# 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