, patients uniformly showed storage activity was seen in 4 patients. In the bilaterally good enhancement of the regional remaining 3, the storage was intense on the lymph nodes. affected side. In one patient, the radiopharmaceutical was found at the origin of the Phleboedema thoracic duct suggestive of accelerated lymph transport. Two patients showed supramalleolar Quantitative evaluation: Epifascially, activity at a site with lipodermatosclerotic uptake was significantly increased compared changes. Subfascially, all 7 patients showed with the control groups suggesting accele- well demarcated inguinal and parailiac rated lymph transport. Subfascially, the lymph nodes. uptake was similar to those of the control group (Table 1).

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Fig. 5. Two compartment lymphoscin- ?lJ.t;,fas'c.jC) I tigraphy in a 33-year old woman with ...... :'\ '. .. ' .. .. cyclic idiopathic edema. The scintigram .' .-" /> .. shows a symmetrical, "supernormal" •... enhanced uptake in lymph nodes '.. ,., '.; :'. '.' .": .. ' . .' . draining the legs suggestive of accelerated lymph transport. Increased lymphatic drainage is also suggested by activity in the distal thoracic duct (arrowhead), likely representing physiologic "pooling" before entry into the bloodstream. As the scintigrams display, radio tracer uptake values are increased bilaterally as lymph transport is accelerated with high lymph volume overload (dynamic insufficiency).

'; " .

.: ......

. ; .... ". ':.'

R v L

Deep Venous Occlusion (Post-Thrombotic Visual assessment: In the 11 patients Syndrome) with post-thrombotic syndrome, the inguinal lymph nodes were either not or just faintly Quantitative evaluation: Subfascially, seen. Epifascially, on the other hand, the uptake was sharply reduced (<1.5%) in each uptake in the inguinal lymph nodes was well of 11 patients (Fig. 2). In contrast, radiotracer depicted in most of the patients (Fig. 6). Only uptake was within the normal range or higher in 3 patients with longstanding skin ulceration epifascially in 5 patients who had developed were the regional lymph nodes not visualized. deep vein thrombosis within the last few In 5 of 9 patients after epifascial injection, years. In the other 6 patients with advanced lymphatic drainage was impaired only above lipodermatosderotic and ulcerated skin the malleolus at a site where lymph vessels changes, the epifascial uptake was reduced were likely obliterated by ulceration. (Fig. 3).

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Fig. 6. A 49-year old patient with deep femoral venous occlusion (post- thrombotic syndrome) in the right leg for 6 years and on the left for 5 years. The scintigram shows good epifascial lymph drainage on both sides although prominent supra malleolar dermal backflow is demonstrable. This local disturbance of lymph drainage corresponds to ulceration of the skin. In contrast, subfascially the inguinal lymph nodes are poorly seen suggesting damage to the subfascial lymphatic system.

R v L R v L

Obesity (Upedema) Proper assessment of peripheral edema requires entertaining a variety of causative Quantitative evaluation: The uptake of factors. Among these are chronic superficial these 9 patients was similar to that of the venous insufficiency, deep vein thrombosis control group (Table 1, Figs. 2,3). (post-thrombotic syndrome), lymphedema, lipedema or obesity, and cyclic idiopathic Visual assessment: Each patient edema (2). There are often several indeter- displayed a normal and usually symmetrical minant forms of edema, in which the lymph transport in both compartments with individual etiologic components can not be normal activity of the draining lymph nodes. easily distinguished. If not properly A regional lymph transport disturbance was recognized, undue consequences may arise. not observed. For example, where venous or phleboedema is combined with primary lymphedema, DISCUSSION venous stripping and ligation may result in

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY . 52 severe worsening of the peripheral edema, work of lymphatics, which is pathophysio- especially the lymphedema component. logically similar to the situation in cyclic Scintigraphic assessment of the lymphatic idiopathic edema. system is therefore strongly recommended. Radiotracer active retention at the site of Electron microscopy suggests that cyclic local trophic skin disturbances was detected idiopathic edema derives from a microangio- in some patients. These localized lymph pathy (2) with increased permeability for transport disturbances, however, did not plasma protein leakage and subsequent high necessarily reflect global lymphatic volume lymphatic overload (dynamic insuffi- dysfunction. Tiedjen et al (15) found localized ciency). Two compartment lymphoscintigraphy disturbances of epifasciallymph drainage demonstrates this phenomenon in cyclic without impaired lymph transport in nearly idiopathic edema. A previous report suggested every patient with phleboedema. that normal findings occurred in 2 patients The functional implications of epifascial (12), but these findings were based solely on high volume insufficiency have a morpho- visual and not semiquantitative analysis. logical counterpart in the lymphographic The observed differences between the investigations of Battezzati (16) and Nitzsche slight increase in subfascial uptake and the (17) and their coworkers. They described more prominent epifascial increase in uptake lymphographically dilated and elongated may relate to the fact that greater interstitial lymph collectors with postvalvular dilatation. fluid drainage from the subfasciallymphatic Vitek and Kaspar (18) examined the system is less well handled and that in cyclic subfascial compartment by lymphography. idiopathic edema, the lymph transport They found that in phleboedema, 11 of 12 capacity decreases subfascially before that in patients had morphologically normal lymph the epifascial compartment. A similar mecha- vessels. In contrast to the epifascial, the nism may pertain to primary lymphedema, subfascial compartment exhibited only minor which may lead to a form of subclinical localized dilatations of lymph collectors (18). compartment syndrome (5,6,11). These morphological findings correlate well Analysis of lymphatic drainage by two with our scintigraphic studies, which show compartment lymphoscintigraphy shows that normal subfasciallymph transport in most of high lymph volume overload (dynamic these patients. insufficiency) in cyclic idiopathic edema is In phlebological disorders, our results demonstrable by this technique. In contrast to demonstrate the importance of the lymphatic a high volume overload, the lymphoscin- circulatory system as an important alterna- tigraphic criteria are different in low lymph tive pathway for removal of excess tissue volume impairment (lymphedema). The fluid. In deep venous occlusive disease (post- differential diagnostic criteria in mixed thrombotic syndrome), two compartment forms, for example, a combination of lymphoscintigraphy demonstrated a marked lymphedema and cyclic idiopathic edema, functional disturbance of lymphatic trans- are shown in Table 2 (2,5). port. The pathophysiological disturbance is An accelerated lymph transport in the characterized by an increased lymph load in epifascial compartment observed in phleboe- the presence of reduced lymphatic transport dema results from increased microvascular capacity (Le., termed safety valve insuffi- hydrostatic pressure, and an increase in the ciency) (2). lymphatic load from increased transcapillary Subfascially, each patient studied showed filtration. Similar findings have been markedly reduced lymph transport (Fig. 2). described after radiotracer studies by Impaired lymph transport secondary to Jacobsson and Feldmann (13) and Seki et al venous thrombosis is lymphoscintigraphically (14). These investigators report increased demonstrable shortly after deep vein

Permission granted for single print for individual use. Reproduction not permitted without permission of Journal LYMPHOLOGY . 53 thrombosis of the leg (19). With deep vein becomes clinically important when post- thrombosis, there is acute venous hyper- traumatic edema is examined. The most tension which apparently damages adjacent common differential diagnosis in this lymph vessels by direct mechanical and situation consists of edema from deep venous inflammatory effects (20). Therefore, the occlusion with or without secondary lymphatic transport capacity is reduced at lymphedema (7). Using two compartment the same time the lymph load is increased lymphoscintigraphy, this distinction can be (15,21). readily made (Table 2). Epifascially, a uniform lymphoscin- All patients with pure lipedema (obesity) tigraphic pattern was not observed. There showed normal lymph transport rates in both was, however, a relation between the status the epifascial and subfascial compartments of the lymphatic transport capacity and the confirming previous reports (24,25). In complication rate and duration of the contrast, Bilancini et al (26) observed an underlying disorder. That the epifascial asymmetricallymphoscintigraphic lymphatic transport may be normal or appearance of the inguinal lymph nodes and accelerated in uncomplicated disease has decreased lymph drainage. These results are previously been recognized (15,22). The similar to findings in lymphedema. findings in the epifascial compartment are Nevertheless, such asymmetry, especially by probably explained by venous hypertension quantification of number of lymph nodes, is secondary to insufficient perforating veins. not indicative of the function of the Venous hypertension leads to a high lymph lymphatic system and has not been taken into volume overload or phlebo-lymphodynamic consideration as a proper indicator of insufficiency from increased blood capillary lymphedema in lymphoscintigraphy by others filtration and increased production of lymph (5,6,19,25). (2). As the disease progresses and complica- A transition from pure lipedema to tions ensue (e.g., recurring skin ulceration), lipo-lymphedema and to lymphedema is the epifasciallymphatic transport capacity recognized (2). The sluggish lymph transport and subsequently the lymph transport rate in lipedema, as observed by Bilancini et al decreases. This outcome is likely due to (26), is probably traceable to a lymphe- persistent overburdening of and local dematous component in patients with destruction of lymphatics (dermatolipo- lipedema. Tiejen et al also regarded lipedema sclerosis and skin ulceration) (2,19). In this as a "risk factor" for lymphostatic edema situation, high lymph volume overload (24). This concept is supported by the (dynamic insufficiency) deteriorates into a lymphatic distribution found after indirect functionally less favorable condition termed lymphography at the injection site and by safety valve insufficiency of the lymph remarkably large caliber lymph collectors circulation (2). (20). Again, these morphologic changes are Deep venous occlusion (post-thrombotic not necessarily indicative of functional syndrome) shows coexistent functional abnormalities as no alterations in lymphatic involvement of the lymphatic system as function were seen in pure lipedema. exemplified by two compartment lymphoscin- It is important to recognize that no clear tigraphy. The lymph system is an important cut difference can be detected on lymphoscin- component in post-thrombotic syndrome, tigraphy between a normal functional state which at least during the early phase, tends and a minor functional alteration in lymph to mitigate the edematogenic effect of deep transport. Patients with varicose and vein thrombosis by a compensatory increase epifascial high volume overload (dynamic of lymph transport in the epifascial insufficiency) may have uptake tracer values compartment (23). This phenomenon within the normal range reflecting

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