CHAPTER 48: CHRONIC VENOUS DISEASE AND LYMPHEDEMA

Chronic venous diseases range from telangiectasias and reticular veins, to varicose veins, to chronic venous insufficiency with edema, skin changes, and ulceration. This section of the chapter will focus on identification and treatment of varicose veins and chronic venous insufficiency, since these problems are encountered frequently by the internist. The estimated prevalence of varicose veins in the United States is approximately 15% in men and 30% in women. Chronic venous insufficiency with edema affects approximately 7.5% of men and 5% of women, and the prevalence increases with age ranging from 2% among those less than 50 years of age to 10% of those 70 years of age. Approximately 20% of patients with chronic venous insufficiency develop venous ulcers.

Veins in the extremities can be broadly classified as either superficial or deep. The superficial veins are located between the skin and deep fascia. In the legs, these include the great and small saphenous veins and their tributaries. The great saphenous vein is the longest vein in the body. It originates on the medial side of the foot and ascends anterior to the medial malleolus and then along the medial side of the calf and thigh, and drains into the common femoral vein. The small saphenous vein originates on the dorsolateral aspect of the foot, ascends posterior to the lateral malleolus and along the posterolateral aspect of the calf, and drains into the popliteal vein. The deep veins of the leg accompany the major arteries. There are usually paired peroneal, anterior tibial, and posterior tibial veins in the calf, which converge to form the popliteal vein. Soleal tributary veins drain into the posterior tibial or peroneal veins, and gastrocnemius tributary veins drain into the popliteal vein. The popliteal vein ascends in the thigh as the femoral vein. The confluence of the femoral vein and deep femoral vein form the common femoral vein, which ascends in the pelvis as the external iliac and then common iliac vein, which converges with the contralateral common iliac vein at the inferior vena cava. Perforating veins connect the superficial and deep systems in the legs at multiple locations, normally allowing blood to flow from the superficial to deep veins. In the arms, the superficial veins include the basilic, cephalic, and median cubital veins and their tributaries. The basilic and cephalic veins course along the medial and lateral aspects of the arm, respectively, and these are connected via the median cubital vein in the antecubital fossa. The deep veins of the arms accompany the major arteries and include the radial, ulnar, brachial, axillary, and subclavian veins. The subclavian vein converges with the internal jugular vein to form the brachiocephalic vein, which joins the contralateral brachiocephalic vein to form the superior vena cava. Bicuspid valves are present throughout the venous system to direct the flow of venous blood centrally.

Pathophysiology of chronic venous disease

Varicose veins are dilated, bulging, tortuous superficial veins, measuring at least 3 mm in diameter. The smaller and less tortuous reticular veins are dilated intradermal veins, which appear blue-green, measure 1 to 3 mm in diameter, and do not protrude from the skin surface. Telangiectasias, or spider veins, are small, dilated veins, less than 1 mm in diameter, located near the skin surface, and form blue, purple, or red linear, branching, or spider-web patterns.

Varicose veins can be categorized as primary or secondary. Primary varicose veins originate in the superficial system and result from defective structure and function of the valves of the saphenous veins, intrinsic weakness of the vein wall, and high intraluminal pressure. Approximately one-half of these patients have a family history of varicose veins. Other factors associated with primary varicose veins include aging, pregnancy, hormonal therapy, obesity, and prolonged standing. Secondary varicose veins result from venous hypertension, associated with deep venous insufficiency or deep venous obstruction, and incompetent perforating veins that cause enlargement of superficial veins. Arteriovenous fistulas also cause varicose veins in the affected limb.

Chronic venous insufficiency is a consequence of incompetent veins in which there is venous hypertension and extravasation of fluid and blood elements into the tissue of the limb. It may occur in patients with varicose veins but usually is caused by disease in the deep veins. It also is categorized as primary or secondary. Primary deep venous insufficiency is a consequence of an intrinsic structural or functional abnormality in the vein wall or venous valves leading to valvular reflux. Secondary deep venous insufficiency is caused by obstruction and/or valvular incompetence from previous deep vein thrombosis (Chap. 45). Deep venous insufficiency occurs following deep vein thrombosis, as the delicate valve leaflets become thickened and contracted and can no longer prevent retrograde flow of blood and the vein itself becomes rigid and thick walled. Although most veins recanalize after an episode of thrombosis, the large proximal veins may remain occluded. Secondary incompetence develops in distal valves because high pressures distend the vein and separate the leaflets. Other causes of secondary deep venous insufficiency include May-Thurner syndrome, where the left iliac vein is occluded or stenosed by extrinsic compression from the overlapping right common iliac artery; arteriovenous fistulas resulting in increased venous pressure; congenital deep vein agenesis or hypoplasia; and venous malformations as may occur in Klippel-Trénaunay-Weber and Parkes-Weber syndromes.

Clinical presentation

Patients with venous varicosities are often asymptomatic but still concerned about the cosmetic appearance of their legs. Superficial venous thrombosis may be a recurring problem, and, rarely, a varicosity ruptures and bleeds. Symptoms in patients with varicose veins or venous insufficiency, when they occur, include a dull ache, throbbing or heaviness, or pressure sensation in the legs typically after prolonged standing; these symptoms usually are relieved with leg elevation. Additional symptoms may include cramping, burning, pruritus, leg swelling, and skin ulceration.

The legs are examined in both the supine and standing positions. Visual inspection and palpation of the legs in the standing position confirm the presence of varicose veins. The location and extent of the varicose veins should be noted. Edema, stasis dermatitis, and skin ulceration near the ankle may be present if there is superficial venous insufficiency and venous hypertension. Findings of deep venous insufficiency include increased leg circumference, venous varicosities, edema, and skin changes. The edema, which is usually pitting, may be confined to the ankles, extend above the ankles to the knees, or involve the thighs in severe cases. Over time, the edema may become less pitting and more indurated. Dermatologic findings associated with venous stasis include hyperpigmentation, erythema, eczema, lipodermatosclerosis, atrophie blanche, and a phlebectasia corona. Lipodermatosclerosis is the combination of induration, hemosiderin deposition, and inflammation, and typically occurs in the lower part of the leg just above the ankle. Atrophie blanche is a white patch of scar tissue, often with focal telangiectasias and a hyperpigmented border; it usually develops near the medial malleolus. A phlebectasia corona is a fan-shaped pattern of intradermal veins near the ankle or on the foot. Skin ulceration may occur near the medial and lateral malleoli. A venous ulcer is often shallow and characterized by an irregular border, a base of granulation tissue, and the presence of exudate (Fig. 48-1).

Bedside maneuvers can be used to distinguish primary varicose veins from secondary varicose veins caused by deep venous insufficiency. With the contemporary use of venous ultrasound (see below), however, these maneuvers are employed infrequently. The Brodie-Trendelenburg test is used to determine whether varicose veins are secondary to deep venous insufficiency. As the patient is lying supine, the leg is elevated and the veins allowed to empty. Then, a tourniquet is placed on the proximal part of the thigh and the patient is asked to stand. Filling of the varicose veins within 30 s indicates that the varicose veins are caused by deep venous insufficiency and incompetent perforating veins. Primary varicose veins with superficial venous insufficiency are the likely diagnosis if venous refilling occurs promptly after tourniquet removal. The Perthes test assesses the possibility of deep venous obstruction. A tourniquet is placed on the midthigh after the patient has stood, and the varicose veins are filled. The patient is then instructed to walk for 5 min. A patent deep venous system and competent perforating veins enable the superficial veins below the tourniquet to collapse. Deep venous obstruction is likely to be present if the superficial veins distend further with walking.

Differential diagnosis

The duration of leg edema helps to distinguish chronic venous insufficiency from acute deep vein thrombosis. Lymphedema, as discussed later in this chapter, is often confused with chronic venous insufficiency, and both may occur together. Other disorders that cause leg swelling should be considered and excluded when evaluating a patient with presumed venous insufficiency. Bilateral leg swelling occurs in patients with congestive heart failure, hypoalbuminemia secondary to nephrotic syndrome or severe hepatic disease, myxedema caused by hypothyroidism or pretibial myxedema associated with Graves’ disease, and with drugs such as dihydropyridine calcium channel blockers and thiazolidinediones. Unilateral causes of leg swelling also include ruptured leg muscles, hematomas secondary to trauma, and popliteal cysts. Cellulitis may cause erythema and swelling of the affected limb. Leg ulcers may be caused by severe peripheral artery disease and critical limb ischemia; neuropathies, particularly those associated with diabetes; and less commonly, skin cancer, vasculitis, or rarely as a complication of hydroxyurea. The location and characteristics of venous ulcers help to differentiate these from other causes.

Classification of chronic venous disease

The CEAP (clinical, etiologic, anatomic, pathophysiologic) classification schema incorporates the range of symptoms and signs of chronic venous disease to characterize its severity. It also broadly categorizes the etiology as congenital, primary, or secondary; identifies the affected veins as superficial, deep, or perforating; and characterizes the pathophysiology as reflux, obstruction, both, or neither (Table 48-1).

Diagnostic testing

The principal diagnostic test to evaluate patients with chronic venous disease is venous duplex ultrasonography. A venous duplex ultrasound examination uses a combination of B-mode imaging and spectral Doppler to detect the presence of venous obstruction and venous reflux in superficial and deep veins. Color-assisted Doppler ultrasound is useful to visualize venous flow patterns. Obstruction may be diagnosed by absence of flow, the presence of an echogenic thrombus within the vein, or failure of the vein to collapse when a compression maneuver is applied by the sonographer, the last implicating the presence of an intraluminal thrombus. Venous reflux is detected by prolonged reversal of venous flow direction during a Valsalva maneuver, particularly for the common femoral vein or saphenofemoral junction, or after compression and release of a cuff placed on the limb distal to the area being interrogated.

Some vascular laboratories use air or strange gauge plethysmography to assess the severity of venous reflux and complement findings from the venous ultrasound examination. Venous volume and venous refilling time are measured when the legs are placed in a dependent position and after calf exercise to quantify the severity of venous reflux and the efficiency of the calf muscle pump to affect venous return.

Magnetic resonance, computed tomographic, and conventional venography are rarely required to determine the cause and plan treatment for chronic venous insufficiency unless there is suspicion for pathology that might warrant intervention. These modalities are used to identify obstruction or stenosis of the inferior vena cava and iliofemoral veins, as may occur in patients with previous proximal deep vein thrombosis; occlusion of inferior vena cava filters; extrinsic compression from tumors; and May-Thurner syndrome.

TREATMENT

Lymphedema

Lymphedema is a chronic condition caused by impaired transport of lymph and characterized by swelling of one or more limbs and occasionally the trunk and genitalia. Fluid accumulates in interstitial tissues when there is an imbalance between lymph production and lymph absorption, a process governed in large part by Starling forces. Deficiency, reflux, or obstruction of lymph vessels perturbs the ability of the lymphatic system to reabsorb proteins that had been filtered by blood vessels, and the tissue osmotic load promotes interstitial accumulation of water. Persistent lymphedema leads to inflammatory and immune responses characterized by infiltration of mononuclear cells, fibroblasts, and adipocytes, leading to adipose and collagen deposition in the skin and subcutaneous tissues.

Lymphatic anatomy

Lymphatic capillaries are blind-ended tubes formed by a single layer of endothelial cells. The absent or widely fenestrated basement membrane of lymphatic capillaries allows access to interstitial proteins and particles. Lymphatic capillaries merge to form microlymphatic precollector vessels, which contain few smooth muscle cells. The precollector vessels drain into collecting lymphatic vessels, which comprise endothelial cells, a basement membrane, smooth muscle, and bileaflet valves. The collecting lymphatic vessels in term merge to form larger lymphatic conduits. Analogous to venous anatomy, there are superficial and deep lymphatic vessels in the legs, which communicate at the popliteal and inguinal lymph nodes. Pelvic lymphatic vessels drain into the thoracic duct, which ascends from the abdomen to the thorax and connects with the left brachiocephalic vein. Lymph is propelled centrally by the phasic contractile activity of lymphatic smooth muscle and facilitated by the contractions of contiguous skeletal muscle. The presence of lymphatic valves ensures unidirectional flow.

Etiology

Lymphedema may be categorized as primary or secondary (Table 48-2). The prevalence of primary lymphedema is approximately 1.15 per 100,000 persons less than 20 years of age. Females are affected more frequently than males. Primary lymphedema may be caused by agenesis, hypoplasia, hyperplasia, or obstruction of the lymphatic vessels. There are three clinical subtypes: congenital lymphedema, which appears shortly after birth; lymphedema praecox, which has its onset at the time of puberty; and lymphedema tarda, which usually begins after age 35. Familial forms of congenital lymphedema (Milroy’s disease) and lymphedema praecox (Meige’s disease) may be inherited in an autosomal dominant manner with variable penetrance; autosomal or sex-linked recessive forms are less common. Mutations in genes expressing vascular endothelial growth factor receptor 3 (VEGFR3), which is a determinant of lymphangiogenesis, have been described in patients with Milroy’s disease. A mutation on chromosome 15q is associated with the cholestasis-lymphedema syndrome. A mutation in the FOXC2 gene, which encodes a transcription factor that interacts with a signaling pathway involved in the development of lymphatic vessels, has been reported in patients with the lymphedema-distichiasis syndrome, in which lymphedema praecox occurs in patients who also have a double row of eyelashes. A mutation of SOX18, a transcription factor upstream of lymphatic endothelial cell differentiation, has been described in patients with lymphedema, alopecia, and telangiectasias (hypotrichosis, lymphedema, telangiectasia syndrome). Patients with a chromosomal aneuploidy, such as Turner’s syndrome, Klinefelter’s syndrome, or trisomy 18, 13, or 21, may develop lymphedema. Syndromic vascular anomalies associated with lymphedema include Klippel-Trénaunay syndrome, Parkes-Weber syndrome, and Hennekam’s syndrome. Other disorders associated with lymphedema include Noonan’s syndrome, yellow nail syndrome, intestinal lymphangiectasia syndrome, lymphangiomyomatosis, and neurofibromatosis type 1.

Secondary lymphedema is an acquired condition that results from damage to or obstruction of previously normal lymphatic channels. Recurrent episodes of bacterial lymphangitis, usually caused by streptococci, are a very common cause of lymphedema. The most common cause of secondary lymphedema worldwide is lymphatic filariasis, affecting approximately 129 million children and adults worldwide and causing lymphedema and elephantiasis in 14 million of these affected individuals. Recurrent bacterial lymphangitis by Streptococcus may result in chronic lymphedema. Other infectious causes include lymphogranuloma venereum and tuberculosis. In developed countries, the most common secondary cause of lymphedema is surgical excision or irradiation of axillary and inguinal lymph nodes for treatment of cancers, such as breast, cervical, endometrial, and prostate cancer, sarcomas, and malignant melanoma. Lymphedema of the arm occurs in 13% of breast cancer patients after axillary node dissection and in 22% after both surgery and radiotherapy. Lymphedema of the leg affects approximately 15% of patients with cancer after inguinal lymph node dissection. Tumors, such as prostate cancer and lymphoma, also can infiltrate and obstruct lymphatic vessels. Less common causes include contact dermatitis, rheumatoid arthritis, pregnancy, and self-induced or factitious lymphedema after application of tourniquets.

Clinical presentation

Lymphedema is generally a painless condition, but patients may experience a chronic dull, heavy sensation in the leg, and most often they are concerned about the appearance of the leg. Lymphedema of the lower extremity initially involves the foot and gradually progresses up the leg so that the entire limb becomes edematous (Fig. 48-2). In the early stages, the edema is soft and pits easily with pressure. Over time, subcutaneous adipose tissue accumulates, the limb enlarges further and loses its normal contour, and the toes appear square. Thickening of the skin is detected by Stemmer’s sign, which is the inability to tent the skin at the base of the toes. Peau d’orange is a term used to describe dimpling of the skin, resembling that of an orange peel, caused by lymphedema. In the chronic stages, the edema no longer pits and the limb acquires a woody texture as the tissues become indurated and fibrotic. The International Society of Lymphology describes four clinical stages of lymphedema (Table 48-3).

Differential diagnosis

Lymphedema should be distinguished from other disorders that cause unilateral leg swelling, such as deep vein thrombosis and chronic venous insufficiency. In the latter condition, the edema is softer, and there is often evidence of a stasis dermatitis, hyperpigmentation, and superficial venous varicosities, as described earlier. Other causes of leg swelling that resemble lymphedema are myxedema and lipedema. Lipedema usually occurs in women and is caused by accumulation of adipose tissue in the leg from the thigh to the ankle with sparing of the feet.

Diagnostic testing

The evaluation of patients with lymphedema should include diagnostic studies to clarify the cause. Abdominal and pelvic ultrasound and computed tomography (CT) can be used to detect obstructing lesions such as neoplasms. Magnetic resonance imaging (MRI) of the affected limb may reveal a honeycomb pattern characteristic of lymphedema in the epifascial compartment and identify enlarged lymphatic channels and lymph nodes. MRI also is useful to distinguish lymphedema from lipedema. Lymphoscintigraphy and lymphangiography are rarely indicated, but either can be used to confirm the diagnosis or differentiate primary from secondary lymphedema. Lymphoscintigraphy involves the injection of radioactively labeled technetium-containing colloid into the distal subcutaneous tissue of the affected extremity, which is imaged with a scintigraphic camera to visualize lymphatic vessels and lymph nodes. Findings indicative of primary lymphedema include absent or delayed filling of the lymphatic vessels or dermal back flow caused by lymphatic reflux. Findings of secondary lymphedema include dilated lymphatic vessels distal to an area of obstruction. In lymphangiography, iodinated radiocontrast material is injected into a distal lymphatic vessel that has been isolated and cannulated. In primary lymphedema, lymphatic channels are absent, hypoplastic, or ectatic. In secondary lymphedema, lymphatic channels often appear dilated beneath the level of obstruction. The complexities of lymphatic cannulation and the risk of lymphangitis associated with the contrast agent limit the utility of lymphangiography. A novel technique of optical imaging with a near-infrared fluorescence dye may enable quantitative imaging of lymph flow.