Chapter 174. Cutaneous Changes in Peripheral Venous and Lymphatic Insufficiency

Chronic disease of the peripheral veins includes a spectrum of diseases ranging from edema and tenderness to venous ulceration (Box 174-1).

Anatomy

Veins are thin-walled, distensible, and collapsible structures that function to transport blood toward the heart and act as a reservoir for preventing intravascular volume overload. Microscopically, veins consist of an intima, media, and outer collagenous adventitia. All peripheral veins contain endothelium lined, semilunar, venous valves, which promote unidirectional blood flow toward the heart. Vascular endothelium is described in detail in Chapter 165 and the anatomy of the venous system of the lower extremities is described in Chapter 249.

Epidemiology

Chronic venous disease is extremely common. Although estimated costs and time lost from work have not been objectively assessed in over two decades, estimates state that 6–7 million people in the United States have evidence of venous stasis and that it accounts for 1% to 3% of the total health care budgets in countries with developed health care systems.1

Risk factors for chronic venous disease include heredity, age, female sex, obesity, pregnancy, prolonged standing, and greater height.2

Etiology and Pathogenesis

Venous ulcer occurs after failure of the calf muscle pump (Fig. 174-1). The heart pumps blood down to the foot; the calf muscle pump (when upright), returns venous blood to the heart. Venous blood from the skin and subcutis collects in the superficial venous system including the greater and lesser saphenous veins and its tributaries, moves through the fascia in a series of “perforating” or “communicating” veins, and fills the muscle-enveloped deep venous system. With muscle contraction, the deep veins are compressed; one-way valves in the deep system allow the now high pressure flow to move against gravity, and one-way valves in the perforators close to prevent pressure injury in the skin (see Fig. 174-1). In all patients with venous disease there is failure of these one-way valves and this can result in varicose veins (Fig. 174-2). The severity of venous disease is influenced by the number and distribution of incompetent valves and is worsened by any impairment of leg muscle function or ankle joint range of motion—all critical components of the calf muscle pump. Any obstruction to venous return (thrombosis, radiation fibrosis, etc.), or elevation of right atrial pressure (pulmonary hypertension, heart failure, etc.), further compromises venous return. A more detailed description of the anatomy and hemodynamics of the venous system of the lower extremities is found in Chapter 249.

The most common cause of valvular failure is thrombosis. The nidus for venous thrombosis is typically the valve cusp, and when the thrombus is lysed by plasmin, valve function is often lost as well. Calf muscle pump failure after deep venous thrombosis (DVT) is often referred to as the postphlebitic syndrome.3

Once valves fail, especially those in the perforators, high pressure blood in the deep system refluxes into the unsupported veins of the skin, there is vascular leakage of fibrinogen producing “fibrin cuffs” that may interfere with tissue nourishment, and white blood cell trapping leading to soft tissue injury, inflammation, and eventually fibrosis, as the subcutaneous fat is replaced by scar in a process described by the term lipodermatosclerosis (see Section “Cutaneous Lesions”).

Clinical Findings

History

An approach to the analysis of patients with ulcers is in Fig. 174-3.

Trauma frequently triggers the nonhealing venous ulcer. The events preceding ulceration happen insidiously over many years and may be ignored by the patient. A history of thrombosis may be missing because most episodes of lower extremity venous thrombosis are clinically silent. Relevant inquiry related to thrombosis risk should include a family history of similar problems (suggesting perhaps a familial thrombotic tendency), any episode of leg immobilization including knee or hip surgery and fractures, and any head injury associated with loss of consciousness.

Most patients complain of leg swelling, and many have been given diuretics, though the edema of venous disease, unlike the edema in salt-retaining states, like heart failure, cirrhosis, and nephrotic syndrome, does not respond to diuretics. An edematous leg not responsive to diuretic therapy is a strong clue to the diagnosis. Venous ulcers may or may not be painful.

Cutaneous Lesions

All of the clinical syndromes described are secondary to the initial valvular syndrome and are grouped into clinical categories. Once there is venous valvular failure, a rather predictable series of changes occur in the skin. The earliest (though not universal) physical finding is soft tissue tenderness, even of normal appearing skin, discovered when checking for the presence of edema by palpation. Its association with other cutaneous signs of chronic venous disease is common.

The soft tissue injury that precedes ulceration begins in the subcutis, and visible changes may not appear for some time. Frequently one notes the appearance of petechial lesions, which have the appearance of cayenne pepper sprinkled about the gaiter area. As the hemoglobin in the petechial lesions breaks down, the iron remains in the skin as hemosiderin and may lead to impressive discoloration (Fig. 174-4).

Stasis dermatitis, characterized by erythema, scaling, pruritus, erosions, oozing, crusting, and occasional vesicles may occur during any stage of chronic venous insufficiency (see Fig. 174-4). It typically occurs in the medial supramalleolar region where microangiopathy is most intense. Over time, lesions may lichenify. As 58% to 86% of patients with venous leg ulcers develop contact sensitization to topical therapies, it is important to evaluate for coexisting allergic contact dermatitis.

In lipodermatosclerosis (sclerosing panniculitis, hypodermatitis sclerodermiformis) pliable subcutaneous fat is gradually replaced by fibrosis, and the skin begins to feel indurated. This is a fibrosing panniculitis (see Chapter 70) characterized by a bound-down, indurated plaque that begins at the medial ankle and extends circumferentially around the entire leg.4 As the fibrosis increases, it may constrict and strangle the lower leg further, impeding venous and lymphatic flow and leading to brawny edema above and below the fibrosis. These late changes resemble an inverted champagne bottle (Fig. 174-4).

Varicose veins, especially noticeable when the patient is standing, and smaller varicosities appear about the dorsum of the foot and ankle (see Chapter 249). Although they are usually asymptomatic, patients may complain of symptoms of aching, cramping, itching, fatigue, and swelling that are worse with prolonged standing.

Atrophie blanche refers to skin overlying areas of fibrosis that often appears porcelain white and atrophic. Fully established lesions of atrophie blanche consist of irregular, smooth, atrophic plaques with surrounding hyperpigmentation and telangiectasias (Fig. 174-5). Although mostly related to venous stasis, atrophie blanche may also be associated with an underlying disorder of coagulation (e.g., antiphospholipid syndrome, inherited coagulopathies) livedoid vasculitis (see Chapter 163) or autoimmune disease (e.g., scleroderma, lupus erythematosus).5 Acroangiodermatitis (pseudo-Kaposi sarcoma, congenital dysplastic angiopathy, arteriovenous malformation with angiodermatitis) has purple macules, nodules, or verrucous plaques on the dorsal feet and toes of patients with long-standing venous insufficiency and mimics Kaposi sarcoma clinically and histologically. Identical lesions have been described in arteriovenous malformations of the legs, arteriovenous shunts for hemodialysis, paralyzed limbs, and amputation stumps.

Occasionally, acute inflammation of the subcutaneous fat develops in patients with venous disease, and histologically one finds an acute septal panniculitis in this setting (see Chapter 70).

Though ulceration is classically located in the gaiter area (see Fig. 174-6), venous ulcers have been described anywhere below the knee. Venous ulcers are typically tender, shallow, irregular, red-based ulcers that are always located below the knee (Figs. 174-6 and 174-7). They are usually located on the medial ankle or along the line of the long or short saphenous veins. Clinical distinction should be made with other common ulcers of the lower extremity as discussed later in this chapter and as shown in Box 174-2.

Histopathology

Histologic signs of venous hypertension include hemosiderin deposition, lobular superficial and/or deep dermal neovascularization, and fibrosis of the dermis and subcutaneous tissue in later stages. These histologic findings are found in all clinical manifestations of chronic venous disease.

Laboratory Tests and Imaging Studies

It is crucial to evaluate arterial blood flow. A useful bedside screening test is to calculate the ratio of the systolic blood pressure in the ankle (as measured by Doppler) to the systolic pressure in the brachial artery (also measured by Doppler). This “ankle/brachial index” is greater than or equal to one in normal individuals. Anything less than one is an indication of peripheral arterial disease. The lower the ratio, the more severe the arterial obstruction (see Fig. 174-3). An ankle/brachial index is reliable except in the presence of calcified vessels, which are noncompressible and therefore a true systolic pressure cannot be measured. Having excluded arterial disease as a cause of ulceration, a clinical diagnosis is sufficient for the initiation of empiric therapy in most cases. When the diagnosis is in doubt, skin biopsy may be useful. Functional testing of calf muscle pump function and venous valvular function using plethysmography is occasionally useful. Duplex Doppler ultrasonography can be useful to document valvular incompetence and to evaluate patients for possible sclerotherapy or surgery (see Chapter 249).

Differential Diagnosis

(See Box 174-2)

Complications

Recurrent ulceration is frequent. Any open wound provides a portal of entry for bacteria, and cellulitis, though infrequent, may develop at any time. Given that venous dermatitis may be extremely pruritic, and that these patients are easily sensitized to the topical agents they apply, contact dermatitis, especially due to topical antibiotics, is common. The skin is easily excoriated and may become infected.6 The advent of methicillin-resistant Staphylococcus aureus is a threat to this population. The dermatitis of venous disease may become generalized as an id reaction (see Chapter 17) and may rarely produce an exfoliative erythroderma (see Chapter 23). Many of these individuals are predisposed to thrombi, and recurrent episodes of venous thrombosis are not uncommon.

All patients with advanced venous disease have some degree of lymphatic impairment, though lymphatic impairment may also result from inherited defects in lymphatic development or destruction of lymphatics after cellulitis lymphangitis, surgical interruption, or radiation.7 Loss of lymphatic drainage from the lower leg may lead to verrucous changes and cutaneous hypertrophy, elephantiasis nostras (see Section “Acquired Lymphedema”).

Prognosis and Clinical Course

The prognosis for healing areas of ulceration and inflammation is excellent in the absence of comorbid illness that interferes with healing. The vast majority of uncomplicated patients respond well to ambulatory outpatient therapy as outlined in the section “Treatment.” Permanent changes include hemosiderosis and fibrosis that develop before the initiation of therapy. Loss of valvular function is irreversible. In the absence of continual lifelong cutaneous support in the form of inelastic wraps or elastic stockings, skin and soft tissue injury continues.

Treatment

Treatment of chronic venous insufficiency is outlined in Box 174-3. Treatment for all clinical manifestations of chronic venous insufficiency includes therapies that lower venous pressure and improve venous and lymphatic flow by mechanical means, dressings, drugs, and surgery.

Given the limitations of bed rest as an effective therapy, the focus is now on an ambulatory outpatient approach to the management of venous ulceration. Most experts agree on the essential role of compression in treating chronic venous insufficiency.8 Hence, unless there are contraindications (arterial occlusive disease or abnormal ankle–arm indexes), compression therapy should remain part of any treatment regimen for chronic venous disease.

Toward the end of the nineteenth century, Paul Gerson Unna recognized that by providing a compression bandage to the distal extremity he could heal venous ulcers in an ambulatory patient population using zinc impregnated gauze wrap, the “Unna boot.” Though the literature over the years continued to document the success of this approach, it proved difficult to achieve graduated compression with this wrap, and compliance was poor. Eventually, the addition of a self-adherent second layer (Coban™, for example) over a zinc wrap was introduced as the “Duke boot” and has proven to be easy to apply with reproducible graduated inelastic compression (Fig. 174-8) bandaging to counter the outflow from perforator incompetence is the cornerstone of venous ulcer management.9

In 1962, George Winter reported the use of an occlusive layer enhanced healing in a pig model of acute wounds. His data suggested a roughly 100% improvement in the rate of wound healing simply by providing a moist environment. The impact on wound care has been dramatic. There are now thousands of such dressings on the market and although they differ in composition, absorption, gas exchange, and cost, all provide a moist environment (see Chapter 248). Underneath such dressings, fibrinopurulent and necrotic debris, aided by host and bacterial enzymes, dissolves painlessly (eFig. 174-8.1). One can take advantage of these dressings to provide the best local environment for the wound, followed by a compression wrap to address the underlying hemodynamic disturbance.

The dressings should be changed weekly, or more often for heavily exudating wounds. New tissue is vulnerable to the cytotoxic effects of most topical antiseptics, and these agents are to be avoided. One should not put anything in a wound that you would not be willing to put in your eye. A gentle rinse with tap water or saline is sufficient. It is preferable to have the patient supine during dressing changes if at all possible.

Mechanical therapy is the mainstay of treatment for all clinical manifestations of chronic venous insufficiency. A Cochrane review found that “the use of elastic compression stockings to treat postthrombotic syndrome cannot be supported on the basis of the currently available data,” but did find some evidence for a beneficial effect for intermittent pneumatic compression units. Nevertheless, daily use of elastic compression stockings has been shown to reduce swelling in some patients with postthrombotic syndrome; prevent worsening of established postthrombotic syndrome; and may reduce recurrence of healed venous ulcers.

Each pharmaceutical therapy targets a specific clinical aspect of chronic venous insufficiency. Diuretics may be used in the short term for treating severe edema. Horse chestnut seed extract (often standardized to 50 mg escin twice daily) is an herbal remedy that appears to be safe and effective as a short-term treatment for leg pain and swelling.10 Aspirin (300–325 mg/day)11 and pentoxifylline12 may improve healing of chronic venous ulcers. Finally, topical steroids and emollients aid resolution of stasis dermatitis.

Although all wounds harbor potential pathogens, there is no evidence that routine use of antibiotics is helpful in patients with venous ulcer. If cellulitis is suspected, empiric therapy with coverage for S. aureus and Streptococci is warranted. Topical antibiotics, especially mupirocin, are useful for folliculitis due to S. aureus and Streptococci. With the increasing incidence of community acquired methicillin-resistant S. aureus in this population, culture and sensitivity are suggested for suspected skin and soft tissue infections.

Venous disease is progressive and irreversible. Patients must be educated about the need for continual hemodynamic support after the wound has healed. Graduated stockings that provide a minimum of 30–40 mmHg at the ankle should be carefully fitted to all patients and worn for their lifetime. It is a mistake to place elastic stockings on edematous limbs, especially those that are tender. One should use compression bandaging until all edema, inflammation, and tenderness have resolved before fitting the patient with stockings.

In carefully selected cases, sclerotherapy or surgical techniques, especially endovenous ablation, may close incompetent perforators and correct the hemodynamic abnormalities that lead to venous ulcer (see Chapter 249).13,14

Prevention

Prevention of venous thrombosis prevents venous insufficiency. Because many thrombotic traits are genetic, it is likely those patients at extra risk for thrombosis may be identified and treated for this risk before an event, and efforts to prevent thrombosis during elective surgery and hospitalization should reduce the numbers of postphlebitic limbs. Once a patient develops venous thrombosis, elastic compression stockings are the only proven method to reduce the risk of postthrombotic syndrome.15

Valvular failure may develop during pregnancy. Therefore, the use of supportive stockings throughout maternity, although not proven, can be recommended. If one's occupation or lifestyle involves long periods of immobility (long-distance flights appear to be especially risky), stockings are advisable.

Deep Vein Thrombosis

DVT is important for at least two reasons: (1) the thrombosed veins are the sources of pulmonary embolisms, and (2) the thrombosed leg may progress to chronic venous disease that has already been discussed.16 Superficial thrombophlebitis has associations with internal diseases as well.

For details, see within.

Superficial Venous Thrombosis and Phlebitis

Epidemiology

Obese women at a mean age of approximately 60 years seem to be especially affected by superficial venous thrombosis (SVT) with triggering risk factors proposed, including malignancy, pregnancy, conditions promoting venous stasis, and intravenous drug abuse. The 3-month overall mortality for SVT is very low with estimates ranging from 0% to 1%.

The most worrisome feature of SVT is that DVTs may occur concurrently, with an incidence varying from 5.6% to 36.0% depending on the study.

Etiology and Pathogenesis

In addition to thrombi, inflammation of the veins (phlebitis) may be caused by chemicals (drugs), infections, and as part of inflammatory diseases. Common drugs include potassium chloride, diazepam, antibiotics, and hypotonic or hypertonic solutions. When infectious agents on the skin or intravenous fluid track down catheters, they may cause a septic (suppurative) phlebitis.

Clinical Findings

Superficial phlebitis is the clinical finding of pain, tenderness, induration, and/or erythema in a superficial vein often associated with a palpable cord. These signs may be due to inflammation, infection, and/or thrombosis. Various eponyms are used for phlebitis in certain locations. For example, Mondor disease (sclerosing lymphangitis) refers to superficial phlebitis of the breast or dorsal penile vein, and superficial thrombophlebitis usually refers to superficial phlebitis of a lower extremity vein. Clinically, a thrombus is suggested by superficial phlebitis with a palpable cord that persists after a limb is raised.

Migratory thrombophlebitis (Trousseau sign) is a form of SVT, which develops, resolves, and recurs in normal veins of the body at various times. When migratory thrombophlebitis is associated with cancer (especially adenocarcinoma), the eponym Trousseau syndrome is used. Migratory superficial thrombophlebitis may be seen in Behçet disease, thromboangiitis obliterans with trauma, intravenous drug abuse, and secondary syphilis. Thrombophlebitis in patients with syphilis is rare and should be distinguished from patients with lupus anticoagulants causing biologically false-positive serologic reactions.

Laboratory Tests

Due to the possibility of coexisting occult DVT in patients with superficial venous thrombosis, some experts recommend compression ultrasound for all patients with lower extremity superficial venous thrombosis. However, this recommendation has not been explicitly tested in any trial and clinical judgment should guide further testing.

Additionally, thromboembolism (DVT or SVT) is often the presenting symptom of cancer and some physicians obtain high diagnostic yield through extensive screening for occult malignancy, especially when the thrombosis is idiopathic.

Treatment

As SVT has a much lesser risk of pulmonary embolism than DVT and the clinical importance of preventing SVT recurrence is unclear, less aggressive anticoagulation and treatment are recommended and these patients should be managed in conjunction with an appropriate specialist.

Edema is an excess of fluid in the body tissues. Although most of this fluid is in the interstitial spaces, there is usually excess fluid both in the vascular bed and within cells. When this becomes chronic, inflammatory cells and their cytokines lead to an irreversible state. This chronic accumulation of protein-rich fluid may occur due to conditions that predispose to chronic edema, such as venous stasis; or it may occur due to lymphatic failure secondary to trauma, malignancy, disease, or genetic mutations that give rise to nonfunctional lymphatics. Lymphedema refers specifically to swelling of a part of the body due to impaired lymph transport capacity as a consequence of a malformation or malfunction of the lymphatics.

The typical clinical presentation of lymphedema is an edematous extremity without concurrent pain or inflammation. Acquired lymphedema leaves legs feeling heavy and the patient tired. Although the limb swells during the day, indentations from socks can be seen on the leg at nighttime, returning toward normal during the night, but the leg stays swollen, and initially concerns may be cosmetic in nature. The foot is often involved first and initially lesions pit with pressure. With time, lesions become woody or lardaceous and do not pit. The toe contours are eventually lost. The Kaposi–Stemmer sign, a feature of chronic lymphedema, appears as an inability to pinch up a fold of skin between the second and third toe on the dorsum of the foot. This condition develops due to chronic thickening of the skin overlying the digits.

Primary lymphedema is a congenitally determined intrinsic or constitutional fault in lymphatic drainage. This is most commonly due to mutations in specific genes that are critical to lymphatic development or function, but may arise as a result of a developmental abnormality due to unknown causes in utero. Depending on the cause, primary lymphedema may present at any age (Fig. 174-9).

Secondary lymphedema occurs when previously normal lymphatics suffer an external insult such as disease, infection (repeated episodes of erysipelas), trauma, or surgery, and subsequently lose their functional capability, giving rise to lymphedema. It is due most commonly worldwide to parasitic infection. In industrialized countries, secondary lymphedema occurs following trauma, infection, postsurgery, malignancy, or postradiation.17

In all the clinical disorders discussed, lymphedema may be transient and pitting with pressure but, with time, becomes fixed, and is accompanied by adipose tissue hypertrophy, fibrosis (Fig. 174-9), and epidermal hyperplasia (Fig. 174-10) that eventually makes pitting less evident.18

Patients with lymphedema are susceptible to recurrent erysipelas, physical impairment, and psychosocial stigmatization, and may be at increased risk of malignancy such as lymphangiosarcoma.

Lymphedema-Related Genetic Diseases

Lymphedema in children is almost always primary, with a sex ratio of one male to three females. Primary lymphedema is customarily classified based on age of onset: congenital lymphedema—presents at birth or soon thereafter, lymphedema praecox—presents between age 1 and 35, or lymphedema tarda—presents after age 35. Approximately 77%–94% of the various types of lymphedema occur as lymphedema praecox.18 Disease-causing mutations of primary lymphedema have been determined for Milroy, lymphedema-distichiasis, and hypotrichosis–lymphedema–telangiectasia syndromes. A genetic defect has not been discovered in the other forms of primary lymphedema, including Meige syndrome, and thus require phenotypic classification for a diagnosis.

In lymphedema tardum, where the lymphedema does not become clinically evident until after age 35, the pathologic mechanism is usually due to a developmental abnormality in the lymphatic system that does not present until after it is precipitated by trauma, illness, or physical immobility.

In the diagnosis of lymphedema in children, clinical signs of lymphedema may be subtle. A complete family history is mandatory, and clinical investigation of relatives may be necessary if a hereditary form of lymphedema is suspected. Physical examination of the entire body should be performed to assess the extent of the lymphedema, whether there is limb overgrowth, and if there is associated systemic involvement. In primary lymphedema, facial, conjunctival, and genital lymphedema is typically seen in association with the limbs involved. Another potential clue that primary lymphedema is present is if a child has had more than one attack of erysipelas.19 There is a cohort of patients with primary lymphedema that have associated systemic lymphatic abnormalities, with the most common systemic involvement being the intestine. Therefore, imaging may be reasonable based on findings of the history and physical examination to rule out systemic involvement.

In the initial evaluation of a child with suspected primary lymphedema, qualitative lymphoscintigraphy can be considered in the radiologic evaluation. This modality is not without its limitations, but it can help determine whether persistent swelling in a child is lymphatic in origin. However, it does not assist in the diagnosis or treatment of lymphedema.

Primary Lymphedema

Emberger syndrome is an autosomal dominant primary lymphedema syndrome caused by mutations in GATA2, a transcription factor involved in gene regulation during vascular development and hematopoietic differentiation.20 Patients with this syndrome may have a low CD4/CD8 ratio, immune dysfunction (widespread cutaneous warts), sensorineural deafness, and genital lymphedema in addition to lymphedema of the lower limbs. These patients require monitoring due to their predisposition to AML (acute myeloid leukemia).

Milroy Syndrome

Etiology and Pathogenesis

Milroy syndrome is an autosomal dominant disease that characteristically has a mutation in VEGFR3 (also called the FLT4 gene). This causes impaired tyrosine kinase activity of the VEGFR3 receptor, which disrupts lymphangiogenesis. Penetrance is relatively high (80%), but not complete, suggesting a role of additional genetic or environmental factors. There is a 2.3:1.0 female predominance in pedigrees; this sex ratio may be due to a more severe disease in males that leads to hydrops fetalis and fetal death.

Clinical and Radiologic Findings

Lymphedema is almost always from birth and is confined to the legs with deep creases over the toes and small deformed (“ski jump”) toenails, and is typically characterized by hypoproteinemia from intestinal loss of albumen, chylous ascites, and scrotal edema.21 Thickening of the skin overlying the digits leads to a positive Kaposi–Stemmer sign.18

Prenatal ultrasound can show edematous legs in the fetus. Skin biopsy from swollen feet of patients that possess the VEGFR3 mutation reveals abundant skin lymphatics that are confirmed to be nonfunctional by fluorescence microlymphangiography.22 Interestingly, lymphangiography also demonstrates dysplastic lymphatics in both clinically affected and clinically normal extremities, emphasizing the complexity of the pathophysiology that ultimately leads to disease.

Lymphedema-Distichiasis

Etiology and Pathogenesis

Autosomal dominant nonsense and frameshift mutations in the forkhead transcription factor FoxC2 (MFH1 or mesenchyme forkhead-1), cause abnormalities in morphogenesis of the lymphatic valves in this disease.23 Radiographic studies of patients with lymphedema-distichiasis show lymph and venous reflux of the lower limbs, illustrating the primary valve failure. Distichiasis, a double row of eyelashes, develops as a result of failure of proper differentiation of eyelid follicles into Meibomian glands.18 Although the FoxC2 mutation is specific for lymphedema-distichiasis,24 further investigation has illustrated that lymphedema with ptosis may actually be one of the variable manifestations of FoxC2 mutations, rather than a distinct disorder.25

Clinical and Radiologic Findings

Lymphedema typically develops during puberty, but may be delayed until early adulthood, especially in females. The lymphedema will commonly worsen in severity over time, and may be complicated by recurrent infection and eventual papillomatosis. Aberrant eyelashes are present arising along the posterior border of the eyelid margin, which frequently leads to eyelash irritation of the cornea and photophobia. Other associated findings of this syndrome include cardiac defects, cleft palate, spinal extradural cysts, and other ophthalmologic complications. Given the complexity of this disorder, and possibility of systemic involvement, treatment of this disorder frequently requires a multidisciplinary approach, including dermatologists, pediatricians, and geneticists.18,21,26,27

Hypotrichosis–Lymphedema–Telangiectasia

Etiology and Pathogenesis

This rare form of primary lymphedema is caused by a mutation in the transcription factor gene SOX18. Both autosomal dominant and recessive inheritance have been reported. Mouse models have shown that SOX18 plays a critical role in the activation of the Prox1 gene and the induction of differentiation of the lymphatic vasculature from precursors during development. This mutation leads to the characteristic phenotype of lymphedema, alopecia, and telangiectasia.28

Clinical and Radiologic Findings

Lymphedema presents in puberty, most commonly in the lower extremities, although lymphedema of the eyelids has been reported. Hair is normal at birth, but then is lost in infancy. By early childhood, scalp hair is sparse, and eyebrows and eyelashes are often absent. Skin may be thin and transparent, but may have a cutis marmorata-like appearance. Telangiectasias have a predilection for the palms and soles, but may also be found on the scalp, legs, and genitalia.29

Meige Syndrome

Etiology and Pathogenesis

The genetic basis of Meige syndrome has yet to be been determined, though current studies suggest that mutations in the hepatocyte growth factor (HGF) and receptor (MET) pathway.30,31 However, as Meige syndrome manifests a nonspecific phenotype, it is possible that it arises from a number of congenital lymphatic defects.

Clinical and Radiologic Findings

Lymphedema typically develops during puberty. Facial puffiness with deep creases and wrinkling may occur. It characteristically presents with unilateral lower extremity edema, although involvement of upper extremities has been reported. The delay in onset is theorized to be due to an underlying defect in the lymphatic circulation that is subsequently unmasked by a secondary insult such as trauma, infection, or hormonal factors. There is a female predominance, approximately 1:3, which supports the theory for a hormonal role. It tends to follow an autosomal dominant pattern of inheritance.18,30

There are other inherited syndromes that have lymphedema as a clinical feature. These include Hennekam lymphangiectasia-lymphedema, Aagenaes lymphedema-cholestasis, microcephaly–chorioretinopathy–lymphedema, Irons–Bianchi syndrome, and the Turner's, Noonan's, and Prader–Willi syndromes.

Secondary Lymphedema

The most common cause of secondary, or acquired, lymphedema worldwide is due to lymphatic disruption and obstruction by infection with the nematode Wuchereria bancrofti, also known as filariasis (see Chapter 207). In the industrialized world, the most common cause is malignancy and malignancy-associated therapeutic interventions, such as surgery and radiotherapy.17

Epidemiology

Chronic edema in a community sample in London had a prevalence of 1.33 per 1,000 and was 5.4 per 1,000 for those older than the age of 65 years.32 Twenty-five percent of chronic edema was related to malignancy; and 29% of patients had at least one episode of cellulitis over the year before the survey; 70% to 80% of patients were female.

Worldwide lymphedema due to filariasis is estimated to affect 100 million individuals33,34 and is considered to be the second leading cause of permanent disability in the world.

For epidemiology, and clinical manifestations and treatment of filariasis see Chapter 207.

Other infectious diseases with lymphedema are much less common and include lymphogranuloma venereum, granuloma inguinale (see Chapters 203 and 204), and tuberculosis (see Chapter 184).

In regions of tropical Africa, Central America, and the Indian subcontinent where filariasis is uncommon, there is a condition of chronic lymphedema that is called podoconiosis, or nonfilarial elephantiasis. This condition causes edematous feet and legs, and is usually bilateral. Podoconiosis is not infectious in origin. It is caused by chronic inoculation of microparticles of silica through the soles of barefoot walkers.17

Clinical Findings

Typically, patients will present with a persistently edematous extremity without concurrent pain or inflammation (Box 174-4). The foot is often involved first, and initially lesions pit with pressure. Patients presenting later in the disease course may present with nonpitting edema. Feet may illustrate swollen toes with upturned nails. Thickening of the skin over the digits may be present, as may be the Kaposi–Stemmer sign. If the condition has been long-standing, the skin overlying the affected extremity may show generalized thickening, papillomatosis, or verrucous tissue overgrowth (Fig. 174-10). Fungal infections, erysipelas, or viral warts may also be present.

Unilateral lymphedema suggests localized obstructing factors, but bilateral lymphedema does not rule out anatomic obstruction, as the obstruction may be in the pelvis or abdomen.

Inflammation as manifested by redness, pain, and swelling is not lymphedema, but can be pyogenic infection, most commonly with S. aureus or Streptococcus pyogenes. Systemic antibiotics should be started before waiting for red lymphangitic streaking. A common complication is contact dermatitis from the use of topical antibiotics or multiple emollients and anti-inflammatory creams.

Diagnosis

Chronic venous insufficiency can present with very similar features of early lymphedema. In this clinical context, both conditions will have pitting edema, and the characteristic skin changes in late-stage lymphedema have not yet developed. However, chronic venous insufficiency is typically bilateral, rather than unilateral as in lymphedema. It is imperative to exclude medical causes of lower extremity swelling, such as renal failure, hypoalbuminemia, congestive heart failure, protein-losing nephropathy, pulmonary hypertension, obesity, pregnancy, and drug-induced edema, among others. An uncommon clinical mimic to lymphedema is lipedema of the leg. This syndrome is due to bilateral adipose deposition, usually in the buttocks and lower extremities. This leads to enlargement that stops abruptly at the level of the malleoli, characteristically sparing the feet. This distinctive clinical presentation is referred to as “armchair legs.”17 This condition predominates among overweight women who spend the majority of their time with their legs in a dependent position. Chronic immobility leads to decreased lymphatic drainage and subsequent lymphedema.

Special Tests

Diagnosis of filariasis includes assays to detect filarial antigens, and ultrasound to visualize living adult worms, even in the absence of microfilaremia.34

If there is doubt regarding the clinical diagnosis of lymphedema, especially when trying to differentiate from edema, there are various studies that may be employed for diagnostic confirmation. These include isotopic lymphoscintigraphy or, if necessary, radiocontrast lymphangiography.35,36 Computed tomography (CT) and magnetic resonance imaging (MRI) are other radiographic options, though not ideal. MRI is preferred over CT because of its ability to detect water. These modalities should reveal the characteristic “honeycomb” pattern of the subcutaneous tissue present in chronic lymphedema. This pattern is not present in other types of edema. If there is suspicion for concurrent deep venous thrombosis or venous disease, a venous duplex ultrasound is often required.17

Complications

Prolonged lymphedema leads to fibrosis and epidermal hyperplasia with verrucous hyperkeratosis (Fig. 174-10). Ulceration rarely occurs, although the edema and hyperkeratotic changes may be profound. Lymphangiosarcoma, the Stewart–Treves syndrome when associated with postmastectomy lymphedema, is the common lesion in chronically lymphedematous locations (see Chapter 126).

Treatment

Drug therapy for lymphedema, in general, has been inadequate. Diuretics are frequently prescribed, and not only do they not alleviate the symptoms, they may actually worsen the condition. Diuretics thus should not be used as a primary treatment for lymphedema. There is some evidence to suggest the efficacy of coumarin therapy. Coumarin apparently reduces capillary filtration as well as reduces fibrotic tissue deposition.17

A combination of elevation, exercise, compression garments/devices, skin care aimed to prevent infection, and manual lymphatic drainage, usually via massage, are the mainstay in management of lymphedema.17 In patients with primary and secondary lymphedema, in the absence of venous or arterial disease, manual lymphatic drainage and sequential pneumatic pumps, in addition to compression wraps and garments, may be useful.

Cellulitis or recurrent lymphangitis is a significant problem in lymphedematous sites, and there is both a rationale and results that encourage long-term antibiotic use (e.g., 2.4 million units of benzathine-penicillin G intramuscularly every 2 weeks).37

Microsurgery of lymphatics to bypass obstructed nodes can be considered if nonsurgical treatments are not successful. This procedure is not commonly performed in the United States because it is still considered experimental, but the literature from studies of this procedure performed in Europe is considerable. The surgery consists of the formation of multiple end-to-end lymphatic–venous anastomoses.38 Congenital lymphatic disorders have been treated with this intervention in the early childhood years with dramatic results.39,40

Low-level laser therapy (LLLT), either in combination with pneumatic compression or as a solo intervention, has been studied in patients with postoperative lymphedema, primarily in postmastectomy lymphedema. Results are encouraging, and patients have had improvements in the total volume of affected limbs at follow-up analysis of up to 1 year.41

Excisional or suction-assisted lipectomy (liposuction) may be an option in selected patients in whom are not eligible for other treatment options, or in whom other therapeutic modalities have failed.

Prevention

Any patient with lymphedema, whatever the cause, should keep their feet dry, nails trimmed, and prevent and aggressively treat pyogenic infection. Lymph moves faster during limb activity and exercise (e.g., walking should be encouraged). A combination of flexibility training, aerobic training, and strengthening exercises—while wearing compression garments or devices—have shown to have significant improvement in lymphedema.17

Lymphedema is common in some locations, especially on the face, vulva and penis, and can lead to superficial lesions termed lymphangiectasia. These focal areas of lymphedema occur from obstruction of usually previously normal lymphatics, progressing to lymphatic valve incompetence, lymph reflux, and retrograde lymph flow to the skin. This leads to blister-like lesions full of lymphatic fluid called lymphangiectasias. These most commonly occur after trauma, treatment for malignancy, or infection. These lesions are highly symptomatic and distressing, and frequently are painful, pruritic, and exudative.42,43 A current favored treatment modality for superficial lesions is with carbon dioxide laser ablation. Because the underlying obstructed lymph vessels are not corrected by the superficial laser, recurrences commonly occur.43 Other options for treatment include surgical excision and superficial radiotherapy and sclerotherapy.44

Lipemia (Fat Leg Syndrome, Lipohyperplasia Dolorosa)

Lipedema is an infrequently made diagnosis but can be distinguished from lymphedema by the characteristics that are summarized in eBox 174-4.1. Allen and Hines described this condition in the 1940s and noted its bilaterality, progression, and accentuation by warm weather and activity. Particularly vexing is the aching and pain below the knee in the patients who are generally overweight. Strong familial history is present. Feet swelling and the absence of the Kaposi–Stemmer sign is characteristic. Edematous hyperplastic fat cells characterize the histology. If compression fails, lipectomy has been used.

Cellulite (Orange Peel Skin, Gynoid Lipodystrophy)

Cellulite is a dimpled appearance of the skin, especially in the upper thighs in overweight women, even those who are slightly overweight. It is distinct from lipemia and lymphedema and is more a cosmetic concern than a health concern. Males have a smooth dermal–subcutaneous interface whereas in women superficial fat lobules protrude into the dermis, giving irregular contours. A variety of cosmetic procedures and light-based therapies are purported to reduce these lesions; some are US Food and Drug Administration approved, and are popular for the beauty conscience and in specialized spas. Few have been shown to long-term benefit, and noninvasive approaches to this condition have been advised. Idiopathic cyclic edema is described in young women and may have a relationship to the menstrual cycle.