56 - 293 Chronic Venous Disease and Lymphedema

293 Chronic Venous Disease and Lymphedema

■ ■ERYTHROMELALGIA This disorder is characterized by burning pain and erythema of the extremities (Fig. 292-3E). The feet are involved more frequently than the hands, and males are affected more frequently than females. Eryth­ romelalgia may occur at any age but is most common in middle age. It may be primary (also termed erythermalgia) or secondary. Mutations in the SCN9A gene, which encodes the Nav1.7 voltage-gated sodium chan­ nel expressed in sensory and sympathetic nerves, have been described in inherited forms of erythromelalgia. The most common causes of sec­ ondary erythromelalgia are myeloproliferative disorders such as polycy­ themia vera and essential thrombocytosis. Less common causes include drugs, such as calcium channel blockers, bromocriptine, and pergolide; neuropathies; connective tissue diseases such as SLE; and paraneoplas­ tic syndromes. Patients complain of burning in the extremities that is precipitated by exposure to a warm environment and aggravated by a dependent position. The symptoms are relieved by exposing the affected area to cool air or water or by elevation. Erythromelalgia can be distinguished from ischemia secondary to peripheral arterial disorders because the peripheral pulses are present. There is no specific treatment; aspirin may produce relief in patients with erythromelalgia secondary to myeloproliferative disease. Topical anesthetics, such as lidocaine, or a combination of amitriptyline and ketamine may be considered to relieve pain. Topical midodrine may also be considered. Treatment of associ­ ated disorders in secondary erythromelalgia may be helpful. ■ ■FROSTBITE In this condition, tissue damage results from severe environmental cold exposure or from direct contact with a very cold object. Tissue injury results from both freezing and vasoconstriction. Frostbite usu­ ally affects the distal aspects of the extremities or exposed parts of the face, such as the ears, nose, chin, and cheeks. Superficial frostbite involves the skin and subcutaneous tissue. Patients experience pain or paresthesia, and the skin appears white and waxy. After rewarming, there is cyanosis and erythema, wheal-and-flare formation, edema, and superficial blisters. Deep frostbite involves muscle, nerves, and deeper blood vessels. It may result in edema of the hand or foot, vesicles and bullae, tissue necrosis, and gangrene (Fig. 292-3F). Initial treatment is rewarming, performed in an environment where reexposure to freezing conditions will not occur. Rewarming is accom­ plished by immersion of the affected part in a water bath at tempera­ tures of 40°–44°C (104°–111°F). Massage, application of ice water, and extreme heat are contraindicated. The injured area should be cleansed with soap or antiseptic, and sterile dressings should be applied. Analge­ sics are often required during rewarming. Antibiotics are used if there is evidence of infection. The efficacy of sympathetic blocking drugs is not established. After recovery, the affected extremity may exhibit increased sensitivity to cold. ■ ■FURTHER READING Aboyans V et al: Antithrombotic therapies in aortic and peripheral arterial diseases in 2021: A consensus document from the ESC work­ ing group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and the ESC working group on cardiovascular pharmacotherapy. Eur Heart J 42:4013, 2021. Aday AW, Matsushita K: Epidemiology of peripheral artery disease and polyvascular disease. Circ Res 128:1818, 2021. Bonaca M et al: Contemporary medical management of peripheral artery disease. Circ Res 128:1868, 2021. Choi E, Henkin S: Raynaud’s phenomenon and related vasospastic disorders. Vasc Med 26:56, 2021. Creager MA et al: Reducing nontraumatic lower-extremity amputa­ tions by 20% by 2030: Time to get to our feet: A policy statement from the American Heart Association. Circulation 143:e875, 2021. GBD 2019 Peripheral Artery Disease Collaborators: Global burden of peripheral artery disease and its risk factors, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Glob Health 11:e1553, 2023. Gornik HL et al: First International Consensus on the diagnosis and management of fibromuscular dysplasia. Vasc Med 24:164, 2019.

Gornik HL et al: 2024 AHA/ACC guideline on the management of

patients with lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Associa­ tion Task Force on Clinical Practice Guidelines. Circulation. JACC 83:2497, 2024. Polonsky TS, McDermott MM: Lower extremity peripheral artery CHAPTER 293 disease without chronic limb-threatening ischemia. A review. JAMA 325:2188, 2021. Chronic Venous Disease and Lymphedema Mark A. Creager, Robert T. Eberhardt,

Joseph Loscalzo

Chronic Venous Disease

and Lymphedema ■ ■CHRONIC VENOUS DISEASE 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 ~15% in men and 30% in women. Chronic venous insufficiency with edema affects ~7.5% of men and 5% of women, and the prevalence increases with age ranging from 2% among those <50 years of age to 10% of those 70 years of age. Approximately 20% of patients with chronic venous insufficiency develop venous ulcers. ■ ■VENOUS ANATOMY 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 accom­ pany 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 pop­ liteal 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 con­ nect 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 subcla­ vian vein converges with the internal jugular vein to form the brachio­ cephalic 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 1–3 mm in diameter, and do not protrude from the skin surface. Telangiectasias, or spider veins, are small, dilated veins, <1 mm in diameter, located near the skin surface, and form blue, purple, or red linear, branching, or spider-web patterns.

PART 6 Disorders of the Cardiovascular System 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 obstruc­ tion, 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 and superficial venous disease, but more advanced manifestations are usually caused by disease in the deep veins. It also is categorized as primary or secondary. Primary 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. 290). 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 epi­ sode of thrombosis, the large proximal veins may remain occluded. Secondary incompetence develops in valves distal to the obstruction 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; extrinsic compression from tumor or retroperitoneal fibrosis; arteriovenous fistulas resulting in increased venous pressure; congenital deep-vein agenesis or hypoplasia; and venous malformations as may occur in Klippel-Trénaunay 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. Chronic venous insufficiency is characterized by the development of edema or other skin manifesta­ tions. 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, particularly with the secondary development of lymphatic dysfunction. Dermatologic findings associated with venous stasis include hyperpig­ mentation, erythema, eczema, lipodermatosclerosis, atrophie blanche,

FIGURE 293-1  Venous insufficiency with active venous ulcer near the medial malleolus. (Courtesy of Dr. Steven Dean, with permission.) and a phlebectasia corona. Lipodermatosclerosis is the combination of induration, hemosiderin deposition, and inflammation, and typi­ cally 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 mal­ leolus. 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. 293-1). Bedside maneuvers can be used to distinguish primary varicose veins from secondary varicose veins caused by deep-venous insuffi­ ciency. With the contemporary use of venous ultrasound (see below), however, these maneuvers are employed infrequently. The BrodieTrendelenburg 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 incompe­ tent 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 distin­ guish 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 when venous insufficiency impairs lymphatic function leading to phlebo­ lymphedema. Other disorders that cause leg swelling should be con­ sidered 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, or myxedema caused by hypothyroidism or pre­ tibial 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 chronic limb threaten­ ing 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 incor­ porates the range of symptoms and signs of chronic venous disease to characterize its severity. It also broadly categorizes the etiology as primary, secondary, or congenital; identifies the affected veins as superficial, deep, or perforating; and characterizes the pathophysiology as reflux, obstruction, both, or neither (Table 293-1). Diagnostic Testing  The principal diagnostic test to evaluate patients with chronic venous disease is venous duplex ultrasonogra­ phy. 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. Colorassisted Doppler ultrasound is useful to visualize venous flow patterns. Obstruction may be diagnosed by the absence of flow, the presence of an echogenic thrombus within the vein, or failure of the vein to col­ lapse 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 dur­ ing a Valsalva maneuver, particularly for the common femoral vein or TABLE 293-1  CEAP (Clinical, Etiologic, Anatomic, Pathophysiologic) Classification Clinical Classification C0 No visible or palpable signs of venous disease C1 Telangiectasias or reticular veins C2 Varicose veins   C2r Recurrent varicose veins C3 Edema C4 Changes in skin and subcutaneous secondary to CVD   C4a Pigmentation or eczema   C4b Lipodermatosclerosis or atrophie blanche   C4c Corona phlebectatica C5 Healed venous ulcer C6 Active venous ulcer   C6r Recurrent active venous ulcer Etiologic Classification Ep Primary Es Secondary   Esi Secondary – intravenous   Ese Secondary – extravenous Ec Congenital En No cause identified Anatomic Classification As Superficial Ap Perforator Ad Deep An No venous anatomic location identified Pathophysiologic Classification Pr Reflux Po Obstruction Pr,o Reflux and obstruction Pn No pathophysiology identified Abbreviation: CVD, chronic venous disease. Source: Data from F Lurie et al: J Vasc Surg 8:342, 2020.

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 plethysmogra­ phy 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. CHAPTER 293 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. Chronic Venous Disease and Lymphedema TREATMENT Chronic Venous Disease SUPPORTIVE MEASURES Varicose veins usually are treated with conservative measures. Symptoms often decrease when the legs are elevated periodically, prolonged standing is avoided, and elastic support hose are worn. External compression with elastic stockings, multilayer elastic wraps, stretch bandages, or inelastic garments provides a counter­ balance to the hydrostatic pressure in the veins. Although compres­ sion garments may improve symptoms and are recommended in patients with healed or active venous ulceration, they are not cura­ tive and do not prevent progression of varicose veins. Graduated compression stockings with pressures of 20–30 mmHg are suitable for most patients with simple varicose veins, although higher pres­ sures may be required for patients with varicose veins and manifes­ tations of venous insufficiency such as edema and ulcers. Patients with chronic venous insufficiency also should be advised to avoid prolonged standing or sitting; frequent leg elevation is help­ ful. Graded compression therapy consisting of stockings or multi­ layered compression bandages is the standard of care for advanced chronic venous insufficiency characterized by edema, skin changes, or venous ulcers defined as CEAP clinical class C3–C6. Graduated compression stockings of 30–40 mmHg are more effective than lesser grades for healing venous ulcers. The length of stocking depends on the distribution of edema. Calf-length stockings are tolerated better by most patients, particularly elderly patients; for patients with varicose veins or edema extending to the thigh, thighlength stockings or panty hose should be considered. Exercise train­ ing, including leg muscle strengthening, may improve calf muscle pump function and antegrade venous flow, and reduce the severity of chronic venous insufficiency. Overweight and obese patients should be advised to lose weight via caloric restriction and exercise or consult an obesity specialist for more advanced therapies. In addition to a compression bandage or stocking, patients with venous ulcers also may be treated with low-adherent absorbent dressings that take up exudates while maintaining a moist environ­ ment. Other types of dressings include hydrocolloid (an adhesive dressing composed of polymers such as carboxymethylcellulose that absorbs exudates by forming a gel), hydrogel (a nonabsor­ bent dressing comprising >80% water or glycerin that moisturizes wounds), foam (an absorbent dressing made with polymers such as polyurethane), and alginate (an absorbent, biodegradable dress­ ing that is derived from seaweed), but there is little evidence that these are more effective than low-adherent absorbent dressings. The choice of specific dressing depends on the amount of drain­ age, presence of infection, and integrity of the skin surrounding the ulcer. Ulcers should be debrided of necrotic tissue. Antibiotics are not indicated unless the ulcer is infected. The multilayered com­ pression bandage or graduated compression garment is then put over the dressing.

MEDICAL THERAPIES There are no drugs approved by the U.S. Food and Drug Adminis­ tration for the treatment of chronic venous insufficiency. Diuretics may reduce edema, but at the risk of volume depletion and com­ promise in renal function. Topical steroids may be used for a short period of time to treat inflammation associated with stasis dermati­ tis. Several herbal supplements, such as horse chestnut seed extract (aescin); ruscus extract; flavonoids, including diosmin, hesperidin, or the two combined as micronized purified flavonoid fraction; and French maritime pine bark extract, are touted to have venoconstric­ tive and anti-inflammatory properties. Several meta-analyses have suggested that ruscus extract and micronized purified flavonoid fraction reduce pain, leg heaviness, and/or sensation of swell­ ing, and that micronized purified flavonoid fraction, and perhaps pentoxifylline, in conjunction with compression therapy facilitates venous ulcer healing; however, there remains insufficient evidence to recommend the general use of these substances in patients with chronic venous insufficiency.

PART 6 Disorders of the Cardiovascular System INTERVENTIONAL AND SURGICAL THERAPIES Ablative procedures, including endovenous thermal and nonther­ mal ablation, sclerotherapy, and surgery, are used to treat varicose veins in selected patients who have persistent symptoms, great saphenous vein incompetency, and complications of venous insuf­ ficiency including dermatitis, edema, and ulcers in order to treat symptoms, accelerate healing, and prevent recurrence. Ablative therapy may also be indicated for cosmetic reasons. Endovenous thermal ablation procedures of the saphenous veins include endovenous laser and radiofrequency ablation. To ablate the great saphenous vein, a catheter is placed percutaneously and advanced from the level of the knee to just below the sapheno­ femoral junction via ultrasound guidance. Thermal energy is then delivered as the catheter is pulled back. The heat injures the endo­ thelium and media and promotes thrombosis and fibrosis, resulting in venous occlusion. Average 1- and 5-year occlusion rates exceed 90% following endovenous laser therapy and are slightly less after radiofrequency ablation. Deep-vein thrombosis of the common femoral vein adjacent to the saphenofemoral junction is an uncom­ mon but potential complication of endovenous thermal ablation. Other adverse effects of thermal ablation procedures include pain, paresthesias, bruising, hematoma, and hyperpigmentation. Nonthermal ablation procedures of the saphenous veins include endovenous delivery of a cyanoacrylate tissue adhesive, which causes fibrosis, and mechanochemical ablation, which involves insertion of a rotating wire to injure the endothelium and infusion of a liquid sclerosant. One-year occlusion rates approximate or exceed 90%, respectively. Adverse effects of nonthermal ablation procedures include superficial thrombophlebitis, deep vein throm­ bosis, ecchymoses, hematomas, and hyperpigmentation. Sclerotherapy involves the injection of a chemical into a vein to cause fibrosis and obstruction. Sclerosing agents approved by the U.S. Food and Drug Administration include sodium tetradecyl sulfate, polidocanol, sodium morrhuate, and glycerin. The scleros­ ing agent is administered as a liquid or mixed with air or CO2/O2 to create a foam. It may be used to treat the great saphenous vein, but most commonly sclerotherapy is used to treat the affected tributaries of the great saphenous vein or incompetent perforating veins either as a standalone procedure or concomitant or staged with ablative procedures of the truncal superficial veins. Follow­ ing completion of the procedure, elastic bandages are applied, or 30–40 mmHg compression stockings are worn for 1–2 weeks. Average 1- and 5-year occlusion rates are 81 and 74%, respectively, following sclerotherapy. Complications are uncommon and include deep-vein thrombosis, hematomas, damage to adjacent saphenous or sural nerves, and infection. Anaphylaxis is a very rare but severe complication. Surgical therapy usually involves ligation and stripping of the great and small saphenous veins. The procedure is performed under general anesthesia. Incisions are made at the groin and the upper

calf. The great saphenous vein is ligated below the saphenofemoral junction, and a wire is inserted into the great saphenous vein and advanced distally. The proximal part of the great saphenous vein is secured to the wire and retrieved, i.e., stripped, via the calf incision. Stripping of the great saphenous vein below the knee and stripping of the small saphenous vein usually are not performed because of the respective risks of saphenous and sural nerve injury. Complica­ tions of great saphenous vein ligation and stripping include deepvein thrombosis, bleeding, hematoma, infection, and nerve injury. Recurrent varicose veins occur in up to 50% patients by 5 years, due to technical failures, deep-venous insufficiency, and incompetent perforating veins. Endovenous ablation techniques are generally favored over ligation and stripping. Stab phlebectomy is another surgical treatment for varicose veins. A small incision is made alongside the varicose vein, and it is avulsed by means of a forceps or hook. This procedure may be per­ formed in conjunction with saphenous vein ligation and stripping or thermal or nonthermal ablation. Subfascial endoscopic perfora­ tor surgery (SEPS) uses endoscopy to identify and occlude incom­ petent perforating veins. It has largely been replaced, however, by ablative techniques applied directly to the perforating veins and performed in a staged manner for persistent or recurrent symptoms after treatment for the truncal veins. Endovascular interventions, surgical bypass, and reconstruction of the valves of the deep veins are performed when feasible to treat patients with advanced chronic venous insufficiency who have not responded to other therapies. Catheter-based interventions, usu­ ally involving placement of endovenous stents, may be considered to treat some patients with chronic occlusion or stenosis of the iliac veins. Technical success rates exceed 85% in most series, and long-term patency is achieved in ~75% of these patients. Iliocaval bypass, femoroiliac venous bypass, and femorofemoral crossover venous bypass are procedures used occasionally to treat iliofemoral vein occlusion; saphenopopliteal vein bypass can be used to treat chronic femoropopliteal vein obstruction. Long-term patency rates for venous bypass procedures generally exceed 60% and are associ­ ated with improvement in symptoms. Surgical reconstruction of the valves of the deep veins and valve transfer procedures rarely are used to treat valvular incompetence. Valvuloplasty involves tightening the valve by commissural apposition. With valve trans­ fer procedures, a segment of vein with a competent valve, such as a brachial or axillary vein, or adjacent saphenous or deep femoral vein, is inserted as an interposition graft in the incompetent vein. Both valvuloplasty and vein transfer operations may result in ulcer healing in the majority of patients, although they are uncom­ monly performed and the success rates are somewhat better with valvuloplasty. 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 accumu­ lates 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 per­ turbs 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 turn 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. Superficial and deep lymphatic vessels of the arm communicate with axillary lymph nodes, and the efferent lymphatic vessels join lymphatic vessels from the head to form the right and left subclavian lymphatic trunks, which ultimately enter the right brachiocephalic vein and thoracic duct, respectively. 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 second­ ary (Table 293-2). The prevalence of primary lymphedema is ~1.15 TABLE 293-2  Causes of Lymphedema Primary Sporadic (no identified cause) Genetic disorders   Milroy’s disease (VEGFR3, VEGF-C)   Meige’s disease (gene mutation not established)   Lymphedema-distichiasis syndrome (FOXC2)   Cholestasis-lymphedema (LSC1)   Hennekam’s lymphangiectasia-lymphedema syndrome (LCCBE1)   Emberger’s syndrome-lymphedema and predisposition to AML (GATA2)   Microcephaly-lymphedema syndrome (KIF11)   Hypotrichosis-lymphedema-telangiectasia (SOX18) Chromosomal aneuploidies   Turner’s syndrome   Klinefelter’s syndrome   Trisomy 13, 18, or 21 Other disorders associated with primary lymphedema   Noonan’s syndrome   Klippel-Trénaunay syndrome   Parkes-Weber syndrome   Yellow nail syndrome   Intestinal lymphangiectasia syndrome   Lymphangiomyomatosis   Neurofibromatosis type 1 Secondary Infection   Bacterial lymphangitis (Streptococcus pyogenes, Staphylococcus aureus)   Lymphogranuloma venereum (Chlamydia trachomatis)   Filariasis (Wucheria bancrofti, Brugia malayi, B. timori)   Tuberculosis Neoplastic infiltration of lymph nodes   Lymphoma   Prostate   Others Surgery or irradiation of axillary or inguinal lymph nodes for treatment of cancer Iatrogenic   Lymphatic division (during peripheral bypass surgery, varicose vein surgery, or harvesting of saphenous veins) Miscellaneous Chronic venous insufficiency   Contact dermatitis   Podoconiosis   Rheumatoid arthritis   Pregnancy   Factitious

per 100,000 persons <20 years of age. Females are affected more fre­ quently 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. At least 19 genes are associated with inherited forms of lymphedema. Mutations in the FLT4 gene expressing vascular endothelial growth factor receptor 3 (VEGFR3), which is a determinant of lymphangiogenesis, cause Mil­ roy’s disease; and a mutation of the gene encoding VEGF-C, a ligand for VEGFR3, may cause a Milroy’s disease-like phenotype. A muta­ tion of the LSC1 gene is associated with the cholestasis-lymphedema syndrome. Mutations in the FOXC2 gene, which encodes a transcrip­ tion factor that interacts with a signaling pathway involved in the development of lymphatic vessels, cause 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). Mutations of the CCBE1 gene, which enhances the lymphangiogenic effects of VEGF-C, cause Hennekam’s lymphangiectasia-lymphedema syn­ drome, and KIF11 gene mutations are associated with microcephalylymphedema syndrome. Mutations of the GATA2 gene, which is involved in the development of lymphatic valves, cause lymphedema and a predisposition to acute myeloid leukemia. Patients with a chro­ mosomal aneuploidy, such as Turner’s syndrome, Klinefelter’s syn­ drome, or trisomy 18, 13, or 21, may develop lymphedema. Syndromic vascular anomalies associated with lymphedema also include KlippelTrénaunay syndrome and Parkes-Weber syndrome. Other disorders associated with lymphedema include Noonan’s syndrome, yellow nail syndrome, intestinal lymphangiectasia syndrome, lymphangiomyo­ matosis, and neurofibromatosis type 1.

CHAPTER 293 Chronic Venous Disease and Lymphedema 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 etiology of secondary lymphedema worldwide is lymphatic filariasis, affecting >120 million children and adults and causing lymphedema and elephantiasis in 14 million of these affected individ­ uals (Chap. 240). Recurrent bacterial lymphangitis by Streptococcus may result in chronic lymphedema. Other infectious causes include lymphogranuloma venereum and tuberculosis. A common acquired cause of lymphedema in tropical countries is podoconiosis, which results from barefoot exposure and absorption of silicate particles in soil derived from volcanic rock. In developed countries, the most common secondary cause of lymphedema is surgical excision or irra­ diation 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 ~15% of patients with cancer after inguinal lymph node dissection. Tumors, such as prostate cancer and lymphoma, also can infiltrate and obstruct lymphatic vessels. Chronic venous insufficiency is gaining recognition as a cause of lymphedema termed phlebolymphedema. Less common causes include contact dermatitis, rheumatoid arthritis, pregnancy, and self-induced or factitious lymphedema after applica­ tion of tourniquets. Clinical Presentation  Lymphedema is generally a painless condi­ tion, 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

PART 6 Disorders of the Cardiovascular System B A FIGURE 293-2  A. Lymphedema characterized by swelling of the leg, nonpitting edema, and squaring of the toes. (Courtesy of Dr. Marie Gerhard-Herman, with permission.) B. Advanced chronic stage of lymphedema illustrating the woody appearance of the leg with acanthosis and verrucous overgrowths. (Courtesy of Dr. Jeffrey Olin, with permission.) edematous (Fig. 293-2). 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 293-3). 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 lat­ ter condition, the edema is softer, and there is often evidence of a stasis dermatitis, hyperpigmentation, and superficial venous vari­ cosities, as described earlier. Other causes of leg swelling that resemble TABLE 293-3  Stages of Lymphedema Stage 0 (or Ia) A latent or subclinical condition where swelling is not evident despite impaired lymph transport. It may exist for months or years before overt edema occurs. Stage I Early accumulation of fluid relatively high in protein content that subsides with limb elevation. Pitting may occur. An increase in proliferating cells may also be seen. Stage II Limb elevation alone rarely reduces tissue swelling, and pitting is manifest. Late in stage II, the limb may or may not pit as excess fat and fibrosis supervene. Stage III Lymphostatic elephantiasis where pitting can be absent and trophic skin changes such as acanthosis, further deposition of fat and fibrosis, and warty overgrowths have developed. Source: Adapted from The 2013 Consensus Document of the International Society of Lymphology: Lymphology 46:1, 2013.

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  Physical examination is usually sufficient to establish a diagnosis of lymphedema. 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 pri­ mary 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 lym­ phatic cannulation and the risk of lymphangitis associated with the contrast agent limit the utility of lymphangiography. Optical imaging with a near-infrared fluorescence dye enables quantitative imaging of peripheral superficial lymph flow and is useful in the operative setting. TREATMENT Lymphedema Patients with lymphedema of the lower extremities must be instructed to take meticulous care of their feet and legs to prevent cellulitis and lymphangitis. Skin hygiene is important, and emol­ lients can be used to prevent drying. Prophylactic antibiotics are often helpful, and fungal infection should be treated aggressively. Patients should be encouraged to participate in physical activity, as exercise may minimize symptoms and maintain functionality; fre­ quent leg elevation can reduce the amount of edema. Psychosocial support is indicated to assist patients cope with anxiety or depres­ sion related to body image, self-esteem, functional disability, and fear of limb loss. Physical therapy, including massage to facilitate lymphatic drain­ age, may be helpful. The type of massage, termed manual lymphatic drainage, is part of comprehensive decongestive physiotherapy for lymphedema and involves mild compression of the skin of the affected extremity to dilate the lymphatic channels and enhance lymphatic motility. Multilayered, compressive bandages are applied after each massage session to reduce recurrent edema. After optimal reduction in limb volume by decongestive physiotherapy, patients can be fitted with graduated compression hose or other adjustable compression garments. Sequential intermittent pneumatic com­ pression devices can also be applied at home to facilitate reduc­ tion of the edema, improve quality of life, and reduce recurrent cellulitis. Diuretics are contraindicated and may cause depletion of intravascular volume and metabolic abnormalities. Failure to control limb edema may lead to recurrent infections, progressive trophic skin changes, and rarely a highly lethal complication of lymphangiosarcoma. Liposuction in conjunction with decongestive physiotherapy may be considered to treat lymphedema, particularly postmastectomy